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Sample records for apert syndrome phenotype

  1. Apert syndrome

    Directory of Open Access Journals (Sweden)

    Premalatha

    2010-01-01

    Full Text Available Apert syndrome (acrocephalosyndactyly is a rare developmental malformation characterized by craniosynostosis, mid-face hypoplasia, symmetrical syndactyly of hands and feet. The prodromal characteristics for the typical cranio-facial appearance are early craniosynostosis of the coronal suture, cranial base and agenesis of the sagittal suture. The purpose of this paper is to report a case of Apert syndrome with emphasis on craniofacial and oral features in an eighteen-month-old male child. The patient presented with several craniofacial deformities, including brachycephaly, midface hypoplasia, flat face, hypertelorism, ocular proptosis, downslanting palpebral fissures. Syndactylies with osseous fusion of the hands and feet were also observed. Intraoral findings included delayed eruption of teeth, high arched palate with pseudo cleft in the posterior one third.

  2. Apert syndrome (acrocephalosyndactyly

    Directory of Open Access Journals (Sweden)

    Milovanović J.

    2014-01-01

    Full Text Available Apert syndrome is named for the French physician, Eugen Apert who was, in 1906. described anomalous shape of the skull with coronary suture synostosis and hypoplasia sphenoethmoidmaxillary part of the face and fingers syndactyly of hands and feet. Apert syndrome accounts for about 4,5% of all craniosynostosis. With the prevalence of 1:160 000-200 000, inherited in an autosomal domi­nant, and in 25% of cases are fresh mutations in the gene. This syndrome has no predilection by gender and race, varies in severity form in witch it is manifested. Anomality of internal organs are very rare, but half of the patients with this syndrome have mental retardation. Apert syndrome has no cure, but surgery can help to correct some of the problems.

  3. Apert Syndrome: A Case Report

    Directory of Open Access Journals (Sweden)

    Masoud Gharib

    2012-10-01

    Full Text Available Apert syndrome is a genetic defect which was first described by Eugene Apert in 1906. it's incidence is approximately one in 50000 births. This syndrome is many abnormalities in your body and Central Nervous System. rehabilitation can increase children and their parent's quality of life.We report a case of Apert syndrome and his occupational therapy program.

  4. The spectrum of Apert syndrome: phenotype, particularities in orthodontic treatment, and characteristics of orthognathic surgery

    Science.gov (United States)

    Hohoff, Ariane; Joos, Ulrich; Meyer, Ulrich; Ehmer, Ulrike; Stamm, Thomas

    2007-01-01

    In the PubMed accessible literature, information on the characteristics of interdisciplinary orthodontic and surgical treatment of patients with Apert syndrome is rare. The aim of the present article is threefold: (1) to show the spectrum of the phenotype, in order (2) to elucidate the scope of hindrances to orthodontic treatment, and (3) to demonstrate the problems of surgery and interdisciplinary approach. Children and adolescents who were born in 1985 or later, who were diagnosed with Apert syndrome, and who sought consultation or treatment at the Departments of Orthodontics or Craniomaxillofacial Surgery at the Dental School of the University Hospital of Münster (n = 22; 9 male, 13 female) were screened. Exemplarily, three of these patients (2 male, 1 female), seeking interdisciplinary (both orthodontic and surgical treatment) are presented. Orthodontic treatment before surgery was performed by one experienced orthodontist (AH), and orthognathic surgery was performed by one experienced surgeon (UJ), who diagnosed the syndrome according to the criteria listed in OMIM™. In the sagittal plane, the patients suffered from a mild to a very severe Angle Class III malocclusion, which was sometimes compensated by the inclination of the lower incisors; in the vertical dimension from an open bite; and transversally from a single tooth in crossbite to a circular crossbite. All patients showed dentitio tarda, some impaction, partial eruption, idopathic root resorption, transposition or other aberrations in the position of the tooth germs, and severe crowding, with sometimes parallel molar tooth buds in each quarter of the upper jaw. Because of the severity of malocclusion, orthodontic treatment needed to be performed with fixed appliances, and mainly with superelastic wires. The therapy was hampered with respect to positioning of bands and brackets because of incomplete tooth eruption, dense gingiva, and mucopolysaccharide ridges. Some teeth did not move, or moved

  5. The spectrum of Apert syndrome: phenotype, particularities in orthodontic treatment, and characteristics of orthognathic surgery

    Directory of Open Access Journals (Sweden)

    Ehmer Ulrike

    2007-02-01

    Full Text Available Abstract In the PubMed accessible literature, information on the characteristics of interdisciplinary orthodontic and surgical treatment of patients with Apert syndrome is rare. The aim of the present article is threefold: (1 to show the spectrum of the phenotype, in order (2 to elucidate the scope of hindrances to orthodontic treatment, and (3 to demonstrate the problems of surgery and interdisciplinary approach. Children and adolescents who were born in 1985 or later, who were diagnosed with Apert syndrome, and who sought consultation or treatment at the Departments of Orthodontics or Craniomaxillofacial Surgery at the Dental School of the University Hospital of Münster (n = 22; 9 male, 13 female were screened. Exemplarily, three of these patients (2 male, 1 female, seeking interdisciplinary (both orthodontic and surgical treatment are presented. Orthodontic treatment before surgery was performed by one experienced orthodontist (AH, and orthognathic surgery was performed by one experienced surgeon (UJ, who diagnosed the syndrome according to the criteria listed in OMIM™. In the sagittal plane, the patients suffered from a mild to a very severe Angle Class III malocclusion, which was sometimes compensated by the inclination of the lower incisors; in the vertical dimension from an open bite; and transversally from a single tooth in crossbite to a circular crossbite. All patients showed dentitio tarda, some impaction, partial eruption, idopathic root resorption, transposition or other aberrations in the position of the tooth germs, and severe crowding, with sometimes parallel molar tooth buds in each quarter of the upper jaw. Because of the severity of malocclusion, orthodontic treatment needed to be performed with fixed appliances, and mainly with superelastic wires. The therapy was hampered with respect to positioning of bands and brackets because of incomplete tooth eruption, dense gingiva, and mucopolysaccharide ridges. Some teeth did not

  6. ORAL FINDINGS IN PATIENTS WITH APERT SYNDROME

    OpenAIRE

    Dalben, Gisele da Silva; Neves, Lucimara Teixeira das; Gomide, Marcia Ribeiro

    2006-01-01

    INTRODUCTION: The Apert syndrome is a rare disorder of autosomal dominant inheritance caused by mutations in the FGFR2 gene at locus 10q26; patients with this syndrome present severe syndactyly, exophthalmia, ocular hypertelorism and hypoplastic midface with Class III malocclusion, besides systemic alterations. Most investigations available on the Apert syndrome address the genetic aspect or surgical management, with little emphasis on the oral aspects. OBJECTIVE: to investigate the oral find...

  7. manifestations ophtalmologiques au cours du syndrome d'apert

    African Journals Online (AJOL)

    18 juin 2007 ... Mots clés : crâniosténose, syndrome d'Apert, chirurgie de décompression, atrophie optique. SUMMARY. Introduction : Several craniosynostotic syndromes are described such as Apert syndrome in which collaboration bet- ween different specialists is necessary to preserve visual function and to allow ...

  8. manifestations ophtalmologiques au cours du syndrome d'apert

    African Journals Online (AJOL)

    Il faut insister sur la nécessité d'un bilan ophtalmologique soigneux avant et après la chirurgie. J. TUN ORL - N° 18 JUIN 2007. 47. MANIFESTATIONS OPHTALMOLOGIQUES AU COURS DU SYNDROME D'APERT. Fig. 3 : Champ visuel automatique: scotomes absolus. Fig. 1 : Syndrome d'Apert :exophtalmie. Fig. 2 : Photo ...

  9. Central nervous system and cervical spine abnormalities in Apert syndrome.

    Science.gov (United States)

    Breik, Omar; Mahindu, Antony; Moore, Mark H; Molloy, Cindy J; Santoreneos, Stephen; David, David J

    2016-05-01

    Apert syndrome characterized by acrocephalosyndactyly is a rare autosomal dominant congenital malformation with a prevalence of 1/65,000 births. With an extensive range of phenotypic and developmental manifestations, its management requires a multidisciplinary approach. A variety of craniofacial, central nervous system (CNS), and cervical spine abnormalities have been reported in these patients. This study aimed to determine the incidence of these CNS abnormalities in our case series. Retrospective review of Australian Craniofacial Unit (ACFU) database for Apert patients was performed. Data collected that included demographics, place of origin, age at presentation, imaging performed, and images were reviewed and recorded. Where available, developmental data was also recorded. Ninety-four patients seen and managed at the ACFU had their CNS and cervical spine abnormalities documented. The main CNS abnormalities were prominent convolutional markings (67 %), ventriculomegaly (48 %), crowded foramen magnum (36 %), deficient septum pellucidum (13 %), and corpus callosum agenesis in 11 %. Major C-spine findings were present in 50.8 % of patients and included fusion of posterior elements of C5/C6 (50 %) and C3/4 (27 %). Multilevel fusion was seen in 20 %. Other abnormalities were C1 spina bifida occulta (7 %) and atlanto-axial subluxation (7 %). Multiple CNS and cervical spine (c-spine) abnormalities are common in Apert syndrome. The significance of these abnormalities remains largely unknown. Further research is needed to better understand the impact of these findings on growth, development, and treatment outcomes.

  10. A longitudinal study of dental arch morphology in children with the syndrome of Crouzon or Apert

    NARCIS (Netherlands)

    Reitsma, J.H.; Elmi, P.; Ongkosuwito, E.M.; Buschang, P.H.; Prahl-Andersen, B.

    2013-01-01

    The aim of this study was to compare changes in dental arch morphology between patients with Crouzon syndrome or Apert syndrome and controls. Children between 4 and 14 yr of age with Crouzon syndrome (n = 40) or Apert syndrome (n = 28) were compared with non-syndromic controls (n = 457) in terms of

  11. Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome

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    Slaney, S.F.; Oldridge, M.; Wilkie, A.O.M. [Univ. of Oxford (United Kingdom)] [and others

    1996-05-01

    Apert syndrome is a distinctive human malformation characterized by craniosynostosis and severe syndactyly of the hands and feet. It is caused by specific missense substitutions involving adjacent amino acids (Ser252Trp or Pro253Arg) in the linker between the second and third extracellular immunoglobulin domains of fibroblast growth factor receptor 2 (FGFR2). We have developed a simple PCR assay for these mutations in genomic DNA, based on the creation of novel SfiI and BstUI restriction sites. Analysis of DNA from 70 unrelated patients with Apert syndrome showed that 45 had the Ser252Trp mutation and 25 had the Pro253Arg mutation. Phenotypic differences between these two groups of patients were investigated. Significant differences were found for severity of syndactyly and presence of cleft palate. The syndactyly was more severe with the Pro253Arg mutation, for both the hands and the feet. In contrast, cleft palate was significantly more common in the Ser252Trp patients. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome. We conclude that, although the phenotype attributable to the two mutations is very similar, there are subtle differences. The opposite trends for severity of syndactyly and cleft palate in relation to the two mutations may relate to the varying patterns of temporal and tissue-specific expression of different fibroblast growth factors, the ligands for FGFR2. 54 refs., 5 figs., 3 tabs.

  12. Dental agenesis patterns of permanent teeth in Apert syndrome.

    Science.gov (United States)

    Stavropoulos, Dimitrios; Bartzela, Theodosia; Bronkhorst, Ewald; Mohlin, Bengt; Hagberg, Catharina

    2011-06-01

    Dental agenesis may either occur as an isolated trait (non-syndromic) or as a component in a congenital syndrome. The aim of the present study was to identify the prevalence of dental agenesis for each type of tooth and to look for dental agenesis patterns in persons with Apert syndrome. Serial panoramic radiographs of 23 individuals (five male patients and 18 female patients) were examined. Third molars were excluded. The prevalence of agenesis for at least one tooth was 34.8%. Up to two missing teeth were found for individuals with Apert syndrome. Maxillary lateral incisors and mandibular second premolars were the most frequently missing teeth. Four different dental agenesis patterns of the entire dentition were identified by using the tooth agenesis code (TAC). Two patterns occurred more frequently, both of which were symmetrical. One involved the simultaneous absence of teeth 12 and 22, and the other showed agenesis of teeth 35 and 45. In conclusion, patients with Apert syndrome were found to exhibit a high prevalence of dental agenesis. All dental agenesis patterns in which more than one tooth was missing were symmetrical. © 2011 Eur J Oral Sci.

  13. Ocular manifestations of Apert and Crouzon syndromes: qualitative and quantitative findings

    DEFF Research Database (Denmark)

    Kreiborg, Sven; Cohen, M Michael

    2010-01-01

    There are significant differences in the ocular manifestations of Apert and Crouzon syndromes. Here, we present qualitative and quantitative data about the oculo-orbital region to demonstrate these differences. Although ocular protosis and hypertelorism characterize both disorders, the nature...... protrusion of the lateral orbital wall. The implications account for some of the differences encountered. Asymmetry is associated with Apert syndrome frequently. Exotropia is found in Crouzon syndrome, whereas the V pattern is more characteristic in Apert syndrome with divergent upgaze and esotropic downgaze....... Subluxation of the eyeglobe is found in some cases of Crouzon syndrome but is not found in Apert syndrome. Optic atrophy found in approximately 20% of Crouzon syndrome patients is not characteristic of Apert syndrome. Structural alterations of the extraocular muscles have been associated with some cases...

  14. Original article patterns of tooth agenesis in patients with Crouzon or Apert syndrome

    OpenAIRE

    Reitsma, Jacobus Harmen; Ongkosuwito, Edwin; Wijk, Arjen; Prahl-Andersen, B.

    2014-01-01

    textabstractPurpose: Dental agenesis is the most common anomaly of dental development and can be a component of a congenital syndrome. The purpose of this study was to evaluate the prevalence of agenesis and to describe patterns of tooth agenesis in patients with Crouzon or Apert syndrome compared with nonsyndromic controls. Patients and Methods: Longitudinal records of 67 patients with Crouzon syndrome (n=39) or Apert syndrome (n = 28) from the Erasmus Medical Centre were examined. Syndromic...

  15. Oral findings in patients with Apert Syndrome Achados bucais em pacientes com Síndrome de Apert

    Directory of Open Access Journals (Sweden)

    Gisele da Silva Dalben

    2006-12-01

    Full Text Available INTRODUCTION: The Apert syndrome is a rare disorder of autosomal dominant inheritance caused by mutations in the FGFR2 gene at locus 10q26; patients with this syndrome present severe syndactyly, exophthalmia, ocular hypertelorism and hypoplastic midface with Class III malocclusion, besides systemic alterations. Most investigations available on the Apert syndrome address the genetic aspect or surgical management, with little emphasis on the oral aspects. OBJECTIVE: to investigate the oral findings, including dental anomalies, ectopic eruption of the maxillary permanent first molars and soft tissue alterations, in subjects with Apert syndrome. MATERIALS AND METHODS: clinical and radiographic examination of nine patients with Apert syndrome, aged 6 to 15 years, not previously submitted to orthodontic or orthognathic treatment. RESULTS: dental anomalies were present in all patients, with one to eight anomalies per individual. The most frequent anomalies were tooth agenesis, mainly affecting maxillary canines, and enamel opacities (44.4% for both. Ectopic eruption of maxillary first molars was found in 33.3% of patients; lateral palatal swellings were observed in 88.8% of patients. CONCLUSIONS: The occurrence of typical lateral palatal swellings agrees with the literature. The high prevalence of dental anomalies and ectopic eruption may suggest a possible etiologic relationship with the syndrome.INTRODUÇÃO: A síndrome de Apert é um distúrbio raro de herança autossômica dominante causado por mutações no lócus 10q26 do gene FGFR2; pacientes com esta síndrome apresentam sindactilia severa, exoftalmia, hiperteleorbitismo e hipoplasia da face média com má oclusão de Classe III, além de alterações sistêmicas. A maior parte dos estudos disponíveis sobre a síndrome de Apert aborda o aspecto genético ou manejo cirúrgico, com pouca ênfase nos aspectos bucais. OBJETIVO: investigar os achados bucais, incluindo anomalias dentárias, irrup

  16. An unusual complication after craniofacial surgery for Apert syndrome

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    Abhay A Lune

    2014-01-01

    A case of Apert syndrome who had undergone craniofacial surgery elsewhere 4 years back presented to us with purulent discharge near the lateral orbital margin of right orbit, watering and redness of the right eye. He had telltale signs of this syndrome in the form of skull deformities such as brachycephaly, frontal bony prominence, mid-face hypoplasia, proptosis and syndactyly of both hands and feet. There was a surgical scar of previous craniofacial surgery over the bi-coronal region. He had a discharging granuloma over the lateral orbital margin and the adjacent lower eyelid had developed cicatricial ectropion. X-ray and computed tomography scan orbit confirmed the clinical suspicion of osteomyelitis of the underlying zygomatic bone at the site of miniplate and screw fixation of the earlier surgery. He was treated with excision of granuloma and extraction of loose screw and infected miniplate while ectropion was corrected by rotation advancement of temporal skin flap.

  17. Patterns of tooth agenesis in patients with crouzon or apert syndrome.

    Science.gov (United States)

    Reitsma, Jacobus H; Ongkosuwito, Edwin M; van Wijk, Arjen J; Prahl-Andersen, Birte

    2014-03-01

    Dental agenesis is the most common anomaly of dental development and can be a component of a congenital syndrome. The purpose of this study was to evaluate the prevalence of agenesis and to describe patterns of tooth agenesis in patients with Crouzon or Apert syndrome compared with nonsyndromic controls. Longitudinal records of 67 patients with Crouzon syndrome (n = 39) or Apert syndrome (n = 28) from the Erasmus Medical Centre were examined. Syndromic patients were compared with patients in a nonsyndromic control group (n = 284). Prevalence of tooth agenesis in patients with Crouzon syndrome (35.9%) and patients with Apert syndrome (46.4%) was significantly higher than the prevalence in control subjects (27.5%) (P agenesis excluding third molars was significantly higher in syndromic patients than in control subjects (P agenesis of mandibular second premolars occurred significantly more often in patients with Crouzon and Apert syndrome than in control subjects (P agenesis is more prevalent in patients with Crouzon or Apert syndrome than in control subjects. Tooth agenesis and mandibular symmetrical patterns of second premolar agenesis are more prevalent in syndromic patients.

  18. Apert syndrome: factors involved in the cognitive development Síndrome de Apert: fatores relacionados ao desenvolvimento cognitivo destes pacientes

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    Adriano Yacubian-Fernandes

    2005-12-01

    Full Text Available Apert syndrome is characterized by craniosynostosis, symmetric syndactyly and other systemic malformations, with mental retardation usually present. The objective of this study was to correlate brain malformations and timing for surgery with neuropsychological evaluation. We also tried to determine other relevant aspects involved in cognitive development of these patients such as social classification of families and parents’ education. Eighteen patients with Apert syndrome were studied, whose ages were between 14 and 322 months. Brain abnormalities were observed in 55.6% of them. The intelligence quotient or developmental quotient values observed were between 45 and 108. Mental development was related to the quality of family environment and parents’ education. Mental development was not correlated to brain malformation or age at time of operation. In conclusion, quality of family environment was the most significant factor directly involved in mental development of patients with Apert syndrome.A síndrome de Apert é caracterizada por cranioestenose, sindactilia simétrica e outras malformações sistêmicas. O retardo no desenvolvimento neuropsicomotor é freqüentemente observado. Este trabalho tem como objetivo analisar as malformações do sistema nervoso central, o momento da cirurgia e a classe sócio-econômica associada ao nível educacional dos pais como variáveis que possam influenciar no desenvolvimento cognitivo. Foram estudados 18 pacientes com diagnóstico de síndrome de Apert com idade entre 14 e 322 meses e as alterações encefálicas foram observadas em 55,6%. O quociente de inteligência variou de 45 a 108 e estava correlacionado com a classe sócio-econômica e com o nível de instrução dos pais; não se correlacionou com as alterações encefálicas nem com o momento do tratamento neurocirúrgico. Em conclusão, a condição sócio-econômica e o nível de instrução dos pais foram relevantes na determinação do

  19. Patterns of tooth agenesis in patients with Crouzon or Apert syndrome

    NARCIS (Netherlands)

    Reitsma, J.H.; Ongkosuwito, E.M.; van Wijk, A.J.; Prahl-Andersen, B.

    2014-01-01

    Purpose: Dental agenesis is the most common anomaly of dental development and can be a component of a congenital syndrome. The purpose of this study was to evaluate the prevalence of agenesis and to describe patterns of tooth agenesis in patients with Crouzon or Apert syndrome compared with

  20. Original article patterns of tooth agenesis in patients with Crouzon or Apert syndrome

    NARCIS (Netherlands)

    J.H. Reitsma (Jacobus Harmen); E.M. Ongkosuwito (Edwin); A.J. van Wijk (Arjen); B. Prahl-Andersen (B.)

    2014-01-01

    textabstractPurpose: Dental agenesis is the most common anomaly of dental development and can be a component of a congenital syndrome. The purpose of this study was to evaluate the prevalence of agenesis and to describe patterns of tooth agenesis in patients with Crouzon or Apert syndrome compared

  1. Diagnosis of Apert syndrome in the second-trimester using 2D and 3D ultrasound

    NARCIS (Netherlands)

    David, A. L.; Turnbull, C.; Scott, R.; Freeman, J.; Bilardo, C. M.; van Maarle, M.; Chitty, L. S.

    2007-01-01

    To illustrate how Apert syndrome, a rare autosomal dominant genetic syndrome, can be detected in the second-trimester of pregnancy using 2D ultrasound, and how 3D ultrasound examination may provide parents with a better understanding of the structural defects affecting their baby. Fetal Medicine

  2. Apert Syndrome in Lagos – a Case Report and Literature Review ...

    African Journals Online (AJOL)

    Apert Syndrome is a rare autosomal dominant disorder characterized by premature fusion of sutures of bones of the skull (Craniosynostosis), fingers and toes (Syndactyly) to different degree. Though it is rare, it is pertinent for clinicians to know about this condition so as to improve their ability to manage it and to note that ...

  3. Management of complicated syndactyly in Apert's syndrome: our ...

    African Journals Online (AJOL)

    Background: Management of hand deformities in Apert's acro-cephalo-syndactyly usually poses a great challenge to the reconstructive hand surgeon due to grossly abnormal anatomy of skeletal and soft tissue structures associated with a progressive disease process. Patients and methods: We retrospectively reviewed all ...

  4. Speech and language skills and cognitive functioning in children with Apert syndrome: a pilot study.

    Science.gov (United States)

    Shipster, C; Hearst, D; Dockrell, J E; Kilby, E; Hayward, R

    2002-01-01

    There are few studies that report findings on the speech and language characteristics of Apert syndrome and little is known about the cognitive profile of the syndrome. The current study addresses this gap and explores speech, language, resonance/voice, attention oro-motor and cognitive skills in a group of 10 children (4;1-5;11) with Apert syndrome. The speech and language battery included: the CELF-Pre-school, the PLS-3, the Vocal Profile Analysis, GOS.SP.ASS, PACS; and the Brodsky Drooling Scale. Subscales of the BAS II-Early Years Version were used to assess cognition. Data were also collected on other factors that could influence developmental outcome such as audiological history and management; occlusion/dentition; respiratory problems and management; neuroanatomical abnormalities; the number and nature of cranial surgeries; and the occurrence of raised intracranial pressure. All children for whom a Performance IQ was obtained (n = 8) had abilities within the average range and IQ scores were considerably higher than those reported in previous studies. Eight children had moderate or severe language difficulties and expressive language difficulties were the most frequent. These language difficulties were not associated with a general cognitive deficit. All the children had problems with attention, speech and oro-motor skills. Nine had abnormal voice. In addition, a range of other associated factors that could affect functioning were identified. The discrepancies between the current study and previous investigations are outlined. Parameters for assessment are considered. The implications of these findings for valid assessments of children with Apert syndrome are discussed. Multidisciplinary assessment of children with Apert syndrome across a broad range of dimensions is recommended to obtain a profile of each child's strengths and weaknesses to ensure that appropriate educational placements and early interventions are implemented. Considering patterns of

  5. Radiologic investigation of apert syndrome (acrocephalosyndactyly type 1) -a case report-

    International Nuclear Information System (INIS)

    Lee, Yeon Hee; Cho, Whi Youl; Kim, Myung Soon; Hong, In Soo; Sung, Ki Joon; Yang, Jae Seung

    1991-01-01

    Apert syndrome (Acrocephalosyndactyly type 1) is a rare congenital anomaly characterized by craniosynosis and symmetric-syndactyly of both extremities. Radiological examination of the skull shows hydrocephalus due to aqueductal stenosis. In the facial bones, the hypoplastic maxilla and relatively prominent mandible are observed associated with other anomalies such as cleft palate. Radiologic examination of both hands and feet show bony or subcutaneous syndactylism and typical mitten hands and webbed toes

  6. Rapid detection of de novo P253R mutation in FGFR2 using uncultured amniocytes in a pregnancy affected by polyhydramnios, Blake's pouch cyst, and Apert syndrome

    Directory of Open Access Journals (Sweden)

    Chih-Ping Chen

    2013-06-01

    Conclusion: Prenatal diagnosis of polyhydramnios, frontal bossing, and midface hypoplasia associated with brain and digital abnormalities should include a differential diagnosis of Apert syndrome. A molecular analysis of FGFR2 using uncultured amniocytes is useful for rapid confirmation of Apert syndrome at prenatal diagnosis.

  7. Morphological comparison of the craniofacial phenotypes of mouse models expressing the Apert FGFR2 S252W mutation in neural crest- or mesoderm-derived tissues.

    Science.gov (United States)

    Heuzé, Yann; Singh, Nandini; Basilico, Claudio; Jabs, Ethylin Wang; Holmes, Greg; Richtsmeier, Joan T

    2014-06-01

    Bones of the craniofacial skeleton are derived from two distinct cell lineages, cranial neural crest and mesoderm, and articulate at sutures and synchondroses which represent major bone growth sites. Premature fusion of cranial suture(s) is associated with craniofacial dysmorphogenesis caused in part by alteration in the growth potential at sutures and can occur as an isolated birth defect or as part of a syndrome, such as Apert syndrome. Conditional expression of the Apert FGFR2 S252W mutation in cells derived from mesoderm was previously shown to be necessary and sufficient to cause coronal craniosynostosis. Here we used micro computed tomography images of mice expressing the Apert mutation constitutively in either mesoderm- or neural crest-derived cells to quantify craniofacial shape variation and suture fusion patterns, and to identify shape changes in craniofacial bones derived from the lineage not expressing the mutation, referred to here as secondary shape changes. Our results show that at postnatal day 0: (i) conditional expression of the FGFR2 S252W mutation in neural crest-derived tissues causes a more severe craniofacial phenotype than when expressed in mesoderm-derived tissues; and (ii) both mesoderm- and neural crest-specific mouse models display secondary shape changes. We also show that premature suture fusion is not necessarily dependent on the expression of the FGFR2 S252W mutation in the sutural mesenchyme. More specifically, it appears that suture fusion patterns in both mouse models are suture-specific resulting from a complex combination of the influence of primary abnormalities of biogenesis or signaling within the sutures, and timing. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Effects of multisensory yoga on behavior in a male child with Apert and Asperger syndrome

    OpenAIRE

    Scroggins, Michaela L; Litchke, Lyn G; Liu, Ting

    2016-01-01

    This case focused on a 7-year-old boy with Apert and Asperger's syndrome who attended 8, 45 min multisensory yoga sessions, twice a week, during 4-week camp. Results from the pre- and post-tests on Treatment and Research Institute for Autism Social Skills Assessment showed improvements in the total score changes from 19 to 7 for disruptive behaviors. Sparks Target Behavior Checklist scores changed from eight to one showing progression in ability to stay on task. Yoga Pose Rating Scale display...

  9. Surgical treatment results of hand deformities in patients with Apert syndrome

    Directory of Open Access Journals (Sweden)

    Ufuk Nalbantoglu

    2015-12-01

    Results: The mean age at the first operation was 2.7 years and the mean number of operations was 3 per patient. No patient developed graft-flap necrosis and no patients required amputations. All patients were able to perform grasping and pinching functions and families were satisfied with the cosmetic results. Conclusion: Using a two-stage surgical protocol, achieving satisfactory results with a minimal number of operations is possible in patients with Apert Syndrome. [Hand Microsurg 2015; 4(3.000: 53-57

  10. Discussão genetico-clinica sobre a Síndrome de Apert: a propósito de um caso Apert's syndrome: clinical-genetic discussion and a case report

    Directory of Open Access Journals (Sweden)

    Aguinaldo Gonçalves

    1976-09-01

    Full Text Available Após breve introdução sobre a síndrome de Apert, é relatado um caso clínico, sendo destacada a conduta genético-clínica. A discussão revela como os aspectos genéticos envolvidos orientam o raciocínio clínico.After a short introduction about the so-called Apert's syndrome, a clinical suggestive case is reported. Discussion shows how a clinic-genetical procedure may help the clinicians.

  11. Effects of multisensory yoga on behavior in a male child with Apert and Asperger syndrome.

    Science.gov (United States)

    Scroggins, Michaela L; Litchke, Lyn G; Liu, Ting

    2016-01-01

    This case focused on a 7-year-old boy with Apert and Asperger's syndrome who attended 8, 45 min multisensory yoga sessions, twice a week, during 4-week camp. Results from the pre- and post-tests on Treatment and Research Institute for Autism Social Skills Assessment showed improvements in the total score changes from 19 to 7 for disruptive behaviors. Sparks Target Behavior Checklist scores changed from eight to one showing progression in ability to stay on task. Yoga Pose Rating Scale displayed the transformation in total scores from 80 = emerging to 115 = consistency in pose performance. The field notes revealed the positive development in expressive emotions, social engagement, and decline in looking around. Outside class parent and school behavioral specialist reported the improved ability to self-regulate stress using lion's breath and super brain. These findings indicate an improvement in behaviors that influenced the physical performance, emotional expression, and social interaction after yoga training for this child.

  12. FGF/FGFR signaling coordinates skull development by modulating magnitude of morphological integration: evidence from Apert syndrome mouse models.

    Directory of Open Access Journals (Sweden)

    Neus Martínez-Abadías

    Full Text Available The fibroblast growth factor and receptor system (FGF/FGFR mediates cell communication and pattern formation in many tissue types (e.g., osseous, nervous, vascular. In those craniosynostosis syndromes caused by FGFR1-3 mutations, alteration of signaling in the FGF/FGFR system leads to dysmorphology of the skull, brain and limbs, among other organs. Since this molecular pathway is widely expressed throughout head development, we explore whether and how two specific mutations on Fgfr2 causing Apert syndrome in humans affect the pattern and level of integration between the facial skeleton and the neurocranium using inbred Apert syndrome mouse models Fgfr2(+/S252W and Fgfr2(+/P253R and their non-mutant littermates at P0. Skull morphological integration (MI, which can reflect developmental interactions among traits by measuring the intensity of statistical associations among them, was assessed using data from microCT images of the skull of Apert syndrome mouse models and 3D geometric morphometric methods. Our results show that mutant Apert syndrome mice share the general pattern of MI with their non-mutant littermates, but the magnitude of integration between and within the facial skeleton and the neurocranium is increased, especially in Fgfr2(+/S252W mice. This indicates that although Fgfr2 mutations do not disrupt skull MI, FGF/FGFR signaling is a covariance-generating process in skull development that acts as a global factor modulating the intensity of MI. As this pathway evolved early in vertebrate evolution, it may have played a significant role in establishing the patterns of skull MI and coordinating proper skull development.

  13. The kleeblattschädel anomaly in Apert syndrome: intracranial anatomy, surgical correction, and subsequent cranial vault development.

    Science.gov (United States)

    Gosain, A K; Moore, F O; Hemmy, D C

    1997-12-01

    We present a case of Apert syndrome in which intracranial anomalies of the cranial base were localized to the lesser wings of the sphenoid and sphenoid ridge. The lesser wings of the sphenoid were displaced superiorly to follow the fused coronal sutures bilaterally, where they met at a single point on the skull vertex. Careful preoperative study of the intracranial anatomy in the kleeblattschädel anomaly led to a surgical plan for early correction of the anomaly. The present report indicates that an aggressive approach to the correction of the kleeblattschädel anomaly beginning early in infancy can result in normalization of the trilobar skull configuration. Although this approach can correct the kleeblattschädel anomaly, 3.5-year follow-up in this patient with Apert syndrome demonstrates progressive turricephaly despite repeated cranial vault remodeling. Although the trilobar skull configuration can be corrected through early surgical intervention, the long-term correction of progressive turricephaly in patients with Apert syndrome remains an unsolved problem.

  14. Effects of multisensory yoga on behavior in a male child with Apert and Asperger syndrome

    Directory of Open Access Journals (Sweden)

    Michaela L Scroggins

    2016-01-01

    Full Text Available This case focused on a 7-year-old boy with Apert and Asperger's syndrome who attended 8, 45 min multisensory yoga sessions, twice a week, during 4-week camp. Results from the pre- and post-tests on Treatment and Research Institute for Autism Social Skills Assessment showed improvements in the total score changes from 19 to 7 for disruptive behaviors. Sparks Target Behavior Checklist scores changed from eight to one showing progression in ability to stay on task. Yoga Pose Rating Scale displayed the transformation in total scores from 80 = emerging to 115 = consistency in pose performance. The field notes revealed the positive development in expressive emotions, social engagement, and decline in looking around. Outside class parent and school behavioral specialist reported the improved ability to self-regulate stress using lion's breath and super brain. These findings indicate an improvement in behaviors that influenced the physical performance, emotional expression, and social interaction after yoga training for this child.

  15. Rapid detection of de novo P253R mutation in FGFR2 using uncultured amniocytes in a pregnancy affected by polyhydramnios, Blake's pouch cyst, and Apert syndrome.

    Science.gov (United States)

    Chen, Chih-Ping; Su, Yi-Ning; Chang, Tung-Yao; Chern, Schu-Rern; Chen, Chen-Yu; Su, Jun-Wei; Wang, Wayseen

    2013-06-01

    To present prenatal ultrasound and molecular genetic diagnosis of Apert syndrome. A 30-year-old, gravida 3, para 2 woman was referred for genetic counseling at 32 weeks of gestation because of polyhydramnios and craniofacial and digital abnormalities in the fetus. She had undergone amniocentesis at 18 weeks of gestation because of maternal anxiety. Results of amniocentesis revealed a karyotype of 46,XX. A prenatal ultrasound at 32 weeks of gestation revealed a female fetus with a fetal biometry equivalent to 32 weeks, polyhydramnios with an increased amniotic fluid index of 26.1 cm, frontal bossing, midface hypoplasia, hypertelorism, Blake's pouch cyst with an apparent posterior fossa cyst in communication with the fourth ventricle on axial images, digital fusion, and bilateral syndactyly of the hands and feet. A DNA testing for the FGFR2 gene was immediately performed using uncultured amniocytes obtained by repeated amniocentesis, which revealed a heterozygous c.758C>G, CCT>CGT transversion leading to a p.Pro253Arg (P253R) mutation in the FGFR2 gene. Subsequently, a diagnosis of Apert syndrome was made. Molecular analysis of the FGFR2 gene in the parents did not reveal such a mutation. The fetus postnatally manifested frontal bossing, midface hypoplasia, and bilateral syndactyly of the hands (mitten hands) and feet. Prenatal diagnosis of polyhydramnios, frontal bossing, and midface hypoplasia associated with brain and digital abnormalities should include a differential diagnosis of Apert syndrome. A molecular analysis of FGFR2 using uncultured amniocytes is useful for rapid confirmation of Apert syndrome at prenatal diagnosis. Copyright © 2013. Published by Elsevier B.V.

  16. Mesodermal expression of Fgfr2S252W is necessary and sufficient to induce craniosynostosis in a mouse model of Apert syndrome

    Science.gov (United States)

    Basilico, Claudio

    2013-01-01

    Coordinated growth of the skull and brain are vital to normal human development. Craniosynostosis, the premature fusion of the calvarial bones of the skull, is a relatively common pediatric disease, occurring in 1 in 2500 births, and requires significant surgical management, especially in syndromic cases. Syndromic craniosynostosis is caused by a variety of genetic lesions, most commonly by activating mutations of FGFRs 1–3, and inactivating mutations of TWIST1. In a mouse model of TWIST1 haploinsufficiency, cell mixing between the neural crest-derived frontal bone and mesoderm-derived parietal bone accompanies coronal suture fusion during embryonic development. However, the relevance of lineage mixing in craniosynostosis induced by activating FGFR mutations is unknown. Here, we demonstrate a novel mechanism of suture fusion in the Apert Fgfr2S252W mouse model. Using Cre/lox recombination we simultaneously induce expression of Fgfr2S252W and β-galactosidase in either the neural crest or mesoderm of the skull. We show that mutation of the mesoderm alone is necessary and sufficient to cause craniosynostosis, while mutation of the neural crest is neither. The lineage border is not disrupted by aberrant cell migration during fusion. Instead, the suture mesenchyme itself remains intact and is induced to undergo osteogenesis. We eliminate postulated roles for dura mater or skull base changes in craniosynostosis. The viability of conditionally mutant mice also allows post-natal assessment of other aspects of Apert syndrome. PMID:22664175

  17. Down Syndrome: Cognitive Phenotype

    Science.gov (United States)

    Silverman, Wayne

    2007-01-01

    Down syndrome is the most prevalent cause of intellectual impairment associated with a genetic anomaly, in this case, trisomy of chromosome 21. It affects both physical and cognitive development and produces a characteristic phenotype, although affected individuals vary considerably with respect to severity of specific impairments. Studies…

  18. Phenotypic variability in Patau syndrome.

    Science.gov (United States)

    Caba, Lavinia; Rusu, Cristina; Butnariu, Lacramioara; Panzaru, Monica; Braha, Elena; Volosciuc, M; Popescu, Roxana; Gramescu, Mihaela; Bujoran, C; Martiniuc, Violeta; Covic, M; Gorduza, E V

    2013-01-01

    Patau syndrome has an incidence of 1/10.000-20.000, the clinical diagnosis being suggested by the triad cleft lip and palate, microphthalmia/anophthalmia and postaxial polydactyly. Most frequent cytogenetic abnormality is free and homogeneous trisomy 13 (80.0%), rarely being detected trisomy mosaics or Robertsonian translocations. The objective of the study was to identify phenotypic features of trisomy 13. The retrospective study was conducted on a trial group of 14 cases diagnosed cytogenetically with trisomy 13 between January 2000 and December 2012 at lasi Medical Genetics Centre. Of the 14 cases, 3 were evaluated pathologically (two aborted foetuses and one stillborn), 8 cases were detected in the neonatal period, and 3 in infancy. Clinical diagnosis was supported by the identification of a model of abnormal development, mainly characterized by: maxillary cleft (lip and palate--5 cases; lip--1 case), ocular abnormalities (microphthalmia/anophthalmia--7 cases; cyclopia--1 case), postaxial polydactyly (7 cases), scalp defects (6 cases), congenital heart anomalies (10 cases, 6 patients with atrial septal defect), complete holoprosencephaly (4 cases), ear abnormalities (11 cases), broad nasal root (10 cases). An important issue in confirming the phenotypic variability of Patau syndrome is that the classic clinical triad was identified only in one case. Patau syndrome is a disease with variable expression and is characterized by a pattern of abnormal prenatal development characterized by facial dysmorphia, polydactyly and severe birth defects (heart, brain) that generate an increased in utero and perinatal mortality.

  19. Guide to Understanding Apert Syndrome

    Science.gov (United States)

    ... treatment. Design and Production by Robin Williamson, Williamson Creative Services, Inc., Carrollton, TX. © 2005 Children’s Craniofacial Association, ... advancement within the first twelve months to increase space within the skull and the size of both ...

  20. Phenotype Development in Adolescents With Tourette Syndrome

    DEFF Research Database (Denmark)

    Groth, Camilla; Debes, Nanette Mol; Skov, Liselotte

    2017-01-01

    Tourette syndrome (TS) is a neurodevelopmental disorder characterized by frequent comorbidities and a wide spectrum of phenotype presentations. This study aimed to describe the development of phenotypes in TS and tic-related impairment in a large longitudinal study of 226 children and adolescents...

  1. Auditory Phenotype of Smith-Magenis Syndrome

    Science.gov (United States)

    Brendal, Megan A.; King, Kelly A.; Zalewski, Christopher K.; Finucane, Brenda M.; Introne, Wendy; Brewer, Carmen C.; Smith, Ann C. M.

    2017-01-01

    Purpose: The purpose of this study was to describe the auditory phenotype of a large cohort with Smith-Magenis syndrome (SMS), a rare disorder including physical anomalies, cognitive deficits, sleep disturbances, and a distinct behavioral phenotype. Method: Hearing-related data were collected for 133 individuals with SMS aged 1-49 years. Audiogram…

  2. Cognitive Phenotype of Velocardiofacial Syndrome: A Review

    Science.gov (United States)

    Furniss, Frederick; Biswas, Asit B.; Gumber, Rohit; Singh, Niraj

    2011-01-01

    The behavioural phenotype of velocardiofacial syndrome (VCFS), one of the most common human multiple anomaly syndromes, includes developmental disabilities, frequently including intellectual disability (ID) and high risk of diagnosis of psychotic disorders including schizophrenia. VCFS may offer a model of the relationship between ID and risk of…

  3. The Behavioural Phenotype of Angelman Syndrome

    Science.gov (United States)

    Horsler, K.; Oliver, C.

    2006-01-01

    Background: The purpose of this review is to examine the notion of a behavioural phenotype for Angelman syndrome and identify methodological and conceptual influences on the accepted presentation. Methods: Studies examining the behavioural characteristics associated with Angelman syndrome are reviewed and methodology is described. Results:…

  4. Phenotypic Variations in Wolfhirschhorn Syndrome

    Directory of Open Access Journals (Sweden)

    E. Sukarova-Angelovska

    2014-06-01

    Full Text Available Wolf-Hirschhorn syndrome (WHS is a rare chromosomal disorder caused by terminal deletion of the short arm of chromosome 4. The clinical picture includes growth retardation, severe mental retardation, characteristic “Greek helmet” like face, seizures and midline defects in the brain, heart, palate and genitalia. Recently-used molecular techniques increase the number of diagnosed cases due to the detection of smaller deletions. The severity of the clinical presentation is variable depending on the haploinsufficiency of genes in a deleted region.

  5. Syndromic (phenotypic diarrhea in early infancy

    Directory of Open Access Journals (Sweden)

    Bodemer Christine

    2008-02-01

    Full Text Available Abstract Syndromic diarrhea (SD, also known as phenotypic diarrhea (PD or tricho-hepato-enteric syndrome (THE, is a congenital enteropathy presenting with early-onset of severe diarrhea requiring parenteral nutrition (PN. To date, no epidemiological data are available. The estimated prevalence is approximately 1/300,000–400,000 live births in Western Europe. Ethnic origin does not appear to be associated with SD. Infants are born small for gestational age and present with facial dysmorphism including prominent forehead and cheeks, broad nasal root and hypertelorism. Hairs are woolly, easily removed and poorly pigmented. Severe and persistent diarrhea starts within the first 6 months of life (≤ 1 month in most cases and is accompanied by severe malabsorption leading to early and relentless protein energy malnutrition with failure to thrive. Liver disease affects about half of patients with extensive fibrosis or cirrhosis. There is currently no specific biochemical profile, though a functional T-cell immune deficiency with defective antibody production was reported. Microscopic analysis of the hair show twisted hair (pili torti, aniso- and poilkilotrichosis, and trichorrhexis nodosa. Histopathological analysis of small intestine biopsy shows non-specific villous atrophy with low or no mononuclear cell infiltration of the lamina propria, and no specific histological abnormalities involving the epithelium. The etiology remains unknown. The frequent association of the disorder with parental consanguinity and/or affected siblings suggests a genetic origin with an autosomal recessive mode of transmission. Early management consists of total PN. Some infants have a rather milder phenotype with partial PN dependency or require only enteral feeding. Prognosis of this syndrome is poor, but most patients now survive, and about half of the patients may be weaned from PN at adolescence, but experience failure to thrive and final short stature. Disease name

  6. A vestibular phenotype for Waardenburg syndrome?

    Science.gov (United States)

    Black, F. O.; Pesznecker, S. C.; Allen, K.; Gianna, C.

    2001-01-01

    OBJECTIVE: To investigate vestibular abnormalities in subjects with Waardenburg syndrome. STUDY DESIGN: Retrospective record review. SETTING: Tertiary referral neurotology clinic. SUBJECTS: Twenty-two adult white subjects with clinical diagnosis of Waardenburg syndrome (10 type I and 12 type II). INTERVENTIONS: Evaluation for Waardenburg phenotype, history of vestibular and auditory symptoms, tests of vestibular and auditory function. MAIN OUTCOME MEASURES: Results of phenotyping, results of vestibular and auditory symptom review (history), results of vestibular and auditory function testing. RESULTS: Seventeen subjects were women, and 5 were men. Their ages ranged from 21 to 58 years (mean, 38 years). Sixteen of the 22 subjects sought treatment for vertigo, dizziness, or imbalance. For subjects with vestibular symptoms, the results of vestibuloocular tests (calorics, vestibular autorotation, and/or pseudorandom rotation) were abnormal in 77%, and the results of vestibulospinal function tests (computerized dynamic posturography, EquiTest) were abnormal in 57%, but there were no specific patterns of abnormality. Six had objective sensorineural hearing loss. Thirteen had an elevated summating/action potential (>0.40) on electrocochleography. All subjects except those with severe hearing loss (n = 3) had normal auditory brainstem response results. CONCLUSION: Patients with Waardenburg syndrome may experience primarily vestibular symptoms without hearing loss. Electrocochleography and vestibular function tests appear to be the most sensitive measures of otologic abnormalities in such patients.

  7. Phenotypic variability of Cat-Eye syndrome.

    Science.gov (United States)

    Berends, M J; Tan-Sindhunata, G; Leegte, B; van Essen, A J

    2001-01-01

    Cat-Eye syndrome (CES) is a disorder with a variable pattern of multiple congenital anomalies of which coloboma of the iris and anal atresia are the best known. CES is cytogenetically characterised by the presence of an extra bisatellited marker chromosome, which represents an inverted dicentric duplication of a part of chromosome 22 (inv dup(22)). We report on three CES-patients who carry an inv dup(22) diagnosed with FISH studies. They show remarkable phenotypic variability. The cause of this variability is unknown. Furthermore, we review clinical features of 71 reported patients. Only 41% of the CES-patients have the combination of iris coloboma, anal anomalies and pre-auricular anomalies. Therefore, almost 60% of the CES-patients are hard to recognize by their phenotype alone. Mild to moderate mental retardation was found in 32% (16/50) of the cases. Mental retardation occurs more frequently in male CES-patients. There is no apparent phenotypic difference between mentally retarded and mentally normal CES-patients.

  8. The Down Syndrome Behavioural Phenotype: Taking a Developmental Approach

    Science.gov (United States)

    Fidler, Deborah; Most, David; Philofsky, Amy

    2009-01-01

    Individuals with Down syndrome are predisposed to show a specific behavioural phenotype, or a pattern of strengths and challenges in functioning across different domains of development. It is argued that a developmental approach to researching the Down syndrome behavioural phenotype, including an examination of the dynamic process of the unfolding…

  9. Sheep models of polycystic ovary syndrome phenotype

    Science.gov (United States)

    Veiga-Lopez, Almudena

    2012-01-01

    Polycystic ovary syndrome (PCOS) is a fertility disorder affecting 5–7% of reproductive-aged women. Women with PCOS manifest both reproductive and metabolic defects. Several animal models have evolved, which implicate excess steroid exposure during fetal life in the development of the PCOS phenotype. This review addresses the fetal and adult reproductive and metabolic consequences of prenatal steroid excess in sheep and the translational relevance of these findings to PCOS. By comparing findings in various breeds of sheep, the review targets the role of genetic susceptibility to fetal insults. Disruptions induced by prenatal testosterone excess are evident at both the reproductive and metabolic level with each influencing the other thus creating a self-perpetuating vicious cycle. The review highlights the need for identifying a common mediator of the dysfunctions at the reproductive and metabolic levels and developing prevention and treatment interventions targeting all sites of disruption in unison for achieving optimal success. PMID:23084976

  10. Wolfram Syndrome: New Mutations, Different Phenotype

    Science.gov (United States)

    Pasquali, Lorenzo; Lugani, Francesca; Perri, Katia; Russo, Chiara; Tallone, Ramona; Ghiggeri, Gian Marco; Lorini, Renata; d'Annunzio, Giuseppe

    2012-01-01

    Background Wolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym “DIDMOAD”. The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354. The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation. Methodology/Principal Findings We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females). Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing. Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V) was found. Two new variants c.2663 C>A and c.1381 A>C were detected. Conclusions/Significance Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10), deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA). PMID:22238590

  11. Wolfram syndrome: new mutations, different phenotype.

    Directory of Open Access Journals (Sweden)

    Concetta Aloi

    Full Text Available BACKGROUND: Wolfram Syndrome (WS is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym "DIDMOAD". The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354. The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation. METHODOLOGY/PRINCIPAL FINDINGS: We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females. Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing. Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V was found. Two new variants c.2663 C>A and c.1381 A>C were detected. CONCLUSIONS/SIGNIFICANCE: Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10, deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA.

  12. Phenotypic characteristics of early Wolfram syndrome.

    Science.gov (United States)

    Marshall, Bess A; Permutt, M Alan; Paciorkowski, Alexander R; Hoekel, James; Karzon, Roanne; Wasson, Jon; Viehover, Amy; White, Neil H; Shimony, Joshua S; Manwaring, Linda; Austin, Paul; Hullar, Timothy E; Hershey, Tamara

    2013-04-27

    Wolfram Syndrome (WFS:OMIM 222300) is an autosomal recessive, progressive, neurologic and endocrinologic degenerative disorder caused by mutations in the WFS1 gene, encoding the endoplasmic reticulum (ER) protein wolframin, thought to be involved in the regulation of ER stress. This paper reports a cross section of data from the Washington University WFS Research Clinic, a longitudinal study to collect detailed phenotypic data on a group of young subjects in preparation for studies of therapeutic interventions. Eighteen subjects (ages 5.9-25.8, mean 14.2 years) with genetically confirmed WFS were identified through the Washington University International Wolfram Registry. Examinations included: general medical, neurologic, ophthalmologic, audiologic, vestibular, and urologic exams, cognitive testing and neuroimaging. Seventeen (94%) had diabetes mellitus with the average age of diabetes onset of 6.3 ± 3.5 years. Diabetes insipidus was diagnosed in 13 (72%) at an average age of 10.6 ± 3.3 years. Seventeen (94%) had optic disc pallor and defects in color vision, 14 (78%) had hearing loss and 13 (72%) had olfactory defects, eight (44%) had impaired vibration sensation. Enuresis was reported by four (22%) and nocturia by three (17%). Of the 11 tested for bladder emptying, five (45%) had elevated post-void residual bladder volume. WFS causes multiple endocrine and neurologic deficits detectable on exam, even early in the course of the disease. Defects in olfaction have been underappreciated. The proposed mechanism of these deficits in WFS is ER stress-induced damage to neuronal and hormone-producing cells. This group of subjects with detailed clinical phenotyping provides a pool for testing proposed treatments for ER stress. Longitudinal follow-up is necessary for establishing the natural history and identifying potential biomarkers of progression.

  13. Cornelia de Lange Syndrome: Evolution of the Phenotype

    Science.gov (United States)

    Passarge, Eberhard; And Others

    1971-01-01

    The medical case history of a 2-year-old girl who developed, during the second year of life, the classical phenotype (typical appearance) indicative of the deLange syndrome, with both mental and physical impairment. (KW)

  14. Challenging behavior: Behavioral phenotypes of some genetic syndromes

    Directory of Open Access Journals (Sweden)

    Buha Nataša

    2014-01-01

    Full Text Available Challenging behavior in individuals with mental retardation (MR is relatively frequent, and represents a significant obstacle to adaptive skills. The frequency of specific forms and manifestations of challenging behavior can depend on a variety of personal and environmental factors. There are several prominent theoretical models regarding the etiology of challenging behavior and psychopathology in persons with MR: behavioral, developmental, socio-cultural and biological. The biological model emphasizes the physiological, biochemical and genetic factors as the potential source of challenging behavior. The progress in the field of genetics and neuroscience has opened the opportunity to study and discover the neurobiological basis of phenotypic characteristics. Genetic syndromes associated with MR can be followed by a specific set of problems and disorders which constitutes their behavioral phenotype. The aim of this paper was to present challenging behaviors that manifest in the most frequently studied syndromes: Down syndrome, Fragile X syndrome, Williams syndrome, Prader-Willi syndrome and Angelman syndrome. The concept of behavioral phenotype implies a higher probability of manifesting specific developmental characteristics and specific behaviors in individuals with a certain genetic syndrome. Although the specific set of (possible problems and disorders is distinctive for the described genetic syndromes, the connection between genetics and behavior should be viewed through probabilistic dimension. The probabilistic concept takes into consideration the possibility of intra-syndrome variability in the occurrence, intensity and time onset of behavioral characteristics, at which the higher variability the lower is the specificity of the genetic syndrome. Identifying the specific pattern of behavior can be most important for the process of early diagnosis and prognosis. In addition, having knowledge about behavioral phenotype can be a landmark in

  15. Unique phenotype in a patient with CHARGE syndrome

    Directory of Open Access Journals (Sweden)

    Ten Svetlana

    2011-10-01

    Full Text Available Abstract CHARGE is a phenotypically heterogeneous autosomal dominant disorder recognized as a cohesive syndrome since the identification of CHD7 as a genetic etiology. Classic features include: Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genitourinary abnormalities, and Ear anomalies and/or deafness. With greater accessibility to genetic analysis, a wider spectrum of features are emerging, and overlap with disorders such as DiGeorge syndrome, Kallmann syndrome, and Hypoparathyroidism Sensorineural Deafness and Renal Disease syndrome, is increasingly evident. We present a patient with a unique manifestation of CHARGE syndrome, including primary hypoparathyroidism and a limb anomaly; to our knowledge, he is also the first CHARGE subject reported with bilateral multicystic dysplastic kidneys. Furthermore, with structural modeling and murine expression studies, we characterize a putative CHD7 G744S missense mutation. Our report continues to expand the CHARGE phenotype and highlights that stringent fulfillment of conventional criteria should not strictly guide genetic analysis.

  16. Towards a Behavioral Phenotype for Rett Syndrome.

    Science.gov (United States)

    Mount, Rebecca H.; Hastings, Richard P.; Reilly, Sheena; Cass, Hilary; Charman, Tony

    2003-01-01

    A study compared 143 girls (ages 6-14) with Rett syndrome with 85 girls with severe mental retardation on the Developmental Behavior Checklist. Girls with Rett syndrome presented more "autistic relating" and fewer antisocial behaviors. When compared to children with autism, they did not present with classic autistic behavioral features.…

  17. Phenotypic Characterization of Derivative 22 Syndrome: Case ...

    Indian Academy of Sciences (India)

    DEEPTI

    E-mail: shubharaophadke@gmail.com. Conflict of Interest Statement: There is no conflict of interest among the authors. Key words: Emanuel syndrome; derivative chromosome 22; microarray; intellectual disability; chromosomal rearrangement. Abstract. Emanuel syndrome is characterized by severe intellectual disability, ...

  18. Phenotypic variability of cat-eye syndrome

    NARCIS (Netherlands)

    Berends, MJW; Tan-Sindhunata, G; Leegte, B; Van Essen, AJ

    2001-01-01

    Cat-Eye syndrome (CES) is a disorder with a variable pattern of multiple congenital anomalies of which coloboma of the iris and anal atresia are the best known. CES is cyogenetically characterised by the presence of an extra bisatellited marker chromosome, which represents an inverted dicentric

  19. Low bone turnover phenotype in Rett syndrome

    DEFF Research Database (Denmark)

    Roende, Gitte; Petersen, Janne; Ravn, Kirstine

    2014-01-01

    Background:Patients with Rett syndrome (RTT) are at risk of having low bone mass and low-energy fractures.Methods:We characterised bone metabolism by both bone formation and resorption markers in blood in a RTT population of 61 girls and women and 122 well-matched healthy controls. Levels of N...

  20. The phenotypic spectrum of congenital Zika syndrome.

    Science.gov (United States)

    Del Campo, Miguel; Feitosa, Ian M L; Ribeiro, Erlane M; Horovitz, Dafne D G; Pessoa, André L S; França, Giovanny V A; García-Alix, Alfredo; Doriqui, Maria J R; Wanderley, Hector Y C; Sanseverino, Maria V T; Neri, João I C F; Pina-Neto, João M; Santos, Emerson S; Verçosa, Islane; Cernach, Mirlene C S P; Medeiros, Paula F V; Kerbage, Saile C; Silva, André A; van der Linden, Vanessa; Martelli, Celina M T; Cordeiro, Marli T; Dhalia, Rafael; Vianna, Fernanda S L; Victora, Cesar G; Cavalcanti, Denise P; Schuler-Faccini, Lavinia

    2017-04-01

    In October 2015, Zika virus (ZIKV) outbreak the Brazilian Ministry of Health (MoH). In response, the Brazilian Society of Medical Genetics established a task force (SBGM-ZETF) to study the phenotype of infants born with microcephaly due to ZIKV congenital infection and delineate the phenotypic spectrum of this newly recognized teratogen. This study was based on the clinical evaluation and neuroimaging of 83 infants born during the period from July, 2015 to March, 2016 and registered by the SBGM-ZETF. All 83 infants had significant findings on neuroimaging consistent with ZIKV congenital infection and 12 had confirmed ZIKV IgM in CSF. A recognizable phenotype of microcephaly, anomalies of the shape of skull and redundancy of the scalp consistent with the Fetal Brain Disruption Sequence (FBDS) was present in 70% of infants, but was most often subtle. In addition, features consistent with fetal immobility, ranging from dimples (30.1%), distal hand/finger contractures (20.5%), and feet malpositions (15.7%), to generalized arthrogryposis (9.6%), were present in these infants. Some cases had milder microcephaly or even a normal head circumference (HC), and other less distinctive findings. The detailed observation of the dysmorphic and neurologic features in these infants provides insight into the mechanisms and timings of the brain disruption and the sequence of developmental anomalies that may occur after prenatal infection by the ZIKV. © 2017 Wiley Periodicals, Inc.

  1. KBG syndrome and the establishment of its neuropsychological phenotype

    NARCIS (Netherlands)

    Egger, J.I.M.; Dongen, L.C.M. van; Stumpel, C.; Wingbermühle, P.A.M.; Kleefstra, T.

    2017-01-01

    Objective: KBG syndrome is caused by a mutation in the ANKRD11 gene, characterized by short stature and specific dental, craniofacial and skeletal anomalies. Scarce literature on the phenotypical presentation mention delayed speech and motor development as well as mild to moderate intellectual

  2. Alpha-1 antitrypsin phenotypes in patients with Klinefelter's syndrome

    Indian Academy of Sciences (India)

    Klinefelter's syndrome (KS) is the most common human sex chromosome disorder, with a prevalence of 1 in 660 men. The phenotype is variable, but the most constant findings are small and firm testes, decreased testosterone level, infertility, eunuchoid body proportion, increased height, and learning disabilities, due to the ...

  3. Nicolaides-Baraitser Syndrome: Delineation of the Phenotype

    NARCIS (Netherlands)

    Sousa, Sérgio B.; Abdul-Rahman, Omar A.; Bottani, Armand; Cormier-Daire, Valérie; Fryer, Alan; Gillessen-Kaesbach, Gabriele; Horn, Denise; Josifova, Dragana; Kuechler, Alma; Lees, Melissa; Macdermot, Kay; Magee, Alex; Morice-Picard, Fanny; Rosser, Elizabeth; Sarkar, Ajoy; Shannon, Nora; Stolte-Dijkstra, Irene; Verloes, Alain; Wakeling, Emma; Wilson, Louise; Hennekam, Raoul C. M.

    2009-01-01

    Nicolaides-Baraitser syndrome (NBS) is an infrequently described condition, thus far reported in five cases. In order to delineate the phenotype and its natural history in more detail, we gathered data on 18 hitherto unreported patients through a multi-center collaborative study, and follow-up data

  4. Nicolaides-Baraitser Syndrome : Delineation of the Phenotype

    NARCIS (Netherlands)

    Sousa, Sergio B.; Abdul-Rahman, Omar A.; Bottani, Armand; Cormier-Daire, Valerie; Fryer, Alan; Gillessen-Kaesbach, Gabriele; Horn, Denise; Josifova, Dragana; Kuechler, Alma; Lees, Melissa; MacDermot, Kay; Magee, Alex; Morice-Picard, Fanny; Rosser, Elizabeth; Sarkar, Ajoy; Shannon, Nora; Stolte-Dijkstra, Irene; Verloes, Alain; Wakeling, Emma; Wilson, Louise; Hennekam, Raoul C. M.

    Nicolaides-Baraitser syndrome (NBS) is an infrequently described condition, thus far reported in five cases. In order to delineate the phenotype and its natural history in more detail, we gathered data on 18 hitherto unreported patients through a multi-center collaborative study, and follow-up data

  5. Milder phenotypes of glucose transporter type 1 deficiency syndrome

    NARCIS (Netherlands)

    Anand, G.; Padeniya, A.; Hanrahan, D.; Scheffer, H.; Zaiwalla, Z.; Cox, D.; Mann, N.; Hewertson, J.; Price, S.; Nemeth, A.; Arsov, T.; Scheffer, I.; Jayawant, S.; Pike, M.; McShane, T.

    2011-01-01

    Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a treatable condition resulting from impaired glucose transport into the brain. The classical presentation is with infantile-onset epilepsy and severe developmental delay. Non-classical phenotypes with movement disorders and early-onset

  6. Genetic Mechanisms Involved in the Phenotype of Down Syndrome

    Science.gov (United States)

    Patterson, David

    2007-01-01

    Down syndrome (DS) is the most common genetic cause of significant intellectual disability in the human population, occurring in roughly 1 in 700 live births. The ultimate cause of DS is trisomy of all or part of the set of genes located on chromosome 21. How this trisomy leads to the phenotype of DS is unclear. The completion of the DNA…

  7. Thoracic Outlet Syndrome: A Significant Family Genetic Phenotypic Presentation.

    Science.gov (United States)

    Janák, David; Novotný, Karel; Roček, Miloslav; Rohn, Vilém

    We report on a very rare case of diagnosis and successful surgical treatment of three young family members with a four-fold presentation of thoracic outlet syndrome. In the relevant family case, we are considering and discussing the population incidence, a possible HOX genes disorder, and a significant phenotypic presentation.

  8. Phenotype in 18 Danish subjects with genetically verified CHARGE syndrome

    DEFF Research Database (Denmark)

    Husu, E; Hove, Hd; Farholt, Stense

    2013-01-01

    problems (12/15) were other frequent cranial nerve dysfunctions. Three-dimensional reconstructions of MRI scans showed temporal bone abnormalities in >85%. CHARGE syndrome present a broad phenotypic spectrum, although some clinical features are more frequently occurring than others. Here, we suggest...

  9. The Fragile X Syndrome: Behavioral Phenotype and Learning Disabilities

    Directory of Open Access Journals (Sweden)

    Claudia GRAU RUBIO

    2016-04-01

    Full Text Available In this article, we describe the behavioral phenotype of individuals with Fragile X Syndrome and its impact in the educational scope. This syndrome is characterized by difficulties in sensory integration, cognitive deficits (verbal reasoning, abstract/ visual and cuantitative skills, short term memory, sequential processing, attention and executive processes, language disorders (phonetic-phonologicals, semanticals, morphosyntacticals and pragmaticals and communication disorders, social anxiety, general hyperarousal, autism, non autistic social difficulties, attention deficit and hyperactivity, and learning disabilities. The behavioral phenotype is highly variable and depends on sex, age, and mutation status (full mutation or premutation. The behavioural phenotype has important repercussions in education, as it enables us to understand the learning disabilities and to develop specific intervention strategies.

  10. Thoughts on the behavioural phenotypes in Prader-Willi syndrome and velo-cardio-facial syndrome: A novel approach

    NARCIS (Netherlands)

    Verhoeven, W.M.A.; Egger, J.I.M.; Tuinier, S.

    2007-01-01

    In both Prader-Willi syndrome (PWS) and 22q11 deletion syndrome [velo-cardio-facial syndrome (VCFS)], an increased risk for psychotic disorders is reported, which are as a rule not included in the behavioural phenotype of these two syndromes. For the description of a behavioural phenotype, the

  11. Metformin treatment in different phenotypes of polycystic ovary syndrome.

    Science.gov (United States)

    Hosseini, Marzieh Agha; Alleyassin, Ashraf; Sarvi, Fatemeh; Safdarian, Leila; Kokab, Abas; Fanisalek, Mehran

    2013-11-01

    The aim of this study was to evaluate the effectiveness of Metformin on ovulation and eventual clinical pregnancy in different phenotypes of polycystic ovary syndrome (PCOS). A total of 359 subjects who had proven PCOS according to Rotterdam criteria were prospectively selected. Patients' PCOS phenotypes were determined and recorded. All patients were younger than 35 years. Clinical and biochemical assays in all patients were initially obtained. Then patients were divided into two separate groups. One group received both 1,500 mg of Metformin and 1 mg of folic acid per day and the other group received only 1 mg of folic acid for a total of 2 months. Subsequently, all patients underwent ovulation stimulation with 5 mg of Letrozole per day for 5 days followed by an intra-uterine insemination. Finally, ovulation and pregnancy rates were evaluated for all four PCOS phenotypes. Effect of Metformin therapy was evaluated for each group and each phenotype. The pregnancy rate in Metformin and non-Metformin groups were, respectively, as follows: in phenotype A (39.2 vs. 33.7 %, p = 0.270), phenotype B (43.8 vs. 20 %, p = 0.210), phenotype C (44 vs. 20 %, p = 0.064), and phenotype D (36.5 vs. 28.6 %, p = 0.279). Although there was a little improvement in ovulation and pregnancy rates among patients with B and C phenotypes, there was not a statistically significant difference between the two groups. Based on our study, Metformin therapy does not change the ovulation and pregnancy rate.

  12. Phenotype of asthma-chronic obstructive pulmonary disease overlap syndrome.

    Science.gov (United States)

    Rhee, Chin Kook

    2015-07-01

    Many patients with asthma or chronic obstructive pulmonary disease (COPD) have overlapping characteristics of both diseases. By spirometric definition, patients with both fixed airflow obstruction (AO) and bronchodilator reversibility or fixed AO and bronchial hyperresponsiveness can be considered to have asthma-COPD overlap syndrome (ACOS). However, patients regarded to have ACOS by spirometric criteria alone are heterogeneous and can be classified by phenotype. Eosinophilic inflammation, a history of allergic disease, and smoke exposure are important components in the classification of ACOS. Each phenotype has a different underlying pathophysiology, set of characteristics, and prognosis. Medical treatment for ACOS should be tailored according to phenotype. A narrower definition of ACOS that includes both spirometric and clinical criteria is needed.

  13. Phenotypic expression of polycystic ovary syndrome in South Asian women.

    Science.gov (United States)

    Mehta, Jaya; Kamdar, Vikram; Dumesic, Daniel

    2013-03-01

    Polycystic ovary syndrome (PCOS) occurs in 6% to 10% of women and, as the most common worldwide endocrinopathy of reproductive-aged women, is linked to a constellation of reproductive and metabolic abnormalities, including anovulatory infertility, hirsutism, acne, and insulin resistance in association with metabolic syndrome. Despite a genetic component to PCOS, ethnicity plays an important role in the phenotypic expression of PCOS, with South Asian PCOS women having more severe reproductive and metabolic symptoms than other ethnic groups. South Asians with PCOS seek medical care at an earlier age for reproductive abnormalities; have a higher degree of hirsutism, infertility, and acne; and experience lower live birth rates following in vitro fertilization than do whites with PCOS. Similarly, South Asians with PCOS have a higher prevalence of insulin resistance and metabolic syndrome than do other PCOS-related ethnic groups of a similar body mass index. Inheritance of PCOS appears to have a complex genetic basis, including genetic differences based on ethnicity, which interact with lifestyle and other environmental factors to affect PCOS phenotypic expression. Obstetricians and Gynecologists, Family Physicians Learning Objectives: After completing this CME activity, physicians should be better able to state an ethnic difference in reproductive dysfunction between South Asian and white women with polycystic ovary syndrome (PCOS), state an ethnic difference in metabolic dysfunction between South Asian and white women with PCOS, identify a genetic abnormality found in South Asian women with PCOS, and list 2 environmental factors that predispose South Asian women to metabolic dysfunction.

  14. New approach to phenotypic variability and karyotype-phenotype correlation in Turner syndrome.

    Science.gov (United States)

    Miguel-Neto, Jamil; Carvalho, Annelise B; Marques-de-Faria, Antonia Paula; Guerra-Júnior, Gil; Maciel-Guerra, Andréa T

    2016-04-01

    Phenotypic variability of Turner syndrome (TS) challenges clinicians, and undiagnosed mosaicism may lead to conflicting results of karyotype-phenotype correlations. This study assessed the extent of phenotypic variability and investigated the presence of karyotype-phenotype correlations. The sample comprised 80 patients with ≥50 cells analyzed in karyotype. Twenty were 45,X/46,X,+mar; three groups of 20 patients were constructed by matching those girls with the nearest-aged patient with 45,X, 45,X/46,XX and 45,X/46,X,i(Xq) or 46,X,i(Xq) karyotype. Data were obtained on height z-score, dysmorphic features, echocardiogram and urinary system sonography. The number of dysmorphic features ranged from one to 16 and was not correlated to age at diagnosis or height. The groups did not differ in height, number of dysmorphic features, cardiovascular and urinary system anomalies and frequency of any specific feature, except for short fourth metacarpal. Wide phenotypical variability of TS may be objectively described and its clinical picture is not correlated to karyotype.

  15. Obesity Differentially Affects Phenotypes of Polycystic Ovary Syndrome

    Directory of Open Access Journals (Sweden)

    Carlos Moran

    2012-01-01

    Full Text Available Obesity or overweight affect most of patients with polycystic ovary syndrome (PCOS. Phenotypes are the clinical characteristics produced by the interaction of heredity and environment in a disease or syndrome. Phenotypes of PCOS have been described on the presence of clinical hyperandrogenism, oligoovulation and polycystic ovaries. The insulin resistance is present in the majority of patients with obesity and/or PCOS and it is more frequent and of greater magnitude in obese than in non obese PCOS patients. Levels of sexual hormone binding globulin are decreased, and levels of free androgens are increased in obese PCOS patients. Weight loss treatment is important for overweight or obese PCOS patients, but not necessary for normal weight PCOS patients, who only need to avoid increasing their body weight. Obesity decreases or delays several infertility treatments. The differences in the hormonal and metabolic profile, as well as the different focus and response to treatment between obese and non obese PCOS patients suggest that obesity has to be considered as a characteristic for classification of PCOS phenotypes.

  16. Congenital Heart Diseases associated with Identified Syndromes ...

    African Journals Online (AJOL)

    Recognised syndromes were seen in 69(68%) cases. Down syndrome with 54 children contributed 78.3% of those with known syndromes. Other identified syndromes and associations were Marfan's, Noonan's, Edwards, Prune Belly, Apert, Ellis-van creveld syndrome and congenital rubella syndrome. Congenital heart ...

  17. Down syndrome phenotypes: The consequences of chromosomal imbalance

    Energy Technology Data Exchange (ETDEWEB)

    Korenberg, J.R.; Chen, X.N.; Schipper, R.; Sun, Z.; Gonsky, R.; Gerwehr, S.; Graham, J.M. Jr. (Univ. of California, Los Angeles, CA (United States)); Carpenter, N.; Say, B. (H.A. Chapman Institute of Medical Genetics, Tulsa, OK (United States)); Daumer, C. (Univ. of Munich (Germany)) (and others)

    1994-05-24

    Down syndrome (DS) is a major cause of mental retardation and congenital heart disease. Besides a characteristic set of facial and physical features, DS is associated with congenital anomalies of the gastrointestinal tract, an increased risk of leukemia, immune system defects, and an Alzheimer-like dementia. Moreover, DS is a model for the study of human aneuploidy. Although usually caused by the presence of an extra chromosome 21, subsets of the phenotypic features of DS may be caused by the duplication of small regions of the chromosome. The physical map of chromosome 21 allows the molecular definition of the regions duplicated in these rare cases of partial trisomy. As a first step in identifying the genes responsible for individual DS features and their pathophysiology, a panel of cell lines derived from 16 such individuals has been established and the molecular break points have been determined using fluorescence in situ hybridization and Southern blot dosage analysis of 32 markers unique to human chromosome 21. Combining this information with detailed clinical evaluations of these patients, the authors have now constructed a [open quotes]phenotypic map[close quotes] that includes 25 features and assigns regions of 2-20 megabases as likely to contain the genes responsible. This study provides evidence for a significant contribution of genes outside the D21S55 region to the DS phenotypes, including the facies, microcephaly, short stature, hypotonia, abnormal dermatoglyphics, and mental retardation. This strongly suggests DS is a contiguous gene syndrome and augurs against a single DS chromosomal region responsible for most of the DS phenotypic features.

  18. Cardio-facio-cutaneous syndrome: does genotype predict phenotype?

    Science.gov (United States)

    Allanson, Judith E; Annerén, Göran; Aoki, Yoki; Armour, Christine M; Bondeson, Marie-Louise; Cave, Helene; Gripp, Karen W; Kerr, Bronwyn; Nystrom, Anna-Maja; Sol-Church, Katia; Verloes, Alain; Zenker, Martin

    2011-05-15

    Cardio-facio-cutaneous (CFC) syndrome is a sporadic multiple congenital anomalies/mental retardation condition principally caused by mutations in BRAF, MEK1, and MEK2. Mutations in KRAS and SHOC2 lead to a phenotype with overlapping features. In approximately 10–30% of individuals with a clinical diagnosis of CFC, a mutation in one of these causative genes is not found. Cardinal features of CFC include congenital heart defects, a characteristic facial appearance, and ectodermal abnormalities. Additional features include failure to thrive with severe feeding problems, moderate to severe intellectual disability and short stature with relative macrocephaly. First described in 1986, more than 100 affected individuals are reported. Following the discovery of the causative genes, more information has emerged on the breadth of clinical features. Little, however, has been published on genotype–phenotype correlations. This clinical study of 186 children and young adults with mutation-proven CFC syndrome is the largest reported to date. BRAF mutations are documented in 140 individuals (approximately 75%), while 46 (approximately 25%) have a mutation in MEK 1 or MEK 2. The age range is 6 months to 32 years, the oldest individual being a female from the original report [Reynolds et al. (1986); Am J Med Genet 25:413–427]. While some clinical data on 136 are in the literature, 50 are not previously published. We provide new details of the breadth of phenotype and discuss the frequency of particular features in each genotypic group. Pulmonary stenosis is the only anomaly that demonstrates a statistically significant genotype–phenotype correlation, being more common in individuals with a BRAF mutation.

  19. Cri du chat syndrome: changing phenotype in older patients.

    Science.gov (United States)

    Van Buggenhout, G J; Pijkels, E; Holvoet, M; Schaap, C; Hamel, B C; Fryns, J P

    2000-01-31

    The cri du chat syndrome or 5p deletion syndrome is a well-delineated clinical entity and has an incidence of 1/50,000 in newborn infants. A de novo deletion is present in 85% of the patients. Ten to 15% are familial cases with more than 90% due to a parental translocation and 5% due to an inversion of chromosome 5. Although the size of the deleted segment varies, the critical segment that is deleted in all patients appears to be 5p15.2. The clinical picture is well known in younger patients and includes the typical high-pitched cry, psychomotor retardation, microcephaly, growth rate failure, and craniofacial abnormalities including round face, hypertelorism, broad nasal bridge, downward slanting palpebral fissures, and micrognathia. With advancing age, the clinical picture becomes less striking. We present seven patients with 5p deletion syndrome, who were between age 16 and 47 years. Comparing their phenotype at several ages, a change of their phenotype was noted. Some of the clinical characteristics became more evident such as long face, macrostomia, and scoliosis. All patients were severely or profoundly mentally retarded except one patient who was mildly mentally retarded. The diagnosis was difficult to make in some of the patients who were first seen at an older age. In some of them, the craniofacial appearance resembled that seen in Angelman syndrome. Most patients had periods of destructive behavior, self mutilation, and aggression. The clinical diagnosis should be confirmed as soon as possible with cytogenetic investigation to provide specific support, prevention, and treatment of complications. Therefore, it is important to perform follow-up studies in young children to determine their outcome after infant-stimulation programs.

  20. [Social cognition disorders in Klinefelter syndrome: A specific phenotype? (KS)].

    Science.gov (United States)

    Babinet, M-N; Rigard, C; Peyroux, É; Dragomir, A-R; Plotton, I; Lejeune, H; Demily, C

    2017-10-01

    The Klinefelter syndrome (KS) is a genetic condition characterized by an X supernumerary sex chromosome in males. The syndrome is frequently associated with cognitive impairment. Indeed, the different areas of the executive sphere can be affected such as inhibition, cognitive flexibility but also attentional and visual-spatial domain. Social cognition disorders, predominantly on emotional recognition processes, have also been documented. In addition, the syndrome may be associated with psychiatric symptoms. Our study aims to characterize of the various components of social cognition in the SK: facial emotional recognition, theory of mind and attributional style. For this two groups (SK group versus control group) of participants (n=16) matched for age and sociocultural level were recruited. Participants with intellectual disabilities, psychiatric or neurological disorders were excluded. Three social cognition tests were available: the TREF, the MASC, the AIHQ. Neurocognitive functions were assessed by the fNart, the subtest "logical memory" of the MEM-III, the subtests of the two VOSP battery, the d2, the TMT and the Stroop test. The SK group had specific social cognition disorders in comparison to the control group. Two emotions in particular were less well recognized: fear and contempt. In addition, the SK group had significantly lower results in theory of mind. Regarding the hostile attribution bias, no significant difference was found. Finally, the results showed correlations between specific attentional disorders and facial emotional recognition. Our study emphasizes social cognition disorders in SK. These disorders could be considered as a phenotypic trait in the syndrome. The interest of better characterizing the cognitive phenotype of genetic disorders that can affect the neurodevelopment is to offer specific cognitive remediation strategies. Copyright © 2016. Published by Elsevier Masson SAS.

  1. Phenotypic and behavioral variability within Angelman Syndrome group with UPD

    Directory of Open Access Journals (Sweden)

    Cintia Fridman

    2002-01-01

    Full Text Available The Angelman syndrome (AS (developmental delay, mental retardation, speech impairment, ataxia, outbursts of laughter, seizures can result either from a 15q11-q13 deletion, or from paternal uniparental disomy (UPD, imprinting, or UBE3A mutations. We describe here the phenotypic and behavioral variability detected in eight UPD patients out of a group of 58 AS patients studied. All of them presented developmental delay, mental retardation, ataxia, speech impairment, and frequent drooling. Only one had microcephaly, whereas in two of them the OFC (head circumference was above the 98th percentile. The weight of all patients was above the 50th percentile, and in three of them the height was above the 90th percentile. Three were able to say a few words and to communicate by gestures. Two patients presented hyperphagia, and three presented skin picking, common features in the Prader-Willi syndrome (PWS. Four patients (4/7 had wide-spaced teeth. Five presented seizures, and two others did not manifest frequent laughter. One patient was very different from the others, as he showed a better understanding and abilities to communicate, to play video games and to draw. We suggest here that there seems to be an extreme phenotypic and behavioral variability within the UPD group, and that both typical patients and those with mental retardation, language impairment, happy disposition, and hyperactivity should be tested for AS.

  2. Bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: phenotypes and prognosis.

    Science.gov (United States)

    Bergeron, A; Godet, C; Chevret, S; Lorillon, G; Peffault de Latour, R; de Revel, T; Robin, M; Ribaud, P; Socié, G; Tazi, A

    2013-06-01

    Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic SCT (HSCT) is recognized as a new-onset obstructive lung defect (OLD) in pulmonary function testing and is related to pulmonary chronic GVHD. Little is known about the different phenotypes of patients with BOS and their outcomes. We reviewed the data of all allogeneic HSCT recipients referred to our pulmonary department for a non-infectious bronchial disease between 1999 and 2010. We identified 103 patients (BOS (n=77), asthma (n=11) and chronic bronchitis (n=15)). In patients with BOS, we identified two functional phenotypes: a typical OLD, that is, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7 (n=53), and an atypical OLD with a concomitant decrease in the FEV1 <80% and FVC <80% predicted with a normal total lung capacity (n=24). The typical OLD was characterized by more severe FEV1 and fewer centrilobular nodules on the computed tomography scan. The FEV1 was not significantly affected during the follow-up, regardless of the phenotype. In addition to acute and extensive chronic GVHD, only the occurrence of BOS soon after transplantation and the intentional treatment of BOS with steroids were associated with a poor survival. The determination of patient subgroups should be explored to improve the management of this condition.

  3. DOORS syndrome: phenotype, genotype and comparison with Coffin-Siris syndrome.

    Science.gov (United States)

    Campeau, Philippe M; Hennekam, Raoul C

    2014-09-01

    DOORS syndrome (Deafness, Onychodystrophy, Osteodystrophy, mental Retardation, Seizures) is characterized mainly by sensorineural deafness, shortened terminal phalanges with small nails of hands and feet, intellectual deficiency, and seizures. Half of the patients with all clinical features have mutations in TBC1D24. We review here the manifestations of patients clinically diagnosed with DOORS syndrome. In this cohort of 32 families (36 patients) we detected 13 individuals from 10 families with TBC1D24 mutations. Subsequent whole exome sequencing in the cohort showed the same de novoSMARCB1 mutation (c.1130G>A), known to cause Coffin-Siris syndrome, in two patients. Distinguishing features include retinal anomalies, Dandy-Walker malformation, scoliosis, rocker bottom feet, respiratory difficulties and absence of seizures, and 2-oxoglutaric aciduria in the patients with the SMARCB1 mutation. We briefly discuss the heterogeneity of the DOORS syndrome phenotype and the differential diagnosis of this condition. © 2014 Wiley Periodicals, Inc.

  4. Mcleod syndrome: Report of an Indian family with phenotypic heterogeneity

    Science.gov (United States)

    Chakravarty, Ambar; Bhattacharya, P.; Banerjee, D.; Mukherjee, S.

    2011-01-01

    The present report deals with the clinical phenomenology of three members (brothers) of one family with McLeod syndrome (MLS). In two, the clinical pictures were of choreiform disorders with amyotrophy, which were found to be neurogenic in origin by detailed electrophysiological study. The index case had peripheral acanthocytosis; immunohematological and molecular genetic studies confirmed diagnosis of MLS. However, one brother only had a slowly progressive motor neuron disease like picture but no abnormal movement disorder. He had peripheral acanthocytes as well. The inheritance seems to be X-linked recessive in nature. The affected family members exhibited much phenotypic heterogeneity. This appears to be the first report of MLS from India. PMID:21655208

  5. Molecular Bases and Phenotypic Determinants of Aromatase Excess Syndrome

    Directory of Open Access Journals (Sweden)

    Maki Fukami

    2012-01-01

    Full Text Available Aromatase excess syndrome (AEXS is a rare autosomal dominant disorder characterized by gynecomastia. This condition is caused by overexpression of CYP19A1 encoding aromatase, and three types of cryptic genomic rearrangement around CYP19A1, that is, duplications, deletions, and inversions, have been identified in AEXS. Duplications appear to have caused CYP19A1 overexpression because of an increased number of physiological promoters, whereas deletions and inversions would have induced wide CYP19A1 expression due to the formation of chimeric genes consisting of a noncoding exon(s of a neighboring gene and CYP19A1 coding exons. Genotype-phenotype analysis implies that phenotypic severity of AEXS is primarily determined by the expression pattern of CYP19A1 and the chimeric genes and by the structural property of the fused exons with a promoter function (i.e., the presence or the absence of a natural translation start codon. These results provide novel information about molecular mechanisms of human genetic disorders and biological function of estrogens.

  6. The neurobehavioral and molecular phenotype of Angelman Syndrome.

    Science.gov (United States)

    Wink, Logan K; Fitzpatrick, Sarah; Shaffer, Rebecca; Melnyk, Sophia; Begtrup, Amber H; Fox, Emma; Schaefer, Tori L; Mathieu-Frasier, Lauren; Ray, Balmiki; Lahiri, Debomoy; Horn, Paul A; Erickson, Craig A

    2015-11-01

    Angelman Syndrome (AS) is a rare neurodevelopmental disorder associated with developmental delay, speech impairment, gait ataxia, and a unique behavioral profile. AS is caused by loss of maternal expression of the paternally imprinted UBE3A gene. In this study we aim to contribute to understanding of the neurobehavioral phenotype of AS with particular focus on the neuropsychiatric presentation of the disorder. We also undertake initial exploration of brain-derived neurotrophic factor (BDNF) plasma levels in AS. Twelve individuals ages 3 years or older with a confirmed genetic diagnosis of AS underwent detailed medical history, phenotypic characterization, and BDNF plasma sampling. The results of this study demonstrate that individuals with AS suffer from significant developmental delay, impaired adaptive behavior, and sleep disruption. Additionally, hyperactivity/impulsivity appears to be the primary behavioral domain noted in these individuals. The majority of individuals in this project met criteria for autism spectrum disorder on the Autism Diagnostic Observation Schedule (ADOS); however, a negative correlation was noted between ADOS score and developmental age. BDNF plasma levels in AS individuals were significantly elevated compared to neurotypical controls. This is the first report of abnormal BDNF levels in AS, and one that necessitates larger future studies. The results provide a clue to understanding abnormal neuronal development in AS and may help guide future AS research. © 2015 Wiley Periodicals, Inc.

  7. A Marfan syndrome gene expression phenotype in cultured skin fibroblasts

    Directory of Open Access Journals (Sweden)

    Emond Mary

    2007-09-01

    Full Text Available Abstract Background Marfan syndrome (MFS is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms. Results We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR. Conclusion Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value -6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status. An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater.

  8. Dissecting the phenotypes of Dravet syndrome by gene deletion.

    Science.gov (United States)

    Rubinstein, Moran; Han, Sung; Tai, Chao; Westenbroek, Ruth E; Hunker, Avery; Scheuer, Todd; Catterall, William A

    2015-08-01

    Neurological and psychiatric syndromes often have multiple disease traits, yet it is unknown how such multi-faceted deficits arise from single mutations. Haploinsufficiency of the voltage-gated sodium channel Nav1.1 causes Dravet syndrome, an intractable childhood-onset epilepsy with hyperactivity, cognitive deficit, autistic-like behaviours, and premature death. Deletion of Nav1.1 channels selectively impairs excitability of GABAergic interneurons. We studied mice having selective deletion of Nav1.1 in parvalbumin- or somatostatin-expressing interneurons. In brain slices, these deletions cause increased threshold for action potential generation, impaired action potential firing in trains, and reduced amplification of postsynaptic potentials in those interneurons. Selective deletion of Nav1.1 in parvalbumin- or somatostatin-expressing interneurons increases susceptibility to thermally-induced seizures, which are strikingly prolonged when Nav1.1 is deleted in both interneuron types. Mice with global haploinsufficiency of Nav1.1 display autistic-like behaviours, hyperactivity and cognitive impairment. Haploinsufficiency of Nav1.1 in parvalbumin-expressing interneurons causes autistic-like behaviours, but not hyperactivity, whereas haploinsufficiency in somatostatin-expressing interneurons causes hyperactivity without autistic-like behaviours. Heterozygous deletion in both interneuron types is required to impair long-term spatial memory in context-dependent fear conditioning, without affecting short-term spatial learning or memory. Thus, the multi-faceted phenotypes of Dravet syndrome can be genetically dissected, revealing synergy in causing epilepsy, premature death and deficits in long-term spatial memory, but interneuron-specific effects on hyperactivity and autistic-like behaviours. These results show that multiple disease traits can arise from similar functional deficits in specific interneuron types. © The Author (2015). Published by Oxford University Press on

  9. Phenotype of a child with Angelman syndrome born to a woman with Prader-Willi syndrome.

    Science.gov (United States)

    Ostergaard, John R

    2015-09-01

    This report describes the phenotype, from early childhood to adolescence, of a girl with Angelman syndrome (AS) born following a maternal transmission of a germline paternal 15q11.2-q13 deletion. During early childhood, she showed a typical AS phenotype, such as jerky movements, poor sleep, high voltage electroencephalography pattern, epilepsy, and a severe developmental disability. As she grew older, indications of phenotypical traits similar to Prader-Willi syndrome (PWS) appeared, in particular hyperphagic behavior and a body fat distribution similar to that reported in PWS. She generally showed cheerful AS behavior and had the characteristic outbursts of laughter, but her attitude to other people did not reflect the usual shared enjoyment of interaction seen in children with AS. In unfamiliar surroundings, she withdrew socially, similar to children with PWS, and her insistence on the same, rigid routines was similar to behavior patterns in PWS. The dysmorphic facial features that characterize AS were blurred in adolescence. The specified features that this AS patient had in common with PWS were hardly incidental and, if verified by upcoming case reports of children born to women with a paternal 15q11.2-q13 deletion, they may show new aspects of genetic imprinting. © 2015 Wiley Periodicals, Inc.

  10. Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome.

    Science.gov (United States)

    Cooper, Wendy N; Luharia, Anita; Evans, Gail A; Raza, Hussain; Haire, Antonita C; Grundy, Richard; Bowdin, Sarah C; Riccio, Andrea; Sebastio, Gianfranco; Bliek, Jet; Schofield, Paul N; Reik, Wolf; Macdonald, Fiona; Maher, Eamonn R

    2005-09-01

    Beckwith-Wiedemann Syndrome (BWS) results from mutations or epigenetic events involving imprinted genes at 11p15.5. Most BWS cases are sporadic and uniparental disomy (UPD) or putative imprinting errors predominate in this group. Sporadic cases with putative imprinting defects may be subdivided into (a) those with loss of imprinting (LOI) of IGF2 and H19 hypermethylation and silencing due to a defect in a distal 11p15.5 imprinting control element (IC1) and (b) those with loss of methylation at KvDMR1, LOI of KCNQ1OT1 (LIT1) and variable LOI of IGF2 in whom there is a defect at a more proximal imprinting control element (IC2). We investigated genotype/epigenotype-phenotype correlations in 200 cases with a confirmed molecular genetic diagnosis of BWS (16 with CDKN1C mutations, 116 with imprinting centre 2 defects, 14 with imprinting centre 1 defects and 54 with UPD). Hemihypertrophy was strongly associated with UPD (Pmanagement and surveillance of BWS children such that screening for Wilms' tumour and hepatoblastoma can be focused on those at highest risk.

  11. Behavioral Phenotype of Fragile X Syndrome in Adolescence and Adulthood

    Science.gov (United States)

    Smith, Leann E.; Barker, Erin T.; Seltzer, Marsha Mailick; Abbeduto, Leonard; Greenberg, Jan S.

    2012-01-01

    The present study explored the behavioral profile of individuals with fragile X syndrome during adolescence and adulthood. Individuals with both fragile X syndrome and autism (n = 30) were compared with (a) individuals diagnosed with fragile X syndrome (but not autism; n = 106) and (b) individuals diagnosed with autism (but not fragile X syndrome;…

  12. Chronic intestinal pseudo-obstruction syndrome and gastrointestinal malrotation in an infantwith schaaf-yang syndrome - Expanding the phenotypic spectrum

    DEFF Research Database (Denmark)

    Bayat, Allan; Bayat, Michael; Lozoya, Ricardo

    2018-01-01

    We report a novel patient with the phenotypic characteristics of Schaaf-Yang syndrome. In addition, the patient has a severe chronic digestive malfunction, rendering him dependent on intermittent enteral supplementation. To our knowledge, this is the first report of Schaaf-Yang syndrome associate...

  13. Are current chronic fatigue syndrome criteria diagnosing different disease phenotypes?

    Directory of Open Access Journals (Sweden)

    Laura Maclachlan

    Full Text Available Chronic fatigue syndrome (CFS is characterised by a constellation of symptoms diagnosed with a number of different polythetic criteria. Heterogeneity across these diagnostic criteria is likely to be confounding research into the as-yet-unknown pathophysiology underlying this stigmatised and debilitating condition and may diagnose a disease spectrum with significant implications for clinical management. No studies to date have objectively investigated this possibility using a validated measure of CFS symptoms-the DePaul Symptom Questionnaire (DSQ.To examine whether current CFS diagnostic criteria are identifying different disease phenotypes using the DSQ.Case control study.Clinical Research Facility of the Royal Victoria Infirmary, Newcastle upon Tyne, UK.49 CFS subjects and ten matched, sedentary community controls, excluded for co-morbid depression.Self-reported autonomic and cognitive features were assessed with the Composite Autonomic Symptom Score (COMPASS and Cognitive Failures Questionnaire (COGFAIL respectively. Objective autonomic cardiovascular parameters were examined using the Task Force® Monitor and a battery of neuropsychological tests administered for objective cognitive assessment.Self-reported autonomic and cognitive symptoms were significantly greater in CFS subjects compared to controls. There were no statistically significant differences in objective autonomic measures between CFS and controls. There were clinically significant differences between DSQ subgroups on objective autonomic testing. Visuospatial memory, verbal memory and psychomotor speed were significantly different between DSQ subgroups.The finding of no significant differences in objective autonomic testing between CFS and control subjects may reflect the inclusion of sedentary controls or exclusion for co-morbid depression. Consistent exclusion criteria would enable better delineation of these two conditions and their presenting symptoms. Findings across CFS

  14. Further patient with Angelman syndrome due to paternal disomy of chromosome 15 and a milder phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Gillessen-Kaesbach, G.; Passarge, E.; Horsthemke, B. [Institut fuer Humangenetik, Essen (Germany)

    1995-04-10

    This {open_quotes}Letter to the Editor{close_quotes} decribes a patient with Angelman syndrome due to paternal uniparental disomy of chromosome 15 and a milder phenotype compared to Angelman syndrome patients with a 15q deletion. 10 refs., 1 fig.

  15. The Behavioural Phenotype of Smith-Magenis Syndrome: Evidence for a Gene-Environment Interaction

    Science.gov (United States)

    Taylor, L.; Oliver, C.

    2008-01-01

    Background: Behaviour problems and a preference for adult contact are reported to be prominent in the phenotype of Smith-Magenis syndrome. In this study we examined the relationship between social interactions and self-injurious and aggressive/disruptive behaviour in Smith-Magenis syndrome to explore potential operant reinforcement of problem…

  16. An Atypical Rett Syndrome Phenotype Due to a Novel Missense Mutation in CACNA1A.

    Science.gov (United States)

    Epperson, Madison V; Haws, Michael E; Standridge, Shannon M; Gilbert, Donald L

    2018-03-01

    Some typical and atypical Rett syndrome patients lack known genetic mutations. Mutations in the P/Q type calcium channel CACNA1A have been implicated in epileptic encephalopathy, familial hemiplegic migraine, episodic ataxia 2, and spinocerebellar ataxia 6, but not Rett syndrome. Patient Description: The authors describe a female patient with developmental regression and a de novo, likely pathogenic mutation in CACNA1A who meets 3 of 4 main criteria (stereotypic hand movements, loss of purposeful hand movements, gait disturbance), and 6 of 11 supportive criteria (impaired sleep, abnormal tone, vasomotor disturbance, scoliosis, growth retardation, and screaming spells) for atypical Rett syndrome. Furthermore, she resembles the early seizure variant of Rett syndrome. Previously, 3 children with similar CACNA1A mutations have been reported, but a Rett syndrome phenotype has not been described. CACNA1A mutations should be considered in children presenting with an atypical Rett syndrome phenotype, specifically, the early seizure variant.

  17. Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

    DEFF Research Database (Denmark)

    Ivanovski, Ivan; Djuric, Olivera; Caraffi, Stefano Giuseppe

    2018-01-01

    PurposeMowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed...... to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental...

  18. Craniofacial and Dental Aspects of Crouzon and Apert Syndrome

    NARCIS (Netherlands)

    J.H. Reitsma (Jacobus Harmen)

    2014-01-01

    markdownabstract__Abstract__ The cranium of an infant or young child consists of different bony plates intersected by sutures. A calvarial suture is a type of fibrous joint in the cranium. The growth of the cranium is effectuated mainly in the sutures. Two important functions of the calvarial

  19. Phenotype-genotype discordance in congenital malformations with communication disorders resembling trisomy 18 (Edwards syndrome)

    Science.gov (United States)

    Pruszewicz, Antoni; Wiskirska-Woźnica, Bożena; Wojnowski, Waldemar; Czerniejewska, Hanna; Jackowska, Joanna; Jarmuż, Małgorzata; Szyfter, Krzysztof; Leszczyńska, Małgorzata

    2014-01-01

    Patient: Female, 6 Final Diagnosis: Phenotype-genotype discordance in congenital malformations with communication disorders resembling trisomy 18 (Edwards syndrome) Symptoms: — Medication: — Clinical Procedure: — Specialty: Otolaryngology Objective: Congenital defects Background: Communication process disorders are very frequent in rare cases of chromosomal aberrations (deletions, insertions, and trisomies) such as Down syndrome (trisomy 21), Turner syndrome, Edwards syndrome (trisomy 18), or Patau syndrome (trisomy 13). Sometimes phenotype may delusively correspond to the characteristic features of a given syndrome, but genotype tests do not confirm its presence. Case Report: We present the case of a 6-year-old girl admitted to the Clinic of Phoniatrics and Audiology for the assessment of communication in the course of congenital malformations with phenotype characteristic for trisomy 18 (Edwards syndrome). Immediately upon birth, dysmorphic changes suggesting trisomy 18 (Edwards syndrome) were observed, but trisomy 18 was excluded after karyotype test results were normal (46, XX). Conclusions: Disturbed articulation was diagnosed: deformed linguo-dental and palatal sounds, interdental realization with flat tongue of the /s/, /z/, /c/, /dz/, /ś/, /ź/, /ć/, /dz/ sounds (sigmatismus interdentalis). Hearing loss was confirmed. PMID:24478819

  20. Phenotype-genotype discordance in congenital malformations with communication disorders resembling trisomy 18 (Edwards syndrome).

    Science.gov (United States)

    Pruszewicz, Antoni; Wiskirska-Woźnica, Bożena; Wojnowski, Waldemar; Czerniejewska, Hanna; Jackowska, Joanna; Jarmuż, Małgorzata; Szyfter, Krzysztof; Leszczyńska, Małgorzata

    2014-01-01

    Female, 6 FINAL DIAGNOSIS: Phenotype-genotype discordance in congenital malformations with communication disorders resembling trisomy 18 (Edwards syndrome) Symptoms: - - Clinical Procedure: - Specialty: Otolaryngology. Congenital defects. Communication process disorders are very frequent in rare cases of chromosomal aberrations (deletions, insertions, and trisomies) such as Down syndrome (trisomy 21), Turner syndrome, Edwards syndrome (trisomy 18), or Patau syndrome (trisomy 13). Sometimes phenotype may delusively correspond to the characteristic features of a given syndrome, but genotype tests do not confirm its presence. We present the case of a 6-year-old girl admitted to the Clinic of Phoniatrics and Audiology for the assessment of communication in the course of congenital malformations with phenotype characteristic for trisomy 18 (Edwards syndrome). Immediately upon birth, dysmorphic changes suggesting trisomy 18 (Edwards syndrome) were observed, but trisomy 18 was excluded after karyotype test results were normal (46, XX). DISTURBED ARTICULATION WAS DIAGNOSED: deformed linguo-dental and palatal sounds, interdental realization with flat tongue of the /s/, /z/, /c/, /dz/, /ś/, /ź/, /ć/, /dz/ sounds (sigmatismus interdentalis). Hearing loss was confirmed.

  1. [Clinical, hormonal and metabolic characteristics of different phenotypes of polycystic ovary syndrome, in Bulgarian population].

    Science.gov (United States)

    Kavardzhikova, S; Pechlivanov, B

    2010-01-01

    Our aim was to investigate the percentage occurrence of different phenotypes of polycystic ovary syndrome (PCOS) in a Bulgarian population, and their clinical, metabolic and hormonal characteristics. The study included 110 women with PCOS, diagnosed according to the Europian Society of Human Reproduction & Embriology/American Society for Reproductive Medicine criteria. The women were divided into four phenotypes: hyperandrogenism (HA) + oligo-/ anovulation (OA) + polycystic ovaries at ultrasound (PCO) ( full-blown syndrome, phenotype A); HA + OA (former Institute of Health definition, phenotype B); OA + PCO (phenotype C); and HA + PCO (phenotype D). Serum levels of testosteron, immune-reactive insulin, sex hormone-binding globulin, dehydroepiandrosterone sulfate and lipid metabolism parameters were measured. Free androgen index and homeostasis model assessment of insulin resistance were calculated. Body mass index and waist- to--hip ratio were assessed. The percentage of phenotypes A, B, C and D in a Bulgarian Population are 53.6%, 12.8%, 11%, 22.6% respectively. The women with the classical form of PCOS (phenotypes A and B) were more obese, had more strongly expressed hyperandrogenemia, and were more insulin--resistant compared with the women of phenotypes C and D. There is a significant difference in anthropometric, hormonal and metabolic indices between the classical form and the clinical variants of PCOS in the studied Bulgarian population.

  2. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype

    NARCIS (Netherlands)

    K. Tatton-Brown (Katrina); A. Murray (Anna); S. Hanks (Sandra); J. Douglas (Jenny); R. Armstrong (Ruth); S. Banka (Siddharth); L.M. Bird (Lynne); C.L. Clericuzio (Carol); V. Cormier-Daire (Valerie); T. Cushing (Tom); F. Flinter (Frances); S. Jacquemont (Sébastien); S. Joss (Shelagh); E. Kinning (Esther); S.A. Lynch; A. Magee (Alex); V. Mcconnell (Vivienne); A. Medeira (Ana); K. Ozono (Keiichi); M. Patton (Michael); J. Rankin (Julia); D.J. Shears (Deborah); M.E.H. Simon (Marleen); M. Splitt (M.); V. Strenger (Volker); K.E. Stuurman (Kyra); C. Taylor (Clare); H. Titheradge (Hannah); L. van Maldergem (Lionel); I.K. Temple; T.J. Cole (Trevor); S. Seal (Sheila); N. Rahman (Nazneen)

    2013-01-01

    textabstractWeaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with

  3. Phenotypic expansion of the supernumerary derivative (22) chromosome syndrome: VACTERL and Hirschsprung's disease.

    Science.gov (United States)

    Prieto, Juan C; Garcia, Nilda M; Elder, Frederick F; Zinn, Andrew R; Baker, Linda A

    2007-11-01

    Phenotypically healthy carriers of the balanced 11;22 translocation, the most frequent non-Robertsonian constitutional translocation known in human beings, are at risk of having a progeny with supernumerary derivative (22)t(11;22) syndrome [der(22) syndrome]. We present the cases of 2 male patients with supernumerary der(22) syndrome [47,XY,+der(22)t(11;22)(q23;q11.2)mat], yielding partial trisomy for 22pter-q11 and 11q23-qter. These cases expand the phenotype of the der(22) syndrome, with the first case highlighting the phenotypic overlap of VACTERL and the second adding Hirschsprung's disease and intestinal malrotation to the list of associated anorectal anomalies. Because der(22) syndrome and cat eye syndrome (partial tetrasomy of 22q11) share a similar region of extra dosage on 22q11 and both typically manifest an anorectal phenotype, a dosage-sensitive gene for anorectal anomalies may be present in this locus.

  4. Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013.

    Science.gov (United States)

    Pavone, Piero; Striano, Pasquale; Falsaperla, Raffaele; Pavone, Lorenzo; Ruggieri, Martino

    2014-10-01

    The current spectrum of disorders associated to clinical spasms with onset in infancy is wider than previously thought; accordingly, its terminology has changed. Nowadays, the term Infantile spasms syndrome (ISs) defines an epileptic syndrome occurring in children younger than 1 year (rarely older than 2 years), with clinical (epileptic: i.e., associated to an epileptiform EEG) spasms usually occurring in clusters whose most characteristic EEG finding is hypsarrhythmia [the spasms are often associated with developmental arrest or regression]. The term West syndrome (WS) refers to a form (a subset) of ISs, characterised by the combination of clustered spasms and hypsarrhythmia on an EEG and delayed brain development or regression [currently, it is no longer required that delayed development occur before the onset of spasms]. Less usually, spasms may occur singly rather than in clusters [infantile spasms single-spasm variant (ISSV)], hypsarrhythmia can be (incidentally) recorded without any evidence of clinical spasms [hypsarrhythmia without infantile spasms (HWIS)] or typical clinical spasms may manifest in absence of hypsarrhythmia [infantile spasms without hypsarrhythmia (ISW)]. There is a growing evidence that ISs and related phenotypes may result, besides from acquired events, from disturbances in key genetic pathways of brain development: specifically, in the gene regulatory network of GABAergic forebrain dorsal-ventral development, and abnormalities in molecules expressed at the synapse. Children with these genetic associations also have phenotypes beyond epilepsy, including dysmorphic features, autism, movement disorders and systemic malformations. The prognosis depends on: (a) the cause, which gives origin to the attacks (the complex malformation forms being more severe); (b) the EEG pattern(s); (c) the appearance of seizures prior to the spasms; and (d) the rapid response to treatment. Currently, the first-line treatment includes the adrenocorticotropic

  5. Sleep phenotypes in infants and toddlers with neurogenetic syndromes.

    Science.gov (United States)

    Abel, Emily A; Tonnsen, Bridgette L

    2017-10-01

    Although sleep problems are well characterized in preschool- and school-age children with neurogenetic syndromes, little is known regarding the early emergence of these problems in infancy and toddlerhood. To inform syndrome-specific profiles and targets for intervention, we compared parent-reported sleep problems in infants and toddlers with Angelman syndrome (AS), Williams syndrome (WS), and Prader-Willi syndrome (PWS) with patterns observed among same-aged typically developing (TD) controls. Mothers of 80 children (18 AS, 19 WS, 19 PWS, and 24 TD) completed the Brief Infant Sleep Questionnaire. Primary dependent variables included (1) sleep onset latency, (2) total sleep duration, (3) daytime and nighttime sleep duration, and (4) sleep problem severity, as measured by both maternal impression and National Sleep Foundation guidelines. Sleep problems are relatively common in children with neurogenetic syndromes, with 41% of mothers reporting problematic sleep and 29% of children exhibiting abnormal sleep durations as per national guidelines. Across genetic subgroups, problems are most severe in children with AS and WS, particularly in relation to nighttime sleep duration. Although atypical sleep is characteristically reported in each syndrome later in development, infants and toddlers with PWS exhibited largely typical patterns, potentially indicating delayed onset of sleep problems in concordance with other medical features of PWS. Our findings suggest that sleep problems in neurogenetic syndromes emerge as early as infancy and toddlerhood, with variable profiles across genetic subgroups. This work underscores the importance of early sleep screenings as part of routine medical care of neurosyndromic populations and the need for targeted, syndrome-sensitive treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Refining the clinical phenotype of Okur–Chung neurodevelopmental syndrome

    Science.gov (United States)

    Akahira-Azuma, Moe; Tsurusaki, Yoshinori; Enomoto, Yumi; Mitsui, Jun; Kurosawa, Kenji

    2018-01-01

    We describe an 8-year-old Japanese boy with a de novo recurrent missense mutation in CSNK2A1, c.593A>G, that is causative of Okur–Chung neurodevelopmental syndrome. He exhibited distinctive facial features, severe growth retardation with relative macrocephaly, and friendly, hyperactive behavior. His dysmorphic features might suggest a congenital histone modification defect syndrome, such as Kleefstra, Coffin–Siris, or Rubinstein–Taybi syndromes, which are indicative of functional interactions between the casein kinase II, alpha 1 gene and histone modification factors. PMID:29619237

  7. Cardiovascular Malformations in CHARGE Syndrome with DiGeorge Phenotype: Two Case Reports

    Directory of Open Access Journals (Sweden)

    Kazushi Yasuda

    2016-01-01

    Full Text Available Both CHARGE syndrome and DiGeorge anomaly are frequently accompanied by cardiovascular malformations. Some specific cardiovascular malformations such as interrupted aortic arch type B and truncus arteriosus are frequently associated with 22q11.2 deletion syndrome, while conotruncal defects and atrioventricular septal defects are overrepresented in patients with CHARGE syndrome. CHD7 gene mutation is identified in approximately two-thirds of patients with CHARGE syndrome, and chromosomal microdeletion at 22q11.2 is found in more than 95% of patients with 22q11.2 deletion syndrome. CHARGE syndrome is occasionally accompanied by DiGeorge phenotype. We report two patients with dysmorphic features of both CHARGE syndrome and 22q11.2 deletion syndrome. Although both of the two cases did not have 22q11.2 deletion, they had typical dysmorphic features of 22q11.2 deletion syndrome including cardiovascular malformations such as interrupted aortic arch type B. They also had characteristic features of CHARGE syndrome including ear malformation, genital hypoplasia, limb malformation, and endocrinological disorders. CHD7 gene mutation was confirmed in one of the two cases. When a patient with cardiovascular malformations frequently associated with 22q11.2 deletion syndrome does not have 22q11.2 deletion, we suggest that associated malformations characteristic of CHARGE syndrome should be searched for.

  8. The insulin-resistant phenotype of polycystic ovary syndrome

    DEFF Research Database (Denmark)

    Svendsen, Pernille Fog; Madsbad, Sten; Nilas, Lisbeth

    2009-01-01

    OBJECTIVE: To investigate the individual parameters included in the diagnosis of polycystic ovary syndrome (PCOS), and their impact on insulin sensitivity. DESIGN: Cross-sectional study. SETTING: Department of Obstetrics and Gynaecology, Copenhagen University Hospital, Hvidovre, Denmark. PATIENT...

  9. Overview of Social Cognitive Dysfunctions in Rare Developmental Syndromes With Psychiatric Phenotype

    Directory of Open Access Journals (Sweden)

    Aurore Morel

    2018-05-01

    Full Text Available Rare neurodevelopmental syndromes often present social cognitive deficits that may underlie difficulties in social interactions and increase the risk of psychosis or autism spectrum disorders. However, little is known regarding the specificities of social cognitive impairment across syndromes while it remains a major challenge for the care. Our review provides an overview of social cognitive dysfunctions in rare diseases associated with psychiatric symptoms (with a prevalence estimated between 1 in 1,200 and 1 in 25,000 live births: 22q11.2 deletion syndrome, Angelman syndrome, Fragile X syndrome, Klinefelter syndrome, Prader–Willi syndrome, Rett syndrome, Smith–Magenis syndrome, Turner syndrome, and Williams syndrome and shed some light on the specific mechanisms that may underlie these skills in each clinical presentation. We first detail the different processes included in the generic expression “social cognition” before summarizing the genotype, psychiatric phenotype, and non-social cognitive profile in each syndrome. Then, we offer a systematic review of the social cognitive abilities and the disturbed mechanisms they are likely associated with. We followed the PRISMA process, including the definition of the relevant search terms, the selection of studies based on clear inclusion, and exclusion criteria and the quality appraisal of papers. We finally provide insights that may have considerable influence on the development of adapted therapeutic interventions such as social cognitive training (SCT therapies specifically designed to target the psychiatric phenotype. The results of this review suggest that social cognition impairments share some similarities across syndromes. We propose that social cognitive impairments are strongly involved in behavioral symptoms regardless of the overall cognitive level measured by intelligence quotient. Better understanding the mechanisms underlying impaired social cognition may lead to adapt

  10. Parkinsonian syndroms: Clinical phenotype, differential diagnosis and disease progression

    International Nuclear Information System (INIS)

    Storch, A.

    2002-01-01

    Parkinsonian syndromes include idiopathic Parkinson's disease (IPD), other neurodegenerative diseases with parkinsonism, the so-called atypical parkinsonian syndromes, and symptomatic parkinsonian syndromes, such as Wilson's disease. IPD is the most frequent disease with parkinsonism as the main clinical feature and is responsible for approx. 80% of all parkinsonian syndromes. Atypical parkinsonian syndromes are the most important differential diagnoses of IPD. The two most frequent types are multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). For clinical diagnosis it is essential to take a careful medical history and to examine the patients physically in regular intervals. However, various clinico-pathological studies have shown that approx. 25% of patients with clinical diagnosis of IPD may have other causes of parkinsonism. Selected technical investigations, in particular functional imaging of the central dopaminergic system using PET or SPECT, may help to make clinical diagnosis more secure. This paper reviews the clinical features and diagnostic findings in diseases with parkinsonism and summarises the difficulties in establishing early and differential diagnoses. (orig.) [de

  11. Alpha-1 antitrypsin phenotypes in patients with Klinefelter's syndrome

    Indian Academy of Sciences (India)

    1Department of Human Biology and Genetics, Institute of General and Molecular Pathology,. University of Tartu, Ravila Street 19, Tartu 50411, Estonia. 2Centre of Andrology, Tartu University Hospital, Puusepa Street 1a, Tartu 50406, Estonia. Introduction. Klinefelter's syndrome (KS) is the most common human sex.

  12. Phenotypic characterization of derivative 22 syndrome: case series ...

    Indian Academy of Sciences (India)

    DEEPTI SAXENA

    2018-03-05

    Mar 5, 2018 ... Abstract. Emanuel syndrome is caused due to an additional derivative chromosome 22 and is characterized by severe intellectual disability, microcephaly, failure to thrive, preauricular tags or pits, ear anomalies, cleft or high-arched palate, micrognathia, kidney abnormalities, congenital heart defects and ...

  13. Epigenotype-phenotype correlations in Silver-Russell syndrome

    NARCIS (Netherlands)

    Wakeling, E. L.; Amero, S. Abu; Alders, M.; Bliek, J.; Forsythe, E.; Kumar, S.; Lim, D. H.; Macdonald, F.; Mackay, D. J.; Maher, E. R.; Moore, G. E.; Poole, R. L.; Price, S. M.; Tangeraas, T.; Turner, C. L. S.; van Haelst, M. M.; Willoughby, C.; Temple, I. K.; Cobben, J. M.

    2010-01-01

    Silver-Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are

  14. The phenotype of polycystic ovary syndrome ameliorates with aging

    NARCIS (Netherlands)

    Brown, Zoe A.; Louwers, Yvonne V.; Fong, Sharon Lie; Valkenburg, Olivier; Birnie, Erwin; de Jong, Frank H.; Fauser, Bart C. J. M.; Laven, Joop S. E.

    2011-01-01

    Objective: To assess the effects of aging on the features of polycystic ovary syndrome (PCOS). Design: Retrospective longitudinal follow-up study. Setting: Tertiary care center. Patient(s): Patients with PCOS, diagnosed according to the 2003 Rotterdam criteria, who visited the outpatient clinic on

  15. Clinical and molecular phenotype of Aicardi-Goutieres syndrome

    NARCIS (Netherlands)

    Rice, Gillian; Patrick, Teresa; Parmar, Rekha; Taylor, Claire F.; Aeby, Alec; Aicardi, Jean; Artuch, Rafael; Montalto, Simon Attard; Bacino, Carlos A.; Barroso, Bruno; Baxter, Peter; Benko, Willam S.; Bergmann, Carsten; Bertini, Enrico; Biancheri, Roberta; Blair, Edward M.; Blau, Nenad; Bonthron, David T.; Briggs, Tracy; Brueton, Louise A.; Brunner, Han G.; Burke, Christopher J.; Carr, Ian M.; Carvalho, Daniel R.; Chandler, Kate E.; Christen, Hans-Jurgen; Corry, Peter C.; Cowan, Frances M.; Cox, Helen; D'Arrigo, Stefano; Dean, John; de Laet, Corinne; de Praeter, Claudine; Dery, Catherine; Ferrie, Colin D.; Flintoff, Kim; Frints, Suzanna G. M.; Garcia-Cazorla, Angels; Gener, Blanca; Goizet, Cyril; Goutieres, Francoise; Green, Andrew J.; Guet, Agnes; Hamel, Ben C. J.; Hayward, Bruce E.; Heiberg, Arvid; Hennekam, Raoul C.; Husson, Marie; Jackson, Andrew P.; Jayatunga, Rasieka; Jiang, Yong-Hui; Kant, Sarina G.; Kao, Amy; King, Mary D.; Kingston, Helen M.; Klepper, Joerg; van der Knaap, Marjo S.; Kornberg, Andrew J.; Kotzot, Dieter; Kratzer, Wilfried; Lacombe, Didier; Lagae, Lieven; Landrieu, Pierre Georges; Lanzi, Giovanni; Leitch, Andrea; Lim, Ming J.; Livingston, John H.; Lourenco, Charles M.; Lyall, E. G. Hermione; Lynch, Sally A.; Lyons, Michael J.; Marom, Daphna; McClure, John P.; McWilliam, Robert; Melancon, Serge B.; Mewasingh, Leena D.; Moutard, Marie-Laure; Nischal, Ken K.; Ostergaard, John R.; Prendiville, Julie; Rasmussen, Magnhild; Rogers, R. Curtis; Roland, Dominique; Rosser, Elisabeth M.; Rostasy, Kevin; Roubertie, Agathe; Sanchis, Amparo; Schiffmann, Raphael; Scholl-Burgi, Sabine; Seal, Sunita; Shalev, Stavit A.; Corcoles, C. Sierra; Sinha, Gyan P.; Soler, Doriette; Spiegel, Ronen; Stephenson, John B. P.; Tacke, Uta; Tan, Tiong Yang; Till, Marianne; Tolmie, John L.; Tomlin, Pam; Vagnarelli, Federica; Valente, Enza Maria; van Coster, Rudy N. A.; van der Aa, Nathalie; Vanderver, Adeline; Vles, Johannes S. H.; Voit, Thomas; Wassmer, Evangeline; Weschke, Bernhard; Whiteford, Margo L.; Willemsen, Michel A. A.; Zankl, Andreas; Zuberi, Sameer M.; Orcesi, Simona; Fazzi, Elisa; Lebon, Pierre; Crow, Yanick J.

    2007-01-01

    Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease

  16. Environmental Influences on the Behavioral Phenotype of Angelman Syndrome

    Science.gov (United States)

    Horsler, Kate; Oliver, Chris

    2006-01-01

    Using observational methods, we examined the social influences on laughing and smiling behavior in children with Angelman syndrome by systematically manipulating aspects of social interaction. Seven boys and 4 girls who were between 4 and 11 years of age and who had a confirmed maternal deletion of chromosome 15q11-q13 completed the study. Each…

  17. Behavioural phenotype in Borjeson-Forssman-Lehmann syndrome

    NARCIS (Netherlands)

    de Winter, C. F.; van Dijk, F.; Stolker, J. J.; Hennekam, R. C. M.

    2009-01-01

    Borjeson-Forssman-Lehmann syndrome (BFLs) is an X-linked inherited disorder characterised by unusual facial features, abnormal fat distribution and intellectual disability. As many genetically determined disorders are characterised not only by physical features but also by specific behaviour, we

  18. Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome

    NARCIS (Netherlands)

    Cooper, Wendy N.; Luharia, Anita; Evans, Gail A.; Raza, Hussain; Haire, Antonita C.; Grundy, Richard; Bowdin, Sarah C.; Riccio, Andrea; Sebastio, Gianfranco; Bliek, Jet; Schofield, Paul N.; Reik, Wolf; Macdonald, Fiona; Maher, Eamonn R.

    2005-01-01

    Beckwith-Wiedemann Syndrome (BWS) results from mutations or epigenetic events involving imprinted genes at 11p15.5. Most BWS cases are sporadic and uniparental disomy (UPD) or putative imprinting errors predominate in this group. Sporadic cases with putative imprinting defects may be subdivided into

  19. Simultaneous analysis of the behavioural phenotype, physical factors, and parenting stress in people with Cornelia de Lange syndrome

    NARCIS (Netherlands)

    Wulffaert, J.; van Berckelaer-Onnes, I.; Kroonenberg, P.; Scholte, E.; Bhuiyan, Z.; Hennekam, R.

    2009-01-01

    BACKGROUND: Studies into the phenotype of rare genetic syndromes largely rely on bivariate analysis. The aim of this study was to describe the phenotype of Cornelia de Lange syndrome (CdLS) in depth by examining a large number of variables with varying measurement levels. Virtually the only suitable

  20. Simultaneous Analysis of the Behavioural Phenotype, Physical Factors, and Parenting Stress in People with Cornelia De Lange Syndrome

    Science.gov (United States)

    Wulffaert, J.; van Berckelaer-Onnes, I.; Kroonenberg, P.; Scholte, E.; Bhuiyan, Z.; Hennekam, R.

    2009-01-01

    Background: Studies into the phenotype of rare genetic syndromes largely rely on bivariate analysis. The aim of this study was to describe the phenotype of Cornelia de Lange syndrome (CdLS) in depth by examining a large number of variables with varying measurement levels. Virtually the only suitable multivariate technique for this is categorical…

  1. Phelan-McDermid syndrome in two adult brothers: Atypical bipolar disorder as its psychopathological phenotype?

    NARCIS (Netherlands)

    W.M.A. Verhoeven (Wim); J.I.M. Egger (Jos); M.H. Willemsen; G.J.M. de Leijer (Gert); T. Kleefstra (Tjitske)

    2012-01-01

    textabstractThe 22q13.3 deletion, or Phelan-McDermid syndrome, is characterized by global intellectual disability, generalized hypotonia, severely delayed or absent speech associated with features of autism spectrum disorder, and minor dysmorphisms. Its behavioral phenotype comprises sleep

  2. Phelan-McDermid syndrome in two adult brothers: Atypical bipolar disorder as its psychopathological phenotype?

    NARCIS (Netherlands)

    Verhoeven, W.M.A.; Egger, J.I.M.; Willemsen, M.H.; Leijer, G.J.M. de; Kleefstra, T.

    2012-01-01

    The 22q13.3 deletion, or Phelan-McDermid syndrome, is characterized by global intellectual disability, generalized hypotonia, severely delayed or absent speech associated with features of autism spectrum disorder, and minor dysmorphisms. Its behavioral phenotype comprises sleep disturbances,

  3. Phelan-McDermid syndrome in two adult brothers: atypical bipolar disorder as its psychopathological phenotype?

    NARCIS (Netherlands)

    Verhoeven, W.M.; Egger, J.I.; Willemsen, M.H.; de Leijer, G.J.; Kleefstra, T.

    2012-01-01

    The 22q13.3 deletion, or Phelan-McDermid syndrome, is characterized by global intellectual disability, generalized hypotonia, severely delayed or absent speech associated with features of autism spectrum disorder, and minor dysmorphisms. Its behavioral phenotype comprises sleep disturbances,

  4. Genotype and phenotype in Klinefelter syndrome - impact of androgen receptor polymorphism and skewed X inactivation

    DEFF Research Database (Denmark)

    Bojesen, A; Hertz, Jens Michael; Gravholt, Claus Højbjerg

    2011-01-01

    The phenotypic variation of Klinefelter syndrome (KS) is wide and may by caused by various genetic and epigenetic effects. Skewed inactivation of the supra-numerical X chromosome and polymorphism in the androgen receptor (AR) have been suggested as plausible causes. We wanted to describe X...

  5. Mastery Motivation in Children with Intellectual Disability: Is There Evidence for a Down Syndrome Behavioural Phenotype?

    Science.gov (United States)

    Gilmore, Linda; Cuskelly, Monica; Browning, Melissa

    2015-01-01

    The main purpose of the current study was to provide empirical evidence to support or refute assumptions of phenotypic deficits in motivation for children with Down syndrome (DS). Children with moderate intellectual disability (MID) associated with etiologies other than DS were recruited in an extension of a previous study that involved children…

  6. Hyperandrogenism and phenotypes of polycystic ovary syndrome are not associated with differences in obstetric outcomes

    DEFF Research Database (Denmark)

    Mumm, Hanne; Jensen, Dorte Møller; Sørensen, Jens Aage

    2015-01-01

    OBJECTIVES: To investigate obstetric outcomes in Danish women with different phenotypes of polycystic ovary syndrome (PCOS) and isolated hyperandrogenism (HA) and describe the risk of adverse obstetric outcomes in women with PCOS and HA compared to controls. DESIGN: Cohort study. SETTING: Odense...

  7. A new case of a severe clinical phenotype of the cat-eye syndrome.

    Science.gov (United States)

    Denavit, T Martin; Malan, V; Grillon, C; Sanlaville, D; Ardalan, A; Jacquemont, M L; Burglen, L; Taillemite, J L; Portnoi, M F

    2004-01-01

    A new case of severe clinical phenotype of the cat-eye syndrome: We report on a female infant with severe clinical phenotype of Cat-Eye Syndrome (CES). At birth, she had respiratory distress and marked hypotonia. Physical examination showed major craniofacial anomalies including microcephaly, bilateral total absence of the external ears, hypertelorism, bilateral ocular coloboma of iris and micrognathia. In addition, she had anal stenosis, a patent ductus arteriosus and intra- and extra- hepatic biliary atresia. She deteriorated with the development of bradycardia. She died at age one month of cardiac failure. Cytogenetic analysis of the proband showed an extra de novo small bisatelllited marker chromosome in all cells examined. Molecular cytogenetic analysis with fluorescence in situ hybridization (FISH) identified the marker as a CES chromosome. Thus, the patient's karyotype was: 47, XX, +idic(22)(pter-->q11.2 ::q11.2-->pter). The duplication breakpoints giving rise to the CES chromosome were distal to the DiGeorge Syndrome (DGS) locus 22q11.2. The marker could be classed as a type 11 symmetrical (10). According to a recent review of CES literature (1) only 41 % of the CES patients have the combination of iris coloboma, anal anomalies and preauricular anomalies. Almost 60% are hard to recognize by their phenotype alone. Only twelve patients showed a severe clinical phenotype leading to the death of the child. This phenotypic variability increases the difficulties of genetic counseling.

  8. Phenotypic variability of the cat eye syndrome. Case report and review of the literature.

    Science.gov (United States)

    Rosias, P R; Sijstermans, J M; Theunissen, P M; Pulles-Heintzberger, C F; De Die-Smulders, C E; Engelen, J J; Van Der Meer, S B

    2001-01-01

    We present a male infant with preauricular skin tags and pits, downslanting palpebral fissures, hypertelorism, ectopic anus, hypospadias, and hypoplastic left heart syndrome. The clinical features in our patient show phenotypic overlap with the cat eye syndrome, as illustrated by the review of 105 reported cases. Cytogenetic analysis revealed a supernumerary marker chromosome, which was identified by microdissection and fluorescence in situ hybridization as an isodicentric chromosome 22(pter --> q11.2::q11.2 --> pter). It was proved with probes specific for the cat eye syndrome critical region that this region was present in quadruplicate in the propositus. We conclude that CES is characterized by large phenotypic variability, ranging from near normal to severe malformations, as reflected in the neurodevelopmental outcome. Preauricular skin tags and/or pits are the most consistent features, and suggest the presence of a supernumerary bisatellited marker chromosome 22 derived from duplication of the CES critical region.

  9. Neurodevelopmental outcome in Angelman syndrome: Genotype-phenotype correlations

    DEFF Research Database (Denmark)

    Mertz, Line Granild Bie; Thaulov, Per; Trillingsgaard, Anegen

    2014-01-01

    Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, developmental delay, lack of speech, and epileptic seizures. Previous studies have indicated that children with AS due to 15q11.2-q13 deletions have a more severe developmental delay and present more often...... developmental age in terms of visual perception, receptive language, and expressive language when compared to those with a UBE3A mutation and pUPD. Within all subgroups, expressive language performance was significantly reduced when compared to the receptive performance. A follow-up study of seven AS cases...

  10. Clinical and molecular phenotype of Aicardi-Goutieres syndrome

    DEFF Research Database (Denmark)

    Rice, Gillian; Patrick, Teresa; Parmar, Rekha

    2007-01-01

    Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease...... identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from...

  11. Expanding the phenotype of congenital central hypoventilation syndrome impacts management decisions.

    Science.gov (United States)

    Byers, Heather M; Chen, Maida; Gelfand, Andrew S; Ong, Bruce; Jendras, Marisa; Glass, Ian A

    2018-04-25

    Congenital central hypoventilation syndrome (CCHS) is a neurocristopathy caused by pathogenic heterozygous variants in the gene paired-like homeobox 2b (PHOX2B). It is characterized by severe infantile alveolar hypoventilation. Individuals may also have diffuse autonomic nervous system dysfunction, Hirschsprung disease and neural crest tumors. We report three individuals with CCHS due to an 8-base pair duplication in PHOX2B; c.691_698dupGGCCCGGG (p.Gly234Alafs*78) with a predominant enteral and neural crest phenotype and a relatively mild respiratory phenotype. The attenuated respiratory phenotype reported here and elsewhere suggests an emergent genotype:phenotype correlation which challenges the current paradigm of invoking mechanical ventilation for all infants diagnosed with CCHS. Best treatment requires careful clinical judgment and ideally the assistance of a care team with expertise in CCHS. © 2018 Wiley Periodicals, Inc.

  12. A further case of a Prader-Willi syndrome phenotype in a patient with Angelman syndrome molecular defect

    Directory of Open Access Journals (Sweden)

    De Molfetta Greice Andreotti

    2002-01-01

    Full Text Available Angelman syndrome (AS and Prader-Willi syndrome (PWS are distinct human neurogenetic disorders; however, a clinical overlap between AS and PWS has been identified. We report on a further case of a patient showing the PWS phenotype with the AS molecular defect. Despite the PWS phenotype, the DNA methylation analysis of SNRPN revealed an AS pattern. Cytogenetic and FISH analysis showed normal chromosomes 15 and microsatellite analysis showed heterozygous loci inside and outside the 15q11-13 region. The presence of these atypical cases could be more frequent than previously expected and we reinforce that the DNA methylation analysis is important for the correct diagnosis of severe mental deficiency, congenital hypotonia and obesity.

  13. The phenotypic spectrum of Schaaf-Yang syndrome – 18 new affected individuals from 14 families

    Science.gov (United States)

    Fountain, Michael D.; Aten, Emmelien; Cho, Megan T.; Juusola, Jane; Walkiewicz, Magdalena A.; Ray, Joseph W.; Xia, Fan; Yang, Yaping; Graham, Brett H.; Bacino, Carlos A.; Potocki, Lorraine; van Haeringen, Arie; Ruivenkamp, Claudia A.L.; Mancias, Pedro; Northrup, Hope; Kukolich, Mary K.; Weiss, Marjan M.; van Ravenswaaij-Arts, Conny M.A.; Mathijssen, Inge B.; Levesque, Sebastien; Meeks, Naomi; Rosenfeld, Jill A.; Lemke, Danielle; Hamosh, Ada; Lewis, Suzanne K.; Race, Simone; Stewart, Laura L.; Hay, Beverly; Lewis, Andrea M.; Guerreiro, Rita L.; Bras, Jose T.; Martins, Marcia P.; Derksen-Lubsen, Gerarda; Peeters, Els; Stumpel, Connie; Stegmann, Sander; Bok, Levinus A.; Santen, Gijs W.E.; Schaaf, Christian P.

    2016-01-01

    Purpose Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease, manifesting developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients’ phenotypes was questioned, as MAGEL2 whole gene deletions appear to cause little to no clinical phenotype. Methods Here we report a total of 18 new individuals with Schaaf-Yang syndrome from 14 families, including one family with three individuals found to be affected with a truncating variant of MAGEL2, 11 individuals clinically affected, but not tested molecularly, and a presymptomatic fetal sibling with carrying the pathogenic MAGEL2 variant. Results All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and one fetus harboring a c.1996dupC (p.Q666fs) mutation and two fetuses harboring a c.1996delC (p.Q666fs). The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to individuals with neurobehavioral disease and contractures of the small finger joints. Conclusion This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling of affected families. PMID:27195816

  14. Epilepsy and cataplexy in Angelman syndrome. Genotype-phenotype correlations

    DEFF Research Database (Denmark)

    Granild Bie Mertz, Line; Christensen, Rikke; Vogel, Ida

    2016-01-01

    Background: Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, epilepsy, and low threshold for laughter. Aims: We investigated the occurrence and severity of epilepsy and laughter-induced loss of postural muscle tone determined by the different genetic...... subtypes. Methods: This study included 39 children with AS. Deletion breakpoints were determined by high resolution CGH microarray (1 x 1 M Agilent). Clinical data were based on a parent interview and medical record review. Results: All patients with AS based on a deletion had epilepsy. Epilepsy...... was present in 3/4 children with UBE3A mutation, and 4/5 with pUPD. Onset of epilepsy occurred earlier in deletion cases compared to pUPD or UBE3A mutations cases. Laughter-induced postural muscle tone loss occurred only among deletion cases. We found no differences in severity of epilepsy between children...

  15. Angelman Syndrome: Insights into Genomic Imprinting and Neurodevelopmental Phenotypes

    Science.gov (United States)

    Mabb, Angela M.; Judson, Matthew C.; Zylka, Mark J.; Philpot, Benjamin D.

    2011-01-01

    Angelman syndrome (AS) is a severe genetic disorder caused by mutations or deletions of the maternally inherited UBE3A gene. UBE3A encodes an E3 ubiquitin ligase that is expressed biallelically in most tissues but is maternally expressed in almost all neurons. In this review, we describe recent advances in understanding the expression and function of UBE3A in the brain and the etiology of AS. We highlight current AS model systems, epigenetic mechanisms of UBE3A regulation, and the identification of potential UBE3A substrates in the brain. In the process, we identify major gaps in our knowledge that, if bridged, could move us closer to identifying treatments for this debilitating neurodevelopmental disorder. PMID:21592595

  16. Marfan syndrome--a diagnostic challenge caused by phenotypic and genetic heterogeneity.

    Science.gov (United States)

    Baumgartner, C; Mátyás, G; Steinmann, B; Baumgartner, D

    2005-01-01

    Marfan syndrome (MFS) is an autosomal dominant inherited connective tissue disorder caused by mutations in the fibrillin-1 (FBN1) gene with variable clinical manifestations in the cardiovascular, musculoskeletal and ocular systems. Data of moleculor genetic analysis and a catalogue of clinical manifestations including aortic elastic parameters were mined in order to (i) assess aortic abnormality before and during medical treatment, and to (ii) identify novel correlations between the genotype and phenotype of the disease using hierarchical cluster analysis and logistic regression analysis. A score measure describing the similarity between a patient's clinical symptoms and a characteristic phenotype class was introduced. A probabilistic model for monitoring the loss of aortic elasticity was built on merely aortic parameters of 34 patients with classic MFS and 43 control subjects showing a sensitivity of 82% and a specificity of 96%. The clinical phenotypes of 100 individuals with classical or suspected MFS were clustered yielding four different phenotypic expressions. The highest correlation was found between FBN1 missense mutations, which manifested as ectopia lentis, skeletal major and skin minor criteria, and two out of four clustered phenotypes. The probability of the presence of a missense mutation in both phenotype classes is approximately 70%. Monitoring of aortic elastic properties during medical treatment may serve as additional criterion to indicate elective surgical interventions. Genotype-phenotype correlation may contribute to anticipate the clinical consequences of specific FBN1 mutations more comprehensively and may be helpful to identify MFS patients at risk at on early stage of disease.

  17. Incidence, Phenotypic Features and Molecular Genetics of Kallmann Syndrome in Finland

    Directory of Open Access Journals (Sweden)

    Tommiska Johanna

    2011-06-01

    Full Text Available Abstract Background Kallmann syndrome (KS, comprised of congenital hypogonadotropic hypogonadism (HH and anosmia, is a clinically and genetically heterogeneous disorder. Its exact incidence is currently unknown, and a mutation in one of the identified KS genes has only been found in ~30% of the patients. Methods Herein, we investigated epidemiological, clinical, and genetic features of KS in Finland. Results The minimal incidence estimate of KS in Finland was 1:48 000, with clear difference between males (1:30 000 and females (1:125 000 (p = 0.02. The reproductive phenotype of 30 probands (25 men; 5 women ranged from severe HH to partial puberty. Comprehensive mutation analysis of all 7 known KS genes (KAL1, FGFR1, FGF8, PROK2, PROKR2, CHD7, and WDR11 in these 30 well-phenotyped probands revealed mutations in KAL1 (3 men and FGFR1 (all 5 women vs. 4/25 men, but not in other genes. Conclusions Our results suggest that Finnish KS men harbor mutations in gene(s yet-to-be discovered with sex-dependent penetrance of the disease phenotype. In addition, some KS patients without CHD7 mutations display CHARGE-syndrome associated phenotypic features (e.g. ear or eye anomalies, possibly implying that, in addition to CHD7, there may be other genes associated with phenotypes ranging from KS to CHARGE.

  18. Investigating genotype-phenotype relationships in Rett syndrome using an international data set.

    Science.gov (United States)

    Bebbington, A; Anderson, A; Ravine, D; Fyfe, S; Pineda, M; de Klerk, N; Ben-Zeev, B; Yatawara, N; Percy, A; Kaufmann, W E; Leonard, H

    2008-03-11

    Rett syndrome is an uncommon neurodevelopmental disorder with an incidence of 1:9,000 live female births. The principal genetic cause was first reported in 1999 when the association with mutations in the methyl-CpG-binding protein 2 (or MECP2) gene was identified. This study uses data from a large international database, InterRett, to examine genotype-phenotype relationships and compares these with previous findings in a population-based cohort. The data set for these analyses was derived from a subset of InterRett cases with subject information collected from the family, the clinician, or both. Individual phenotypic characteristics and clinical severity using three scales were compared among those with eight known recurrent pathogenic MECP2 mutations as well as those with C-terminal deletions (n = 272). Overall, p.R270X and p.R255X were the most severe and p.R133C and p.R294X were the mildest mutations. Significant differences by mutation were seen for individual phenotypic characteristics such as hand use, ambulation, and language. This multicenter investigation into the phenotypic correlates of MECP2 mutations in Rett syndrome has provided a greater depth of understanding than hitherto available about the specific phenotypic characteristics associated with commonly occurring mutations. Although the modifying influence of X inactivation on clinical severity could not be included in the analysis, the findings confirm clear genotype-phenotype relationships in Rett syndrome and show the benefits of collaboration crucial to effective research in rare disorders.

  19. Oculo-facio-cardio-dental syndrome in three succeeding generations: genotypic data and phenotypic features

    Energy Technology Data Exchange (ETDEWEB)

    Lozić, B. [Department of Pediatrics, University Hospital Split, Split (Croatia); Ljubković, J. [Department of Pathology, Forensic Medicine and Cytology, University Hospital Split, Split (Croatia); Gabrić Pandurić, D. [Department of Oral Surgery, School of Dental Medicine, University of Zagreb, Zagreb (Croatia); Saltvig, I. [Jessenius Faculty of Medicine of Commenius, University in Bratislava, Martin (Slovakia); Kutsche, K. [Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg (Germany); Krželj, V. [Department of Pediatrics, University Hospital Split, Split (Croatia); Zemunik, T. [Department of Medical Biology, School of Medicine, University of Split, Split (Croatia)

    2012-09-21

    Oculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked disorder mainly manifesting in females. Patients show ocular, facial, cardiac, and dental abnormalities. OFCD syndrome is caused by heterozygous mutations in the BCOR gene, located in Xp11.4, encoding the BCL6 co-repressor. We report a Croatian family with four female members (grandmother, mother and monozygotic female twins) diagnosed with OFCD syndrome who carry the novel BCOR mutation c.4438C>T (p.R1480*). They present high intrafamilial phenotypic variability with special regard to cardiac defect and cataract that showed more severe disease expression in successive generations. Clinical and radiographic examination of the mother of the twins revealed a talon cusp involving the permanent maxillary right central incisor. This is the first known report of a talon cusp in OFCD syndrome with a novel mutation in the BCOR gene.

  20. A case of Pitt-Hopkins syndrome presented with Angelman-like syndromic phenotypes.

    Science.gov (United States)

    Hong, Syuan-Yu; Chou, I-Ching; Lin, Wei-De; Tsai, Fuu-Jen

    2016-12-01

    Pitt-Hopkins syndrome (PTHS), caused by a TCF4 gene mutation, is a condition characterized by intellectual disability and developmental delay, breathing anomalies, epilepsy, and distinctive facial dysmorphism [1]. Its diverse clinical appearance causes pediatricians to confuse it with Angelman syndrome, which is considered one of the family members of Angelman-like syndrome. Herein, we report on a 4 y/o boy with PTHS and discuss its similarities and differences with Angelman syndrome. In doing so we hope to provide a feasible pathway to diagnose rare diseases, especially Angelman-like syndrome.

  1. Multi-layered mutation in hedgehog-related genes in Gorlin syndrome may affect the phenotype.

    Directory of Open Access Journals (Sweden)

    Shoko Onodera

    Full Text Available Gorlin syndrome is a genetic disorder of autosomal dominant inheritance that predisposes the affected individual to a variety of disorders that are attributed largely to heterozygous germline patched1 (PTCH1 mutations. PTCH1 is a hedgehog (Hh receptor as well as a repressor, mutation of which leads to constitutive activation of Hh pathway. Hh pathway encompasses a wide variety of cellular signaling cascades, which involve several molecules; however, no associated genotype-phenotype correlations have been reported. Recently, mutations in Suppressor of fused homolog (SUFU or PTCH2 were reported in patients with Gorlin syndrome. These facts suggest that multi-layered mutations in Hh pathway may contribute to the development of Gorlin syndrome. We demonstrated multiple mutations of Hh-related genes in addition to PTCH1, which possibly act in an additive or multiplicative manner and lead to Gorlin syndrome. High-throughput sequencing was performed to analyze exome sequences in four unrelated Gorlin syndrome patient genomes. Mutations in PTCH1 gene were detected in all four patients. Specific nucleotide variations or frameshift variations of PTCH1 were identified along with the inferred amino acid changes in all patients. We further filtered 84 different genes which are closely related to Hh signaling. Fifty three of these had enough coverage of over ×30. The sequencing results were filtered and compared to reduce the number of sequence variants identified in each of the affected individuals. We discovered three genes, PTCH2, BOC, and WNT9b, with mutations with a predicted functional impact assessed by MutationTaster2 or PolyPhen-2 (Polymorphism Phenotyping v2 analysis. It is noticeable that PTCH2 and BOC are Hh receptor molecules. No significant mutations were observed in SUFU. Multi-layered mutations in Hh pathway may change the activation level of the Hh signals, which may explain the wide phenotypic variability of Gorlin syndrome.

  2. Distinct neutrophil subpopulations phenotype by flow cytometry in myelodysplastic syndromes.

    Science.gov (United States)

    Vikentiou, Myrofora; Psarra, Katerina; Kapsimali, Violetta; Liapis, Konstantinos; Michael, Michalis; Tsionos, Konstantinos; Lianidou, Evi; Papasteriades, Chryssa

    2009-03-01

    The cardinal feature of myelodysplastic syndromes (MDS) is dysplasia involving one or more myeloid cell lineages. In the present study, we used 4-color flow cytometric analysis to investigate dysgranulopoiesis in bone marrow specimens from 65 patients with MDS. The antigen expression patterns of total neutrophil granulocytes (TNG) and of the two distinct neutrophil granulocytic subpopulations (NGSs), NGS-1 (dimmer CD45 expression) and NGS-2 (stronger CD45 expression) identified on the side scatter (SS) vs. CD45-intensity plot, were studied. The neutrophil granulocytes from patients with MDS showed characteristic antigen expression aberrancies which were more pronounced in NGS-2 subpopulation. Studying separately the NGS-2 subpopulation with the CD16/MPO/LF combination, the low CD16(+)/MPO(+) and low CD16(+)/LF(+) percentages seemed to discriminate between lower-risk and higher-risk patients with MDS in most occasions. Furthermore, a detailed assessment of the NGS-1 and NGS-2 immunophenotypic patterns revealed early dysplastic changes, not otherwise observed by standard TNG analysis, especially in cases of lower-risk MDS.

  3. Epilepsy and cataplexy in Angelman syndrome. Genotype-phenotype correlations.

    Science.gov (United States)

    Granild Bie Mertz, Line; Christensen, Rikke; Vogel, Ida; Hertz, Jens Michael; Østergaard, John R

    2016-09-01

    Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, epilepsy, and low threshold for laughter. We investigated the occurrence and severity of epilepsy and laughter-induced loss of postural muscle tone determined by the different genetic subtypes. This study included 39 children with AS. Deletion breakpoints were determined by high resolution CGH microarray (1×1M Agilent). Clinical data were based on a parent interview and medical record review. All patients with AS based on a deletion had epilepsy. Epilepsy was present in 3/4 children with UBE3A mutation, and 4/5 with pUPD. Onset of epilepsy occurred earlier in deletion cases compared to pUPD or UBE3A mutations cases. Laughter-induced postural muscle tone loss occurred only among deletion cases. We found no differences in severity of epilepsy between children with a larger Class I or a smaller Class II deletions, or between the total group with a deletion compared to children with pUPD or a UBE3A mutation. The drugs most frequently prescribed were benzodiazepines in monotherapy, or a combination of benzodiazepines and valproic acid. Epilepsy is very common in patients with AS, especially in patients with a deletion. Postural muscle tone loss and collapsing during outbursts of laughter were seen in patients with a deletion only. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Neurodevelopmental outcome in Angelman syndrome: genotype-phenotype correlations.

    Science.gov (United States)

    Mertz, Line Granild Bie; Thaulov, Per; Trillingsgaard, Anegen; Christensen, Rikke; Vogel, Ida; Hertz, Jens Michael; Ostergaard, John R

    2014-07-01

    Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, developmental delay, lack of speech, and epileptic seizures. Previous studies have indicated that children with AS due to 15q11.2-q13 deletions have a more severe developmental delay and present more often autistic features than those with AS caused by other genetic etiologies. The present study investigated the neurodevelopmental profiles of the different genetic etiologies of AS, and examined the evolution of mental development and autistic features over a 12-year period in children with a 15q11.2-q13 deletion. This study included 42 children with AS. Twelve had a Class I deletion, 18 had Class II deletions, three showed atypical large deletions, five had paternal uniparental disomy (pUPD) and four had UBE3A mutations. Children with a deletion (Class I and Class II) showed significantly reduced developmental age in terms of visual perception, receptive language, and expressive language when compared to those with a UBE3A mutation and pUPD. Within all subgroups, expressive language performance was significantly reduced when compared to the receptive performance. A follow-up study of seven AS cases with 15q11.2-q13 deletions revealed that over 12 years, the level of autistic features did not change, but both receptive and expressive language skills improved. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Multigenerational pedigree with STAR syndrome: A novel FAM58A variant and expansion of the phenotype.

    Science.gov (United States)

    Boczek, Nicole J; Kruisselbrink, Teresa; Cousin, Margot A; Blackburn, Patrick R; Klee, Eric W; Gavrilova, Ralitza H; Lanpher, Brendan C

    2017-05-01

    STAR syndrome is a rare X-linked dominant disorder characterized by toe Syndactyly, Telecanthus, Anogenital malformations, and Renal malformations, and is caused by loss-of-function variants in FAM58A. Our proband presented with the hallmark features of STAR syndrome, as well as some additional less typical features including tethered cord and hearing loss. The proband's mother and maternal half-sister had similar clinical histories, but had variability in phenotypic severity. Clinical whole exome sequencing revealed a novel pathogenic nonsense variant, c.651G>A (p.Trp217X; NM_152274), in FAM58A in the proband, mother, and maternal half-sister. This pedigree represents the 11-13th patients described with STAR syndrome and the third instance of familial inheritance. To our knowledge, this is the first occurrence of a nonsense variant in FAM58A described in individuals with STAR syndrome and the phenotype in this pedigree suggests that tethered cord and hearing loss are features of STAR syndrome. © 2017 Wiley Periodicals, Inc.

  6. Intrafamilial and interfamilial variability of phenotype in familial velo-cardio-facial syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Hajianpour, M.J. [Alfigen/The Genetics Institute, Pasadena, CA (United States); Lamb, A. [Integrated Genetics, Santa Fe, NM (United States); Covle, M.

    1994-09-01

    Two half-sisters and their mother from one family, and two full-brothers and their mother from another family presented with features of velo-cardio-facial syndrome (VCSF)/DiGeorge syndrome (DS) with intrafamilial and interfamilial variability of phenotypic expression. None of these patients had an apparent cleft palate. Cardiac anomaly, jejunal atresia and hypocalcemia were present only in the newborn patient. Fluorescence in situ hybridization for VCFS/DS with probe D22S75 showed a deletion in the 22q11.2 region in patients available for the study.

  7. Monogenic disorders that mimic the phenotype of Rett syndrome.

    Science.gov (United States)

    Srivastava, Siddharth; Desai, Sonal; Cohen, Julie; Smith-Hicks, Constance; Barañano, Kristin; Fatemi, Ali; Naidu, SakkuBai

    2018-01-01

    Rett syndrome (RTT) is caused by mutations in methyl-CpG-binding protein 2 (MECP2), but defects in a handful of other genes (e.g., CDKL5, FOXG1, MEF2C) can lead to presentations that resemble, but do not completely mirror, classical RTT. In this study, we attempted to identify other monogenic disorders that share features with RTT. We performed a retrospective chart review on n = 319 patients who had undergone clinical whole exome sequencing (WES) for further etiological evaluation of neurodevelopmental diagnoses that remained unexplained despite extensive prior workup. From this group, we characterized those who (1) possessed features that were compatible with RTT based on clinical judgment, (2) subsequently underwent MECP2 sequencing and/or MECP2 deletion/duplication analysis with negative results, and (3) ultimately arrived at a diagnosis other than RTT with WES. n = 7 patients had clinical features overlapping RTT with negative MECP2 analysis but positive WES providing a diagnosis. These seven patients collectively possessed pathogenic variants in six different genes: two in KCNB1 and one each in FOXG1, IQSEC2, MEIS2, TCF4, and WDR45. n = 2 (both with KCNB1 variants) fulfilled criteria for atypical RTT. RTT-associated features included the following: loss of hand or language skills (n = 3; IQSEC2, KCNB1 x 2); disrupted sleep (n = 4; KNCB1, MEIS2, TCF4, WDR45); stereotyped hand movements (n = 5; FOXG1, KNCB1 x 2, MEIS2, TCF4); bruxism (n = 3; KCNB1 x 2; TCF4); and hypotonia (n = 7). Clinically based diagnoses can be misleading, evident by the increasing number of genetic conditions associated with features of RTT with negative MECP2 mutations.

  8. Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism.

    Science.gov (United States)

    Stamou, Maria I; Georgopoulos, Neoklis A

    2017-11-03

    Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency (IGD) IGD is a genetically and clinically heterogeneous disorder. Mutations in many different genes are able to explain ~40% of the causes of IGD, with the rest of cases remaining genetically uncharacterized. While most mutations are inherited in X-linked, autosomal dominant, or autosomal recessive pattern, several IGD genes are shown to interact with each other in an oligogenic manner. In addition, while the genes involved in the pathogenesis of IGD act on either neurodevelopmental or neuroendocrine pathways, a subset of genes are involved in both pathways, acting as "overlap genes". Thus, some IGD genes play the role of the modifier genes or "second hits", providing an explanation for incomplete penetrance and variable expressivity associated with some IGD mutations. The clinical spectrum of IGD includes a variety of disorders including Kallmann Syndrome (KS), i.e. hypogonadotropic hypogonadism with anosmia, and its normosmic variation normosmic idiopathic hypogonadotropic hypogonadism (nIHH), which represent the most severe aspects of the disorder. Apart from these disorders, there are also "milder" and more common reproductive diseases associated with IGD, including hypothalamic amenorrhea (HA), constitutional delay of puberty (CDP) and adult-onset hypogonadotropic hypogonadism (AHH). Interestingly, neurodeveloplmental genes are associated with the KS form of IGD, due to the topographical link between the GnRH neurons and the olfactory placode. On the other hand, neuroendocrine genes are mostly linked to nIHH. However, a great deal of clinical and genetic overlap characterizes the spectrum of the IGD disorders. IGD is also characterized by a wide variety of non-reproductive features, including midline facial defects such as cleft lip and/or palate, renal agenesis, short metacarpals and other bone abnormalities, hearing loss, synkinesia, eye movement abnormalities, poor balance due to cerebellar ataxia

  9. De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient.

    Science.gov (United States)

    Hara, Munetsugu; Ohba, Chihiro; Yamashita, Yushiro; Saitsu, Hirotomo; Matsumoto, Naomichi; Matsuishi, Toyojiro

    2015-07-01

    Rett syndrome (RTT) is a neurodevelopmental disorder predominantly affecting females. Females with the MECP2 mutations exhibit a broad spectrum of clinical manifestations ranging from classical Rett syndrome to asymptomatic carriers. Mutations of genes encoding cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are also found in early onset RTT variants. Here, we present the first report of a female patient with RTT-like phenotype caused by SHANK3 (SH3 and multiple ankylin repeat domain 3) mutation, indicating that the clinical spectrum of SHANK3 mutations may extend to RTT-like phenotype in addition to (severe) developmental delay, absence of expressive speech, autistic behaviors and intellectual disability. © 2015 Wiley Periodicals, Inc.

  10. A FBN1 mutation association with different phenotypes of Marfan syndrome in a Chinese family.

    Science.gov (United States)

    Li, Yapeng; Xu, Jianhua; Chen, Mingjie; Du, Binbin; Li, Qiaoli; Xing, Qinghe; Zhang, Yanzhou

    2016-09-01

    Previous studies demonstrated that patients with different FBN1 mutations often present more considerable phenotypic variation compared to different members of the related family carrying a same mutation. The purpose of our study was to identify pathogenic mutation and provide more information about genotype-phenotypic correlations in a large Chinese family with Marfan syndrome. 15 related family members from a Chinese 4-generation pedigree with Marfan syndrome underwent physical, ophthalmologic, radiological and cardiovascular examinations. The propositus has De Bakey III aortic dissection and didn't fulfill the revised Ghent criteria for Marfan syndrome. Nine family members have ectopia lentis and their echocardiogram was normal. Five other family members have no evidence of Marfan syndrome. Genomic DNA was isolated from blood leukocytes. The exome sequencing was employed on the propositus, then the Sanger sequencing was conducted for mutation verification in other 14 participants of this family. The causative mutation in FBN1 discovered in the propositus was a known heterozygous missense mutation, c.1633T>G (p.R545C), in exon 14 (NM 000138). This same mutation was also identified in all 9 ectopia lentis patients and one unaffected 8-year-old girl. However, the same mutation was not discovered in other 4 unaffected family members. Our data enhance the information of genotype-phenotype correlation owing to FBN1 mutations. To our current knowledge, we firstly reported that the same FBN1 mutation, c. 1633C>T (Arg545Cys), was detected simultaneously in three different cardinal phenotypes (ectopia lentis, aortic dissection and unaffected) within one family. The unaffected girl with FBN1 mutation may presumably represent a rare case of nonpenetrance. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Candidate Genes and the Behavioral Phenotype in 22q11.2 Deletion Syndrome

    Science.gov (United States)

    Prasad, Sarah E.; Howley, Sarah; Murphy, Kieran C.

    2008-01-01

    There is an overwhelming evidence that children and adults with 22q11.2 deletion syndrome (22q11.2DS) have a characteristic behavioral phenotype. In particular, there is a growing body of evidence that indicates an unequivocal association between 22q11.2DS and schizophrenia, especially in adulthood. Deletion of 22q11.2 is the third highest risk…

  12. Metabolic profiles characterizing different phenotypes of polycystic ovary syndrome: plasma metabolomics analysis

    OpenAIRE

    Zhao, Yue; Fu, Li; Li, Rong; Wang, Li-Na; Yang, Yan; Liu, Na-Na; Zhang, Chun-Mei; Wang, Ying; Liu, Ping; Tu, Bin-Bin; Zhang, Xue; Qiao, Jie

    2012-01-01

    Background Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder accompanied with an increased risk of developing type 2 diabetes mellitus and cardiovascular disease; despite being a common condition, the pathogenesis of PCOS remains unclear. Our aim was to investigate the potential metabolic profiles for different phenotypes of PCOS, as well as for the early prognosis of complications. Methods A total of 217 women with PCOS and 48 healthy women as normal controls were studie...

  13. Vascular smooth muscle cell phenotypic changes in patients with Marfan syndrome.

    Science.gov (United States)

    Crosas-Molist, Eva; Meirelles, Thayna; López-Luque, Judit; Serra-Peinado, Carla; Selva, Javier; Caja, Laia; Gorbenko Del Blanco, Darya; Uriarte, Juan José; Bertran, Esther; Mendizábal, Yolanda; Hernández, Vanessa; García-Calero, Carolina; Busnadiego, Oscar; Condom, Enric; Toral, David; Castellà, Manel; Forteza, Alberto; Navajas, Daniel; Sarri, Elisabet; Rodríguez-Pascual, Fernando; Dietz, Harry C; Fabregat, Isabel; Egea, Gustavo

    2015-04-01

    Marfan's syndrome is characterized by the formation of ascending aortic aneurysms resulting from altered assembly of extracellular matrix microfibrils and chronic tissue growth factor (TGF)-β signaling. TGF-β is a potent regulator of the vascular smooth muscle cell (VSMC) phenotype. We hypothesized that as a result of the chronic TGF-β signaling, VSMC would alter their basal differentiation phenotype, which could facilitate the formation of aneurysms. This study explores whether Marfan's syndrome entails phenotypic alterations of VSMC and possible mechanisms at the subcellular level. Immunohistochemical and Western blotting analyses of dilated aortas from Marfan patients showed overexpression of contractile protein markers (α-smooth muscle actin, smoothelin, smooth muscle protein 22 alpha, and calponin-1) and collagen I in comparison with healthy aortas. VSMC explanted from Marfan aortic aneurysms showed increased in vitro expression of these phenotypic markers and also of myocardin, a transcription factor essential for VSMC-specific differentiation. These alterations were generally reduced after pharmacological inhibition of the TGF-β pathway. Marfan VSMC in culture showed more robust actin stress fibers and enhanced RhoA-GTP levels, which was accompanied by increased focal adhesion components and higher nuclear localization of myosin-related transcription factor A. Marfan VSMC and extracellular matrix measured by atomic force microscopy were both stiffer than their respective controls. In Marfan VSMC, both in tissue and in culture, there are variable TGF-β-dependent phenotypic changes affecting contractile proteins and collagen I, leading to greater cellular and extracellular matrix stiffness. Altogether, these alterations may contribute to the known aortic rigidity that precedes or accompanies Marfan's syndrome aneurysm formation. © 2015 American Heart Association, Inc.

  14. Is Neurofibromatosis Type 1-Noonan Syndrome a Phenotypic Result of Combined Genetic and Epigenetic Factors?

    Science.gov (United States)

    Yapijakis, Christos; Pachis, Nikos; Natsis, Stavros; Voumvourakis, Costas

    2016-01-01

    Neurofibromatosis 1-Noonan syndrome (NFNS) presents combined characteristics of both autosomal dominant disorders: NF1 and Noonan syndrome (NS). The genes causing NF1 and NS are located on different chromosomes, making it uncertain whether NFNS is a separate entity as previously suggested, or rather a clinical variation. We present a four-membered Greek family. The father was diagnosed with familial NF1 and the mother with generalized epilepsy, being under hydantoin treatment since the age of 18 years. Their two male children exhibited NFNS characteristics. The father and his sons shared R1947X mutation in the NF1 gene. The two children with NFNS phenotype presented with NF1 signs inherited from their father and fetal hydantoin syndrome-like phenotype due to exposure to that anticonvulsant during fetal development. The NFNS phenotype may be the result of both a genetic factor (mutation in the NF1 gene) and an epigenetic/environmental factor (e.g. hydantoin). Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  15. Coffin-Siris syndrome: phenotypic evolution of a novel SMARCA4 mutation.

    Science.gov (United States)

    Tzeng, Michael; du Souich, Christèle; Cheung, Helen Wing-Hong; Boerkoel, Cornelius F

    2014-07-01

    Coffin-Siris Syndrome (CSS) is an intellectual disability disorder caused by mutation of components of the SWI/SNF chromatin-remodeling complex. We describe the evolution of the phenotypic features for a male patient with CSS from birth to age 7 years and 9 months and by review of reported CSS patients, we expand the phenotype to include neonatal and infantile hypertonia and upper airway obstruction. The propositus had a novel de novo heterozygous missense mutation in exon 17 of SMARCA4 (NM_001128849.1:c.2434C>T (NP_001122321.1:p.Leu812Phe)). This is the first reported mutation within motif Ia of the SMARCA4 SNF2 domain. In summary, SMARCA4-associated CSS is a pleiotropic disorder in which the pathognomic clinical features evolve and for which the few reported individuals do not demonstrate a clear genotype-phenotype correlation. © 2014 Wiley Periodicals, Inc.

  16. Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation.

    Science.gov (United States)

    Teber, Ozge Altug; Gillessen-Kaesbach, Gabriele; Fischer, Sven; Böhringer, Stefan; Albrecht, Beate; Albert, Angelika; Arslan-Kirchner, Mine; Haan, Eric; Hagedorn-Greiwe, Monika; Hammans, Christof; Henn, Wolfram; Hinkel, Georg Klaus; König, Rainer; Kunstmann, Erdmute; Kunze, Jürgen; Neumann, Luitgard M; Prott, Eva-Christina; Rauch, Anita; Rott, Hans-Dieter; Seidel, Heide; Spranger, Stephanie; Sprengel, Martin; Zoll, Barbara; Lohmann, Dietmar R; Wieczorek, Dagmar

    2004-11-01

    To define the range of phenotypic expression in Treacher Collins syndrome (TCS; Franceschetti-Klein syndrome), we performed mutation analysis in the TCOF1 gene in 46 patients with tentative diagnosis of TCS and evaluated the clinical data, including a scoring system. A total of 27 coding exons of TCOF1 and adjacent splice junctions were analysed by direct sequencing. In 36 patients with a clinically unequivocal diagnosis of TCS, we detected 28 pathogenic mutations, including 25 novel alterations. No mutation was identified in the remaining eight patients with unequivocal diagnosis of TCS and 10 further patients, in whom the referring diagnosis of TCS was clinically doubtful. There is no overt genotype-phenotype correlation except that conductive deafness is significantly less frequent in patients with mutations in the 3' part of the open reading frame. Inter- and intrafamilial variation is wide. Some mutation carriers, parents of typically affected patients, are so mildly affected that the diagnosis might be overlooked clinically. This suggests that modifying factors are important for phenotypic expression. Based on these findings, minimal diagnostic criteria were defined: downward slanting palpebral fissures and hypoplasia of the zygomatic arch. The difficulties in genetic counselling, especially diagnosis of family members with a mild phenotype, are described.

  17. [Phenotype-genotype correlation analysis of 12 cases with Angelman/Prader-Willi syndrome].

    Science.gov (United States)

    Chen, Chen; Peng, Ying; Xia, Yan; Li, Haoxian; Zhu, Huimin; Pan, Qian; Yin, Fei; Wu, Lingqian

    2014-12-01

    To investigate the genotype-phenotype correlation in patients with Angelman syndrome/Prader-Willi syndrome (AS/PWS) and assess the application value of high-resolution single nucleotide polymorphism microarrays (SNP array) for such diseases. Twelve AS/PWS patients were diagnosed through SNP array, fluorescence in situ hybridization (FISH) and karyotype analysis. Clinical characteristics were analyzed. Deletions ranging from 4.8 Mb to 7.0 Mb on chromosome 15q11.2-13 were detected in 11 patients. Uniparental disomy (UPD) was detected in only 1 patient. Patients with deletions could be divided into 2 groups, including 7 cases with class I and 4 with class II. The two groups however had no significant phenotypic difference. The UPD patient had relatively better development and language ability. Deletions of 6 patients were confirmed by FISH to be of de novo in origin. The risk to their sibs was determined to be less than 1%. The phenotypic differences between AS/PWS patients with class I and class II deletion need to be further studied. SNP array is useful in detecting and distinguishing of patients with deletion or UPD. This method may be applied for studying the genotype-phenotype association and the mechanism underlying AS/PWS.

  18. Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype.

    Science.gov (United States)

    Rohayem, Julia; Ehlers, Christian; Wiedemann, Bärbel; Holl, Reinhard; Oexle, Konrad; Kordonouri, Olga; Salzano, Giuseppina; Meissner, Thomas; Burger, Walter; Schober, Edith; Huebner, Angela; Lee-Kirsch, Min Ae

    2011-07-01

    To describe the diabetes phenotype in Wolfram syndrome compared with type 1 diabetes, to investigate the effect of glycemic control on the neurodegenerative process, and to assess the genotype-phenotype correlation. The clinical data of 50 patients with Wolfram syndrome-related diabetes (WSD) were reviewed and compared with the data of 24,164 patients with type 1 diabetes. Patients with a mean HbA1c during childhood and adolescence of ≤7.5 and >7.5% were compared with respect to the occurrence of additional Wolfram syndrome symptoms. The wolframin (WFS1) gene was screened for mutations in 39 patients. WFS1 genotypes were examined for correlation with age at onset of diabetes. WSD was diagnosed earlier than type 1 diabetes (5.4±3.8 vs. 7.9±4.2 years; P7.5% (P=0.031). Thirteen novel WSF1 mutations were identified. Predicted functional consequence of WFS1 mutations correlated with age at WSD onset (P=0.028). Endoplasmic reticulum stress-mediated decline of β-cells in WSD occurs earlier in life than autoimmune-mediated β-cell destruction in type 1 diabetes. This study establishes a role for WFS1 in determining the age at onset of diabetes in Wolfram syndrome and identifies glucose toxicity as an accelerating feature in the progression of disease.

  19. Behavioral Phenotype and Autism Spectrum Disorders in Cornelia de Lange Syndrome.

    Science.gov (United States)

    Parisi, Lucia; Di Filippo, Teresa; Roccella, Michele

    2015-09-30

    Cornelia de Lange syndrome (CdLS) is a congenital disorder characterized by distinctive facial features, growth retardation, limb abnormalities, intellectual disability, and behavioral problems. Cornelia de Lange syndrome is associated with abnormalities on chromosomes 5, 10 and X. Heterozygous point mutations in three genes (NIPBL, SMC3 and SMC1A), are responsible for approximately 50-60% of CdLS cases. CdLS is characterized by autistic features, notably excessive repetitive behaviors and expressive language deficits. The prevalence of autism spectrum disorder (ASD) symptomatology is comparatively high in CdLS. However, the profile and developmental trajectories of these ASD characteristics are potentially different to those observed in individuals with idiopathic ASD. A significantly higher prevalence of self-injury are evident in CdLS. Self-injury was associated with repetitive and impulsive behavior. This study describes the behavioral phenotype of four children with Cornelia de Lange syndrome and ASDs and rehabilitative intervention that must be implemented.

  20. A developmental, longitudinal investigation of autism phenotypic profiles in fragile X syndrome.

    Science.gov (United States)

    Lee, Michelle; Martin, Gary E; Berry-Kravis, Elizabeth; Losh, Molly

    2016-01-01

    Targeting overlapping behavioral phenotypes in neurogenetic disorders can help elucidate gene-behavior relationships. Fragile X syndrome (FXS) and autism spectrum disorder (ASD) have been studied as a model for this approach, and important areas of phenotypic overlap and divergence have been documented. However, few studies have examined how the manifestation of ASD-related phenotypes in FXS may change over development, a question which has important implications for conceptualizing shared etiologies of these disorders and their constituent phenotypes. The goal of this study was to characterize ASD phenotypes in boys and girls with FXS across development, as well as to compare individual component phenotypes among boys with FXS and boys with idiopathic ASD (ASD-O) over time. Sixty-five boys and girls with FXS and 19 boys with ASD-O completed a battery of diagnostic, cognitive, and language assessments at two time points (mean 2.5 years apart). Nonparametric tests assessed changes in diagnostic classification in FXS over time, and hierarchical linear modeling and repeated measures assessed changes in individual ASD symptoms in FXS over time. Additionally, ANCOVAs compared ASD symptom severity and component phenotypes in boys with FXS-O, FXS-ASD, and ASD-O at both time points. Overall, ASD symptom manifestation for children with FXS significantly increased over time, and developmental predictors varied based on the domain of symptoms assessed. The greatest degree of overlap was observed between boys with FXS-ASD and ASD-O in the domain of reciprocal social communication across time points, whereas boys with ASD-O demonstrated greater impairment in restricted and repetitive behaviors at the later time point. ASD symptoms increased in FXS with age, and social language impairment emerged as a potential core shared feature of FXS and ASD that may help elucidate underlying molecular genetic variation related to phenotypic variance, and aid intervention planning for

  1. AMH MEASUREMENT VERSUS OVARIAN ULTRASOUND IN THE DIAGNOSIS OF POLYCYSTIC OVARY SYNDROME IN DIFFERENT PHENOTYPES.

    Science.gov (United States)

    Carmina, Enrico; Campagna, Anna M; Fruzzetti, Franca; Lobo, Rogerio A

    2016-03-01

    This study was designed to assess the value of serum anti-Müllerian hormone (AMH) in the diagnosis of polycystic ovary syndrome (PCOS) in various phenotypes and to assess ovarian ultrasound parameters. We performed a retrospective matched controlled study of 113 females with various PCOS phenotypes and 47 matched controls. The diagnostic utility of AMH measurement and ovarian ultrasound were compared. Using receiver operating characteristic (ROC) curve analyses, the threshold for AMH (>4.7 ng/mL) and ultrasound parameters (follicle number per ovary [FNPO] >22 and ovarian volume [OV] >8 cc) were established. In the entire cohort, AMH had a low sensitivity of 79%; while FNPO and OV were 93% and 68%, respectively. Specificities ranged from 85 to 96%. In classic anovulatory PCOS, AMH exhibited a sensitivity of 91%, and for FNPO and OV the corresponding sensitivities were 92% and 72%. In the ovulatory phenotype, AMH sensitivity was only 50%, while FNPO and OV were 95% and 50%, respectively. In the nonhyperandrogenic phenotype, the sensitivity of AMH was 53% while those for FNPO and OV were 93% and 67%. AMH does not appear to be helpful for all subjects with PCOS but may be of some value in those who are anovulatory. However, FNPO was highly sensitive in all phenotypes, and was the single best criterion assessed for all subjects, suggesting the important role of ultrasound.

  2. Genotype-phenotype correlation in 21 patients with Wolf-Hirschhorn syndrome using high resolution array comparative genome hybridisation (CGH)

    NARCIS (Netherlands)

    Maas, N. M. C.; Van Buggenhout, G.; Hannes, F.; Thienpont, B.; Sanlaville, D.; Kok, K.; Midro, A.; Andrieux, J.; Anderlid, B-M; Schoumans, J.; Hordijk, R.; Devriendt, K.; Fryns, J-P; Vermeesch, J. R.

    Background: The Wolf-Hirschhorn syndrome (WHS) is usually caused by terminal deletions of the short arm of chromosome 4 and is phenotypically defined by growth and mental retardation, seizures, and specific craniofacial manifestations. Large variation is observed in phenotypic expression of these

  3. Phenotypic Heterogeneity by Germline Mismatch Repair Gene Defect in Lynch Syndrome Patients.

    Science.gov (United States)

    Hernâni-Eusébio, Jorge; Barbosa, Elisabete

    2016-10-01

    Lynch syndrome is the most common form of hereditary colorectal cancer, being also responsible for endometrial and other types of cancers. It is associated with germline mutations in DNA mismatch repair genes and microsatellite instability. MLH1 and MSH2 mutations have a "classical" Lynch syndrome phenotype, with MSH2 having a higher association with extracolonic cancer. MSH6 and PMS2 mutations have an atypical phenotype. Clinical expression is heterogeneous, with correlation between mismatch repair mutated gene and phenotypic patterns. We retrospectively analyzed data from patients fulfilling Amsterdam criteria or having mismatch repair gene mutations, between September 2012 and October 2015. We identified 28 patients. Seventeen had colorectal cancer with right colon predominance. Five developed endometrial cancer (median age of diagnosis - 53), with no MSH6 mutations. Five developed other cancers. All mutated mismatch repair cases studied had microsatellite instability. Most cases had MSH2 mutations despite MLH1 being described in the literature as the most frequently mutated. Interestingly, colorectal cancer patients showed no tendency for high inflammatory infiltrate. Despite the high incidence of synchronous and metachronous tumours, most patients underwent a partial colectomy. Prophylactic hysterectomy and adnexectomy was performed in menopausal/perimenopausal patients. A standardized registration of patient's data may lead to better management and knowledge about Lynch syndrome. Use of Bethesda Guidelines might identify new cases non-identified by Amsterdam criteria. Microsatellite instability analysis must be performed in a much larger scale. The genotypic/phenotypic correlation described in the literature was not verified in our study with statistical significance, perhaps due to small data sample and insufficient clinical registration.

  4. The Prevalence of Metabolic Syndrome and Different Obesity Phenotype in Iranian Male Military Personnel.

    Science.gov (United States)

    Payab, Moloud; Hasani-Ranjbar, Shirin; Merati, Yaser; Esteghamati, Alireza; Qorbani, Mostafa; Hematabadi, Mahboobeh; Rashidian, Hoda; Shirzad, Nooshin

    2017-03-01

    Obesity, especially when concentrated in the abdominal area, is often associated with the presence of metabolic syndrome. Stress, particularly occupational stress, is one of the most important factors contributing to the increased prevalence of metabolic syndrome components among different populations. This study aimed to investigate the prevalence of overweight and obesity as well as the criteria for metabolic syndrome and its risk factors and different obesity phenotype in a population of military personnel aged 20 to 65 years. This study is a retrospective cross-sectional study in which data are extracted from the database of a military hospital (2,200 participants). The records of participants contained information such as age, marital status, educational level, weight, height, body mass index, blood pressure, waist circumference, history of drug use and smoking, as well as the results of tests including lipid profile and fasting blood glucose. The Adult Treatment Panel III criteria as well as two national criteria were used to identify metabolic syndrome among participants. Data analysis was p1erformed using SPSS version 16. The average age of participants was 33.37 (7.75) years. The prevalence of metabolic syndrome according to Iranian cutoff was 26.6% for the waist circumference >90 cm (585 persons) and 19.6% for the waist circumference >95 cm (432 persons). The rate of metabolic syndrome was identified as 11.1% (432 cases) according to Adult Treatment Panel III criteria. Results of the current study identified that the prevalence of metabolic syndrome among military individuals is less than other populations, but the prevalence of the syndrome is higher than other military personnel in other countries.

  5. DOORS Syndrome: Phenotype, Genotype and Comparison With Coffin-Siris Syndrome

    NARCIS (Netherlands)

    Campeau, Philippe M.; Hennekam, Raoul C.; Aftimos, Salim; Banka, Siddharth; Begleiter, Michael L.; Bilo, Leonilda; Blair, Edward; Burrage, Lindsay C.; Liu, David S.; de Bie, Isabelle; Félix, Têmis Maria; Giltay, Jacques C.; Gibbs, Richard A.; Giuliano, Fabienne; Hadzsiev, Kinga; Hori, Mutsuki; Kariminejad, Ariana; Kayserili, Hülya; Kerr, Bronwyn; Lee, Brendan H.; Lu, James T.; Male, Alison; Meenakshi, Girish; Mey, Antje; Murray, Mitzi L.; Nair, Lal D. V.; Nampoothiri, Sheela; Newman, William G.; Peluso, Silvio; Peters, Heidi; Powell, R.; Repetto, Gabriela M.; Rump, Patrick; Santos-Simarro, Fernando; Stewart, Fiona; van Bever, Yolande; van den Ende, Jenneke; Wieczorek, Dagmar; Wisniewska, Marzena; Sisodiya, Sanjay M.

    2014-01-01

    DOORS syndrome (Deafness, Onychodystrophy, Osteodystrophy, mental Retardation, Seizures) is characterized mainly by sensorineural deafness, shortened terminal phalanges with small nails of hands and feet, intellectual deficiency, and seizures. Half of the patients with all clinical features have

  6. EEC syndrome, Arg227Gln TP63 mutation and micturition difficulties: Is there a genotype-phenotype correlation?

    NARCIS (Netherlands)

    Maclean, K.; Holme, S.A.; Gilmour, E.; Taylor, M.; Scheffer, H.; Graf, N.; Smith, G.H.; Onikul, E.; Bokhoven, J.H.L.M. van; Moss, C.; Ades, L.C.

    2007-01-01

    We report on two unrelated families with EEC syndrome (ectrodactyly, ectodermal dysplasia, cleft lip/palate), each with an Arg227Gln TP63 gene mutation, where the phenotype overlapped extensively with the allelic disorder, limb-mammary syndrome (LMS). Features common to both families were an

  7. Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients

    DEFF Research Database (Denmark)

    Hoornaert, Kristien P; Vereecke, Inge; Dewinter, Chantal

    2010-01-01

    Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation...

  8. Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients

    DEFF Research Database (Denmark)

    Hoornaert, Kristien P; Vereecke, Inge; Dewinter, Chantal

    2010-01-01

    Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation ...

  9. Hydrogen sulfide restores a normal morphological phenotype in Werner syndrome fibroblasts, attenuates oxidative damage and modulates mTOR pathway

    NARCIS (Netherlands)

    Talaei, F.; van Praag, V. M.; Henning, R. H.

    Werner syndrome (WS) protein is involved in DNA repair and its truncation causes Werner syndrome, an autosomal recessive genetic disorder with a premature aging phenotype. WRN protein mutation is currently known as the primary cause of WS. In cultured WS fibroblasts, we found an increase in

  10. Phelan-McDermid syndrome in two adult brothers: atypical bipolar disorder as its psychopathological phenotype?

    Directory of Open Access Journals (Sweden)

    Verhoeven WMA

    2012-04-01

    Full Text Available Willem MA Verhoeven1,2, Jos IM Egger1,3,4, Marjolein H Willemsen5, Gert JM de Leijer6, Tjitske Kleefstra51Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Venray, 2Erasmus University Medical Centre, Department of Psychiatry, Rotterdam, 3Donders Centre for Cognition, Radboud University Nijmegen, Nijmegen, 4Behavioural Science Institute, Radboud University Nijmegen, Nijmegen, 5Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, 6Dichterbij, Institutes for Intellectual Disabilities, Gennep, The NetherlandsAbstract: The 22q13.3 deletion, or Phelan-McDermid syndrome, is characterized by global intellectual disability, generalized hypotonia, severely delayed or absent speech associated with features of autism spectrum disorder, and minor dysmorphisms. Its behavioral phenotype comprises sleep disturbances, communication deficits, and motor perseverations. Data on psychological dysfunctions are so far not available. Previous studies have suggested that the loss of one copy of the gene SH3 and multiple ankyrin repeat domains 3 (SHANK3 is related to the neurobehavioral phenotype. Additional genes proximal to SHANK3 are also likely to play a role in the phenotype of patients with larger deletions. The present paper describes two adult brothers with an identical 2.15 Mb 22qter (22q13.32q13.33 deletion, of whom the youngest was referred for evaluation of recurrent mood changes. In both patients, magnetic resonance imaging of the brain showed hypoplasia of the vermis cerebelli. Extensive clinical examinations led to a final diagnosis of atypical bipolar disorder, of which symptoms fully remitted during treatment with a mood stabilizer. In the older brother, a similar psychopathological picture appeared to be present, although less severe and with a later onset. It is concluded that the behavioral phenotype of the 22q13.3 deletion syndrome comprises absent or delayed speech and perseverations

  11. Study of phenotype evolution during childhood in Marfan syndrome to improve clinical recognition.

    Science.gov (United States)

    Stheneur, Chantal; Tubach, Florence; Jouneaux, Marlène; Roy, Carine; Benoist, Gregoire; Chevallier, Bertrand; Boileau, Catherine; Jondeau, Guillaume

    2014-03-01

    Because diagnosis of Marfan syndrome is difficult during infancy, we used a large cohort of children to describe the evolution of the Marfan syndrome phenotype with age. Two hundred and fifty-nine children carrying an FBN1 gene mutation and fulfilling Ghent criteria were compared with 474 non-Marfan syndrome children. Prevalence of skeletal features changed with aging: prevalence of pectus deformity increased from 43% at 0-6 years to 62% at 15-17 years, wrist signs increased from 28 to 67%, and scoliosis increased from 16 to 59%. Hypermobility decreased from 67 to 47% and pes planus decreased from 73 to 65%. Striae increased from 2 to 84%. Prevalence of ectopia lentis remained stable, varying from 66 to 72%, similar to aortic root dilatation (varying from 75 to 80%). Aortic root dilatation remained stable during follow-up in this population receiving β-blocker therapy. When comparing Marfan syndrome children with non-Marfan syndrome children, height appeared to be a simple and discriminant criterion when it was >3.3 SD above the mean. Ectopia lentis and aortic dilatation were both similarly discriminating. Ectopia lentis and aortic dilatation are the best-discriminating features, but height remains a simple discriminating variable for general practitioners when >3.3 SD above the mean. Mean aortic dilatation remains stable in infancy when children receive a β-blocker.

  12. Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.

    Science.gov (United States)

    Yuan, Bo; Pehlivan, Davut; Karaca, Ender; Patel, Nisha; Charng, Wu-Lin; Gambin, Tomasz; Gonzaga-Jauregui, Claudia; Sutton, V Reid; Yesil, Gozde; Bozdogan, Sevcan Tug; Tos, Tulay; Koparir, Asuman; Koparir, Erkan; Beck, Christine R; Gu, Shen; Aslan, Huseyin; Yuregir, Ozge Ozalp; Al Rubeaan, Khalid; Alnaqeb, Dhekra; Alshammari, Muneera J; Bayram, Yavuz; Atik, Mehmed M; Aydin, Hatip; Geckinli, B Bilge; Seven, Mehmet; Ulucan, Hakan; Fenercioglu, Elif; Ozen, Mustafa; Jhangiani, Shalini; Muzny, Donna M; Boerwinkle, Eric; Tuysuz, Beyhan; Alkuraya, Fowzan S; Gibbs, Richard A; Lupski, James R

    2015-02-01

    Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" rather than cohesinopathies.

  13. Angelman syndrome due to paternal uniparental disomy of chromosome 15: A milder phenotype?

    Energy Technology Data Exchange (ETDEWEB)

    Bottani, A.; Robinson, W.P.; DeLoizer-Blanchet, C.D.; Engel, E.; Morris, M.A.; Schmitt, Thun-Hohenstein, L.; Schinzel, A. [Univ. of Zuerich (Switzerland)

    1994-05-15

    The Angelman syndrome (AS) is a neurological disorder characterized by severe mental retardation, absent speech, seizures, gait disturbances, and a typical age-dependent facial phenotype. Most cases are due to an interstitial deletion on the maternally inherited chromosome 15, in the critical region q11-q13. Rare cases also result from paternal uniparental disomy of chromosome 15. In a group of 14 patients with sporadic AS diagnosed in Switzerland, we found 2 unrelated females with paternal isodisomy for the entire chromosome 15. Their phenotypes were milder than usually seen in this syndrome: one girl did not show the typical AS facial changes; both patients had late-onset mild seizures; as they grow older, they had largely undisturbed gross motor functions, in particular no severe ataxia. Both girls were born to older fathers (45 and 43 years old, respectively). The apparent association of a relatively milder phenotype in AS with paternal uniparental disomy will have to be confirmed by detailed clinical descriptions of further patients. 25 refs., 2 figs., 1 tab.

  14. SNORD116 deletions cause Prader-Willi syndrome with a mild phenotype and macrocephaly.

    Science.gov (United States)

    Fontana, P; Grasso, M; Acquaviva, F; Gennaro, E; Galli, M L; Falco, M; Scarano, F; Scarano, G; Lonardo, F

    2017-10-01

    Prader-Willi syndrome is a complex condition caused by lack of expression of imprinted genes in the paternally derived region of chromosome 15 (15q11q13). A small number of patients with Prader-Willi phenotype have been discovered to have narrow deletions, not encompassing the whole critical region, but only the SNORD116 cluster, which includes genes codifying for small nucleolar RNAs. This kind of deletion usually is not detected by the classic DNA methylation analysis test. We present the case of a male patient with a mild Prader-Willi phenotype and a small deletion including SNORD116, diagnosed by methylation-sensitive multiplex ligation-dependent probe amplification (MLPA. The patient showed neonatal hypotonia, hyperphagia, obesity, central hypogonadism, hypothyroidism, strabismus. Stature and intellectual development are within the normal range. The presence of macrocephaly, observed in other cases of SNORD116 deletions as well, is uncommon for the classic phenotype of the syndrome. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Quantitative, Phenotypical, and Functional Characterization of Cellular Immunity in Children and Adolescents With Down Syndrome.

    Science.gov (United States)

    Schoch, Justine; Rohrer, Tilman R; Kaestner, Michael; Abdul-Khaliq, Hashim; Gortner, Ludwig; Sester, Urban; Sester, Martina; Schmidt, Tina

    2017-05-15

    Infections and autoimmune disorders are more frequent in Down syndrome, suggesting abnormality of adaptive immunity. Although the role of B cells and antibodies is well characterized, knowledge regarding T cells is limited. Lymphocyte subpopulations of 40 children and adolescents with Down syndrome and 51 controls were quantified, and phenotype and functionality of antigen-specific effector T cells were analyzed with flow cytometry after polyclonal and pathogen-specific stimulation (with varicella-zoster virus [VZV] and cytomegalovirus [CMV]). Results were correlated with immunoglobulin (Ig) G responses. Apart from general alterations in the percentage of lymphocytes, regulatory T cells, and T-helper 1 and 17 cells, all major T-cell subpopulations showed higher expression of the inhibitory receptor PD-1. Polyclonally stimulated effector CD4+ T-cell frequencies were significantly higher in subjects with Down syndrome, whereas their inhibitory receptor expression (programmed cell death 1 [PD-1] and cytotoxic T-lymphocyte antigen 4 [CTLA-4]) was similar to that of controls and cytokine expression profiles were only marginally altered. Pathogen-specific immunity showed age-appropriate levels of endemic infection, with correlation of CMV-specific cellular and humoral immunity in all subjects. Among VZV IgG-positive individuals, a higher percentage of VZV-specific T-cell-positive subjects was seen in those with Down syndrome. Despite alterations in lymphocyte subpopulations, individuals with Down syndrome can mount effector T-cell responses with similar phenotype and functionality as controls but may require higher effector T-cell frequencies to ensure pathogen control. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  16. Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.

    Science.gov (United States)

    Parenti, Ilaria; Teresa-Rodrigo, María E; Pozojevic, Jelena; Ruiz Gil, Sara; Bader, Ingrid; Braunholz, Diana; Bramswig, Nuria C; Gervasini, Cristina; Larizza, Lidia; Pfeiffer, Lutz; Ozkinay, Ferda; Ramos, Feliciano; Reiz, Benedikt; Rittinger, Olaf; Strom, Tim M; Watrin, Erwan; Wendt, Kerstin; Wieczorek, Dagmar; Wollnik, Bernd; Baquero-Montoya, Carolina; Pié, Juan; Deardorff, Matthew A; Gillessen-Kaesbach, Gabriele; Kaiser, Frank J

    2017-03-01

    The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed "transcriptomopathies" that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin-Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.

  17. Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS).

    Science.gov (United States)

    Pearson, Toni S; Akman, Cigdem; Hinton, Veronica J; Engelstad, Kristin; De Vivo, Darryl C

    2013-04-01

    Glut1 deficiency syndrome (Glut1 DS) was originally described in 1991 as a developmental encephalopathy characterized by infantile onset refractory epilepsy, cognitive impairment, and mixed motor abnormalities including spasticity, ataxia, and dystonia. The clinical condition is caused by impaired glucose transport across the blood brain barrier. The past 5 years have seen a dramatic expansion in the range of clinical syndromes that are recognized to occur with Glut1 DS. In particular, there has been greater recognition of milder phenotypes. Absence epilepsy and other idiopathic generalized epilepsy syndromes may occur with seizure onset in childhood or adulthood. A number of patients present predominantly with movement disorders, sometimes without any accompanying seizures. In particular, paroxysmal exertional dyskinesia is now a well-documented clinical feature that occurs in individuals with Glut1 DS. A clue to the diagnosis in patients with paroxysmal symptoms may be the triggering of episodes during fasting or exercise. Intellectual impairment may range from severe to very mild. Awareness of the broad range of potential clinical phenotypes associated with Glut1 DS will facilitate earlier diagnosis of this treatable neurologic condition. The ketogenic diet is the mainstay of treatment and nourishes the starving symptomatic brain during development.

  18. Silver-Russell Syndrome and Beckwith-Wiedemann Syndrome: Opposite Phenotypes with Heterogeneous Molecular Etiology

    Science.gov (United States)

    Õunap, Katrin

    2016-01-01

    Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 clinically opposite growth-affecting disorders belonging to the group of congenital imprinting disorders. The expression of both syndromes usually depends on the parental origin of the chromosome in which the imprinted genes reside. SRS is characterized by severe intrauterine and postnatal growth retardation with various additional clinical features such as hemihypertrophy, relative macrocephaly, fifth finger clinodactyly, and triangular facies. BWS is an overgrowth syndrome with many additional clinical features such as macroglossia, organomegaly, and an increased risk of childhood tumors. Both SRS and BWS are clinically and genetically heterogeneous, and for clinical diagnosis, different diagnostic scoring systems have been developed. Six diagnostic scoring systems for SRS and 4 for BWS have been previously published. However, neither syndrome has common consensus diagnostic criteria yet. Most cases of SRS and BWS are associated with opposite epigenetic or genetic abnormalities in the 11p15 chromosomal region leading to opposite imbalances in the expression of imprinted genes. SRS is also caused by maternal uniparental disomy 7, which is usually identified in 5-10% of the cases, and is therefore the first imprinting disorder that affects 2 different chromosomes. In this review, we describe in detail the clinical diagnostic criteria and scoring systems as well as molecular causes in both SRS and BWS. PMID:27587987

  19. Functional Cathepsin C mutations cause different Papillon-Lefèvre syndrome phenotypes.

    Science.gov (United States)

    Noack, Barbara; Görgens, Heike; Schacher, Beate; Puklo, Magda; Eickholz, Peter; Hoffmann, Thomas; Schackert, Hans Konrad

    2008-04-01

    The autosomal-recessive Papillon-Lefèvre syndrome (PLS) is characterized by severe aggressive periodontitis, combined with palmoplantar hyperkeratosis, and is caused by mutations in the Cathepsin C (CTSC) gene. This study aimed to identify CTSC mutations in different PLS phenotypes, including atypical forms and isolated pre-pubertal aggressive periodontitis (PAP). Thirteen families with different phenotypes were analysed by direct sequencing of the entire coding region and the regulatory regions of CTSC. The function of novel mutations was tested with enzyme activity measurements. In 11 of 13 families, 12 different pathogenic CTSC mutations were found in 10 typical PLS patients, three atypical cases and one PAP patient. Out of four novel mutations, three result in protein truncation and are thus considered to be pathogenic. The homozygous c.854C>T nucleotide exchange (p.P285L) was associated with an almost complete loss of enzyme activity. The observed phenotypic heterogeneity could not be associated with specific genotypes. The phenotypic variability of the PLS associated with an identical genetic background may reflect the influence of additional genetic or environmental factors on disease characteristics. CTSC mutation analyses should be considered for differential diagnosis in all children suffering from severe aggressive periodontitis.

  20. Clinical and psychological parameters associated with pain pattern phenotypes in women with interstitial cystitis/bladder pain syndrome.

    Science.gov (United States)

    Nickel, J Curtis; Tripp, Dean A

    2015-01-01

    It was recently suggested that 2 distinct clinical phenotypes can be described in patients with urological chronic pelvic pain syndrome, including pelvic pain only and pelvic pain beyond. We examined data on patients with interstitial cystitis/bladder pain syndrome, including body pain location mapping, and associated medical and psychosocial phenotyping to validate these body pain maps in a cohort of female patients with interstitial cystitis/bladder pain syndrome undergoing tertiary care. Validated questionnaires from 173 diagnosed outpatient female patients with interstitial cystitis/bladder pain syndrome included a body pain area diagram, demographics/history, pain assessment, interstitial cystitis/bladder pain syndrome symptoms, depression, anxiety, stress, fatigue, sexual functioning, catastrophizing, quality of life and data on other chronic pain conditions. Two pain phenotypes based on counts of body locations, pelvic pain only and pelvic pain beyond, were comprehensively examined. The 157 patients (81%) identified with pelvic pain beyond reported more sensory type pain, poorer physical quality of life, and greater somatic depression and sleep disturbance than the 36 (19%) categorized with pelvic pain only. The sexual pain score was higher in the pelvic pain only group. Furthermore, patients with the pelvic pain beyond phenotype reported a higher prevalence of irritable bowel syndrome and fibromyalgia as well as more general fatigue symptoms and psychiatric conditions. Two distinct pain location phenotypes, including pelvic pain only and pelvic pain beyond, were identified by our independent analysis of patients with interstitial cystitis/bladder pain syndrome. Assessing clinical phenotypes based on pain patterns has significant ramifications in our improved understanding of the etiology and treatment of female patients diagnosed with interstitial cystitis/bladder pain syndrome. Copyright © 2015 American Urological Association Education and Research, Inc

  1. Phenotype characteristics of patients with colonic serrated polyposis syndrome: a study of 23 cases.

    Science.gov (United States)

    Elorza, Garazi; Enríquez-Navascués, José M; Bujanda, Luis; Larzábal, Mikel; Gil Lasa, Inés; Martí, Laura

    2014-12-01

    Serrated polyposis syndrome (SPS) is a rare entity characterized by the presence of multiple hyperplastic polyps in the colon and an increased risk of presentation and development of colorectal cancer (CRC). To evaluate the clinical and phenotypical characteristics of patients that present one of the 3 WHO criteria for the diagnosis of SPS diagnosed and treated a tour hospital. Patients with the diagnosis of SPS during 2005-2012 were revised; 24.208 colonoscopies were performed during this period. Age, sex, family history of CRC (APC/MYH), proximal/mixed/distal phenotype, indication for colonoscopy, number, size, location of the hyperplastic polyps, presence of mixed/adenomatous polyps, CRCI, follow-up and endoscopio/surgical treatment. A total of 23 cases were included (19 male). The median age was 51. A total of 34% had a prior family history of CRC or polpyps. Distal phenotype was more frequent (48%). Another 73% presented synchronous adenomatous polyps, and 26% a CRC. A total of 57% were asymptomatic. Surgery was performed in 9 cases (6 for cancer and 3 for polyposis), and 14 were treated by polypectomy and observation. Eleven patients (47%) presented recurrent/persistent lesions after initial surgical/endoscopic treatment. SPS is an heterogeneous syndrome that is variable in the type, size, distribution and number of polyps, and is more common in male smokers with a distal phenotype. The majority of patients also present synchronous adenomatous polyps. These patients require an organized multidisciplinary evaluation. Copyright © 2013 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients.

    Science.gov (United States)

    Santen, Gijs W E; Aten, Emmelien; Vulto-van Silfhout, Anneke T; Pottinger, Caroline; van Bon, Bregje W M; van Minderhout, Ivonne J H M; Snowdowne, Ronelle; van der Lans, Christian A C; Boogaard, Merel; Linssen, Margot M L; Vijfhuizen, Linda; van der Wielen, Michiel J R; Vollebregt, M J Ellen; Breuning, Martijn H; Kriek, Marjolein; van Haeringen, Arie; den Dunnen, Johan T; Hoischen, Alexander; Clayton-Smith, Jill; de Vries, Bert B A; Hennekam, Raoul C M; van Belzen, Martine J

    2013-11-01

    De novo germline variants in several components of the SWI/SNF-like BAF complex can cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1) and identified pathogenic variants in 45 (71%) patients. We found a high proportion of variants in ARID1B (68%). All four pathogenic variants in ARID1A appeared to be mosaic. By using all variants from the Exome Variant Server as test data, we were able to classify variants in ARID1A, ARID1B, and SMARCB1 reliably as being pathogenic or nonpathogenic. For SMARCA2, SMARCA4, and SMARCE1 several variants in the EVS remained unclassified, underlining the importance of parental testing. We have entered all variant and clinical information in LOVD-powered databases to facilitate further genotype-phenotype correlations, as these will become increasingly important because of the uptake of targeted and untargeted next generation sequencing in diagnostics. The emerging phenotype-genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay. The variability in phenotype seems most marked in ARID1A and ARID1B patients. Distal limbs anomalies are most marked in ARID1A patients and least in SMARCB1 patients. Numbers are small however, and larger series are needed to confirm this correlation. © 2013 WILEY PERIODICALS, INC.

  3. Interstitial duplication of proximal 22q: phenotypic overlap with cat eye syndrome.

    Science.gov (United States)

    Knoll, J H; Asamoah, A; Pletcher, B A; Wagstaff, J

    1995-01-16

    We describe a child with downslanting palpebral fissures, preauricular malfunctions, congenital heart defect (total anomalous pulmonary venous return), unilateral absence of a kidney, and developmental delay with an apparent interstitial duplication of proximal 22q. Fluorescent in situ hybridization (FISH) analysis showed duplication of the IGLC locus, and C-banding of the duplicated region was negative. The duplication appears to involve 22q11.2-q12. Although the child has neither colobomas nor microphthalmia, he shows phenotypic overlap with the cat eye syndrome, which is caused by a supernumerary bisatellited chromosome arising from inverted duplication of the short arm and proximal long arm of chromosome 22. Further molecular studies of this patient should help to define the regions responsible for the manifestations of cat eye syndrome.

  4. Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype-phenotype relationships.

    Science.gov (United States)

    Brioude, Frédéric; Bouligand, Jérôme; Trabado, Séverine; Francou, Bruno; Salenave, Sylvie; Kamenicky, Peter; Brailly-Tabard, Sylvie; Chanson, Philippe; Guiochon-Mantel, Anne; Young, Jacques

    2010-05-01

    Congenital hypogonadotropic hypogonadism (CHH) results from abnormal gonadotropin secretion, and it is characterized by impaired pubertal development. CHH is caused by defective GNRH release, or by a gonadotrope cell dysfunction in the pituitary. Identification of genetic abnormalities related to CHH has provided major insights into the pathways critical for the development, maturation, and function of the reproductive axis. Mutations in five genes have been found specifically in Kallmann's syndrome, a disorder in which CHH is related to abnormal GNRH neuron ontogenesis and is associated with anosmia or hyposmia. In combined pituitary hormone deficiency or in complex syndromic CHH in which gonadotropin deficiency is either incidental or only one aspect of a more complex endocrine disorder or a non-endocrine disorder, other mutations affecting GNRH and/or gonadotropin secretion have been reported. Often, the CHH phenotype is tightly linked to an isolated deficiency of gonadotropin secretion. These patients, who have no associated signs or hormone deficiencies independent of the deficiency in gonadotropin and sex steroids, have isolated CHH. In some familial cases, they are due to genetic alterations affecting GNRH secretion (mutations in GNRH1, GPR54/KISS1R and TAC3 and TACR3) or the GNRH sensitivity of the gonadotropic cells (GNRHR). A minority of patients with Kallmann's syndrome or a syndromic form of CHH may also appear to have isolated CHH, but close clinical, familial, and genetic studies can reorient the diagnosis, which is important for genetic counseling in the context of assisted reproductive medicine. This review focuses on published cases of isolated CHH, its clinical and endocrine features, genetic causes, and genotype-phenotype relationships.

  5. Dubowitz syndrome is a complex comprised of multiple, genetically distinct and phenotypically overlapping disorders.

    Directory of Open Access Journals (Sweden)

    Douglas R Stewart

    Full Text Available Dubowitz syndrome is a rare disorder characterized by multiple congenital anomalies, cognitive delay, growth failure, an immune defect, and an increased risk of blood dyscrasia and malignancy. There is considerable phenotypic variability, suggesting genetic heterogeneity. We clinically characterized and performed exome sequencing and high-density array SNP genotyping on three individuals with Dubowitz syndrome, including a pair of previously-described siblings (Patients 1 and 2, brother and sister and an unpublished patient (Patient 3. Given the siblings' history of bone marrow abnormalities, we also evaluated telomere length and performed radiosensitivity assays. In the siblings, exome sequencing identified compound heterozygosity for a known rare nonsense substitution in the nuclear ligase gene LIG4 (rs104894419, NM_002312.3:c.2440C>T that predicts p.Arg814X (MAF:0.0002 and an NM_002312.3:c.613delT variant that predicts a p.Ser205Leufs*29 frameshift. The frameshift mutation has not been reported in 1000 Genomes, ESP, or ClinSeq. These LIG4 mutations were previously reported in the sibling sister; her brother had not been previously tested. Western blotting showed an absence of a ligase IV band in both siblings. In the third patient, array SNP genotyping revealed a de novo ∼ 3.89 Mb interstitial deletion at chromosome 17q24.2 (chr 17:62,068,463-65,963,102, hg18, which spanned the known Carney complex gene PRKAR1A. In all three patients, a median lymphocyte telomere length of ≤ 1st centile was observed and radiosensitivity assays showed increased sensitivity to ionizing radiation. Our work suggests that, in addition to dyskeratosis congenita, LIG4 and 17q24.2 syndromes also feature shortened telomeres; to confirm this, telomere length testing should be considered in both disorders. Taken together, our work and other reports on Dubowitz syndrome, as currently recognized, suggest that it is not a unitary entity but instead a collection of

  6. Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations.

    Science.gov (United States)

    Fergelot, Patricia; Van Belzen, Martine; Van Gils, Julien; Afenjar, Alexandra; Armour, Christine M; Arveiler, Benoit; Beets, Lex; Burglen, Lydie; Busa, Tiffany; Collet, Marie; Deforges, Julie; de Vries, Bert B A; Dominguez Garrido, Elena; Dorison, Nathalie; Dupont, Juliette; Francannet, Christine; Garciá-Minaúr, Sixto; Gabau Vila, Elisabeth; Gebre-Medhin, Samuel; Gener Querol, Blanca; Geneviève, David; Gérard, Marion; Gervasini, Cristina Giovanna; Goldenberg, Alice; Josifova, Dragana; Lachlan, Katherine; Maas, Saskia; Maranda, Bruno; Moilanen, Jukka S; Nordgren, Ann; Parent, Philippe; Rankin, Julia; Reardon, Willie; Rio, Marlène; Roume, Joëlle; Shaw, Adam; Smigiel, Robert; Sojo, Amaia; Solomon, Benjamin; Stembalska, Agnieszka; Stumpel, Constance; Suarez, Francisco; Terhal, Paulien; Thomas, Simon; Touraine, Renaud; Verloes, Alain; Vincent-Delorme, Catherine; Wincent, Josephine; Peters, Dorien J M; Bartsch, Oliver; Larizza, Lidia; Lacombe, Didier; Hennekam, Raoul C

    2016-12-01

    Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients

    DEFF Research Database (Denmark)

    Hoornaert, Kristien P; Vereecke, Inge; Dewinter, Chantal

    2010-01-01

    Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation...... in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation...... with Stickler syndrome....

  8. Recognition of the Cornelia de Lange syndrome phenotype with facial dysmorphology novel analysis.

    Science.gov (United States)

    Basel-Vanagaite, L; Wolf, L; Orin, M; Larizza, L; Gervasini, C; Krantz, I D; Deardoff, M A

    2016-05-01

    Facial analysis systems are becoming available to healthcare providers to aid in the recognition of dysmorphic phenotypes associated with a multitude of genetic syndromes. These technologies automatically detect facial points and extract various measurements from images to recognize dysmorphic features and evaluate similarities to known facial patterns (gestalts). To evaluate such systems' usefulness for supporting the clinical practice of healthcare professionals, the recognition accuracy of the Cornelia de Lange syndrome (CdLS) phenotype was examined with FDNA's automated facial dysmorphology novel analysis (FDNA) technology. In the first experiment, 2D facial images of CdLS patients with either an NIPBL or SMC1A gene mutation as well as non-CdLS patients which were assessed by dysmorphologists in a previous study were evaluated by the FDNA technology; the average detection rate of experts was 77% while the system's detection rate was 87%. In the second study, when a new set of NIPBL, SMC1A and non-CdLS patient photos was evaluated, the detection rate increased to 94%. The results from both studies indicated that the system's detection rate was comparable to that of dysmorphology experts. Therefore, utilizing such technologies may be a useful tool in a clinical setting. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Shared monocyte subset phenotypes in HIV-1 infection and in uninfected subjects with acute coronary syndrome.

    Science.gov (United States)

    Funderburg, Nicholas T; Zidar, David A; Shive, Carey; Lioi, Anthony; Mudd, Joseph; Musselwhite, Laura W; Simon, Daniel I; Costa, Marco A; Rodriguez, Benigno; Sieg, Scott F; Lederman, Michael M

    2012-11-29

    The mechanisms responsible for increased cardiovascular risk associated with HIV-1 infection are incompletely defined. Using flow cytometry, in the present study, we examined activation phenotypes of monocyte subpopulations in patients with HIV-1 infection or acute coronary syndrome to find common cellular profiles. Nonclassic (CD14(+)CD16(++)) and intermediate (CD14(++)CD16(+)) monocytes are proportionally increased and express high levels of tissue factor and CD62P in HIV-1 infection. These proportions are related to viremia, T-cell activation, and plasma levels of IL-6. In vitro exposure of whole blood samples from uninfected control donors to lipopolysaccharide increased surface tissue factor expression on all monocyte subsets, but exposure to HIV-1 resulted in activation only of nonclassic monocytes. Remarkably, the profile of monocyte activation in uncontrolled HIV-1 disease mirrors that of acute coronary syndrome in uninfected persons. Therefore, drivers of immune activation and inflammation in HIV-1 disease may alter monocyte subpopulations and activation phenotype, contributing to a pro-atherothrombotic state that may drive cardiovascular risk in HIV-1 infection.

  10. Genomic imprinting: genetic mechanisms and phenotypic consequences in Prader-Willi and Angelman syndromes

    Directory of Open Access Journals (Sweden)

    Fridman Cintia

    2000-01-01

    Full Text Available Chromosomal 15q11-q13 region is of great interest in Human Genetics because many structural rearrangements have been described for it (deletions, duplications and translocations leading to phenotypes resulting in conditions such as the Prader-Willi (PWS and Angelman (AS syndromes which were the first human diseases found to be related to the differential expression of parental alleles (genomic imprinting. Contrary to Mendelian laws where the parental inheritance of genetic information does not influence gene expression, genomic imprinting is characterized by DNA modifications that produce different phenotypes depending on the parental origin of the mutation. Clinical manifestation of PWS appears when the loss of paternally expressed genes occurs and AS results from the loss of a maternally expressed gene. Different genetic mechanisms can lead to PWS or AS, such as deletions, uniparental disomy or imprinting mutation. In AS patients an additional class occurs with mutations on the UBE3A gene. Studies of PWS and AS patients can help us to understand the imprinting process, so that other genomic regions with similar characteristics can be located, and different syndromes can have their genetic mechanisms elucidated.

  11. Phenotypic variation and allelic heterogeneity in young patients with Papillon-Lefèvre syndrome.

    Science.gov (United States)

    Ullbro, Christer; El-Samadi, Safia; Boumah, Christine; Al-Yousef, Nujoud; Wakil, Salma; Twetman, Svante; Alfadley, Abdullah; Thestrup-Pedersen, Kristian; Meyer, Brian

    2006-01-01

    Papillon-Lefèvre syndrome is an autosomal recessive disorder characterized by palmoplantar hyperkeratosis and aggressive periodontitis. The aim of the study was to identify underlying cathepsin C mutations in 39 subjects with Papillon-Lefèvre syndrome and to explore any phenotypic associations. Genotyping and mutation analyses were performed using standard molecular techniques, and dermatological and oral characteristics were assessed with a semiquantitative clinical score. Three genotypes were present at microsatellite marker D11S1780 and two underlying mutations were identified. The most common genotype (183/183) was associated with an 815G --> C mutation in exon 6 resulting in an arginine to proline change at amino acid 272 (R272P). Patients with the 173/173 genotype revealed an exon 7 G300D mutation resulting in a glycine to aspartic acid change at amino acid 300. The mutation in a family with 189/189 genotype remained unknown. A significant difference in hyperkeratosis of the feet was found between the patients with mutations G300D and R272P ( p periodontal condition. Young girls displayed significantly less palmoplantar hyperkeratosis ( p < 0.05) than young boys. In conclusion, considerable phenotypic heterogeneity was observed within the two cardinal mutations and in the 189/189 genotype.

  12. Perfluorocarbons and Gilbert syndrome (phenotype) in the C8 Health Study Population

    Energy Technology Data Exchange (ETDEWEB)

    Fan, Hongmin [Cancer Center, School of Public Health, West Virginia University, Morgantown, WV 265050-9190 (United States); Department of Epidemiology and Statistics, School of Public Health, Hebei United University, Hebei 063000 (China); Ducatman, Alan [Department of Occupational and Environmental Health, School of Public Health, West Virginia University (United States); Department of Medicine, School of Medicine, West Virginia University (United States); Clinical Translational Science Institute, West Virginia University (United States); Zhang, Jianjun [Department of Biostatistics, School Public Health, West Virginia University (United States)

    2014-11-15

    Background: Gilbert syndrome (GS) is an inherited defect of bilirubin conjugation, most commonly caused by a gene mutation for the enzyme UGT1A. GS is known to affect the metabolism and excretion of drugs and xenobiotics. Perfluorocarbon compounds (PFCs) are bio-persistent environmental contaminants that affect metabolic regulation. In this study, we examined the associations of GS phenotype and serum PFCs in the C8 Health Study Population. Materials and methods: Using 2005–2006 data from a large PFC-exposure population survey, we compared serum PFCs concentrations between GS and non GS clinical phenotypes, in a cross sectional design, adjusting for standard risk factors, including age, BMI, smoking status, socioeconomic status and gender. Results: Among 10 PFC compounds considered, only perfluorohexanoic acid (PFHxA) was seen at a significantly higher concentration in GS men and women. Conclusion: PFHxA exposure may be associated with GS. Our findings do not support increased exposure in GS for other PFCs. - Highlights: • Most serum PFCs are not associated with clinically evident Gilbert syndrome. • However, serum perfluorohexanoic acid is positively associated. • The investigation addresses the clinical presentation, not the genetic mutation.

  13. A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype.

    Science.gov (United States)

    Romaniello, Romina; Saettini, Francesco; Panzeri, Elena; Arrigoni, Filippo; Bassi, Maria T; Borgatti, Renato

    2015-03-25

    This study reports on a 9-year-old girl who developed West syndrome and showed clinical features fulfilling the main revised diagnostic criteria for typical Rett syndrome (hand washing, severe cognitive impairment with absence of language, ataxic gait, progressive scoliosis and autistic features). Mutation analyses for methyl-CpG-binding protein 2 (MECP2), cyclin-dependent kinase-like 5 (CDKL5/STK9), ARX and Forkhead box G1 (FOXG1) genes were carried out, with negative results. A known de-novo c.1217G>A missense mutation in exon 14 leading to the substitution of a conserved residue, p.R406H in domain3b of the syntaxin-binding protein 1 (STXBP1) gene, was detected. The STXBP1 gene encodes the syntaxin-binding protein 1, a neuron-specific protein involved in synaptic vesicle release at both glutaminergic and GABAergic synapses. This function is also affected by MECP2 gene mutations, which are known to lead to a decrease in glutamate and GABA receptors' density. It is possible to speculate that the impairment in synaptic plasticity represents the pathogenic link between MECP2 and STXBP1 gene mutations. On reviewing the clinical features of the reported patients with the same mutation in the STXBP1 gene, it has been observed that poor eye contact, tremour, dyskinesia, head/hand stereotypies and both cognitive and motor progressive deterioration are common symptoms, although never considered as indicative of a Rett syndrome phenotype. In conclusion, the case described here suggests a relationship between the Rett syndrome and the STXBP1 gene not described so far, making the search for STXBP1 gene mutations advisable in patients with Rett syndrome and early onset of epilepsy. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

  14. Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome.

    Science.gov (United States)

    Mannini, Linda; Cucco, Francesco; Quarantotti, Valentina; Krantz, Ian D; Musio, Antonio

    2013-12-01

    Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. Clinical features include growth retardation, intellectual disability, limb defects, typical facial dysmorphism, and other systemic involvement. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of the phenotype. Mutations in five genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8), all regulators or structural components of cohesin, have been identified. Approximately 60% of CdLS cases are due to NIPBL mutations, 5% caused by mutations in SMC1A, RAD21, and HDAC8 and one proband was found to carry a mutation in SMC3. To date, 311 CdLS-causing mutations are known including missense, nonsense, small deletions and insertions, splice site mutations, and genomic rearrangements. Phenotypic variability is seen both intra- and intergenically. This article reviews the spectrum of CdLS mutations with a particular emphasis on their correlation to the clinical phenotype. © 2013 WILEY PERIODICALS, INC.

  15. Congenital Heart Disease in Cornelia de Lange Syndrome: Phenotype and Genotype Analysis

    Science.gov (United States)

    Chatfield, Kathryn C.; Schrier, Samantha A.; Li, Jennifer; Clark, Dinah; Kaur, Maninder; Kline, Antonie D.; Deardorff, Matthew A.; Jackson, Laird S.; Goldmuntz, Elizabeth; Krantz, Ian D.

    2013-01-01

    Congenital heart disease (CHD) has been reported to occur in 14–70% of individuals with Cornelia de Lange syndrome (CdLS, OMIM 122470) and accounts for significant morbidity and mortality when present. Charts from a cohort of 479 patients with CdLS were reviewed for cardiac evaluations, gene testing and information to determine phenotypic severity. Two hundred fifty-nine individuals had either documented structural defects or minor cardiac findings. The presence of CHD was then quantified as a function of mutation status and severity of CdLS: mild, moderate, or severe. Different types of CHD were also evaluated by mutation status to assess for any genotype –phenotype correlation. NIPBL, SMC1A, and SMC3 mutation-positive patients were equally likely to have CHD, although the number of SMC1A and SMC3 mutation-positive patients were small in comparison. Structural CHDs were more likely to be present in individuals with moderate and severe CdLS than in the mild phenotype. This study evaluates the trends of CHD seen in the CdLS population and correlates these findings with genotype. PMID:22965847

  16. Mutation Spectrum and Genotype–Phenotype Correlation in Cornelia de Lange Syndrome

    Science.gov (United States)

    Mannini, Linda; Cucco, Francesco; Quarantotti, Valentina; Krantz, Ian D.; Musio, Antonio

    2013-01-01

    Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. Clinical features include growth retardation, intellectual disability, limb defects, typical facial dysmorphism, and other systemic involvement. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of the phenotype. Mutations in five genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8), all regulators or structural components of cohesin, have been identified. Approximately 60% of CdLS cases are due to NIPBL mutations, 5% caused by mutations in SMC1A, RAD21, and HDAC8 and one proband was found to carry a mutation in SMC3. To date, 311 CdLS-causing mutations are known including missense, nonsense, small deletions and insertions, splice site mutations, and genomic rearrangements. Phenotypic variability is seen both intra- and intergenically. This article reviews the spectrum of CdLS mutations with a particular emphasis on their correlation to the clinical phenotype. PMID:24038889

  17. Genotype-phenotype correlations in Cornelia de Lange syndrome: Behavioral characteristics and changes with age.

    Science.gov (United States)

    Moss, Joanna; Penhallow, Jessica; Ansari, Morad; Barton, Stephanie; Bourn, David; FitzPatrick, David R; Goodship, Judith; Hammond, Peter; Roberts, Catherine; Welham, Alice; Oliver, Chris

    2017-06-01

    Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder associated with unusual facial features, limb abnormalities, a wide range of health conditions, and intellectual disability. Mutations in five genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex have been identified in up to 70% of individuals. Genetic cause remains unknown for a proportion of individuals. There is substantial heterogeneity in all aspects of CdLS but very little is known about what predicts phenotypic heterogeneity. In this study, we evaluated genotype-phenotype associations in 34 individuals with CdLS. Participants with NIPBL mutations had significantly lower self help skills and were less likely to have verbal skills relative to those who were negative for the NIPBL mutation. No significant differences were identified between the groups in relation to repetitive behavior, mood, interest and pleasure, challenging behavior, activity, impulsivity, and characteristics of autism spectrum disorder whilst controlling differences in self help skills. Significant correlations indicating lower mood, interest and pleasure, and increased insistence on sameness with older age were identified for those who were NIPBL mutation positive. The findings suggest similarities in the behavioral phenotype between those with and without the NIPBL mutation once differences in self help skills are controlled for. However, there may be subtle differences in the developmental trajectory of these behaviors according to genetic mutation status in CdLS. © 2017 Wiley Periodicals, Inc.

  18. Tetralogy of Fallot and Hypoplastic Left Heart Syndrome – Complex Clinical Phenotypes Meet Complex Genetic Networks

    Science.gov (United States)

    Lahm, Harald; Schön, Patric; Doppler, Stefanie; Dreßen, Martina; Cleuziou, Julie; Deutsch, Marcus-André; Ewert, Peter; Lange, Rüdiger; Krane, Markus

    2015-01-01

    In many cases congenital heart disease (CHD) is represented by a complex phenotype and an array of several functional and morphological cardiac disorders. These malformations will be briefly summarized in the first part focusing on two severe CHD phenotypes, hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). In most cases of CHD the genetic origin remains largely unknown, though the complexity of the clinical picture strongly argues against a dysregulation which can be attributed to a single candidate gene but rather suggests a multifaceted polygenetic origin with elaborate interactions. Consistent with this idea, genome-wide approaches using whole exome sequencing, comparative sequence analysis of multiplex families to identify de novo mutations and global technologies to identify single nucleotide polymorphisms, copy number variants, dysregulation of the transcriptome and epigenetic variations have been conducted to obtain information about genetic alterations and potential predispositions possibly linked to the occurrence of a CHD phenotype. In the second part of this review we will summarize and discuss the available literature on identified genetic alterations linked to TOF and HLHS. PMID:26069455

  19. Rett syndrome - biological pathways leading from MECP2 to disorder phenotypes.

    Science.gov (United States)

    Ehrhart, Friederike; Coort, Susan L M; Cirillo, Elisa; Smeets, Eric; Evelo, Chris T; Curfs, Leopold M G

    2016-11-25

    Rett syndrome (RTT) is a rare disease but still one of the most abundant causes for intellectual disability in females. Typical symptoms are onset at month 6-18 after normal pre- and postnatal development, loss of acquired skills and severe intellectual disability. The type and severity of symptoms are individually highly different. A single mutation in one gene, coding for methyl-CpG-binding protein 2 (MECP2), is responsible for the disease. The most important action of MECP2 is regulating epigenetic imprinting and chromatin condensation, but MECP2 influences many different biological pathways on multiple levels although the molecular pathways from gene to phenotype are currently not fully understood. In this review the known changes in metabolite levels, gene expression and biological pathways in RTT are summarized, discussed how they are leading to some characteristic RTT phenotypes and therefore the gaps of knowledge are identified. Namely, which phenotypes have currently no mechanistic explanation leading back to MECP2 related pathways? As a result of this review the visualization of the biologic pathways showing MECP2 up- and downstream regulation was developed and published on WikiPathways which will serve as template for future omics data driven research. This pathway driven approach may serve as a use case for other rare diseases, too.

  20. A Marfan syndrome-like phenotype caused by a neocentromeric supernumerary ring chromosome 15.

    Science.gov (United States)

    Quinonez, Shane C; Gelehrter, Thomas D; Uhlmann, Wendy R

    2017-01-01

    Small supernumerary marker chromosomes (sSMC) are abnormal chromosomes that cannot be characterized by standard banding cytogenetic techniques. A minority of sSMC contain a neocentromere, which is an ectopic centromere lacking the characteristic alpha-satellite DNA. The phenotypic manifestations of sSMC and neocentromeric sSMC are variable and range from severe intellectual disability and multiple congenital anomalies to a normal phenotype. Here we report a patient with a diagnosis of Marfan syndrome and infertility found to have an abnormal karyotype consisting of a chromosome 15 deletion and a ring-type sSMC likely stabilized by a neocentromere derived via a mechanism initially described by Barbara McClintock in 1938. Analysis of the sSMC identified that it contained the deleted chromosome 15 material and also one copy of FBN1, the gene responsible for Marfan syndrome. We propose that the patient's diagnosis arose from disruption of the FBN1 allele on the sSMC. To date, a total of 29 patients have been reported with an sSMC derived from a chromosomal deletion. We review these cases with a specific focus on the resultant phenotypes and note significant difference between this class of sSMC and other types of sSMC. Through this review we also identified a patient with a clinical diagnosis of neurofibromatosis type 1 who lacked a family history of the condition but was found to have a chromosome 17-derived sSMC that likely contained NF1 and caused the patient's disorder. We also review the genetic counseling implications and recommendations for a patient or family harboring an sSMC. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. Variable phenotype of Marfan syndrome in two large Australian pedigrees, one of Australian aboriginal origin

    Energy Technology Data Exchange (ETDEWEB)

    Wong, K.K.; Summers, K.M.; West, M.J. [Univ. of Queensland (Australia)] [and others

    1994-09-01

    Marfan syndrome may affect the cardiovascular, ocular and skeletal systems. The gene for this autosomal dominant disease maps to chromosome 15 and codes for the extracellular matrix protein fibrillin. Phenotypic expression is very variable both within and between families, possibly due to the influence of other, unlinked, genetic factors interacting with the fibrillin gene. We report two Australian families which demonstrate the extent of inter- and intra-family phenotypic variability. Eye, cardiac and skeletal assessments were made independently. In the first family, 8 of 12 siblings and 11 of 19 of their children had ectopia lentis with or without other ocular findings. There were few cardiac signs. One child had mitral valve prolapse. He and three other children had mild dilatation of the aorta. Skeletal abnormalities were also found (3 adults and 7 children). Chest wall asymmetry was the most common skeletal finding. This family has less cardiac and skeletal involvement than is usual in Marfan syndrome, although the disease maps to chromosome 15 in the region of the fibrillin gene (LOD=4.8 at {theta}=0 with respect to CYP19). The second family is partly of Australian aboriginal origin. The disease has been traced through 5 generations. To date we have examined 37 of 84 living members. Twenty-three in 3 generations are affected. Five adults and 4 children have moderate to severe aortic dilatation and there has been at least one death due to aortic dissection. However, two adolescents with subluxed lenses and marked skeletal abnormalities have normal aortic diameters, two children have aortic dilatation without other signs and two children have only subluxed lenses. This family shows the range of phenotypic variation which can arise from mutation in the fibrillin gene, which may be influenced by the admixture of Australian aboriginal genes. These two families provide an invaluable resource for studying genetic interactions in this disease.

  2. Swedish CDKN2A mutation carriers do not present the atypical mole syndrome phenotype.

    Science.gov (United States)

    Nielsen, Kari; Harbst, Katja; Måsbäck, Anna; Jönsson, Göran; Borg, Ake; Olsson, Håkan; Ingvar, Christian

    2010-08-01

    Phenotypic characteristics were examined in melanoma-prone southern Swedish CDKN2A (p16-113insArg/p14ARF-128insSer) mutation families, in relation to the CDKN2A genotype, nevi, clinically atypical nevi (CAN) and melanoma. Individuals from eight melanoma-prone families, with index patients carrying the CDKN2A mutation, were offered skin examinations and genotyping (CDKN2A and MC1R). Ninety-three individuals above 18 years of age participated; 29 invasive melanomas in 16 patients were recorded, all in the 38 verified CDKN2A mutation carriers. Median age at diagnosis was 36 years. Several MC1R variants were observed. A significant correlation to CAN (P=0.01) and red hair colour (P=0.02) could be confirmed in melanoma patients. A positive mutation status (CDKN2A) was correlated to one or more CAN (P=0.007) but neither to blue eyes, red hair colour, heavy freckling nor high number of nevi. For mutation carriers, median total naevus count was 24 and interquartile range was 12-47 (mean 31); whereas for the whole cohort, median total naevus count was 12 and interquartile range was 5-25 (mean 22). No participant fulfilled the atypical mole syndrome phenotype criteria. Melanomas were diagnosed only in mutation carriers, and melanoma diagnosis was statistically correlated to the presence of one or more CAN and red hair colour, supporting the possible synergistic effect of a MC1R mutation on increased risk of melanoma in patients with a CDKN2A mutation. Family history, with verified tumour diagnoses, remains an important clinical tool for finding mutation carriers for referral to clinical geneticists and simultaneous presence of CAN in probable mutation carriers might strengthen this indication. The atypical mole syndrome phenotype was, however, not verified in the studied families and total naevus counts were low.

  3. Childhood bladder and bowel dysfunction predicts irritable bowel syndrome phenotype in adult interstitial cystitis/bladder pain syndrome patients.

    Science.gov (United States)

    Doiron, R Christopher; Kogan, Barry A; Tolls, Victoria; Irvine-Bird, Karen; Nickel, J Curtis

    2017-08-01

    Many clinicians have suggested that a history of bladder and bowel dysfunction (BBD) in childhood predisposes to the development of interstitial cystitis/bladder pain syndrome (IC/BPS) or irritable bowel syndrome (IBS) in adulthood. We hypothesized that BBD symptoms in childhood would predict the IBS-associated phenotype in adult IC/BPS patients. Consecutive female patients (n=190) with a diagnosis of IC/BPS were administered a modified form of a clinical BBD questionnaire (BBDQ) to capture childhood BBD-like symptoms, as well as Interstitial Cystitis Symptoms Index (ICSI), Interstitial Cystitis Problem Index (ICPI), Pelvic Pain and Urgency/Frequency (PUF) questionnaires and UPOINT categorization. Patients were stratified to IBS-positive or IBS-negative according to clinical assessment of IBS-like symptoms. The 127 patients (67%) identified with IBS-like symptoms recalled significantly higher BBDQ scores than the 63 patients (33%) who were IBS-negative (2.8 vs. 2.3; p=0.05). The IBS-positive patients also reported a higher number of UPOINT domains than their non-IBS counterparts (3.8 vs. 2.9; p=0.0001), while their PUF total scores were significantly higher (13.6 vs. 12.3; p=0.04). IBS-positive patients more often recalled that in childhood they did not have a daily bowel movement (BM) (p=0.04) and had "to push for a BM" (p=0.009). In childhood, they "urinated only once or twice per day" (p=0.03) and recalled "painful urination" more than those without IBS (p=0.03). There were no significant differences between the groups in answers to the other five questions of the BBDQ. Our symptom recollection survey was able to predict the IBS phenotype of IC/BPS based on a childhood BBDQ. Further prospective studies are needed to further evaluate these novel findings.

  4. Cervical artery dissection expands the cardiovascular phenotype in FBN1-related Weill-Marchesani syndrome.

    Science.gov (United States)

    Newell, Kelsey; Smith, Wendy; Ghoshhajra, Brian; Isselbacher, Eric; Lin, Angela; Lindsay, Mark E

    2017-09-01

    Weill-Marchesani syndrome (WMS) is a rare form of acromelic dysplasia that is characterized by distinctive skeletal, ocular, and cardiovascular abnormalities. Previously described cardiac manifestations of WMS include aortic and pulmonary valve stenosis, mitral valve prolapse, mitral stenosis, and QTc prolongation. Autosomal dominant forms of WMS result from heterozygous pathogenic variants in FBN1, a gene with a well characterized role in the pathogenesis of thoracic aortic aneurysm (TAA) in the context of Marfan syndrome. In contrast, only one patient has been reported with aortic disease in WMS. Although the risk of aortic dissection from preceding TAA remains the leading cause of morbidity for individuals with Marfan syndrome, rare reports of arterial dissection in the peripheral vasculature have been described. Peripheral artery dissection has not been previously reported in other FBN1-related diseases. We describe a three generation family with FBN1-related WMS whose cardiovascular manifestations include TAA and cervical artery dissection, thus expanding the cardiovascular phenotype of WMS. Further research is required to quantify these risks and establish appropriate recommendations for cardiovascular imaging, medical management, and prophylactic surgical intervention in individuals with FBN1--related acromelic dysplasia. © 2017 Wiley Periodicals, Inc.

  5. Behavioral phenotype and autism spectrum disorders in Cornelia de Lange syndrome

    Directory of Open Access Journals (Sweden)

    Lucia Parisi

    2015-09-01

    Full Text Available Cornelia de Lange syndrome (CdLS is a congenital disorder characterized by distinctive facial features, growth retardation, limb abnormalities, intellectual disability, and behavioral problems. Cornelia de Lange syndrome is associated with abnormalities on chromosomes 5, 10 and X. Heterozygous point mutations in three genes (NIPBL, SMC3 and SMC1A, are responsible for approximately 50-60% of CdLS cases. CdLS is characterized by autistic features, notably excessive repetitive behaviors and expressive language deficits. The prevalence of autism spectrum disorder (ASD symptomatology is comparatively high in CdLS. However, the profile and developmental trajectories of these ASD characteristics are potentially different to those observed in individuals with idiopathic ASD. A significantly higher prevalence of self-injury are evident in CdLS. Self-injury was associated with repetitive and impulsive behavior. This study describes the behavioral phenotype of four children with Cornelia de Lange syndrome and ASDs and rehabilitative intervention that must be implemented.

  6. Expanding the SHOC2 Mutation Associated Phenotype of Noonan Syndrome with Loose Anagen Hair: Structural Brain Anomalies and Myelofibrosis

    OpenAIRE

    Gripp, Karen W.; Zand, Dina J.; Demmer, Laurie; Anderson, Carol E.; Dobyns, William B.; Zackai, Elaine H.; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L.; Sol-Church, Katia

    2013-01-01

    Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mut...

  7. Phenotypic and molecular assessment of seven patients with 6p25 deletion syndrome: Relevance to ocular dysgenesis and hearing impairment

    Directory of Open Access Journals (Sweden)

    Ritch Robert

    2004-06-01

    Full Text Available Abstract Background Thirty-nine patients have been described with deletions involving chromosome 6p25. However, relatively few of these deletions have had molecular characterization. Common phenotypes of 6p25 deletion syndrome patients include hydrocephalus, hearing loss, and ocular, craniofacial, skeletal, cardiac, and renal malformations. Molecular characterization of deletions can identify genes that are responsible for these phenotypes. Methods We report the clinical phenotype of seven patients with terminal deletions of chromosome 6p25 and compare them to previously reported patients. Molecular characterization of the deletions was performed using polymorphic marker analysis to determine the extents of the deletions in these seven 6p25 deletion syndrome patients. Results Our results, and previous data, show that ocular dysgenesis and hearing impairment are the two most highly penetrant phenotypes of the 6p25 deletion syndrome. While deletion of the forkhead box C1 gene (FOXC1 probably underlies the ocular dysgenesis, no gene in this region is known to be involved in hearing impairment. Conclusions Ocular dysgenesis and hearing impairment are the two most common phenotypes of 6p25 deletion syndrome. We conclude that a locus for dominant hearing loss is present at 6p25 and that this locus is restricted to a region distal to D6S1617. Molecular characterization of more 6p25 deletion patients will aid in refinement of this locus and the identification of a gene involved in dominant hearing loss.

  8. Poor phenotype-genotype association in a large series of patients with Type III Bartter syndrome.

    Directory of Open Access Journals (Sweden)

    Alejandro García Castaño

    Full Text Available Type III Bartter syndrome (BS is an autosomal recessive renal tubule disorder caused by loss-of-function mutations in the CLCNKB gene, which encodes the chloride channel protein ClC-Kb. In this study, we carried out a complete clinical and genetic characterization in a cohort of 30 patients, one of the largest series described. By comparing with other published populations, and considering that 80% of our patients presented the p.Ala204Thr Spanish founder mutation presumably associated with a common phenotype, we aimed to test the hypothesis that allelic differences could explain the wide phenotypic variability observed in patients with type III BS.Clinical data were retrieved from the referral centers. The exon regions and flanking intronic sequences of the CLCNKB gene were screened for mutations by polymerase chain reaction (PCR followed by direct Sanger sequencing. Presence of gross deletions or duplications in the region was checked for by MLPA and QMPSF analyses.Polyuria, polydipsia and dehydration were the main common symptoms. Metabolic alkalosis and hypokalemia of renal origin were detected in all patients at diagnosis. Calciuria levels were variable: hypercalciuria was detected in 31% of patients, while 23% had hypocalciuria. Nephrocalcinosis was diagnosed in 20% of the cohort. Two novel CLCNKB mutations were identified: a small homozygous deletion (c.753delG in one patient and a small deletion (c.1026delC in another. The latter was present in compound heterozygosis with the already previously described p.Glu442Gly mutation. No phenotypic association was obtained regarding the genotype.A poor correlation was found between a specific type of mutation in the CLCNKB gene and type III BS phenotype. Importantly, two CLCNKB mutations not previously described were found in our cohort.

  9. Genotype-phenotype correlation in 22q11.2 deletion syndrome

    Directory of Open Access Journals (Sweden)

    Michaelovsky Elena

    2012-12-01

    Full Text Available Abstract Background The 22q11.2 deletion syndrome (22q11.2DS is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. We explored the genotype-phenotype relationship in a relatively large 22q11.2DS cohort treated and monitored in our clinic using comprehensive clinical evaluation and detailed molecular characterization of the deletion. Methods Molecular analyses in 142 subjects with 22q11.2DS features were performed by FISH and MLPA methods. Participants underwent clinical assessment of physical symptoms and structured psychiatric and cognitive evaluation. Results Deletions were found in 110 individuals including one with an atypical nested distal deletion which was missed by the FISH test. Most subjects (88.2% carried the 3Mb typically deleted region and 11.8% carried 4 types of deletions differing in size and location. No statistically significant genotype-phenotype correlations were found between deletion type and clinical data although some differences in hypocalcemia and cardiovascular anomalies were noted. Analysis of the patient with the distal nested deletion suggested a redundancy of genes causing the physical and neuropsychiatric phenotype in 22q11.2DS and indicating that the psychiatric and cognitive trajectories may be governed by different genes. Conclusions MLPA is a useful and affordable molecular method combining accurate diagnosis and detailed deletion characterization. Variations in deletion type and clinical manifestations impede the detection of significant differences in samples of moderate size, but analysis of individuals with unique deletions may provide insight into the underlying biological mechanisms. Future genotype-phenotype studies should involve large multicenter collaborations employing uniform clinical standards and high-resolution molecular methods.

  10. Hyperandrogenism and phenotypes of polycystic ovary syndrome are not associated with differences in obstetric outcomes.

    Science.gov (United States)

    Mumm, Hanne; Jensen, Dorte Møller; Sørensen, Jens Aage; Andersen, Lise Lotte Torvin; Ravn, Pernille; Andersen, Marianne; Glintborg, Dorte

    2015-02-01

    To investigate obstetric outcomes in Danish women with different phenotypes of polycystic ovary syndrome (PCOS) and isolated hyperandrogenism (HA) and describe the risk of adverse obstetric outcomes in women with PCOS and HA compared to controls. Cohort study. Odense University Hospital, Denmark. Women with PCOS were identified prospectively starting in 1997. Singleton pregnancies in women with PCOS and HA during 2003-2011 were included (n = 199). A control group was matched to the patient cohort according to date of childbirth (n = 995). Data on clinical characteristics and obstetric outcomes were collected in patients with PCOS and HA and controls. In PCOS and HA, total and free testosterone, sex hormone binding globulin, and hemoglobin A1c were measured outside pregnancy. During pregnancy, oral glucose tolerance tests were performed in 39 patients and 123 controls according to Danish national guidelines. PCOS phenotypes were based on the Rotterdam criteria. Gestational diabetes mellitus, pregnancy-induced hypertension, preeclampsia, delivery by emergency cesarean section, preterm delivery and anthropometric measures in the newborn. The incidence of adverse obstetric outcomes and anthropometric measures among the newborns were comparable between different phenotypes of PCOS and patients with HA. In the oral glucose tolerance test, patients had a higher risk of gestational diabetes mellitus compared with controls; the odds ratio (95% confidence interval) was 3.3 (1.5-6.9) after adjustment for age, parity, and body mass index (p = 0.002). The incidence of other adverse obstetric outcomes was similar in patients and controls. Obstetric outcomes were comparable in women with different PCOS phenotypes. © 2014 Nordic Federation of Societies of Obstetrics and Gynecology.

  11. Clinical Auditory Phenotypes Associated with GATA3 Gene Mutations in Familial Hypoparathyroidism-deafness-renal Dysplasia Syndrome

    Science.gov (United States)

    Wang, Li; Lin, Qiong-Fen; Wang, Hong-Yang; Guan, Jing; Lan, Lan; Xie, Lin-Yi; Yu, Lan; Yang, Ju; Zhao, Cui; Liang, Jin-Long; Zhou, Han-Lin; Yang, Huan-Ming; Xiong, Wen-Ping; Zhang, Qiu-Jing; Wang, Da-Yong; Wang, Qiu-Ju

    2017-01-01

    Background: Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is an autosomal dominant disorder primarily caused by haploinsufficiency of GATA binding protein 3 (GATA3) gene mutations, and hearing loss is the most frequent phenotypic feature. This study aimed at identifying the causative gene mutation for a three-generation Chinese family with HDR syndrome and analyzing auditory phenotypes in all familial HDR syndrome cases. Methods: Three affected family members underwent otologic examinations, biochemistry tests, and other clinical evaluations. Targeted genes capture combining next-generation sequencing was performed within the family. Sanger sequencing was used to confirm the causative mutation. The auditory phenotypes of all reported familial HDR syndrome cases analyzed were provided. Results: In Chinese family 7121, a heterozygous nonsense mutation c.826C>T (p.R276*) was identified in GATA3. All the three affected members suffered from sensorineural deafness and hypocalcemia; however, renal dysplasia only appeared in the youngest patient. Furthermore, an overview of thirty HDR syndrome families with corresponding GATA3 mutations revealed that hearing impairment occurred earlier in the younger generation in at least nine familial cases (30%) and two thirds of them were found to carry premature stop mutations. Conclusions: This study highlights the phenotypic heterogeneity of HDR and points to a possible genetic anticipation in patients with HDR, which needs to be further investigated. PMID:28303854

  12. The autistic phenotype in Down syndrome: differences in adaptive behaviour versus Down syndrome alone and autistic disorder alone.

    Science.gov (United States)

    Dressler, Anastasia; Perelli, Valentina; Bozza, Margherita; Bargagna, Stefania

    2011-01-01

    The autistic phenotype in Down syndrome (DS) is marked by a characteristic pattern of stereotypies, anxiety and social withdrawal. Our aim was to study adaptive behaviour in DS with and without autistic comorbidity using the Vineland Adaptive Behaviour Scales (VABS), the Childhood Autism Rating Scales (CARS) and the DSM IV-TR criteria. We assessed 24 individuals and established three groups: Down syndrome (DS), DS and autistic disorder (DS-AD), and autistic disorder (AD). The DS and DS-AD groups showed statistically significantly similar strengths on the VABS (in receptive and domestic skills). The DS and DS-AD subjects also showed similar strengths on the CARS (in imitation and relating), differing significantly from the AD group. The profile of adaptive functioning and symptoms in DS-AD seemed to be more similar to that found in DS than to the profile emerging in AD. We suggest that the comorbidity of austistic symptoms in DS hampered the acquisition of adaptive skills more than did the presence of DS alone.

  13. New observations in the fragile X-associated tremor/ataxia syndrome (FXTAS phenotype

    Directory of Open Access Journals (Sweden)

    Avram eFraint

    2014-10-01

    Full Text Available Purpose: Fragile X-associated tremor/ataxia syndrome (FXTAS was originally defined as tremor, ataxia, cognitive decline and parkinsonism in individuals who carry between 55-200 CGG repeats in the promoter region of the fragile X mental retardation 1 (FMR1 gene. This paper describes a series of patients who meet the definition of FXTAS who presented for care between 2009-2014. Methods/Results: Retrospective chart review of patients seen in the FXTAS clinic at Rush University in Chicago. Conclusions: Patients with FXTAS may present with a progressive supranuclear palsy-like phenotype and eye movement abnormalities are common in these patients. Rapid worsening of gait abnormalities in FXTAS may be due to a secondary spinal issue and should be aggressively treated to regain function. Finally, the FXTAS Rating Scale score does not reliably inform the certainty of diagnosis or CGG repeat size in these patients.

  14. Broad spectrum of neuropsychiatric phenotypes associated with white matter disease in PTEN hamartoma tumor syndrome.

    Science.gov (United States)

    Balci, Tugce B; Davila, Jorge; Lewis, Denice; Boafo, Addo; Sell, Erick; Richer, Julie; Nikkel, Sarah M; Armour, Christine M; Tomiak, Eva; Lines, Matthew A; Sawyer, Sarah L

    2018-01-01

    White matter lesions have been described in patients with PTEN hamartoma tumor syndrome (PHTS). How these lesions correlate with the neurocognitive features associated with PTEN mutations, such as autism spectrum disorder (ASD) or developmental delay, has not been well established. We report nine patients with PTEN mutations and white matter changes on brain magnetic resonance imaging (MRI), eight of whom were referred for reasons other than developmental delay or ASD. Their clinical presentations ranged from asymptomatic macrocephaly with normal development/intellect, to obsessive compulsive disorder, and debilitating neurological disease. To our knowledge, this report constitutes the first detailed description of PTEN-related white matter changes in adult patients and in children with normal development and intelligence. We present a detailed assessment of the neuropsychological phenotype of our patients and discuss the relationship between the wide array of neuropsychiatric features and observed white matter findings in the context of these individuals. © 2017 Wiley Periodicals, Inc.

  15. The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome.

    Science.gov (United States)

    Brown, Kyla; Selfridge, Jim; Lagger, Sabine; Connelly, John; De Sousa, Dina; Kerr, Alastair; Webb, Shaun; Guy, Jacky; Merusi, Cara; Koerner, Martha V; Bird, Adrian

    2016-02-01

    Rett syndrome is caused by mutations in the X-linked MECP2 gene, which encodes a chromosomal protein that binds to methylated DNA. Mouse models mirror the human disorder and therefore allow investigation of phenotypes at a molecular level. We describe an Mecp2 allelic series representing the three most common missense Rett syndrome (RTT) mutations, including first reports of Mecp2[R133C] and Mecp2[T158M] knock-in mice, in addition to Mecp2[R306C] mutant mice. Together these three alleles comprise ∼25% of all RTT mutations in humans, but they vary significantly in average severity. This spectrum is mimicked in the mouse models; R133C being least severe, T158M most severe and R306C of intermediate severity. Both R133C and T158M mutations cause compound phenotypes at the molecular level, combining compromised DNA binding with reduced stability, the destabilizing effect of T158M being more severe. Our findings contradict the hypothesis that the R133C mutation exclusively abolishes binding to hydroxymethylated DNA, as interactions with DNA containing methyl-CG, methyl-CA and hydroxymethyl-CA are all reduced in vivo. We find that MeCP2[T158M] is significantly less stable than MeCP2[R133C], which may account for the divergent clinical impact of the mutations. Overall, this allelic series recapitulates human RTT severity, reveals compound molecular aetiologies and provides a valuable resource in the search for personalized therapeutic interventions. © The Author 2015. Published by Oxford University Press.

  16. Fragile X-associated tremor/ataxia syndrome: another phenotype of the fragile X gene.

    Science.gov (United States)

    Hessl, David; Grigsby, Jim

    2016-08-01

    Neuropsychologists have an important role in evaluating patients with fragile X-associated disorders, but most practitioners are unaware of the recently identified neurodegenerative movement disorder known as fragile X-associated tremor ataxia syndrome (FXTAS). The objective of this editorial is to orient the reader to FXTAS and highlight the importance of clinical neuropsychology in describing the fragile X premutation phenotype and the role practitioners may have in assessing and monitoring patients with or at risk for neurodegeneration. We issued a call for papers for the special issue, highlighting the primary objective of familiarizing clinical neuropsychologists with FXTAS, and with the neuropsychological phenotype of both male and female asymptomatic carriers. Eight papers are included, including an overview of the fragile X-associated disorders (Grigsby), a review of the neuroradiological and neurological aspects of FXTAS and how the disorder compares to other movement disorders (O'Keefe et al.), a perspective on the prominence of white matter disease and dementia in FXTAS (Filley), and a review of mouse models of FXTAS (Foote). There are four research papers, including one on self-reported memory problems in FXTAS (Birch et al.), and three papers focused on the neuropsychiatric aspects of the fragile X premutation, a review (Bourgeois), an examination of autism-related traits (Schneider), and a research paper on executive functioning and psychopathology (Grigsby). The issue highlights the importance of awareness of fragile X-associated disorders for neuropsychologists, an awareness that must reach beyond neurodevelopmental aspects related to fragile X syndrome into the realm of neurodegenerative disease and aging.

  17. Risorse educative aperte e professione docente nell'era dell'accesso

    Directory of Open Access Journals (Sweden)

    Paolo Tosato

    2011-08-01

    Full Text Available L’uso di risorse educative aperte (Open Educational Resources-OER è stato indicato come una valida strategia per il rinnovo di modelli educativi centrati sui processi di apprendimento. In effetti, dopo la formalizzazione del concetto, realizzata dall’UNESCO, sia la sistematizzazione di modelli ed esperienze d’uso che la condivisione di risorse educative aperte sono cresciute in modo significativo. Tuttavia, questa nuova modalità di interazione richiede nuove competenze sull’uso e condivisione di conoscenza nel Web. Questo articolo introduce uno studio preliminare sulle conoscenze degli insegnanti riguardo il concetto di OER, all’interno della propria pratica professionale, nel contesto del progetto OER-UNIVIRTUA, del laboratorio UNIVIRTUAL e-Learning Technologies. L’analisi dei risultati emergenti crea la base per pensare ad un modello formativo che punti a colmare i gap di competenze degli insegnanti con riguardo all’implementazione di percorsi di educazione aperta nel contesto di pratica dell’insegnamento secondario.

  18. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias

    NARCIS (Netherlands)

    Schwartz, P. J.; Priori, S. G.; Spazzolini, C.; Moss, A. J.; Vincent, G. M.; Napolitano, C.; Denjoy, I.; Guicheney, P.; Breithardt, G.; Keating, M. T.; Towbin, J. A.; Beggs, A. H.; Brink, P.; Wilde, A. A.; Toivonen, L.; Zareba, W.; Robinson, J. L.; Timothy, K. W.; Corfield, V.; Wattanasirichaigoon, D.; Corbett, C.; Haverkamp, W.; Schulze-Bahr, E.; Lehmann, M. H.; Schwartz, K.; Coumel, P.; Bloise, R.

    2001-01-01

    The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary

  19. Genetic and phenotypic overlap of specific obsessive-compulsive and attention-deficit/hyperactive subtypes with Tourette syndrome

    NARCIS (Netherlands)

    Hirschtritt, M. E.; Darrow, S. M.; Illmann, C.; Osiecki, L.; Grados, M.; Sandor, P.; Dion, Y.; King, R. A.; Pauls, D.; Budman, C. L.; Cath, D. C.; Greenberg, E.; Lyon, G. J.; Yu, D.; McGrath, L. M.; McMahon, W. M.; Lee, P. C.; Delucchi, K. L.; Scharf, J. M.; Mathews, C. A.

    Background. The unique phenotypic and genetic aspects of obsessive-compulsive (OCD) and attention-deficit/hyperactivity disorder (ADHD) among individuals with Tourette syndrome (TS) are not well characterized. Here, we examine symptom patterns and heritability of OCD and ADHD in TS families. Method.

  20. Adapting Phonological Awareness Interventions for Children with Down Syndrome Based on the Behavioral Phenotype: A Promising Approach?

    Science.gov (United States)

    Lemons, Christopher J.; King, Seth A.; Davidson, Kimberly A.; Puranik, Cynthia S.; Fulmer, Deborah; Mrachko, Alicia A.; Partanen, Jane; Al Otaiba, Stephanie; Fidler, Deborah J.

    2015-01-01

    Many children with Down syndrome demonstrate deficits in phonological awareness, a prerequisite to learning to read in an alphabetic language. The purpose of this study was to determine whether adapting a commercially available phonological awareness program to better align with characteristics associated with the behavioral phenotype of Down…

  1. Evidence for a discrete behavioral phenotype in the oculocerebrorenal syndrome of Lowe

    Energy Technology Data Exchange (ETDEWEB)

    Kenworthy, L.; Charnas, L. [National Institute of Health, Bethesda, MD (United States)

    1995-11-20

    The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, cognitive impairment, and renal tubular dysfunction. Although there is a wide range of intellectual function in affected individuals, it is often compromised by a high prevalence of maladaptive behaviors, including tantrums, stubbornness, and stereotypy. Whether these behaviors simply reflect the multiple disabilities found in some developmentally impaired individuals with or without OCRL, or a specific genetically-determined behavioral phenotype of OCRL, is unknown. Controls were matched for sex, age, visual impairment, and adaptive functioning and compared with OCRL patients on three standardized measures of adaptive/maladaptive behaviors. Forty-three matched pairs of OCRL and control subjects were identified. Both groups were similar in communication, daily living, socialization, and motor skills, in socioeconomic status, and in measures of parental stress. Individuals with OCRL displayed significantly more severe maladaptive behaviors than control boys, as measured by the Vineland Adaptive Behavior Scales (VABS), with 41% of the difference between the two groups attributable to the diagnosis of OCRL. Twelve maladaptive behaviors measured on the VABS appeared more frequently in OCRL than in controls. Five of these 12 behaviors, i.e., temper tantrums, irritability, complex repetitive behaviors (stereotypy)/mannerisms, obsessions/unusual preoccupations, and negativism, were identified by discriminant function analysis to significantly distinguish between controls and OCRL individuals. The diagnosis of OCRL is associated with a behavioral phenotype consisting of temper tantrums, stereotypy, stubbornness, and obsessions/unusual preoccupations. This phenotype cannot be attributed solely to the visual, motor, and intellectual disabilities characteristic of OCRL, and may represent a specific effect of the OCRL gene on the central nervous system. 57 refs., 5 tabs.

  2. Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders.

    Science.gov (United States)

    Robertson, Erin E; Hall, Deborah A; McAsey, Andrew R; O'Keefe, Joan A

    2016-08-01

    The purpose of this paper is to review the typical cognitive and motor impairments seen in fragile X-associated tremor/ataxia syndrome (FXTAS), essential tremor (ET), Parkinson disease (PD), spinocerebellar ataxias (SCAs), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) in order to enhance diagnosis of FXTAS patients. We compared the cognitive and motor phenotypes of FXTAS with each of these other movement disorders. Relevant neuropathological and neuroimaging findings are also reviewed. Finally, we describe the differences in age of onset, disease severity, progression rates, and average lifespan in FXTAS compared to ET, PD, SCAs, MSA, and PSP. We conclude with a flow chart algorithm to guide the clinician in the differential diagnosis of FXTAS. By comparing the cognitive and motor phenotypes of FXTAS with the phenotypes of ET, PD, SCAs, MSA, and PSP we have clarified potential symptom overlap while elucidating factors that make these disorders unique from one another. In summary, the clinician should consider a FXTAS diagnosis and testing for the Fragile X mental retardation 1 (FMR1) gene premutation if a patient over the age of 50 (1) presents with cerebellar ataxia and/or intention tremor with mild parkinsonism, (2) has the middle cerebellar peduncle (MCP) sign, global cerebellar and cerebral atrophy, and/or subcortical white matter lesions on MRI, or (3) has a family history of fragile X related disorders, intellectual disability, autism, premature ovarian failure and has neurological signs consistent with FXTAS. Peripheral neuropathy, executive function deficits, anxiety, or depression are supportive of the diagnosis. Distinct profiles in the cognitive and motor domains between these movement disorders may guide practitioners in the differential diagnosis process and ultimately lead to better medical management of FXTAS patients.

  3. Identification of novel genetic causes of Rett syndrome-like phenotypes.

    Science.gov (United States)

    Lopes, Fátima; Barbosa, Mafalda; Ameur, Adam; Soares, Gabriela; de Sá, Joaquim; Dias, Ana Isabel; Oliveira, Guiomar; Cabral, Pedro; Temudo, Teresa; Calado, Eulália; Cruz, Isabel Fineza; Vieira, José Pedro; Oliveira, Renata; Esteves, Sofia; Sauer, Sascha; Jonasson, Inger; Syvänen, Ann-Christine; Gyllensten, Ulf; Pinto, Dalila; Maciel, Patrícia

    2016-03-01

    The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT. Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  4. Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects.

    Science.gov (United States)

    Varela, Monica Castro; Kok, Fernando; Otto, Paulo Alberto; Koiffmann, Celia Priszkulnik

    2004-12-01

    Angelman syndrome (AS) can result from either a 15q11-q13 deletion (del), paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. Here, we describe the phenotypic and behavioral variability detected in 49 patients with different classes of deletions and nine patients with UPD. Diagnosis was made by methylation pattern analysis of exon 1 of the SNRPN-SNURF gene and by microsatellite profiling of loci within and outside the 15q11-q13 region. There were no major phenotypic differences between the two main classes (BP1-BP3; BP2-BP3) of AS deletion patients, except for the absence of vocalization, more prevalent in patients with BP1-BP3 deletions, and for the age of sitting without support, which was lower in patients with BP2-BP3 deletions. Our data suggest that gene deletions (NIPA1, NIPA2, CYF1P1, GCP5) mapped to the region between breakpoints BP1 and BP2 may be involved in the severity of speech impairment, since all BP1-BP3 deletion patients showed complete absence of vocalization, while 38.1% of the BP2-BP3 deletion patients were able to pronounce syllabic sounds, with doubtful meaning. Compared to UPD patients, deletion patients presented a higher incidence of swallowing disorders (73.9% del x 22.2% UPD) and hypotonia (73.3% del x 28.57% UPD). In addition, children with UPD showed better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia and higher cognitive skills. As a consequence of their milder or less typical phenotype, AS may remain undiagnosed, leading to an overall underdiagnosis of the disease.

  5. An Extra X or Y Chromosome: Contrasting the Cognitive and Motor Phenotypes in Childhood in Boys with 47,XYY Syndrome or 47,XXY Klinefelter Syndrome

    Science.gov (United States)

    Ross, Judith L.; Zeger, Martha P. D.; Kushner, Harvey; Zinn, Andrew R.; Roeltgen, David P.

    2009-01-01

    Objective: The goal of this study was to contrast the cognitive phenotypes in boys with 47,XYY (XYY) karyotype and boys with 47,XXY karyotype [Klinefelter syndrome, (KS)], who share an extra copy of the X-Y pseudoautosomal region but differ in their dosage of strictly sex-linked genes. Methods: Neuropsychological evaluation of general cognitive…

  6. [Phenotypic and genetic analysis of a patient presented with Tietz/Waardenburg type II a syndrome].

    Science.gov (United States)

    Wang, Huanhuan; Tang, Lifang; Zhang, Jingmin; Hu, Qin; Chen, Yingwei; Xiao, Bing

    2015-08-01

    To determine the genetic cause for a patient featuring decreased pigmentation of the skin and iris, hearing loss and multiple congenital anomalies. Routine chromosomal banding was performed to analyze the karyotype of the patient and his parents. Single nucleotide polymorphism array (SNP array) was employed to identify cryptic chromosome aberrations, and quantitative real-time PCR was used to confirm the results. Karyotype analysis has revealed no obvious anomaly for the patient and his parents. SNP array analysis of the patient has demonstrated a 3.9 Mb deletion encompassing 3p13p14.1, which caused loss of entire MITF gene. The deletion was confirmed by quantitative real-time PCR. Clinical features of the patient have included severe bilateral hearing loss, decreased pigmentation of the skin and iris and multiple congenital anomalies. The patient, carrying a 3p13p14.1 deletion, has features of Tietz syndrome/Waardenburg syndrome type IIa. This case may provide additional data for the study of genotype-phenotype correlation of this disease.

  7. Sequence homology at the breakpoint and clinical phenotype of mitochondrial DNA deletion syndromes.

    Directory of Open Access Journals (Sweden)

    Bekim Sadikovic

    2010-12-01

    Full Text Available Mitochondrial DNA (mtDNA deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM, progressive external ophthalmoplegia (PEO, and Kearns-Sayre syndrome (KSS, to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH followed by PCR-sequencing of the deletion junctions. Sequence homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in sequence homology flanking the deletion compared to mtDNA background. The youngest patient group (<6 years old showed a diffused pattern of deletion distribution in size and locations, with a significantly lower sequence homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41. Only 15% (3/20 of the young patients (<6 years old carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17 exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, sequence homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of sequence homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier

  8. Sequence homology at the breakpoint and clinical phenotype of mitochondrial DNA deletion syndromes.

    Science.gov (United States)

    Sadikovic, Bekim; Wang, Jing; El-Hattab, Ayman W; Landsverk, Megan; Douglas, Ganka; Brundage, Ellen K; Craigen, William J; Schmitt, Eric S; Wong, Lee-Jun C

    2010-12-20

    Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in sequence homology flanking the deletion compared to mtDNA background. The youngest patient group (deletion distribution in size and locations, with a significantly lower sequence homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, sequence homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of sequence homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier onset and more severe disease with multisystem involvement.

  9. An inferential study of the phenotype for the chromosome 15q24 microdeletion syndrome: a bootstrap analysis.

    Science.gov (United States)

    Palazón-Bru, Antonio; Ramírez-Prado, Dolores; Cortés, Ernesto; Aguilar-Segura, María Soledad; Gil-Guillén, Vicente Francisco

    2016-01-01

    In January 2012, a review of the cases of chromosome 15q24 microdeletion syndrome was published. However, this study did not include inferential statistics. The aims of the present study were to update the literature search and calculate confidence intervals for the prevalence of each phenotype using bootstrap methodology. Published case reports of patients with the syndrome that included detailed information about breakpoints and phenotype were sought and 36 were included. Deletions in megabase (Mb) pairs were determined to calculate the size of the interstitial deletion of the phenotypes studied in 2012. To determine confidence intervals for the prevalence of the phenotype and the interstitial loss, we used bootstrap methodology. Using the bootstrap percentiles method, we found wide variability in the prevalence of the different phenotypes (3-100%). The mean interstitial deletion size was 2.72 Mb (95% CI [2.35-3.10 Mb]). In comparison with our work, which expanded the literature search by 45 months, there were differences in the prevalence of 17% of the phenotypes, indicating that more studies are needed to analyze this rare disease.

  10. Phenotype in girls and women with turner syndrome: Association between dysmorphic features, karyotype and cardio-aortic malformations.

    Science.gov (United States)

    Noordman, Iris; Duijnhouwer, Anthonie; Kapusta, Livia; Kempers, Marlies; Roeleveld, Nel; Schokking, Michiel; Smeets, Dominique; Freriks, Kim; Timmers, Henri; van Alfen-van der Velden, Janiëlle

    2018-01-12

    Turner syndrome (TS) is a genetic disorder characterized by the (partial) absence or a structural aberration of the second sex chromosome and is associated with a variety of phenotypes with specific physical features and cardio-aortic malformations. The objective of this study was to gain a better insight into the differences in dysmorphic features between girls and women with TS and to explore the association between these features, karyotype and cardio-aortic malformations. This prospective study investigated 14 dysmorphic features of TS girls and women using a checklist. Three major phenotypic patterns were recognized (severe phenotype, lymphatic phenotype and skeletal phenotype). Patient data including karyotype and cardio-aortic malformations (bicuspid aortic valve (BAV) and aortic coarctation (COA)) were collected. Associations between the prevalence of dysmorphic features, karyotype and cardio-aortic malformations were analysed using chi 2 -test and odds ratios. A total of 202 patients (84 girls and 118 women) were analysed prospectively. Differences in prevalence of dysmorphic features were found between girls and women. A strong association was found between monosomy 45,X and the phenotypic patterns. Furthermore, an association was found between COA and lymphatic phenotype, but no association was found between karyotype and cardio-aortic malformations. This study uncovered a difference in dysmorphic features between girls and women. Monosomy 45,X is associated with a more severe phenotype, lymphatic phenotype and skeletal phenotype. All patients with TS should be screened for cardio-aortic malformations, because in contrast to previous reports, karyotype and cardio-aortic malformations showed no significant association. Copyright © 2018. Published by Elsevier Masson SAS.

  11. Chediak-Higashi syndrome: description of two novel homozygous missense mutations causing divergent clinical phenotype.

    Science.gov (United States)

    Sánchez-Guiu, Isabel; Antón, Ana I; García-Barberá, Nuria; Navarro-Fernández, José; Martínez, Constantino; Fuster, Jose L; Couselo, Jose M; Ortuño, Francisco J; Vicente, Vicente; Rivera, Jose; Lozano, Maria L

    2014-01-01

    Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease resulting from mutations in the LYST/CHS1 gene, which encodes for a 429 kDa protein, CHS1/LYST, that regulates vesicle trafficking and determines the size of lysosomes and other organelles. To date, 60 different mutations have been characterized, and a reasonably straightforward phenotype-genotype correlation has been suggested. We describe two patients on opposite ends of the CHS clinical spectrum with novel missense mutations. We characterized these patients in terms of their mutations, protein localization and expression, mRNA stability, and electrostatic potential. Patient 1 is the first report of a severe early-onset CHS with a homozygous missense mutation (c.11362 G>A, p.G3725R) in the LYST/CHS1 gene. This molecular change results in a reduction at the CHS1 protein level, not due to an mRNA effect, but maybe a consequence of both, a change in the structure of the protein and most likely attributable to the remarkable serious perturbation in the electrostatic potential. Patient 2, who exhibited the adolescence form of the disease, was found to be homozygous for a novel missense mutation c.961 T>C, p.C258R, which seemed to have minor effect on the structure of the CHS1/LYST protein. Reexamining accepted premises of missense mutant alleles being reported among patients with clinically mild forms of the disorder should be carried out, and attempts to link genotype and clinical phenotype require identifying the actual molecular effect of the mutation. Early and accurate diagnosis of the severity of the disease is extremely important to early differentiate patients who would benefit from premature enrollment into a transplantation protocol. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Prevalence and Phenotype of Sleep Disorders in 60 Adults With Prader-Willi Syndrome.

    Science.gov (United States)

    Ghergan, Adelina; Coupaye, Muriel; Leu-Semenescu, Smaranda; Attali, Valérie; Oppert, Jean-Michel; Arnulf, Isabelle; Poitou, Christine; Redolfi, Stefania

    2017-12-01

    Excessive sleepiness is a common symptom in Prader-Willi syndrome (PWS), and it negatively impacts the quality of life. Obstructive sleep apnea and narcolepsy phenotypes have been reported in PWS. We characterized sleep disorders in a large cohort of adults with PWS. All consecutive patients with genetically confirmed PWS unselected for sleep-related symptoms, underwent a clinical interview, polysomnography, and multiple sleep latency tests (MSLT, n = 60), followed by long-term (24 hours) polysomnography (n = 22/60). Among 60 adults evaluated (57% female, aged 25 ± 10 years, body mass index: 39 ± 12 kg/m2), 67% reported excessive sleepiness. According to the sleep study results, 43% had a previously unrecognized hypersomnia disorder, 15% had an isolated sleep breathing disorder, 12% had combined hypersomnia disorder and untreated breathing sleep disorder, and only 30% had normal sleep. Isolated hypersomnia disorder included narcolepsy in 35% (type 1, n = 1, and type 2, n = 8), hypersomnia in 12% (total sleep time >11 hours, n = 2, and MSLT sleep onset in REM periods and MSLT >8 minutes, n = 10, and 8 minutes Sleep breathing disorders, isolated and combined, included obstructive sleep apnea (n = 14, already treated in seven), sleep hypoxemia (n = 1) and previously undiagnosed hypoventilation (n = 5). Modafinil was taken by 16 patients (well tolerated in 10), resulting in improved sleepiness over a mean 5-year follow-up period. Sleepiness affects more than half of adult patients with PWS, with a variety of hypersomnia disorder (narcolepsy, hypersomnia, and borderline phenotypes) and breathing sleep disorders. Earlier diagnosis and management of sleep disorders may improve sleepiness, cognition, and behavior in these patients. © Sleep Research Society 2017. Published by Oxford University Press [on behalf of the Sleep Research Society]. All rights reserved. For permissions, please email: journals.permissions@oup.com

  13. PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

    Science.gov (United States)

    Reijnders, Margot R F; Janowski, Robert; Alvi, Mohsan; Self, Jay E; van Essen, Ton J; Vreeburg, Maaike; Rouhl, Rob P W; Stevens, Servi J C; Stegmann, Alexander P A; Schieving, Jolanda; Pfundt, Rolph; van Dijk, Katinke; Smeets, Eric; Stumpel, Connie T R M; Bok, Levinus A; Cobben, Jan Maarten; Engelen, Marc; Mansour, Sahar; Whiteford, Margo; Chandler, Kate E; Douzgou, Sofia; Cooper, Nicola S; Tan, Ene-Choo; Foo, Roger; Lai, Angeline H M; Rankin, Julia; Green, Andrew; Lönnqvist, Tuula; Isohanni, Pirjo; Williams, Shelley; Ruhoy, Ilene; Carvalho, Karen S; Dowling, James J; Lev, Dorit L; Sterbova, Katalin; Lassuthova, Petra; Neupauerová, Jana; Waugh, Jeff L; Keros, Sotirios; Clayton-Smith, Jill; Smithson, Sarah F; Brunner, Han G; van Hoeckel, Ceciel; Anderson, Mel; Clowes, Virginia E; Siu, Victoria Mok; DDD study, The; Selber, Paulo; Leventer, Richard J; Nellaker, Christoffer; Niessing, Dierk; Hunt, David; Baralle, Diana

    2018-01-01

    Background De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. Objectives To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. Methods Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. Results We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. Conclusion We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and

  14. Phenotype and polyp landscape in serrated polyposis syndrome: a series of 100 patients from genetics clinics.

    Science.gov (United States)

    Rosty, Christophe; Buchanan, Daniel D; Walsh, Michael D; Pearson, Sally-Ann; Pavluk, Erika; Walters, Rhiannon J; Clendenning, Mark; Spring, Kevin J; Jenkins, Mark A; Win, Aung K; Hopper, John L; Sweet, Kevin; Frankel, Wendy L; Aronson, Melyssa; Gallinger, Steve; Goldblatt, Jack; Woodall, Sonja; Arnold, Julie; Walker, Neal I; Jass, Jeremy R; Parry, Susan; Young, Joanne P

    2012-06-01

    Serrated polyposis syndrome (SPS), also known as hyperplastic polyposis, is a syndrome of unknown genetic basis defined by the occurrence of multiple serrated polyps in the large intestine and associated with an increased risk of colorectal cancer (CRC). There are a variety of SPS presentations, which may encompass a continuum of phenotypes modified by environmental and genetic factors. To explore the phenotype of SPS, we recorded the histologic and molecular characteristics of multiple colorectal polyps in patients with SPS recruited between 2000 and 2010 from genetics clinics in Australia, New Zealand, Canada, and the United States. Three specialist gastrointestinal pathologists reviewed the polyps, which they classified into conventional adenomas or serrated polyps, with various subtypes, according to the current World Health Organization criteria. Mutations in BRAF and KRAS and mismatch repair protein expression were determined in a subset of polyps. A total of 100 patients were selected for the study, of whom 58 were female and 42 were male. The total polyp count per patient ranged from 6 to 150 (median 30). The vast majority of patients (89%) had polyposis affecting the entire large intestine. From this cohort, 406 polyps were reviewed. Most of the polyps (83%) were serrated polyps: microvesicular hyperplastic polyps (HP) (n=156), goblet cell HP (n=25), sessile serrated adenoma/polyps (SSA/P) (n=110), SSA/P with cytologic dysplasia (n=28), and traditional serrated adenomas (n=18). A further 69 polyps were conventional adenomas. BRAF mutation was mainly detected in SSA/P with dysplasia (95%), SSA/P (85%), microvesicular HP (76%), and traditional serrated adenoma (54%), whereas KRAS mutation was present mainly in goblet cell HP (50%) and in tubulovillous adenoma (45%). Four of 6 SSA/Ps with high-grade dysplasia showed loss of MLH1/PMS2 expression. CRC was diagnosed in 39 patients who were more often found to have a conventional adenoma compared with patients

  15. A new syndrome: multiple congenital abnormalities and mental retardation in two brothers.

    Science.gov (United States)

    Dundar, M; Ozdemir, S Y; Fryns, J P

    2012-01-01

    In this report we present two brothers with abnormal neurological development, hypotonia, short stature, pylorus stenosis, pectus excavatum, brachycephaly due to craniosynostosis, frontal bossing, depressed nasal bridge, high arched-wide palate, downslant palpebral fissures, low-set, large ears, thin upper lip and bilateral cryptorchidism. The brothers were born to a couple of second cousins and were the third and fourth pregnancies of the mother. The father, the mother and the eldest sibling were phenotypically and chromosomally normal. The clinical findings of the brothers were found to be similar. These clinical findings were compared with syndromes showing some of the symptoms, namely Apert, FG, Floating-Harbor, Shprintzen-Goldberg and Rett Syndromes. However, when the findings were detailed, we observed that they did not match completely any of the syndromes in a discernable way. The MECP2 gene mutation was analysed because of mental retardation, poor neurological evolution and large ears, but no mutation was found. So these cases are presented as a new syndrome with apparent autosomal recessive inheritance.

  16. Chronic granulomatous disease, the McLeod phenotype and the contiguous gene deletion syndrome-a review

    Directory of Open Access Journals (Sweden)

    Watkins Casey E

    2011-11-01

    Full Text Available Abstract Chronic Granulomatous Disease (CGD, a disorder of the NADPH oxidase system, results in phagocyte functional defects and subsequent infections with bacterial and fungal pathogens (such as Aspergillus species and Candida albicans. Deletions and missense, frameshift, or nonsense mutations in the gp91phox gene (also termed CYBB, located in the Xp21.1 region of the X chromosome, are associated with the most common form of CGD. When larger X-chromosomal deletions occur, including the XK gene deletion, a so-called "Contiguous Gene Deletion Syndrome" may result. The contiguous gene deletion syndrome is known to associate the Kell phenotype/McLeod syndrome with diseases such as X-linked chronic granulomatous disease, Duchenne muscular dystrophy, and X-linked retinitis pigmentosa. These patients are often complicated and management requires special attention to the various facets of the syndrome.

  17. Lyme Disease Diagnosed by Alternative Methods: A Phenotype Similar to That of Chronic Fatigue Syndrome.

    Science.gov (United States)

    Patrick, David M; Miller, Ruth R; Gardy, Jennifer L; Parker, Shoshana M; Morshed, Muhammad G; Steiner, Theodore S; Singer, Joel; Shojania, Kam; Tang, Patrick

    2015-10-01

    A subset of patients reporting a diagnosis of Lyme disease can be described as having alternatively diagnosed chronic Lyme syndrome (ADCLS), in which diagnosis is based on laboratory results from a nonreference Lyme specialty laboratory using in-house criteria. Patients with ADCLS report symptoms similar to those reported by patients with chronic fatigue syndrome (CFS). We performed a case-control study comparing patients with ADCLS and CFS to each other and to both healthy controls and controls with systemic lupus erythematosus (SLE). Subjects completed a history, physical exam, screening laboratory tests, 7 functional scales, reference serology for Lyme disease using Centers for Disease Control and Prevention criteria, reference serology for other tick-associated pathogens, and cytokine expression studies. The study enrolled 13 patients with ADCLS (12 of whom were diagnosed by 1 alternative US laboratory), 25 patients with CFS, 25 matched healthy controls, and 11 SLE controls. Baseline clinical data and functional scales indicate significant disability among ADCLS and CFS patients and many important differences between these groups and controls, but no significant differences between each other. No ADCLS patient was confirmed as having positive Lyme serology by reference laboratory testing, and there was no difference in distribution of positive serology for other tick-transmitted pathogens or cytokine expression across the groups. In British Columbia, a setting with low Lyme disease incidence, ADCLS patients have a similar phenotype to that of CFS patients. Disagreement between alternative and reference laboratory Lyme testing results in this setting is most likely explained by false-positive results from the alternative laboratory. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  18. A new structural rearrangement associated to Wolfram syndrome in a child with a partial phenotype.

    Science.gov (United States)

    Elli, Francesca M; Ghirardello, Stefano; Giavoli, Claudia; Gangi, Silvana; Dioni, Laura; Crippa, Milena; Finelli, Palma; Bergamaschi, Silvia; Mosca, Fabio; Spada, Anna; Beck-Peccoz, Paolo

    2012-11-01

    Wolfram syndrome (WS) is a rare autosomal recessive disorder characterized by diabetes insipidus (DI), insulin-dependent diabetes mellitus (DM), optic atrophy (OA) and deafness caused by mutations in WFS1 gene (4p16.1), which encodes an endoplasmic reticulum protein, called Wolframin. We describe the case of an infant who presented hypernatremia and severe hypoplasia of the left eyeball with alteration of visual evoked potentials. Persistent hypernatremia, iposmolar polyuria and high plasma osmolality suggested DI, confirmed by a normal urine concentration after vasopressin test. Treatment with vasopressin allowed a normalization of sodium levels and urine output. Brain magnetic resonance imaging showed absence of the neurohypophysis hyperintense signal, normal adenohypophysis and optic tracts hypoplasia. The concomitant presence of DI and OA, even in the absence of DM and deafness, prompted the suspicion of WS and complete genetic analysis was performed. Genomic DNA sequencing of WFS1 showed no inactivating mutations described to date, but suggested a structural mutation as markers genotyping revealed a segmental paternal heterodisomy involving the upstream regulatory region (promoter and 5'UTR). cDNA sequencing revealed the coexistence of the wild-type transcript and two splice variants; one variant, probably benign, is known in literature and the other one causes the loss of exon 2, containing the translation initiation site. Western blot confirmed a marked protein reduction. During the clinical follow-up child's condition remained stable and glucose metabolism is still in the standard. In conclusion, the phenotype associated with this structural rearrangement, which substantially reduces the synthesis of Wolframin, confirms a tissue-specific pattern of expression of WFS1, suggests the presence of a different protein dosage sensitivity in different tissues and could be causative of DI and OA in our patient. The "incomplete" phenotype here described, usually

  19. Repint of "Reframing autism as a behavioral syndrome and not a specific mental disorder: Implications of genetic and phenotypic heterogeneity".

    Science.gov (United States)

    Tordjman, S; Cohen, D; Anderson, G M; Botbol, M; Canitano, R; Coulon, N; Roubertoux, P L

    2018-06-01

    Clinical and molecular genetics have advanced current knowledge on genetic disorders associated with autism. A review of diverse genetic disorders associated with autism is presented and for the first time discussed extensively with regard to possible common underlying mechanisms leading to a similar cognitive-behavioral phenotype of autism. The possible role of interactions between genetic and environmental factors, including epigenetic mechanisms, is in particular examined. Finally, the pertinence of distinguishing non-syndromic autism (isolated autism) from syndromic autism (autism associated with genetic disorders) will be reconsidered. Given the high genetic and etiological heterogeneity of autism, autism can be viewed as a behavioral syndrome related to known genetic disorders (syndromic autism) or currently unknown disorders (apparent non-syndromic autism), rather than a specific categorical mental disorder. It highlights the need to study autism phenotype and developmental trajectory through a multidimensional, non-categorical approach with multivariate analyses within autism spectrum disorder but also across mental disorders, and to conduct systematically clinical genetic examination searching for genetic disorders in all individuals (children but also adults) with autism. Copyright © 2018. Published by Elsevier Ltd.

  20. Reframing autism as a behavioral syndrome and not a specific mental disorder: Implications of genetic and phenotypic heterogeneity.

    Science.gov (United States)

    Tordjman, S; Cohen, D; Coulon, N; Anderson, G M; Botbol, M; Canitano, R; Roubertoux, P L

    2017-01-30

    Clinical and molecular genetics have advanced current knowledge on genetic disorders associated with autism. A review of diverse genetic disorders associated with autism is presented and for the first time discussed extensively with regard to possible common underlying mechanisms leading to a similar cognitive-behavioral phenotype of autism. The possible role of interactions between genetic and environmental factors, including epigenetic mechanisms, is in particular examined. Finally, the pertinence of distinguishing non-syndromic autism (isolated autism) from syndromic autism (autism associated with genetic disorders) will be reconsidered. Given the high genetic and etiological heterogeneity of autism, autism can be viewed as a behavioral syndrome related to known genetic disorders (syndromic autism) or currently unknown disorders (apparent non-syndromic autism), rather than a specific categorical mental disorder. It highlights the need to study autism phenotype and developmental trajectory through a multidimensional, non-categorical approach with multivariate analyses within autism spectrum disorder but also across mental disorders, and to conduct systematically clinical genetic examination searching for genetic disorders in all individuals (children but also adults) with autism. Copyright © 2017. Published by Elsevier Ltd.

  1. NIPBL rearrangements in Cornelia de Lange syndrome: evidence for replicative mechanism and genotype–phenotype correlation

    Science.gov (United States)

    Pehlivan, Davut; Hullings, Melanie; Carvalho, Claudia M.B.; Gonzaga-Jauregui, Claudia G.; Loy, Elizabeth; Jackson, Laird G.; Krantz, Ian D.; Deardorff, Matthew A.; Lupski, James R.

    2013-01-01

    Purpose Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder characterized by mental retardation, limb abnormalities, distinctive facial features, and hirsutism. Mutations in three genes involved in sister chromatid cohesion, NIPBL, SMC1A, and SMC3, account for ~55% of CdLS cases. The molecular etiology of a significant fraction of CdLS cases remains unknown. We hypothesized that large genomic rearrangements of cohesin complex subunit genes may play a role in the molecular etiology of this disorder. Methods Custom high-resolution oligonucleotide array comparative genomic hybridization analyses interrogating candidate cohesin genes and breakpoint junction sequencing of identified genomic variants were performed. Results Of the 162 patients with CdLS, for whom mutations in known CdLS genes were previously negative by sequencing, deletions containing NIPBL exons were observed in 7 subjects (~5%). Breakpoint sequences in five patients implicated microhomology-mediated replicative mechanisms—such as serial replication slippage and fork stalling and template switching/microhomology-mediated break-induced replication—as a potential predominant contributor to these copy number variations. Most deletions are predicted to result in haploinsuflciency due to heterozygous loss-of-function mutations; such mutations may result in a more severe CdLS phenotype. Conclusion Our findings suggest a potential clinical utility to testing for copy number variations involving NIPBL when clinically diagnosed CdLS cases are mutation-negative by DNA-sequencing studies. PMID:22241092

  2. Expanding the phenotypic spectrum in EP300-related Rubinstein-Taybi syndrome.

    Science.gov (United States)

    Solomon, Benjamin D; Bodian, Dale L; Khromykh, Alina; Mora, Gabriela Gomez; Lanpher, Brendan C; Iyer, Ramaswamy K; Baveja, Rajiv; Vockley, Joseph G; Niederhuber, John E

    2015-05-01

    Rubinstein-Taybi syndrome (RSTS) can be caused by heterozygous mutations or deletions involving CREBBP or, less commonly, EP300. To date, only 15 patients with EP300 mutations have been clinically described. Frequently reported manifestations in these patients include characteristic facial and limb features, varying degrees of neurocognitive dysfunction, and maternal preeclampsia. Other congenital anomalies are less frequently reported. We describe a child found to have a de novo EP300 mutation (c.4933C>T, predicted to result in p.Arg1645X) through research-based whole-genome sequencing of the family trio. The child's presentation involved dysmorphic features as well as unilateral renal agenesis, a myelomeningocele, and minor genitourinary anomalies. The involvement of congenital anomalies in all 16 clinically described patients with EP300 mutations (25% of which have been identified by "hypothesis free" methods, including microarray, exome, and whole-genome sequencing) is reviewed. In summary, genitourinary anomalies have been identified in 38%, cardiovascular anomalies in 25%, spinal/vertebral anomalies in 19%, other skeletal anomalies in 19%, brain anomalies in 13%, and renal anomalies in 6%. Our patient expands the phenotypic spectrum in EP300-related RSTS; this case demonstrates the evolving practice of clinical genomics related to increasing availability of genomic sequencing methods. © 2015 Wiley Periodicals, Inc.

  3. Mild Angelman syndrome phenotype due to a mosaic methylation imprinting defect.

    Science.gov (United States)

    Fairbrother, Laura C; Cytrynbaum, Cheryl; Boutis, Paula; Buiting, Karin; Weksberg, Rosanna; Williams, Charles

    2015-07-01

    Angelman syndrome (AS) is a neurogenetic disorder causing severe to profound intellectual disability, absent or very limited speech and a high risk for seizures. AS is caused by a loss of function of the maternally-derived UBE3A allele due to one of several mechanisms including imprinting defects (ImpDs). We present a girl with AS due to a mosaic ImpD who has relatively high developmental function (VABS-II composite score of 76) and communication skills (as demonstrated in supplemental video links). Given the patient's relatively mild developmental impairment, without clinical evidence of seizures, gait disturbance or inappropriate laughter, the diagnosis of AS was not initially suspected. Initial laboratory testing for AS was inconclusive but additional studies suggested mosaic ImpD and characteristic EEG findings provided further support for the clinical diagnosis. Our patient, along with other case reports of children with AS and relatively mild phenotypes, raises the question as to whether there exists an undiagnosed group of individuals with mild intellectual disability and expressive speech delays due to mosaic methylation defects of the chromosome 15q11.2-13 region. Population studies may be needed to determine if such an undiagnosed group exists. © 2015 Wiley Periodicals, Inc.

  4. Arrhythmia phenotype during fetal life suggests long-QT syndrome genotype: risk stratification of perinatal long-QT syndrome.

    Science.gov (United States)

    Cuneo, Bettina F; Etheridge, Susan P; Horigome, Hitoshi; Sallee, Denver; Moon-Grady, Anita; Weng, Hsin-Yi; Ackerman, Michael J; Benson, D Woodrow

    2013-10-01

    Fetal arrhythmias characteristic of long QT syndrome (LQTS) include torsades de pointes (TdP) and/or 2° atrioventricular block, but sinus bradycardia, defined as fetal heart ratearrhythmias were reviewed. Fetal echocardiograms, neonatal ECG, and genetic testing were evaluated. We studied 43 subjects exhibiting fetal LQTS arrhythmias: TdP±2° atrioventricular block (group 1, n=7), isolated 2° atrioventricular block (group 2, n=4), and sinus bradycardia (group 3, n=32). Mutations in known LQTS genes were found in 95% of subjects tested. SCN5A mutations occurred in 71% of group 1, whereas 91% of subjects with KCNQ1 mutations were in group 3. Small numbers of subjects with KCNH2 mutations (n=4) were scattered in all 3 groups. Age at presentation did not differ among groups, and most subjects (n=42) were live-born with gestational ages of 37.5±2.8 weeks (mean±SD). However, those with TdP were typically delivered earlier. Prenatal treatment in group 1 terminated (n=2) or improved (n=4) TdP. The neonatal heart rate-corrected QT interval (mean±SE) of group 1 (664.7±24.9) was longer than neonatal heart rate-corrected QT interval in both group 2 (491.2±27.6; P=0.004) and group 3 (483.1±13.7; Pneonatal TdP. Rhythm phenotypes of fetal LQTS have genotype-suggestive features that, along with heart rate-corrected QT interval duration, may risk stratify perinatal management.

  5. Novel TTC37 Mutations in a Patient with Immunodeficiency without Diarrhea: Extending the Phenotype of Trichohepatoenteric Syndrome.

    Directory of Open Access Journals (Sweden)

    Nicholas L Rider

    2015-01-01

    Full Text Available Unbiased genetic diagnosis has increasingly associated seemingly unrelated somatic and immunological phenotypes. We report a male infant who presented within the first year of life with physical growth impairment, feeding difficulties, hyperemesis without diarrhea, and abnormal hair findings suggestive of trichorrhexis nodosa. With advancing age, moderate global developmental delay, susceptibility to frequent viral illnesses, otitis media and purulent conjunctivitis were identified. Because of the repeated infections an immunological evaluation was pursued and identified impaired antibody memory responses following pneumococcal vaccine administration. Immunoglobulin replacement therapy and nutritional support were employed as mainstays of therapy. The child is now aged 12 years and still without diarrhea. Whole exome sequencing identified compound heterozygous mutations in the TTC37 gene, a known cause of the Trichohepatoenteric Syndrome (THES. This case extends the known phenotype of THES and defines a potential subset for inclusion as an immune overlap syndrome.

  6. Prospective study of autism phenomenology and the behavioural phenotype of Phelan-McDermid syndrome: comparison to fragile X syndrome, Down syndrome and idiopathic autism spectrum disorder.

    Science.gov (United States)

    Richards, Caroline; Powis, Laurie; Moss, Jo; Stinton, Christopher; Nelson, Lisa; Oliver, Christopher

    2017-11-10

    The limited behavioural phenotype literature on Phelan-McDermid syndrome (PMS) indicates atypically high levels of activity, impulsivity and autism spectrum disorder (ASD) behaviours. Divergent profiles of ASD in PMS are also reported, with some studies demonstrating similarities to idiopathic ASD and others indicating an uneven profile of social and communication impairments and repetitive behaviours. An evaluation of the behavioural phenotype of PMS and the prevalence and phenomenology of ASD is warranted, particularly given the causal involvement of the SHANK3 gene in the aetiology of PMS. Carers of individuals with PMS (N = 30; mean age = 10.55, SD = 7.08) completed questionnaires relating to impulsivity, overactivity, mood, interest and pleasure, repetitive behaviour and ASD phenomenology. These data were compared to data from matched samples of individuals with fragile X and Down syndromes and idiopathic ASD. In order to evaluate the profile of ASD phenomenology in PMS, two comparisons were made: first, including the total sample with PMS, and second, including only those who met the threshold indicative of autism on an ASD screening measure. The results revealed lower mood in individuals with PMS, but no differences in impulsivity and overactivity. Compulsive and routine-driven repetitive behaviours were less common in the total sample with PMS; however, motor-based stereotyped behaviours were more common. ASD phenomenology was highly prevalent, with 87% of the sample meeting the cutoff score for ASD and 57% meeting the cutoff for autism. The profile of ASD phenomenology in the total sample with PMS differed from those with idiopathic ASD across impairments in communication and social interaction and repetitive behaviour. However, the profile of those who met the threshold for autism was commensurate to those with idiopathic ASD. ASD phenomenology is common within PMS. Whilst the total sample may display an atypical profile of ASD behaviour, the profile

  7. SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies.

    Science.gov (United States)

    Bissay, Véronique; Van Malderen, Sophie C H; Keymolen, Kathelijn; Lissens, Willy; Peeters, Uschi; Daneels, Dorien; Jansen, Anna C; Pappaert, Gudrun; Brugada, Pedro; De Keyser, Jacques; Van Dooren, Sonia

    2016-03-01

    SCN5A mutations involving the α-subunit of the cardiac voltage-gated muscle sodium channel (NaV1.5) result in different cardiac channelopathies with an autosomal-dominant inheritance such as Brugada syndrome. On the other hand, mutations in SCN4A encoding the α-subunit of the skeletal voltage-gated sodium channel (NaV1.4) cause non-dystrophic myotonia and/or periodic paralysis. In this study, we investigated whether cardiac arrhythmias or channelopathies such as Brugada syndrome can be part of the clinical phenotype associated with SCN4A variants and whether patients with Brugada syndrome present with non-dystrophic myotonia or periodic paralysis and related gene mutations. We therefore screened seven families with different SCN4A variants and non-dystrophic myotonia phenotypes for Brugada syndrome and performed a neurological, neurophysiological and genetic work-up in 107 Brugada families. In the families with an SCN4A-associated non-dystrophic myotonia, three patients had a clinical diagnosis of Brugada syndrome, whereas we found a remarkably high prevalence of myotonic features involving different genes in the families with Brugada syndrome. One Brugada family carried an SCN4A variant that is predicted to probably affect function, one family suffered from a not genetically confirmed non-dystrophic myotonia, one family was diagnosed with myotonic dystrophy (DMPK gene) and one family had a Thomsen disease myotonia congenita (CLCN1 variant that affects function). Our findings and data suggest a possible involvement of SCN4A variants in the pathophysiological mechanism underlying the development of a spontaneous or drug-induced type 1 electrocardiographic pattern and the occurrence of malignant arrhythmias in some patients with Brugada syndrome.

  8. 14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype

    Science.gov (United States)

    Ellaway, Carolyn J; Ho, Gladys; Bettella, Elisa; Knapman, Alisa; Collins, Felicity; Hackett, Anna; McKenzie, Fiona; Darmanian, Artur; Peters, Gregory B; Fagan, Kerry; Christodoulou, John

    2013-01-01

    Rett syndrome is a clinically defined neurodevelopmental disorder almost exclusively affecting females. Usually sporadic, Rett syndrome is caused by mutations in the X-linked MECP2 gene in ∼90–95% of classic cases and 40–60% of individuals with atypical Rett syndrome. Mutations in the CDKL5 gene have been associated with the early-onset seizure variant of Rett syndrome and mutations in FOXG1 have been associated with the congenital Rett syndrome variant. We report the clinical features and array CGH findings of three atypical Rett syndrome patients who had severe intellectual impairment, early-onset developmental delay, postnatal microcephaly and hypotonia. In addition, the females had a seizure disorder, agenesis of the corpus callosum and subtle dysmorphism. All three were found to have an interstitial deletion of 14q12. The deleted region in common included the PRKD1 gene but not the FOXG1 gene. Gene expression analysis suggested a decrease in FOXG1 levels in two of the patients. Screening of 32 atypical Rett syndrome patients did not identify any pathogenic mutations in the PRKD1 gene, although a previously reported frameshift mutation affecting FOXG1 (c.256dupC, p.Gln86ProfsX35) was identified in a patient with the congenital Rett syndrome variant. There is phenotypic overlap between congenital Rett syndrome variants with FOXG1 mutations and the clinical presentation of our three patients with this 14q12 microdeletion, not encompassing the FOXG1 gene. We propose that the primary defect in these patients is misregulation of the FOXG1 gene rather than a primary abnormality of PRKD1. PMID:22968132

  9. Pendred syndrome in two Galician families: insights into clinical phenotypes through cellular, genetic, and molecular studies.

    Science.gov (United States)

    Palos, Fernando; García-Rendueles, María E R; Araujo-Vilar, David; Obregon, Maria Jesús; Calvo, Rosa Maria; Cameselle-Teijeiro, Jose; Bravo, Susana B; Perez-Guerra, Oscar; Loidi, Lourdes; Czarnocka, Barbara; Alvarez, Paula; Refetoff, Samuel; Dominguez-Gerpe, Lourdes; Alvarez, Clara V; Lado-Abeal, Joaquin

    2008-01-01

    We studied two families from Galicia (northwest Spain) with Pendred syndrome (PS) and unusual thyroid phenotypes. In family A, the proposita had a large goiter and hypothyroxinemia but normal TSH and free T3 (FT3). In family B, some affected members showed deafness but not goiter. Our objective was to identify the mutations causing PS and molecular mechanisms underlying the thyroid phenotypes. Interventions included extraction of DNA and of thyroid tissue. Propositi and 10 members of the two families participated in the study. Main outcome measures included SLC26A4 gene analysis, deiodinase activities in thyroid tissue, and c.416-1G-->A effects on SLC26A4 splicing. In addition, a primary PS thyrocyte culture, T-PS2, was obtained from propositus B and compared with another culture of normal human thyrocytes, NT, by Western blotting, confocal microscopy, and iodine uptake kinetics. Proposita A was heterozygous for c.578C-->T and c.279delT, presented with goiter, and had normal TSH and FT3 but low FT4 attributable to high type 1 and type 2 iodothyronine deiodinase activities in the goiter. Propositus B bore c.279delT and a novel mutation c.416-1G-->A; some deaf relatives were homozygous for c.416-1G-->A but did not present goiter. The c.279delT mutation was associated with identical haplotype in the two families. T-PS2 showed truncated pendrin retained intracellularly and high iodine uptake with low efflux leading to iodine retention. c.279delT is a founder mutation in Galicia. Proposita A adapted to poor organification by increasing deiodinase activities in the goiter, avoiding hypothyroidism. Lack of goiter in subjects homozygous for c.416-1G-->A was due to incomplete penetrance allowing synthesis of some wild-type pendrin. Intracellular iodine retention, as seen in T-PS2, could play a role in thyroid alterations in PS.

  10. Lennox-Gastaut syndrome of unknown cause: phenotypic characteristics of patients in the Epilepsy Phenome/Genome Project.

    Science.gov (United States)

    Widdess-Walsh, Peter; Dlugos, Dennis; Fahlstrom, Robyn; Joshi, Sucheta; Shellhaas, Renée; Boro, Alex; Sullivan, Joseph; Geller, Eric

    2013-11-01

    Lennox-Gastaut syndrome (LGS) is a devastating childhood-onset epilepsy syndrome. The cause is unknown in 25% of cases. Little has been described about the specific clinical or electroencephalography (EEG) features of LGS of unknown or genetic cause (LGS(u)). The Epilepsy Phenome/Genome Project (EPGP) aims to characterize LGS(u) by phenotypic analysis of patients with LGS(u) and their parents. One hundred thirty-five patients with LGS with no known etiology and their parents were enrolled from 19 EPGP centers in the United States and Australia. Clinical data from medical records, standardized questionnaires, imaging, and EEG were collected with use of online informatics systems developed for EPGP. LGS(u) in the EPGP cohort had a broad range of onset of epilepsy from 1 to 13 years, was male predominant (p syndrome. LGS(u) has distinctive characteristics including a broad age range of onset, male predominance, and often normal development prior to the onset of seizures. Cognitive achievements such as completion of secondary school were possible in half of adult patients. Our phenotypic description of LGS(u) coupled with future genetic studies will advance our understanding of this epilepsy syndrome. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

  11. Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype.

    Science.gov (United States)

    de Heredia, Miguel López; Clèries, Ramón; Nunes, Virginia

    2013-07-01

    Wolfram syndrome is a degenerative, recessive rare disease with an onset in childhood. It is caused by mutations in WFS1 or CISD2 genes. More than 200 different variations in WFS1 have been described in patients with Wolfram syndrome, which complicates the establishment of clear genotype-phenotype correlation. The purpose of this study was to elucidate the role of WFS1 mutations and update the natural history of the disease. This study analyzed clinical and genetic data of 412 patients with Wolfram syndrome published in the last 15 years. (i) 15% of published patients do not fulfill the current -inclusion criterion; (ii) genotypic prevalence differences may exist among countries; (iii) diabetes mellitus and optic atrophy might not be the first two clinical features in some patients; (iv) mutations are nonuniformly distributed in WFS1; (v) age at onset of diabetes mellitus, hearing defects, and diabetes insipidus may depend on the patient's genotypic class; and (vi) disease progression rate might depend on genotypic class. New genotype-phenotype correlations were established, disease progression rate for the general population and for the genotypic classes has been calculated, and new diagnostic criteria have been proposed. The conclusions raised could be important for patient management and counseling as well as for the development of treatments for Wolfram syndrome.

  12. Clinical and Molecular Phenotype of Aicardi-Goutières Syndrome

    Science.gov (United States)

    Rice, Gillian ; Patrick, Teresa ; Parmar, Rekha ; Taylor, Claire F. ; Aeby, Alec ; Aicardi, Jean ; Artuch, Rafael ; Montalto, Simon Attard ; Bacino, Carlos A. ; Barroso, Bruno ; Baxter, Peter ; Benko, Willam S. ; Bergmann, Carsten ; Bertini, Enrico ; Biancheri, Roberta ; Blair, Edward M. ; Blau, Nenad ; Bonthron, David T. ; Briggs, Tracy ; Brueton, Louise A. ; Brunner, Han G. ; Burke, Christopher J. ; Carr, Ian M. ; Carvalho, Daniel R. ; Chandler, Kate E. ; Christen, Hans-Jürgen ; Corry, Peter C. ; Cowan, Frances M. ; Cox, Helen ; D’Arrigo, Stefano ; Dean, John ; De Laet, Corinne ; De Praeter, Claudine ; Déry, Catherine ; Ferrie, Colin D. ; Flintoff, Kim ; Frints, Suzanna G. M. ; Garcia-Cazorla, Angels ; Gener, Blanca ; Goizet, Cyril ; Goutières, Françoise ; Green, Andrew J. ; Guët, Agnès ; Hamel, Ben C. J. ; Hayward, Bruce E. ; Heiberg, Arvid ; Hennekam, Raoul C. ; Husson, Marie ; Jackson, Andrew P. ; Jayatunga, Rasieka ; Jiang, Yong-Hui ; Kant, Sarina G. ; Kao, Amy ; King, Mary D. ; Kingston, Helen M. ; Klepper, Joerg ; van der Knaap, Marjo S. ; Kornberg, Andrew J. ; Kotzot, Dieter ; Kratzer, Wilfried ; Lacombe, Didier ; Lagae, Lieven ; Landrieu, Pierre Georges ; Lanzi, Giovanni ; Leitch, Andrea ; Lim, Ming J. ; Livingston, John H. ; Lourenco, Charles M. ; Lyall, E. G. Hermione ; Lynch, Sally A. ; Lyons, Michael J. ; Marom, Daphna ; McClure, John P. ; McWilliam, Robert ; Melancon, Serge B. ; Mewasingh, Leena D. ; Moutard, Marie-Laure ; Nischal, Ken K. ; Østergaard, John R. ; Prendiville, Julie ; Rasmussen, Magnhild ; Rogers, R. Curtis ; Roland, Dominique ; Rosser, Elisabeth M. ; Rostasy, Kevin ; Roubertie, Agathe ; Sanchis, Amparo ; Schiffmann, Raphael ; Scholl-Bürgi, Sabine ; Seal, Sunita ; Shalev, Stavit A. ; Corcoles, C. Sierra ; Sinha, Gyan P. ; Soler, Doriette ; Spiegel, Ronen ; Stephenson, John B. P. ; Tacke, Uta ; Tan, Tiong Yang ; Till, Marianne ; Tolmie, John L. ; Tomlin, Pam ; Vagnarelli, Federica ; Valente, Enza Maria ; Van Coster, Rudy N. A. ; Van der Aa, Nathalie ; Vanderver, Adeline ; Vles, Johannes S. H. ; Voit, Thomas ; Wassmer, Evangeline ; Weschke, Bernhard ; Whiteford, Margo L. ; Willemsen, Michel A. A. ; Zankl, Andreas ; Zuberi, Sameer M. ; Orcesi, Simona ; Fazzi, Elisa ; Lebon, Pierre ; Crow, Yanick J. 

    2007-01-01

    Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3′→5′ exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation–positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified. PMID:17846997

  13. Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes.

    Science.gov (United States)

    Tae, Hyun-Jin; Petrashevskaya, Natalia; Marshall, Shannon; Krawczyk, Melissa; Talan, Mark

    2016-01-15

    Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/- mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2-4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6-14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS.

  14. Polycystic ovary syndrome in type 2 diabetes: does it predict a more severe phenotype?

    Science.gov (United States)

    Sim, Stephanie Y T; Chin, Sian L; Tan, Jocelyn L K; Brown, Suzanne J; Cussons, Andrea J; Stuckey, Bronwyn G A

    2016-10-01

    To examine the prevalence of a history of polycystic ovary syndrome (PCOS) in women with type 2 diabetes (DM2) and to compare metabolic and reproductive outcomes between women with and without PCOS. Cross-sectional study. Tertiary hospital. Female inpatients age 18-75 years with DM2. A face-to-face questionnaire was administered. Age at diagnosis of diabetes, history of gestational diabetes, family history of diabetes, and reproductive history, fertility history, number of miscarriages, and morbidity in pregnancy. One hundred seventy-one inpatients with DM2 participated. The prevalence of a history of PCOS was 37%. Women with PCOS had an earlier mean age of diagnosis of DM2 (44.2 vs. 48.8 years), higher recalled peak body mass index (BMI; 43.1 kg/m 2 vs. 36.8 kg/m 2 ), higher rate of gestational diabetes (28% vs. 18%), and higher rate of hypertension in pregnancy (40% vs. 22%). Women with PCOS were less likely to have a family history of DM2 than those without PCOS (45% vs. 67%). A history of PCOS in women with DM2 is associated with earlier onset of DM2, higher BMI, and a more severe phenotype. Since PCOS subjects were less likely to have a family history of DM2, lack of a family history of DM2 in women with PCOS is not reassuring for DM2 risk. We recommend identifying PCOS in early life and intervening to reduce the risk of diabetes and its comorbidities and suboptimal reproductive outcomes. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

  15. Metabolic profiles characterizing different phenotypes of polycystic ovary syndrome: plasma metabolomics analysis

    Science.gov (United States)

    2012-01-01

    Background Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder accompanied with an increased risk of developing type 2 diabetes mellitus and cardiovascular disease; despite being a common condition, the pathogenesis of PCOS remains unclear. Our aim was to investigate the potential metabolic profiles for different phenotypes of PCOS, as well as for the early prognosis of complications. Methods A total of 217 women with PCOS and 48 healthy women as normal controls were studied. Plasma samples of subjects were tested using two different analytical platforms of metabolomics: 1H nuclear magnetic resonance (NMR) and gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS). Results Our results showed that carbohydrate, lipid and amino acid metabolisms were influenced in PCOS. The levels of lactate, long-chain fatty acids, triglyceride and very low-density lipoprotein were elevated, while glucose, phosphatidylcholine and high-density lipoprotein (HDL) concentrations were reduced in PCOS patients as compared with controls. Additionally, the levels of alanine, valine, serine, threonine, ornithine, phenylalanine, tyrosine and tryptophan were generally increased, whereas the levels of glycine and proline were significantly reduced in PCOS samples compared to controls. Furthermore, the ratio of branched-chain amino acid to aromatic amino acid concentrations (BCAA/AAA) in PCOS plasma was significantly reduced in PCOS patients and was insusceptible to obesity and insulin sensitivity. Conclusions Our results suggested that the enhanced glycolysis and inhibited tricarboxylic acid cycle (TAC) in women with PCOS. Decrease of BCAA/AAA ratio was directly correlated with the development of PCOS. Ovulatory dysfunction of PCOS patients was associated with raised production of serine, threonine, phenylalanine, tyrosine and ornithine. Elevated levels of valine and leucine, and decreased concentrations of glycine in PCOS plasma could contribute to insulin

  16. A neurodevelopmental survey of Angelman syndrome with genotype-phenotype correlations

    Science.gov (United States)

    Gentile, Jennifer K.; Tan, Wen-Hann; Horowitz, Lucia T.; Bacino, Carlos A.; Skinner, Steven A.; Barbieri-Welge, Rene; Bauer-Carlin, Astrid; Beaudet, Arthur L.; Bichell, Terry Jo; Lee, Hye-Seung; Sahoo, Trilochan; Waisbren, Susan E.; Bird, Lynne M.; Peters, Sarika U.

    2010-01-01

    Objective Angelman syndrome (AS) is a neurodevelopmental disorder caused by a deletion on chromosome 15, uniparental disomy (UPD), imprinting defect, or UBE3A mutation. It is characterized by intellectual disability with minimal speech and certain behavioral characteristics. We used standardized measures to characterize the developmental profile and to analyze genotype-phenotype correlations in AS. Method The study population consisted of 92 children, between 5 months and 5 years of age, enrolled in a Natural History Study. Each participant was evaluated using the Bayley Scales of Infant and Toddler Development (Third Edition) (BSID-III), the Vineland Adaptive Behavior Scales (Second Edition) (VABS-II), and the Aberrant Behavior Checklist. Results 74% had a deletion and 26% had UPD, an imprinting defect or a UBE3A mutation (“non-deletion”). The mean±standard deviation (SD) BSID-III cognitive scale developmental quotient (DQ) was 40.5±15.5. Participants with deletions were more developmentally delayed than the non-deletion participants in all BSID-III domains except in expressive language skills. The cognitive DQ was higher than the DQ in each of the other domains, and the receptive language DQ was higher than the expressive language DQ. In the VABS-II, deletion participants had weaker motor and language skills than the non-deletion participants. Conclusion Children with AS have a distinct developmental and behavioral profile; their cognitive skills are stronger than their language and motor skills, and their receptive language skills are stronger than expressive language skills. Developmental outcomes are associated with genotype, with deletion patients having worse outcomes than non-deletion patients. PMID:20729760

  17. Dietary glycemic index is associated with less favorable anthropometric and metabolic profiles in polycystic ovary syndrome women with different phenotypes.

    Science.gov (United States)

    Graff, Scheila Karen; Mário, Fernanda Missio; Alves, Bruna Cherubini; Spritzer, Poli Mara

    2013-10-01

    To compare glycemic index (GI) in the usual diet of polycystic ovary syndrome (PCOS) and control women and to investigate whether dietary GI is associated with body composition and anthropometric and metabolic variables across PCOS phenotypes. Cross-sectional study. University hospital outpatient clinic. Sixty-one women with PCOS and 44 nonhirsute women with ovulatory cycles. Metabolic work-up, biochemical and hormonal assays, assessment of body composition and rest metabolic rate, physical activity (pedometer), and food consumption (food frequency questionnaire). GI, glycemic load, dietary intake, and hormone and metabolic profile in PCOS versus control and in PCOS women stratified by tertiles of GI and PCOS phenotype. Mean age was 23.7 ± 6.3 years. Participants with PCOS had higher body fat percentage, fasting insulin, insulin resistance, lipid accumulation product, and androgen levels compared with control women. PCOS and control women in the highest tertile of GI had higher body mass index and waist circumference than those in the lowest tertile. Dietary GI was higher in the classic PCOS group. Obesity and this more severe PCOS phenotype explained 28.3% of variance in dietary GI. Dietary GI is increased in the classic PCOS phenotype and associated with a less favorable anthropometric and metabolic profile. Obesity and classic PCOS phenotype are age-independent predictors of higher dietary GI. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  18. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

    DEFF Research Database (Denmark)

    Depienne, Christel; Nava, Caroline; Keren, Boris

    2017-01-01

    Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific...... in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability....... ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm...

  19. Wnt signaling pathway involvement in genotypic and phenotypic variations in Waardenburg syndrome type 2 with MITF mutations.

    Science.gov (United States)

    Wang, Xue-Ping; Liu, Ya-Lan; Mei, Ling-Yun; He, Chu-Feng; Niu, Zhi-Jie; Sun, Jie; Zhao, Yu-Lin; Feng, Yong; Zhang, Hua

    2018-03-12

    Mutation in the gene encoding microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome 2 (WS2), an autosomal dominantly inherited syndrome with auditory-pigmentary abnormalities, which is clinically and genetically heterogeneous. Haploinsufficiency may be the underlying mechanism for WS2. However, the mechanisms explaining the genotypic and phenotypic variations in WS2 caused by MITF mutations are unclear. A previous study revealed that MITF interacts with LEF-1, an important factor in the Wnt signaling pathway, to regulate its own transcription through LEF-1-binding sites on the MITF promoter. In this study, four different WS2-associated MITF mutations (p.R217I, p.R217G, p.R255X, p.R217del) that are associated with highly variable clinical features were chosen. According to the results, LEF-1 can activate the expression of MITF on its own, but MITF proteins inhibited the activation. This inhibition weakens when the dosage of MITF is reduced. Except for p.R217I, p.R255X, p.R217G, and p.R217del lose the ability to activate TYR completely and do not inhibit the LEF-1-mediated activation of the MITF-M promoter, and the haploinsufficiency created by mutant MITF can be overcome; correspondingly, the mutants' associated phenotypes are less severe than that of p.R217I. The dominant negative of p.R217del made it have a second-most severe phenotype. This study's data imply that MITF has a negative feedback loop of regulation to stabilize MITF gene dosage that involves the Wnt signaling pathway and that the interaction of MITF mutants with this pathway drives the genotypic and phenotypic differences observed in Waardenburg syndrome type 2 associated with MITF mutations.

  20. Genotype-phenotype correlations of 39 patients with Cornelia De Lange syndrome: the Dutch experience

    NARCIS (Netherlands)

    Bhuiyan, Z. A.; Klein, M.; Hammond, P.; van Haeringen, A.; Mannens, M. M. A. M.; van Berckelaer-Onnes, I.; Hennekam, R. C. M.

    2006-01-01

    BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multiple congenital anomaly syndrome characterised by a distinctive facial appearance, prenatal and postnatal growth deficiency, psychomotor delay, behavioural problems, and malformations of the upper extremities. Recently mutations in NIPBL, the

  1. Genotype and Phenotype Correlation in Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome)

    Science.gov (United States)

    2018-02-12

    Thrombotic Thrombocytopenic Purpura; Congenital Thrombotic Thrombocytopenic Purpura; Familial Thrombotic Thrombocytopenic Purpura; Thrombotic Thrombocytopenic Purpura, Congenital; Upshaw-Schulman Syndrome

  2. Cardiovascular Malformations in CHARGE Syndrome with DiGeorge Phenotype: Two Case Reports

    OpenAIRE

    Yasuda, Kazushi; Morihana, Eiji; Fusazaki, Naoki; Ishikawa, Shiro

    2016-01-01

    Both CHARGE syndrome and DiGeorge anomaly are frequently accompanied by cardiovascular malformations. Some specific cardiovascular malformations such as interrupted aortic arch type B and truncus arteriosus are frequently associated with 22q11.2 deletion syndrome, while conotruncal defects and atrioventricular septal defects are overrepresented in patients with CHARGE syndrome. CHD7 gene mutation is identified in approximately two-thirds of patients with CHARGE syndrome, and chromosomal micro...

  3. Phenotypic and Molecular Convergence of 2q23.1 Deletion Syndrome with Other Neurodevelopmental Syndromes Associated with Autism Spectrum Disorder

    Science.gov (United States)

    Mullegama, Sureni V.; Alaimo, Joseph T.; Chen, Li; Elsea, Sarah H.

    2015-01-01

    Roughly 20% of autism spectrum disorders (ASD) are syndromic with a well-established genetic cause. Studying the genes involved can provide insight into the molecular and cellular mechanisms of ASD. 2q23.1 deletion syndrome (causative gene, MBD5) is a recently identified genetic neurodevelopmental disorder associated with ASD. Mutations in MBD5 have been found in ASD cohorts. In this study, we provide a phenotypic update on the prevalent features of 2q23.1 deletion syndrome, which include severe intellectual disability, seizures, significant speech impairment, sleep disturbance, and autistic-like behavioral problems. Next, we examined the phenotypic, molecular, and network/pathway relationships between nine neurodevelopmental disorders associated with ASD: 2q23.1 deletion Rett, Angelman, Pitt-Hopkins, 2q23.1 duplication, 5q14.3 deletion, Kleefstra, Kabuki make-up, and Smith-Magenis syndromes. We show phenotypic overlaps consisting of intellectual disability, speech delay, seizures, sleep disturbance, hypotonia, and autistic-like behaviors. Molecularly, MBD5 possibly regulates the expression of UBE3A, TCF4, MEF2C, EHMT1 and RAI1. Network analysis reveals that there could be indirect protein interactions, further implicating function for these genes in common pathways. Further, we show that when MBD5 and RAI1 are haploinsufficient, they perturb several common pathways that are linked to neuronal and behavioral development. These findings support further investigations into the molecular and pathway relationships among genes linked to neurodevelopmental disorders and ASD, which will hopefully lead to common points of regulation that may be targeted toward therapeutic intervention. PMID:25853262

  4. Phenotypic and Molecular Convergence of 2q23.1 Deletion Syndrome with Other Neurodevelopmental Syndromes Associated with Autism Spectrum Disorder

    Directory of Open Access Journals (Sweden)

    Sureni V. Mullegama

    2015-04-01

    Full Text Available Roughly 20% of autism spectrum disorders (ASD are syndromic with a well-established genetic cause. Studying the genes involved can provide insight into the molecular and cellular mechanisms of ASD. 2q23.1 deletion syndrome (causative gene, MBD5 is a recently identified genetic neurodevelopmental disorder associated with ASD. Mutations in MBD5 have been found in ASD cohorts. In this study, we provide a phenotypic update on the prevalent features of 2q23.1 deletion syndrome, which include severe intellectual disability, seizures, significant speech impairment, sleep disturbance, and autistic-like behavioral problems. Next, we examined the phenotypic, molecular, and network/pathway relationships between nine neurodevelopmental disorders associated with ASD: 2q23.1 deletion Rett, Angelman, Pitt-Hopkins, 2q23.1 duplication, 5q14.3 deletion, Kleefstra, Kabuki make-up, and Smith-Magenis syndromes. We show phenotypic overlaps consisting of intellectual disability, speech delay, seizures, sleep disturbance, hypotonia, and autistic-like behaviors. Molecularly, MBD5 possibly regulates the expression of UBE3A, TCF4, MEF2C, EHMT1 and RAI1. Network analysis reveals that there could be indirect protein interactions, further implicating function for these genes in common pathways. Further, we show that when MBD5 and RAI1 are haploinsufficient, they perturb several common pathways that are linked to neuronal and behavioral development. These findings support further investigations into the molecular and pathway relationships among genes linked to neurodevelopmental disorders and ASD, which will hopefully lead to common points of regulation that may be targeted toward therapeutic intervention.

  5. B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies

    NARCIS (Netherlands)

    Maroofian, R.; Riemersma, M.; Jae, L.T.; Zhianabed, N.; Willemsen, M.H.; Wissink-Lindhout, W.M.; Willemsen, M.A.A.P.; Brouwer, A.P.M. de; Mehrjardi, M.Y.V.; Ashrafi, M.R.; Kusters, B.; Kleefstra, T.; Jamshidi, Y.; Nasseri, M.; Pfundt, R.; Brummelkamp, T.R.; Abbaszadegan, M.R.; Lefeber, D.J.; Bokhoven, H. van

    2017-01-01

    BACKGROUND: The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of alpha-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular

  6. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes

    NARCIS (Netherlands)

    Ruijs, M.W.G.; Verhoef, S.; Rookus, M.A.; Pruntel, R.; van der Hout, A.H.; Hogervorst, F.B.L.; Kluijt, I.; Sijmons, R.H.; Aalfs, C.M.; Wagner, A.; Ausems, M.G.E.M.; Hoogerbrugge, N.; van Asperen, C.J.; Gómez García, E.B.; Meijers-Heijboer, H.; ten Kate, L.P.; Menko, F.H.; van 't Veer, L.J.

    2010-01-01

    Background Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour TP53 germline mutations. However, TP53 germline mutations may also occur in less obvious phenotypes. As a result, different criteria

  7. SOX10 mutation causes Waardenburg syndrome associated with distinctive phenotypic features in an Iranian family: A clue for phenotype-directed genetic analysis.

    Science.gov (United States)

    Jalilian, Nazanin; Tabatabaiefar, Mohammad Amin; Alimadadi, Hossein; Noori-Daloii, Mohammad Reza

    2017-05-01

    Waardenburg syndrome (WS) is a neurocristopathy characterized by hearing impairment and pigmentary disturbances in hair, eyes, and skin. WS is clinically heterogeneous and can be subdivided into four major types (WS1-WS4) where WS4 or Shah-Waardenburg is diagnosed when WS2 is accompanied by Hirschsprung disease (HD). Mutations of SOX10, EDN3/EDNRB have been identified in association with WS4. This study was aimed to determine the pathogenic variant in an Iranian pedigree affected with WS4. A two-generation pedigree with three affected members and considerable phenotypic heterogeneity was recruited. The proband was a 15-year-old boy, with severe to profound sensorineural hearing impairment, heterochromia iridis, hypoplastic blue eyes and Hirschprung disease. The other two also presented characteristics of WS2 and complained of chronic constipation with normal anorectal reflex. Sequencing of all exons and exon-intron boundaries of SOX10, EDN3/EDNRB revealed a heterozygous variant c.422T > C in exon 3 of SOX10 confirmed by a series of evidence to be pathogenic. It resulted in p.L141P at the protein level. Leucin 141 is located in Nuclear Export signal, HMG box of the protein. This study is the first report of a WS4 family in the Iranian population. The mutation is associated with distinctive phenotypic profile (association of anosmia and chronic constipation with SOX10 mutations) and could further improve diagnosis and counseling of WS in the Iranian population and can contribute to phenotype-directed genetic analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne).

    Science.gov (United States)

    Demidowich, Andrew P; Freeman, Alexandra F; Kuhns, Douglas B; Aksentijevich, Ivona; Gallin, John I; Turner, Maria L; Kastner, Daniel L; Holland, Steven M

    2012-06-01

    To describe the genotypes, phenotypes, immunophenotypes, and treatments of PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), a rare autoinflammatory disease, in 5 patients. Clinical information was gathered from medical records and through interviews with 5 patients from 4 kindreds. PSTPIP1 (CD2BP1) exon 10 and exon 11 sequencing was performed in each patient. Neutrophil granule content and cytokine levels were determined in plasma and stimulated peripheral blood mononuclear cells (PBMCs) from patients and controls. We identified 2 previously described PAPA syndrome-associated PSTPIP1 mutations, A230T and E250Q, and a novel change, E250K. Disease penetrance was incomplete, with variable expressivity. The cutaneous manifestations included pathergy, cystic acne, and pyoderma gangrenosum. Interleukin-1β (IL-1β) and circulating neutrophil granule enzyme levels were markedly elevated in patients compared to those in controls. PBMC stimulation studies demonstrated impaired production of IL-10 and enhanced production of granulocyte-macrophage colony-stimulating factor. Good resolution of pyoderma gangrenosum was achieved in 3 patients with tumor necrosis factor α (TNFα) blockade treatment. This analysis of 5 patients demonstrates that mutations in PSTPIP1 are incompletely penetrant and variably expressed in the PAPA syndrome. Neutrophil granule proteins are markedly elevated ex vivo and in the plasma, and elevated levels might be compatible with a diagnosis of PAPA syndrome. TNFα blockade appears to be effective in treating the cutaneous manifestations of PAPA syndrome. Copyright © 2012 by the American College of Rheumatology.

  9. Hyperandrogenemia in Polycystic Ovary Syndrome: Exploration of the Role of Free Testosterone and Androstenedione in Metabolic Phenotype

    Science.gov (United States)

    Lerchbaum, Elisabeth; Schwetz, Verena; Rabe, Thomas; Giuliani, Albrecht; Obermayer-Pietsch, Barbara

    2014-01-01

    Objective To evaluate the association between androstenedione, testosterone, and free testosterone and metabolic disturbances in polycystic ovary syndrome. Methods We analyzed the association between androstenedione, testosterone, and free testosterone and metabolic parameters in a cross-sectional study including 706 polycystic ovary syndrome and 140 BMI-matched healthy women. Polycystic ovary syndrome women were categorized into 4 groups: normal androstenedione and normal free testosterone (NA/NFT), elevated androstenedione and normal free testosterone (HA/NFT), normal androstenedione and elevated free testosterone (NA/HFT), elevated androstenedione and free testosterone (HA/HFT). Results Polycystic ovary syndrome women with elevated free testosterone levels (HA/HFT and NA/HFT) have an adverse metabolic profile including 2 h glucose, HbA1c, fasting and 2 h insulin, area under the insulin response curve, insulin resistance, insulin sensitivity index (Matsuda), triglycerides, total and high density lipoprotein cholesterol levels compared to NA/NFT (pmetabolic disorders in polycystic ovary syndrome women with HA/NFT. In multiple linear regression analyses (age- and BMI-adjusted), we found a significant negative association between androstenedione/free testosterone-ratio and area under the insulin response curve, insulin resistance, and total cholesterol/high density lipoprotein cholesterol-ratio and a positive association with Matsuda-index, and high density lipoprotein cholesterol (ptestosterone levels but not with isolated androstenedione elevation have an adverse metabolic phenotype. Further, a higher androstenedione/free testosterone-ratio was independently associated with a beneficial metabolic profile. PMID:25310562

  10. [Chromosome 22q11.2 microdeletion and phenotype analysis of patients with non-syndromic tetralogy of Fallot].

    Science.gov (United States)

    Zhang, Ze-wei; Deng, Jian-ying; Ying, Li-yang; Gao, Zhan; Jin, Jie; Qi, Jian-chuan; Tan, Zheng

    2011-12-01

    To investigate the frequency and clinical phenotypes of 22q11.2 microdeletion in patients with non-syndromic tetralogy of Fallot (TOF). Six-eight non-syndromic TOF patients (38 males and 30 females, aged 0-11 years) were selected and evaluated by history, physical examination and review of medical records. After informed consent was obtained, peripheral blood was drawn for genomic DNA extraction. Chromosome 22q11.2 microdeletion was screened by multiplex ligation-dependent probe amplification (MLPA). Suspected cases were confirmed with fluorescence in situ hybridization (FISH). Data was analyzed with SPSS 11.5 software. Phenotype-genotype correlations were assessed using Fisher's exact test. P values less than 0.05 on a 2-sided test were considered to be significant. Six-eight non-syndromic TOF children were screened for a 22q11.2 deletion, among which 59 (86.8%) presented pulmonary stenosis (PS) and 9 (13.2%) presented pulmonary atresia (PA). Seven patients (10.3%) were found to have carried a deletion. Among these, four had TOF-PS, three had TOF-PA. The frequency of 22q11.2 deletion in patients with TOF-PA (3/9, 33.3%) is much higher than that of TOF-PS (4/59, 6.80%) (P22q11.2 microdeletion is present in approximately 10.3% of patients with non-syndromic TOF. The deletion tends to have a higher prevalence in patients with TOF-PA. 22q11.2 deletion should be screened in non-syndromic TOF children and genetic counselling may be provided.

  11. Recent insights into genotype-phenotype relationships in patients with Rett syndrome using a fine grain scale.

    Science.gov (United States)

    Fabio, Rosa Angela; Colombo, Barbara; Russo, Silvia; Cogliati, Francesca; Masciadri, Maura; Foglia, Silvia; Antonietti, Alessandro; Tavian, Daniela

    2014-11-01

    Mutations in MECP2 gene cause Rett syndrome (RTT), a neurodevelopmental disorder affecting around 1 in 10,000 female births. The clinical picture of RTT appears quite heterogeneous for each single feature. Mutations in MECP2 gene have been associated with the onset of RTT. The most known gene function consists of transcriptional repression of specific target genes, mainly by the binding of its methyl binding domain (MBD) to methylated CpG nucleotides and recruiting co-repressors and histone deacetylase binding to DNA by its transcription repressor domain (TRD). This study aimed at evaluating a cohort of 114 Rett syndrome (RTT) patients with a detailed scale measuring the different kinds of impairments produced by the syndrome. The sample included relatively large subsets of the most frequent mutations, so that genotype-phenotype correlations could be tested. Results revealed that frequent missense mutations showed a specific profile in different areas of impairment. The R306C mutation, considered as producing mild impairment, was associated to a moderate phenotype in which behavioural characteristics were mainly affected. A notable difference emerged by comparing mutations truncating the protein before and after the nuclear localization signal; such a difference concerned prevalently the motor-functional and autonomy skills of the patients, affecting the management of everyday activities. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Evaluation of Potential Modifiers of the Cardiac Phenotype in the 22q11.2 Deletion Syndrome

    Science.gov (United States)

    Goldmuntz, Elizabeth; Driscoll, Deborah A.; Emanuel, Beverly S.; McDonald-McGinn, Donna; Mei, Minghua; Zackai, Elaine; Mitchell, Laura E.

    2010-01-01

    BACKGROUND The phenotype associated with deletion of the 22q11.2 chromosomal region is highly variable, yet little is known about the source of this variability. Cardiovascular anomalies, including tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, perimembranous ventricular septal defects, and aortic arch anomalies, occur in approximately 75% of individuals with a 22q11.2 deletion. METHODS Data from 343 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the cardiac phenotype in this disorder. Subjects with and without cardiac malformations, and subjects with and without aortic arch anomalies were compared with respect to sex and race. In addition, in the subset of subjects from whom a DNA sample was available, genotypes for variants of four genes that are involved in the folate-homocysteine metabolic pathway and that have been implicated as risk factors for other birth defects were compared. Five variants in four genes were genotyped by heteroduplex or restriction digest assays. The chi-square or Fisher’s exact test was used to evaluate the association between the cardiac phenotype and each potential modifier. RESULTS The cardiac phenotype observed in individuals with a 22q11.2 deletion was not significantly associated with either sex or race. The genetic variants that were evaluated also did not appear to be associated with the cardiovascular phenotype. CONCLUSIONS Variation in the cardiac phenotype observed between individuals with a 22q11.2 deletion does not appear to be related to sex, race, or five sequence variants in four folate-related genes that are located outside of the 22q11.2 region. PMID:18770859

  13. Irisin and the Metabolic Phenotype of Adults with Prader-Willi Syndrome.

    Directory of Open Access Journals (Sweden)

    Harry J Hirsch

    Full Text Available Hyperphagia, low resting energy expenditure, and abnormal body composition contribute to severe obesity in Prader Willi syndrome (PWS. Irisin, a circulating myokine, stimulates "browning" of white adipose tissue resulting in increased energy expenditure and improved insulin sensitivity. Irisin has not been previously studied in PWS.Compare plasma and salivary irisin in PWS adults and normal controls. Examine the relationship of irisin to insulin sensitivity and plasma lipids.A fasting blood sample for glucose, lipids, insulin, leptin, adinopectin, and irisin was obtained from 22 PWS adults and 54 healthy BMI-matched volunteers. Saliva was collected for irisin assay in PWS and controls.Fasting glucose (77 ± 9 vs 83 ± 7 mg/dl, p = 0.004, insulin (4.1 ± 2.0 vs 7.9 ± 4.7 μU/ml, p<0.001, and triglycerides (74 ± 34 vs 109 ± 71 mg/dl, p = 0.007 were lower in PWS than in controls. Insulin resistance (HOMA-IR was lower (0.79 ± 0.041 vs 1.63 ± 1.02, p<0.001 and insulin sensitivity (QUICKI was higher (0.41 ± 0.04 vs 0.36 ± 0.03, p<0.001 in PWS. Plasma irisin was similar in both groups, but salivary irisin (64.5 ± 52.0 vs 33.0 ± 12.1ng/ml, plasma leptin (33.5 ± 24.2 vs 19.7 ± 19.3 ng/ml and plasma adinopectin (13.0 ± 10.8 vs 7.6 ± 4.5μg/ml were significantly greater in PWS (p<0.001. In PWS, plasma irisin showed positive Pearson correlations with total cholesterol (r = 0.58, p = 0.005, LDL-cholesterol (r = 0.59, p = 0.004, and leptin (r = 0.43, p = 0.045. Salivary irisin correlated negatively with HDL-cholesterol (r = -0.50, p = 0.043 and positively with LDL-cholesterol (r = 0.51, p = 0.037 and triglycerides (r = 0.50, p = 0.041.Salivary irisin was markedly elevated in PWS although plasma irisin was similar to levels in controls. Significant associations with plasma lipids suggest that irisin may contribute to the metabolic phenotype of PWS.

  14. De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.

    Science.gov (United States)

    Gil-Rodríguez, María Concepción; Deardorff, Matthew A; Ansari, Morad; Tan, Christopher A; Parenti, Ilaria; Baquero-Montoya, Carolina; Ousager, Lilian B; Puisac, Beatriz; Hernández-Marcos, María; Teresa-Rodrigo, María Esperanza; Marcos-Alcalde, Iñigo; Wesselink, Jan-Jaap; Lusa-Bernal, Silvia; Bijlsma, Emilia K; Braunholz, Diana; Bueno-Martinez, Inés; Clark, Dinah; Cooper, Nicola S; Curry, Cynthia J; Fisher, Richard; Fryer, Alan; Ganesh, Jaya; Gervasini, Cristina; Gillessen-Kaesbach, Gabriele; Guo, Yiran; Hakonarson, Hakon; Hopkin, Robert J; Kaur, Maninder; Keating, Brendan J; Kibaek, María; Kinning, Esther; Kleefstra, Tjitske; Kline, Antonie D; Kuchinskaya, Ekaterina; Larizza, Lidia; Li, Yun R; Liu, Xuanzhu; Mariani, Milena; Picker, Jonathan D; Pié, Ángeles; Pozojevic, Jelena; Queralt, Ethel; Richer, Julie; Roeder, Elizabeth; Sinha, Anubha; Scott, Richard H; So, Joyce; Wusik, Katherine A; Wilson, Louise; Zhang, Jianguo; Gómez-Puertas, Paulino; Casale, César H; Ström, Lena; Selicorni, Angelo; Ramos, Feliciano J; Jackson, Laird G; Krantz, Ian D; Das, Soma; Hennekam, Raoul C M; Kaiser, Frank J; FitzPatrick, David R; Pié, Juan

    2015-04-01

    Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ∼ 1%-2% of CdLS-like phenotypes. © 2015 WILEY PERIODICALS, INC.

  15. Phenotypic and genotypic characterization of dengue virus isolates differentiates dengue fever and dengue hemorrhagic fever from dengue shock syndrome.

    Science.gov (United States)

    Tuiskunen, Anne; Monteil, Vanessa; Plumet, Sébastien; Boubis, Laetitia; Wahlström, Maria; Duong, Veasna; Buchy, Philippe; Lundkvist, Ake; Tolou, Hugues; Leparc-Goffart, Isabelle

    2011-11-01

    Dengue viruses (DENV) cause 50-100 million cases of acute febrile disease every year, including 500,000 reported cases of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Viral factors have been proposed to influence the severity of the disease, but markers of virulence have never been identified on DENV. Three DENV serotype-1 isolates from the 2007 epidemic in Cambodia that are derived from patients experiencing the various clinical forms of dengue were characterized both phenotypically and genetically. Phenotypic characteristics in vitro, based on replication kinetics in different cell lines and apoptosis response, grouped isolates from DF and DHF patients together, whereas the virus isolate from a DSS patient showed unique features: a lower level of replication in mammalian cells and extensive apoptosis in mosquito cells. Genomic comparison of viruses revealed six unique amino acid residues in the membrane, envelope, and in non-structural genes in the virus isolated from the DSS patient.

  16. Embryonic type Na+ channel β-subunit, SCN3B masks the disease phenotype of Brugada syndrome.

    Science.gov (United States)

    Okata, Shinichiro; Yuasa, Shinsuke; Suzuki, Tomoyuki; Ito, Shogo; Makita, Naomasa; Yoshida, Tetsu; Li, Min; Kurokawa, Junko; Seki, Tomohisa; Egashira, Toru; Aizawa, Yoshiyasu; Kodaira, Masaki; Motoda, Chikaaki; Yozu, Gakuto; Shimojima, Masaya; Hayashiji, Nozomi; Hashimoto, Hisayuki; Kuroda, Yusuke; Tanaka, Atsushi; Murata, Mitsushige; Aiba, Takeshi; Shimizu, Wataru; Horie, Minoru; Kamiya, Kaichiro; Furukawa, Tetsushi; Fukuda, Keiichi

    2016-09-28

    SCN5A is abundant in heart and has a major role in I Na . Loss-of-function mutation in SCN5A results in Brugada syndrome (BrS), which causes sudden death in adults. It remains unclear why disease phenotype does not manifest in the young even though mutated SCN5A is expressed in the young. The aim of the present study is to elucidate the timing of the disease manifestation in BrS. A gain-of-function mutation in SCN5A also results in Long QT syndrome type 3 (LQTS3), leading to sudden death in the young. Induced pluripotent stem cells (iPSCs) were generated from a patient with a mixed phenotype of LQTS3 and BrS with the E1784K SCN5A mutation. Here we show that electrophysiological analysis revealed that LQTS3/BrS iPSC-derived cardiomyocytes recapitulate the phenotype of LQTS3 but not BrS. Each β-subunit of the sodium channel is differentially expressed in embryonic and adult hearts. SCN3B is highly expressed in embryonic hearts and iPSC-derived cardiomyocytes. A heterologous expression system revealed that I Na of mutated SCN5A is decreased and SCN3B augmented I Na of mutated SCN5A. Knockdown of SCN3B in LQTS3/BrS iPSC-derived cardiomyocytes successfully unmasked the phenotype of BrS. Isogenic control of LQTS3/BrS (corrected-LQTS3/BrS) iPSC-derived cardiomyocytes gained the normal electrophysiological properties.

  17. Molecular Testing of MECP2 Gene in Rett Syndrome Phenotypes in Indian Girls.

    Science.gov (United States)

    Lallar, Meenakshi; Rai, Archana; Srivastava, Priyanka; Mandal, Kausik; Gupta, Neerja; Kabra, Madhulika; Phadke, Shubha R

    2018-02-09

    To assess yield of MECP2 gene sequence variations analysis and large deletions in suspected cases of Rett syndrome. Descriptive study. Tertiary-care medical genetics center. Girls with neuroregression, postnatal microcephaly and signs and symptoms suggestive of classical and atypical Rett syndrome were classified into two groups. Group I consisted of girls with Classical and atypical Rett syndrome on basis on the Revised Rett Syndrome diagnostic criteria, 2010. Group II included girls with neuroregression and postnatal microcephaly and other Rett like features but not fulfilling the above criteria. Sanger sequencing of coding regions and large deletional analysis of MECP2 gene. Identification of mutation in MECP2 gene. Mutation in MECP2 gene was identified in 74% (14/19) in group I and none (0/17) in group II. The mutation detection rate was 92% (13/14) in group I classical Rett syndrome girls (2 with large deletions identified with Multiplex ligation dependent probe amplification) and 20% (1/5) in group I atypical Rett syndrome girls. One novel MECP2 sequence variation was identified in group I classical Rett syndrome. The yield of the mutation detection in MECP2 is much higher in classical than in atypical Rett syndrome. In girls with some Rett like features, but not fulfilling revised Rett syndrome diagnostic criteria, mutation testing for MECP2 gene has a low yield.

  18. Delineation of Behavioral Phenotypes in Genetic Syndromes: Characteristics of Autism Spectrum Disorder, Affect and Hyperactivity

    Science.gov (United States)

    Oliver, Chris; Berg, Katy; Moss, Jo; Arron, Kate; Burbidge, Cheryl

    2011-01-01

    We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n = 104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in…

  19. From Research to Practice: Teacher and Pediatrician Awareness of Phenotypic Traits in Neurogenetic Syndromes

    Science.gov (United States)

    Lee, Tammy H.; Blasey, Christine M.; Dyer-Friedman, Jennifer; Glaser, Bronwyn; Reiss, Allan L.; Eliez, Stephan

    2005-01-01

    Pediatricians' and teachers' knowledge of physical, cognitive, and behavioral features associated with three genetic syndromes were assessed and the effectiveness of information sources about these syndromes evaluated. The surveyed sample included 53 pediatricians and 69 teachers from Northern and Central California. Respondents demonstrated…

  20. Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients

    NARCIS (Netherlands)

    Santen, G.W.; Aten, E.; Silfhout, A.T. van; Pottinger, C.; Bon, B.W.M. van; Minderhout, I.J. van; Snowdowne, R.; Lans, C.A. van der; Boogaard, M. van den; Linssen, M.M.; Vijfhuizen, L.; Wielen, M.J.R. van der; Vollebregt, M.J.; Coffin-Siris, c.; Breuning, M.H.; Kriek, M.; Haeringen, A. van; Dunnen, J.T. den; Hoischen, A.; Clayton-Smith, J.; Vries, L.B.A. de; Hennekam, R.C.M.; Belzen, M.J van

    2013-01-01

    De novo germline variants in several components of the SWI/SNF-like BAF complex can cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2,

  1. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases

    NARCIS (Netherlands)

    Kerr, B.; Delrue, M.-A.; Sigaudy, S.; Perveen, R.; Marche, M.; Burgelin, I.; Stef, M.; Tang, B.; Eden, O. B.; O'Sullivan, J.; de Sandre-Giovannoli, A.; Reardon, W.; Brewer, C.; Bennett, C.; Quarell, O.; M'Cann, E.; Donnai, D.; Stewart, F.; Hennekam, R.; Cavé, H.; Verloes, A.; Philip, N.; Lacombe, D.; Levy, N.; Arveiler, B.; Black, G.

    2006-01-01

    BACKGROUND: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated with failure to thrive and developmental delay. One of the more distinctive features in childhood is the development of facial warts, often nasolabial and in other moist body surfaces. Individuals with

  2. Amniotic fluid RNA gene expression profiling provides insights into the phenotype of Turner syndrome.

    Science.gov (United States)

    Massingham, Lauren J; Johnson, Kirby L; Scholl, Thomas M; Slonim, Donna K; Wick, Heather C; Bianchi, Diana W

    2014-09-01

    Turner syndrome is a sex chromosome aneuploidy with characteristic malformations. Amniotic fluid, a complex biological material, could contribute to the understanding of Turner syndrome pathogenesis. In this pilot study, global gene expression analysis of cell-free RNA in amniotic fluid supernatant was utilized to identify specific genes/organ systems that may play a role in Turner syndrome pathophysiology. Cell-free RNA from amniotic fluid of five mid-trimester Turner syndrome fetuses and five euploid female fetuses matched for gestational age was extracted, amplified, and hybridized onto Affymetrix(®) U133 Plus 2.0 arrays. Significantly differentially regulated genes were identified using paired t tests. Biological interpretation was performed using Ingenuity Pathway Analysis and BioGPS gene expression atlas. There were 470 statistically significantly differentially expressed genes identified. They were widely distributed across the genome. XIST was significantly down-regulated (p Turner syndrome transcriptome from other aneuploidies we previously studied. Manual curation of the differentially expressed gene list identified genes of possible pathologic significance, including NFATC3, IGFBP5, and LDLR. Transcriptomic differences in the amniotic fluid of Turner syndrome fetuses are due to genome-wide dysregulation. The hematologic/immune system differences may play a role in early-onset autoimmune dysfunction. Other genes identified with possible pathologic significance are associated with cardiac and skeletal systems, which are known to be affected in females with Turner syndrome. The discovery-driven approach described here may be useful in elucidating novel mechanisms of disease in Turner syndrome.

  3. Phenotypic consequences of copy number variation: insights from Smith-Magenis and Potocki-Lupski syndrome mouse models.

    Directory of Open Access Journals (Sweden)

    Guénola Ricard

    2010-11-01

    Full Text Available A large fraction of genome variation between individuals is comprised of submicroscopic copy number variation of genomic DNA segments. We assessed the relative contribution of structural changes and gene dosage alterations on phenotypic outcomes with mouse models of Smith-Magenis and Potocki-Lupski syndromes. We phenotyped mice with 1n (Deletion/+, 2n (+/+, 3n (Duplication/+, and balanced 2n compound heterozygous (Deletion/Duplication copies of the same region. Parallel to the observations made in humans, such variation in gene copy number was sufficient to generate phenotypic consequences: in a number of cases diametrically opposing phenotypes were associated with gain versus loss of gene content. Surprisingly, some neurobehavioral traits were not rescued by restoration of the normal gene copy number. Transcriptome profiling showed that a highly significant propensity of transcriptional changes map to the engineered interval in the five assessed tissues. A statistically significant overrepresentation of the genes mapping to the entire length of the engineered chromosome was also found in the top-ranked differentially expressed genes in the mice containing rearranged chromosomes, regardless of the nature of the rearrangement, an observation robust across different cell lineages of the central nervous system. Our data indicate that a structural change at a given position of the human genome may affect not only locus and adjacent gene expression but also "genome regulation." Furthermore, structural change can cause the same perturbation in particular pathways regardless of gene dosage. Thus, the presence of a genomic structural change, as well as gene dosage imbalance, contributes to the ultimate phenotype.

  4. Phenotypic consequences of copy number variation: insights from Smith-Magenis and Potocki-Lupski syndrome mouse models.

    Science.gov (United States)

    Ricard, Guénola; Molina, Jessica; Chrast, Jacqueline; Gu, Wenli; Gheldof, Nele; Pradervand, Sylvain; Schütz, Frédéric; Young, Juan I; Lupski, James R; Reymond, Alexandre; Walz, Katherina

    2010-11-23

    A large fraction of genome variation between individuals is comprised of submicroscopic copy number variation of genomic DNA segments. We assessed the relative contribution of structural changes and gene dosage alterations on phenotypic outcomes with mouse models of Smith-Magenis and Potocki-Lupski syndromes. We phenotyped mice with 1n (Deletion/+), 2n (+/+), 3n (Duplication/+), and balanced 2n compound heterozygous (Deletion/Duplication) copies of the same region. Parallel to the observations made in humans, such variation in gene copy number was sufficient to generate phenotypic consequences: in a number of cases diametrically opposing phenotypes were associated with gain versus loss of gene content. Surprisingly, some neurobehavioral traits were not rescued by restoration of the normal gene copy number. Transcriptome profiling showed that a highly significant propensity of transcriptional changes map to the engineered interval in the five assessed tissues. A statistically significant overrepresentation of the genes mapping to the entire length of the engineered chromosome was also found in the top-ranked differentially expressed genes in the mice containing rearranged chromosomes, regardless of the nature of the rearrangement, an observation robust across different cell lineages of the central nervous system. Our data indicate that a structural change at a given position of the human genome may affect not only locus and adjacent gene expression but also "genome regulation." Furthermore, structural change can cause the same perturbation in particular pathways regardless of gene dosage. Thus, the presence of a genomic structural change, as well as gene dosage imbalance, contributes to the ultimate phenotype.

  5. Natural History and Genotype–Phenotype Correlation in Female X-Linked Alport Syndrome

    Directory of Open Access Journals (Sweden)

    Tomohiko Yamamura

    2017-09-01

    Discussion: This study revealed that phenotypes in female XLAS patients may be severe, but genotype does not help to predict the disease severity. Clinicians must therefore pay careful attention to the clinical course and appropriate treatment in females with XLAS.

  6. Syndromes with supernumerary teeth.

    Science.gov (United States)

    Lubinsky, Mark; Kantaputra, Piranit Nik

    2016-10-01

    While most supernumerary teeth are idiopathic, they can be associated with a number of Mendelian syndromes. However, this can also be a coincidental finding, since supernumerary teeth occur in 6% or more of the normal population. To better define this relationship, we analyzed the evidence for specific associations. We excluded conditions with a single affected patient reported, supernumerary teeth adjacent to clefts or other forms of alveolar disruption (as secondary rather than primary findings), and natal teeth, which can involve premature eruption of a normal tooth. Since, the cause of supernumerary teeth shows considerable heterogeneity, certain findings are less likely to be coincidental, such as five or more supernumerary teeth in a single patient, or locations outside of the premaxilla. We found only eight genetic syndromes with strong evidence for an association: cleidocranial dysplasia; familial adenomatous polyposis; trichorhinophalangeal syndrome, type I; Rubinstein-Taybi syndrome; Nance-Horan syndrome; Opitz BBB/G syndrome; oculofaciocardiodental syndrome; and autosomal dominant Robinow syndrome. There is also suggestive evidence of an association with two uncommon disorders, Kreiborg-Pakistani syndrome (craniosynostosis and dental anomalies), and insulin-resistant diabetes mellitus with acanthosisnigricans. An association of a Mendelian disorder with a low frequency manifestation of supernumerary teeth is difficult to exclude without large numbers, but several commonly cited syndromes lacked evidence for clear association, including Hallermann-Streiff syndrome, Fabry disease, Ehlers-Danlos syndrome, Apert and Crouzon syndromes, Zimmermann-Laband syndrome, and Ellis-van Creveld syndrome. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. Molecular etiology and genotype-phenotype correlation of Chinese Han deaf patients with type I and type II Waardenburg Syndrome

    Science.gov (United States)

    Sun, Lianhua; Li, Xiaohua; Shi, Jun; Pang, Xiuhong; Hu, Yechen; Wang, Xiaowen; Wu, Hao; Yang, Tao

    2016-01-01

    Waardenburg syndrome (WS) characterized by sensorineural hearing loss and pigmentary abnormalities is genetically heterogeneous and phenotypically variable. This study investigated the molecular etiology and genotype-phenotype correlation of WS in 36 Chinese Han deaf probands and 16 additional family members that were clinically diagnosed with WS type I (WS1, n = 8) and type II (WS2, n = 42). Mutation screening of six WS-associated genes detected PAX3 mutations in 6 (86%) of the 7 WS1 probands. Among the 29 WS2 probands, 13 (45%) and 10 (34%) were identified with SOX10 and MITF mutations, respectively. Nineteen of the 26 detected mutations were novel. In WS2 probands whose parental DNA samples were available, de novo mutations were frequently seen for SOX10 mutations (7/8) but not for MITF mutations (0/5, P = 0.005). Excessive freckle, a common feature of WS2 in Chinese Hans, was frequent in WS2 probands with MITF mutations (7/10) but not in those with SOX10 mutations (0/13, P = 4.9 × 10−4). Our results showed that mutations in SOX10 and MITF are two major causes for deafness associated with WS2. These two subtypes of WS2 can be distinguished by the high de novo rate of the SOX10 mutations and the excessive freckle phenotype exclusively associated with the MITF mutations. PMID:27759048

  8. Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency.

    NARCIS (Netherlands)

    Hove, J.L. van; Steyaert, J.; Matthijs, G.; Legius, E.; Theys, P.; Wevers, R.A.; Romstad, A.; Moller, L.B.; Hedrich, K.; Goriounov, D.; Blau, N.; Klein, C.; Casaer, P.

    2006-01-01

    BACKGROUND: Segawa syndrome due to GTP cyclohydrolase deficiency is an autosomal dominant disorder with variable expression, that is clinically characterised by l-dopa responsive, diurnally fluctuating dystonia and parkinsonian symptoms. OBJECTIVE: To delineate the neurological and psychiatric

  9. Social cognition and the behavioural phenotype of 17q21.31 microdeletion syndrome

    NARCIS (Netherlands)

    Egger, J.I.M.; Wingbermühle, P.A.M.; Verhoeven, W.M.A.; Dijkman, M.W.; Kessels, R.P.C.; Koolen, D.A.

    2012-01-01

    Introduction Recently, the 17q21.31 microdeletion syndrome was described with characteristic features including developmental delay, moderate intellectual disability, facial dysmorphisms, and anomalies of the brain and multiple organ systems. With respect to behaviour, scarce data from clinical

  10. Acute Respiratory Distress Syndrome Neutrophils Have a Distinct Phenotype and Are Resistant to Phosphoinositide 3-Kinase Inhibition.

    Science.gov (United States)

    Juss, Jatinder K; House, David; Amour, Augustin; Begg, Malcolm; Herre, Jurgen; Storisteanu, Daniel M L; Hoenderdos, Kim; Bradley, Glyn; Lennon, Mark; Summers, Charlotte; Hessel, Edith M; Condliffe, Alison; Chilvers, Edwin R

    2016-10-15

    Acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this disease's complex pathophysiology, yet these cells have been little studied. To examine the functional and transcriptional profiles of patient blood and alveolar neutrophils compared with healthy volunteer cells, and to define their sensitivity to phosphoinositide 3-kinase inhibition. Twenty-three ventilated patients underwent bronchoalveolar lavage. Alveolar and blood neutrophil apoptosis, phagocytosis, and adhesion molecules were quantified by flow cytometry, and oxidase responses were quantified by chemiluminescence. Cytokine and transcriptional profiling were used in multiplex and GeneChip arrays. Patient blood and alveolar neutrophils were distinct from healthy circulating cells, with increased CD11b and reduced CD62L expression, delayed constitutive apoptosis, and primed oxidase responses. Incubating control cells with disease bronchoalveolar lavage recapitulated the aberrant functional phenotype, and this could be reversed by phosphoinositide 3-kinase inhibitors. In contrast, the prosurvival phenotype of patient cells was resistant to phosphoinositide 3-kinase inhibition. RNA transcriptomic analysis revealed modified immune, cytoskeletal, and cell death pathways in patient cells, aligning closely to sepsis and burns datasets but not to phosphoinositide 3-kinase signatures. Acute respiratory distress syndrome blood and alveolar neutrophils display a distinct primed prosurvival profile and transcriptional signature. The enhanced respiratory burst was phosphoinositide 3-kinase-dependent but delayed apoptosis and the altered transcriptional profile were not. These unexpected findings cast doubt over the utility of phosphoinositide 3-kinase inhibition in acute respiratory distress syndrome and highlight the importance of evaluating novel therapeutic strategies in patient-derived cells.

  11. Role of androgen ratios in the prediction of the metabolic phenotype in polycystic ovary syndrome.

    Science.gov (United States)

    Minooee, Sonia; Ramezani Tehrani, Fahimeh; Tohidi, Maryam; Azizi, Fereidoun

    2017-05-01

    To identify the androgen ratio that best predicts insulin resistance and metabolic syndrome among women with polycystic ovary syndrome (PCOS). Data for 180 women with PCOS and 180 healthy controls were extracted from two previous studies in Iran (conducted during 2008-2010 and 2011-2013). The diagnosis of PCOS was based on the Rotterdam criteria. The serum concentration of different androgens was measured. Receiver operating characteristic curve analysis was used to assess the ability of various androgen ratios to predict insulin resistance and metabolic syndrome. Among women with PCOS, the testosterone-to-androstenedione ratio was the best predictor of insulin resistance (sensitivity 0.83, specificity 0.42) and metabolic syndrome (sensitivity 0.85, specificity 0.70). Among healthy controls, the ratio of free androgen index to testosterone was the best predictor of insulin resistance (sensitivity 0.84, specificity 0.33) and metabolic syndrome (sensitivity 0.91, specificity 0.17). The prediction of insulin resistance and metabolic syndrome among women with PCOS was best accomplished with the testosterone-to-androstenedione ratio. © 2017 International Federation of Gynecology and Obstetrics.

  12. SOS1 frameshift mutations cause pure mucosal neuroma syndrome, a clinical phenotype distinct from multiple endocrine neoplasia type 2B.

    Science.gov (United States)

    Owens, Martina; Kivuva, Emma; Quinn, Anthony; Brennan, Paul; Caswell, Richard; Lango Allen, Hana; Vaidya, Bijay; Ellard, Sian

    2016-05-01

    Mucosal neuromas, thickened corneal nerves and marfanoid body habitus are characteristic phenotypic features of multiple endocrine neoplasia type 2B (MEN2B) and often provide an early clue to the diagnosis of the syndrome. Rarely, patients present with typical physical features of MEN2B but without associated endocrinopathies (medullary thyroid carcinoma or pheochromocytoma) or a RET gene mutation; this clinical presentation is thought to represent a distinct condition termed 'pure mucosal neuroma syndrome'. Exome sequencing was performed in two unrelated probands with mucosal neuromas, thickened corneal nerves and marfanoid body habitus, but no MEN2B-associated endocrinopathy or RET gene mutation. Sanger sequencing was performed to confirm mutations detected by exome sequencing and to test in family members and 3 additional unrelated index patients with mucosal neuromas or thickened corneal nerves. A heterozygous SOS1 gene frameshift mutation (c.3266dup or c.3248dup) was identified in each proband. Sanger sequencing showed that proband 1 inherited the c.3266dup mutation from his affected mother, while the c.3248dup mutation had arisen de novo in proband 2. Sanger sequencing also identified one further novel SOS1 mutation (c.3254dup) in one of the 3 additional index patients. Our results demonstrate the existence of pure mucosal neuroma syndrome as a clinical entity distinct from MEN2B that can now be diagnosed by genetic testing. © 2015 John Wiley & Sons Ltd.

  13. Investigating Risk Factors for Cardiovascular Disease Based on Polycystic Ovary Syndrome phenotypes in the 18-14 year Old High School Girls in Shiraz 2009

    Directory of Open Access Journals (Sweden)

    MH Dabbaghmaneh

    2012-05-01

    Full Text Available Introduction: In patients with polycystic ovary syndrome hyperinsulinaemia, insulin resistance, dyslipidemia and hyperglycemia may represent an increased risk for coronary cardiovascular disease .This study aimed to investigate risk factors for cardiovascular disease based on polycystic ovary syndrome phenotypes in Shiraz. Methods: This Cross-sectional study was performed on 3200 students aged 18-14. Demographic survey, clinical signs of androgen excess (acne, hirsutism, alopecia, Ultrasound were applied in order to find the cyst. Tests included prolactin, dehydroepiandrodion sulfate, and oral glucose tolerance test, fasting blood glucose, blood sugar two hours later, triglycerides, cholesterol, high density lipoprotein. Data were submitted to SPSS software, version 11.5 and then analyzed by chi-square tests. Results: The serum cholesterol mean in four phenotypes had a statistically significant relationship with non-PCOS patients(p<0.05. Mean of serum cholesterol in oligomenorrhea, Hyperandrogenism and polycystic ovary phenotype (195.09±30.28 was higher than the other phenotypes. Mean of serum cholesterol and low density lipoprotein(LDL-C were significantly higher in patients with Hyperandrogenism and polycystic ovarian phenotype(130.046±26.27 and oligomenorrhea, Hyperandrogenism and polycystic ovary syndrome phenotype(138.58±28.34 compared with non-infected individuals. Serum glucose mean in all phenotype was higher than non-infected after two hours and it showed a significant relation in oligomenorrhea and also polycystic ovarian phenotype(98.03 ± 20.98 versus 87.5±12.97 with non-infected individuals. Conclusion: Biochemical factors that lead to increased risk of cardiovascular diseases is increased in patients with polycystic ovary syndrome. Therefore, it should be attended in prevention programs

  14. Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome

    DEFF Research Database (Denmark)

    Maas, Saskia M; Shaw, Adam C; Bikker, Hennie

    2015-01-01

    to delineate phenotype, natural history, variability, and genotype-phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5...... mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate...

  15. Discussão genetico-clinica sobre a Síndrome de Apert: a propósito de um caso

    Directory of Open Access Journals (Sweden)

    Aguinaldo Gonçalves

    1976-09-01

    Full Text Available Após breve introdução sobre a síndrome de Apert, é relatado um caso clínico, sendo destacada a conduta genético-clínica. A discussão revela como os aspectos genéticos envolvidos orientam o raciocínio clínico.

  16. Establishing SON in 21q22.11 as a cause a new syndromic form of intellectual disability: Possible contribution to Braddock-Carey syndrome phenotype.

    Science.gov (United States)

    Takenouchi, Toshiki; Miura, Kiyokuni; Uehara, Tomoko; Mizuno, Seiji; Kosaki, Kenjiro

    2016-10-01

    A recent study of exome analyses in 109 patients with undiagnosed diseases included a 5-year-old girl with intellectual disability and multiple congenital anomalies, who had an apparently de novo frameshift mutation in SON. However, the combination of the truncating mutation in SON and the phenotype has not been reproduced until date, and it remains unclear if this combination represents a distinctive disease entity. Here we report an additional male with intellectual disability, congenital heart disease, distinctive facial features with curly hair and protruding ears, and long slender extremities, and hyperextensible joints. Exome analysis showed that he had the same de novo frameshift mutation in SON in a heterozygous state. Along with the first and original description of the apparently de novo truncating mutation in SON mentioned above, we have established that haploinsufficiency of SON causes a new recognizable syndrome of intellectual disability. SON is located within 21q22.11, a critical region for Braddock-Carey syndrome, which is characterized by congenital thrombocytopenia, intellectual disability, micrognathia, and a distinctive facies. Therefore, we suggest that the intellectual disability observed in Braddock-Carey syndrome could be accounted for by haploinsufficiency of SON. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. Gender, genotype, and phenotype differences in Smith-Magenis syndrome: a meta-analysis of 105 cases.

    Science.gov (United States)

    Edelman, E A; Girirajan, S; Finucane, B; Patel, P I; Lupski, J R; Smith, A C M; Elsea, S H

    2007-06-01

    Smith-Magenis syndrome (SMS) is a multisystem disorder characterized by developmental delay and mental retardation, a distinctive behavioral phenotype, and sleep disturbance. We undertook a comprehensive meta-analysis to identify genotype-phenotype relationships to further understand the clinical variability and genetic factors involved in SMS. Clinical and molecular information on 105 patients with SMS was obtained through research protocols and a review of the literature and analyzed using Fisher's exact test with two-tailed p values. Several differences in these groups of patients were identified based on genotype and gender. Patients with RAI1 mutation were more likely to exhibit overeating, obesity, polyembolokoilamania, self-hugging, muscle cramping, and dry skin and less likely to have short stature, hearing loss, frequent ear infections, and heart defects when compared with patients with deletion, while a subset of small deletion cases with deletions spanning from TNFRSF13B to MFAP4 was less likely to exhibit brachycephaly, dental anomalies, iris abnormalities, head-banging, and hyperactivity. Significant differences between genders were also identified, with females more likely to have myopia, eating/appetite problems, cold hands and feet, and frustration with communication when compared with males. These results confirm previous findings and identify new genotype-phenotype associations including differences in the frequency of short stature, hearing loss, ear infections, obesity, overeating, heart defects, self-injury, self-hugging, dry skin, seizures, and hyperactivity among others based on genotype. Additional studies are required to further explore the relationships between genotype and phenotype and any potential discrepancies in health care and parental attitudes toward males and females with SMS.

  18. A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice1

    Science.gov (United States)

    Kauffman, Alexander S.; Thackray, Varykina G.; Ryan, Genevieve E.; Tolson, Kristen P.; Glidewell-Kenney, Christine A.; Semaan, Sheila J.; Poling, Matthew C.; Iwata, Nahoko; Breen, Kellie M.; Duleba, Antoni J.; Stener-Victorin, Elisabet; Shimasaki, Shunichi; Webster, Nicholas J.; Mellon, Pamela L.

    2015-01-01

    Polycystic ovary syndrome (PCOS) pathophysiology is poorly understood, due partly to lack of PCOS animal models fully recapitulating this complex disorder. Recently, a PCOS rat model using letrozole (LET), a nonsteroidal aromatase inhibitor, mimicked multiple PCOS phenotypes, including metabolic features absent in other models. Given the advantages of using genetic and transgenic mouse models, we investigated whether LET produces a similar PCOS phenotype in mice. Pubertal female C57BL/6N mice were treated for 5 wk with LET, which resulted in increased serum testosterone and normal diestrus levels of estradiol, similar to the hyperandrogenemia and follicular phase estrogen levels of PCOS women. As in PCOS, ovaries from LET mice were larger, polycystic, and lacked corpora lutea versus controls. Most LET females were acyclic, and all were infertile. LET females displayed elevated serum LH levels and higher Lhb mRNA in the pituitary. In contrast, serum FSH and Fshb were significantly reduced in LET females, demonstrating differential effects on gonadotropins, as in PCOS. Within the ovary, LET females had higher Cyp17, Cyp19, and Fsh receptor mRNA expression. In the hypothalamus, LET females had higher kisspeptin receptor mRNA expression but lower progesterone receptor mRNA levels. LET females also gained more weight than controls, had increased abdominal adiposity and adipocyte size, elevated adipose inflammatory mRNA levels, and impaired glucose tolerance, mirroring the metabolic phenotype in PCOS women. This is the first report of a LET paradigm in mice that recapitulates both reproductive and metabolic PCOS phenotypes and will be useful to genetically probe the PCOS condition. PMID:26203175

  19. [Gene mutation and clinical phenotype analysis of patients with Noonan syndrome and hypertrophic cardiomyopathy].

    Science.gov (United States)

    Liu, X H; Ding, W W; Han, L; Liu, X R; Xiao, Y Y; Yang, J; Mo, Y

    2017-10-02

    Objective: To analyze the gene mutations and clinical features of patients with Noonan syndrome and hypertrophic cardiomyopathy. Method: Determined the mutation domain in five cases diagnosed with Noonan syndrome and hypertrophic cardiomyopathy and identified the relationship between the mutant domain and hypertrophic cardiomyopathy by searching relevant articles in pubmed database. Result: Three mutant genes (PTPN11 gene in chromosome 12, RIT1 gene in chromosome 1 and RAF1 gene in chromosome 3) in five cases all had been reported to be related to hypertrophic cardiomyopathy. The reported hypertrophic cardiomyopathy relevant genes MYPN, MYH6 and MYBP3 had also been found in case 1 and 2. Patients with same gene mutation had different clinical manifestations. Both case 4 and 5 had RAF1 mutation (c.770C>T). However, case 4 had special face, low IQ, mild pulmonary artery stenosis, and only mild ventricular hypertrophy. Conclusion: Noonan syndrome is a genetic heterogeneity disease. Our study identified specific gene mutations that could result in Noonan syndrome with hypertrophic cardiomyopathy through molecular biology methods. The results emphasize the importance of gene detection in the management of Noonan syndrome.

  20. Wolfram syndrome in the Polish population: novel mutations and genotype-phenotype correlation.

    Science.gov (United States)

    Zmyslowska, A; Borowiec, M; Antosik, K; Szalecki, M; Stefanski, A; Iwaniszewska, B; Jedrzejczyk, M; Pietrzak, I; Mlynarski, W

    2011-11-01

    Wolfram syndrome is a rare form of diabetes mellitus associated with optic atrophy and disorders of different organs (e.g. diabetes insipidus, hearing loss, ataxia, anaemia and many others). This syndrome is caused by recessive mutations in the wolframin gene (WFS1) localized on chromosome 4p16·1. The aim of this study was to identify the causative mutations in WFS1 in a group of Polish patients with suspected Wolfram syndrome. Nine patients with clinical symptoms consistent with Wolfram syndrome (at least diabetes mellitus and optic atrophy) and 22 first-degree relatives were examined. The molecular analysis was carried out by direct sequencing of the exons, the exon-intron junctions, and the 5' and 3' untranslated regions of WFS1. Nine different mutations in WFS1 (five of them novel) were identified in the nine patients. Six patients were homozygous for the following mutations: V412fs, S443R, W539X, V659fs. They developed diabetes at a mean age of 5·2 years. Three patients were compound-heterozygous for the following mutations: S167fs, Q392X, Y513fs, W648X, V779G. They developed diabetes at a mean age of 6·5 years. Mean age of diagnosis of diabetes among the Polish patients was typical for Wolfram syndrome; however, compound-heterozygous patients were slightly older at diabetes onset. © 2011 Blackwell Publishing Ltd.

  1. Attention deficits predict phenotypic outcomes in syndrome-specific and domain-specific ways

    Directory of Open Access Journals (Sweden)

    Kim eCornish

    2012-07-01

    Full Text Available Attentional difficulties, both at home and in the classroom, are reported across a number of neurodevelopmental disorders. However, exactly how attention influences early socio-cognitive learning remains unclear. We addressed this question both concurrently and longitudinally in a cross-syndrome design, with respect to the communicative domain of vocabulary and to the cognitive domain of early literacy, and then extended the analysis to social behavior. Participants were young children (aged 4 to 9 years at Time 1 with either Williams syndrome (WS, N=26 or Down syndrome (DS, N=26 and typically developing controls (N=103. Children with WS displayed significantly greater attentional deficits (as indexed by teacher report of behavior typical of attention deficit hyperactivity disorder, ADHD than children with DS, but both groups had greater attentional problems than the controls. Despite their attention differences, children with DS and those with WS were equivalent in their cognitive abilities of reading single words, both at Time 1 and 12 months later, at Time 2, although they differed in their early communicative abilities in terms of vocabulary. Greater ADHD-like behaviors predicted poorer subsequent literacy for children with DS, but not for children with WS, pointing to syndrome-specific attentional constraints on specific aspects of early development. Overall, our findings highlight the need to investigate more precisely whether and, if so, how, syndrome-specific profiles of behavioral difficulties constrain learning and socio-cognitive outcomes across different domains.

  2. L’accesso alle chiese aperte al culto: fruizione cultuale, fruizione turistica, questione del ticket

    Directory of Open Access Journals (Sweden)

    Fabio Franceschi

    2014-10-01

    Full Text Available Contributo sottoposto a valutazioneSOMMARIO: 1. Premessa. Posizione del problema - 2. La duplice natura della chiesa-edificio: bene liturgico e bene culturale ecclesiale. Problematiche discendenti dal possibile interagire, in ordine alla fruibilità degli edifici di culto monumentali, della dimensione cultuale e di quella culturale - 3. Il ticket d’ingresso e la “gestione museale” delle chiese: alcuni dati sulla diffusione del fenomeno - 4. Le ragioni a favore del ticket d’ingresso. I benefici ricavabili dagli introiti della bigliettazione. Considerazioni critiche - 5. Le ragioni contrarie: a il necessario rispetto delle esigenze di natura religiosa e pastorale - 6. (segue b le motivazioni giuridiche: elementi di contrasto con la normativa canonica e civile sulle chiese aperte al culto pubblico - 7. (segue c le ragioni di opportunità: l’odiosità della prassi del ticket nella percezione dell’opinione pubblica - 8. I richiami della Commissione paritetica e le iniziative della Conferenza Episcopale Italiana - 9. La nota del Consiglio Episcopale Permanente della CEI: cosa cambia (ma qualcosa cambia davvero? - 10. Riflessioni a margine della nota. Valore giuridico del documento e valenza del richiamo, in esso contenuto, all’osservanza del principio dell’accesso gratuito alle chiese aperte al culto.  Il turismo religioso-culturale come opportunità pastorale (prima ancora che economica - 11 (segue Eliminazione della prassi del ticket e valorizzazione di altre possibili forme di introito legate al turismo religioso - 12. (segue Offerte volontarie, fund raising, sfruttamento dell’indotto - 13. Fruizione differenziata degli edifici di culto monumentali in ragione dei diversi possibili utenti e ipotesi straordinarie di possibile mantenimento del ticket - 14. Promozione e valorizzazione, anche in senso economico, degli edifici di culto monumentali e ruolo delle comunità cristiane. Il volontariato come strumento per garantire il

  3. The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype.

    NARCIS (Netherlands)

    Bon, B.W.M. van; Koolen, D.A.; Brueton, L.; McMullan, D.; Lichtenbelt, K.D.; Ades, L.C.; Peters, G.; Gibson, K.; Moloney, S.; Novara, F.; Pramparo, T.; Bernardina, B. Dalla; Zoccante, L.; Balottin, U.; Piazza, F.; Pecile, V.; Gasparini, P.; Guerci, V.; Kets, M.; Pfundt, R.; Brouwer, A.P.M. de; Veltman, J.A.; Leeuw, N. de; Wilson, M.; Antony, J.; Reitano, S.; Luciano, D.; Fichera, M.; Romano, C; Brunner, H.G.; Zuffardi, O.; Vries, L.B.A. de

    2010-01-01

    Six submicroscopic deletions comprising chromosome band 2q23.1 in patients with severe mental retardation (MR), short stature, microcephaly and epilepsy have been reported, suggesting that haploinsufficiency of one or more genes in the 2q23.1 region might be responsible for the common phenotypic

  4. Ogilvie syndrome: a potentially life-threatening phenotype of immobilization hypercalcemia.

    Science.gov (United States)

    Tsai, Wei-Chi; Chuang, Tzu-Yi; Chen, Mei-Chen; Chen, Jui-Chang; Tsao, Yu-Tzu

    2014-07-01

    Ogilvie syndrome, also known as acute colonic pseudo-obstruction, is characterized by the clinical presentation and imaging evidence of acute colonic obstruction in the absence of a mechanical cause. Several comorbidities and serious associated medical or surgical conditions have been described to be relevant to this syndrome. In general, a preferred initial management with favorable treatment outcomes is virtually to correct underlying disorders. Although disrupted electrolyte homeostasis may induce impaired colonic motility, hypercalcemia secondary to immobilization as a major culprit in this syndrome has rarely been studied. In this report, we profiled radiographic features, therapeutic strategies, and pathogenetic hypothesis of this clinical entity and highlighted the need for clinicians to maintain awareness of this distinct manifestation.

  5. Down syndrome and personalized medicine: changing paradigms from genotype to phenotype to treatment.

    Science.gov (United States)

    McCabe, Linda L; McCabe, Edward R B

    2013-03-01

    Personalized Medicine represents a paradigm shift in the conceptual framework of research and clinical care. This shift argues that Down syndrome is a treatable condition, and therefore we must invest in research to improve outcomes. Individuals with Down syndrome have varying levels of increased risk for a number of co-morbidities, including infantile spasms and early onset Alzheimer's disease. We will review research in these associated conditions to show how investigators are attempting to identify biomarkers, including genomic, epigenomic, proteomic and metabolomic "signatures" that will predict who may be at risk to develop a specific co-morbidity prior to onset and will provide novel targets for therapeutic development. This Personalized Medicine approach will permit predictive and preventive approaches for individuals at increased risk for co-morbidities. The support for clinical trials among individuals with Down syndrome is beginning to overcome the "culture of intractability" that has surrounded this disorder. © 2012 The Authors. Congenital Anomalies © 2012 Japanese Teratology Society.

  6. Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice.

    Science.gov (United States)

    Guo, Weirui; Molinaro, Gemma; Collins, Katie A; Hays, Seth A; Paylor, Richard; Worley, Paul F; Szumlinski, Karen K; Huber, Kimberly M

    2016-02-17

    Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmr1 knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmr1 KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, H1a, rescues many phenotypes of Fmr1 KO mice. These results suggested that disruption of mGlu5-Homer leads to phenotypes of FXS. To test this idea, we examined mice with a knockin mutation of mGlu5 (F1128R; mGlu5(R/R)) that abrogates binding to Homer. Although FMRP levels were normal, mGlu5(R/R) mice mimicked multiple phenotypes of Fmr1 KO mice, including reduced mGlu5 association with the postsynaptic density, enhanced constitutive mGlu5 signaling to protein synthesis, deficits in agonist-induced translational control, protein synthesis-independent LTD, neocortical hyperexcitability, audiogenic seizures, and altered behaviors, including anxiety and sensorimotor gating. These results reveal new roles for the Homer scaffolds in regulation of mGlu5 function and implicate a specific molecular mechanism in a complex brain disease. Abnormal function of the metabotropic, or Gq-coupled, glutamate receptor 5 (mGlu5) has been implicated in neurodevelopmental disorders, including a genetic cause of intellectual disability and autism called fragile X syndrome. In brains of a mouse model of fragile X, mGlu5 is less associated with its binding partner Homer, a scaffolding protein that regulates mGlu5 localization to synapses and its ability to activate biochemical signaling pathways. Here we show that a mouse expressing a mutant mGlu5 that cannot bind to Homer is sufficient to mimic many of the biochemical, neurophysiological, and

  7. A patient with monosomy 1p36, atypical features and phenotypic similarities with Cantu syndrome.

    Science.gov (United States)

    Tan, Tiong Yang; Bankier, Agnes; Slater, Howard R; Northrop, Emma L; Zacharin, Margaret; Savarirayan, Ravi

    2005-12-15

    We report on a 16-year-old boy with a distal 1p36 deletion with some clinical features consistent with Cantu syndrome (OMIM#239850). He also has hypercholesterolemia, type II diabetes, recurrent bony fractures, and non-alcoholic steatohepatitis, not previously described in either condition. The 1p36 deletion was detected in a screen of all chromosome subtelomeres using multiplex ligation-dependent probe amplification and was verified using FISH with a region-specific BAC clone. We suggest that patients suspected of having Cantu syndrome, especially those with unusual or more severe manifestations be analyzed for distal 1p36 deletions. 2005 Wiley-Liss, Inc.

  8. Sodium-potassium ATPase emerges as a player in hippocampal phenotypes of Angelman syndrome mice.

    Science.gov (United States)

    Hallengren, Jada J; Vaden, Ryan J

    2014-07-01

    Angelman syndrome is a neurodevelopmental disorder characterized by intellectual disabilities, ataxia, and unusually happy affect. The hippocampal pyramidal cells of Angelman syndrome model mice have altered intrinsic membrane properties, which Kaphzan et al. (Cell Rep 4: 405-412, 2013) demonstrate can be corrected by genetic reduction of the α1-subunit of the sodium-potassium ATPase. Intriguingly, this manipulation also restores hippocampal long-term potentiation and learning. In this Neuro Forum, we discuss translational implications of this work and remaining questions left in its wake. Copyright © 2014 the American Physiological Society.

  9. Systemic vascular phenotypes of Loeys-Dietz syndrome in a child carrying a de novo R381P mutation in TGFBR2: a case report.

    Science.gov (United States)

    Uike, Kiyoshi; Matsushita, Yuki; Sakai, Yasunari; Togao, Osamu; Nagao, Michinobu; Ishizaki, Yoshito; Nagata, Hazumu; Yamamura, Kenichiro; Torisu, Hiroyuki; Hara, Toshiro

    2013-11-12

    Loeys-Dietz syndrome, also known as Marfan syndrome type II, is a rare connective tissue disorder caused by dominant mutations in transforming growth factor-beta receptors (TGFBR1 and 2). We report a 7-year-old Japanese boy with Loeys-Dietz syndrome who carried a novel, de novo missense mutation in TGFBR2 (c.1142g > c, R381P). He showed dysmorphic faces and skeletal malformations that were typical in previous cases with Loeys-Dietz syndrome. The cardiac studies disclosed the presence of markedly dilated aortic root and patent ductus aorteriosus. The cranial magnetic resonance imaging (MRI) and angiography (MRA) detected the tortuous appearances of the bilateral middle cerebral and carotid arteries. This study depicts the systemic vascular phenotypes of a child with Loeys-Dietz syndrome that were caused by a novel heterozygous mutation of TGFR2. A large cohort with serial imaging studies for vascular phenotypes will be useful for delineating the genotype-phenotype correlations of Loeys-Dietz syndrome.

  10. CT and MRI of congenital nasal lesions in syndromic conditions

    Energy Technology Data Exchange (ETDEWEB)

    Ginat, Daniel T. [University of Chicago, Department of Radiology, Chicago, IL (United States); Robson, Caroline D. [Harvard Medical School, Department of Radiology, Boston Children' s Hospital, Boston, MA (United States)

    2015-07-15

    Congenital malformations of the nose can be associated with a variety of syndromes, including solitary median maxillary central incisor syndrome, CHARGE syndrome, Bosma syndrome, median cleft face syndrome, PHACES association, Bartsocas-Papas syndrome, Binder syndrome, duplication of the pituitary gland-plus syndrome and syndromic craniosynsotosis (e.g., Apert and Crouzon syndromes) among other craniofacial syndromes. Imaging with CT and MRI plays an important role in characterizing the nasal anomalies as well as the associated brain and cerebrovascular lesions, which can be explained by the intimate developmental relationship between the face and intracranial structures, as well as certain gene mutations. These conditions have characteristic imaging findings, which are reviewed in this article. (orig.)

  11. Redefining the non-dystrophic myotonic syndromes. Phenotypic characterisation based on genetic testing.

    NARCIS (Netherlands)

    Trip, J.

    2010-01-01

    Chapter 1 gives a general introduction to non-dystrophic myotonic syndromes (NDMs). Chapter 2 comprises a systematic review about drug treatment for myotonia. Three small crossover studies evaluated myotonia in myotonic dystrophy. Unfortunately, for the treatment of myotonia in NDMs we were unable

  12. Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations

    NARCIS (Netherlands)

    Fergelot, Patricia; van Belzen, Martine; van Gils, Julien; Afenjar, Alexandra; Armour, Christine M.; Arveiler, Benoit; Beets, Lex; Burglen, Lydie; Busa, Tiffany; Collet, Marie; Deforges, Julie; de Vries, Bert B. A.; Dominguez Garrido, Elena; Dorison, Nathalie; Dupont, Juliette; Francannet, Christine; Garciá-Minaúr, Sixto; Gabau Vila, Elisabeth; Gebre-Medhin, Samuel; Gener Querol, Blanca; Geneviève, David; Gérard, Marion; Gervasini, Cristina Giovanna; Goldenberg, Alice; Josifova, Dragana; Lachlan, Katherine; Maas, Saskia; Maranda, Bruno; Moilanen, Jukka S.; Nordgren, Ann; Parent, Philippe; Rankin, Julia; Reardon, Willie; Rio, Marlène; Roume, Joëlle; Shaw, Adam; Smigiel, Robert; Sojo, Amaia; Solomon, Benjamin; Stembalska, Agnieszka; Stumpel, Constance; Suarez, Francisco; Terhal, Paulien; Thomas, Simon; Touraine, Renaud; Verloes, Alain; Vincent-Delorme, Catherine; Wincent, Josephine; Peters, Dorien J. M.; Bartsch, Oliver; Larizza, Lidia; Lacombe, Didier; Hennekam, Raoul C.

    2016-01-01

    Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs

  13. Mapping of pain phenotypes in female patients with bladder pain syndrome/interstitial cystitis and controls

    DEFF Research Database (Denmark)

    Tripp, Dean A; Nickel, J Curtis; Wong, Jennifer

    2012-01-01

    Many bladder pain syndrome/interstitial cystitis (BPS/IC) patients report multiple pain locations outside the pelvis. No research has examined pain using a whole-body diagram, pain-associated adjustment factors, or the impact of pain in multiple body areas on patients' quality of life (QoL)....

  14. Phenotype, Cancer Risk, and Surveillance in Beckwith-Wiedemann Syndrome Depending on Molecular Genetic Subgroups

    NARCIS (Netherlands)

    Maas, Saskia M.; Vansenne, Fleur; Kadouch, Daniel J. M.; Ibrahim, Abdulla; Bliek, Jet; Hopman, Saskia; Mannens, Marcel M.; Merks, Johannes H. M.; Maher, Eamonn R.; Hennekam, Raoul C.

    Patients with Beckwith-Wiedemann syndrome (BWS) have an increased risk to develop cancer in childhood, especially Wilms tumor and hepatoblastoma. The risk varies depending on the cause of BWS. We obtained clinical and molecular data in our cohort of children with BWS, including tumor occurrences,

  15. Phenotype-genotype correlations in patients with Marinesco-Sjogren syndrome

    Czech Academy of Sciences Publication Activity Database

    Ezgu, F.; Krejčí, Pavel; Li, S.; de Sousa, P.

    2014-01-01

    Roč. 86, č. 1 (2014), s. 74-84 ISSN 0009-9163 Institutional support: RVO:68081707 Keywords : BIP-associated protein * endoplasmic reticulum stress * Marinesco-Sjogren Syndrome Subject RIV: BO - Biophysics Impact factor: 3.931, year: 2014

  16. Phenotype guided characterization and molecular analysis of Indian patients with long QT syndromes

    Directory of Open Access Journals (Sweden)

    Bijal Vyas

    2016-01-01

    Conclusions: This study in a cohort of Asian Indian patients highlights the mutation spectrum of common Long QT syndromes. The clinical utility for prevention of unexplained sudden cardiac deaths is an important sequel to identification of the mutation in at-risk family members.

  17. Examining the Language Phenotype in Children with Typical Development, Specific Language Impairment, and Fragile X Syndrome

    Science.gov (United States)

    Haebig, Eileen; Sterling, Audra; Hoover, Jill

    2016-01-01

    Purpose: One aspect of morphosyntax, finiteness marking, was compared in children with fragile X syndrome (FXS), specific language impairment (SLI), and typical development matched on mean length of utterance (MLU). Method: Nineteen children with typical development (mean age = 3.3 years), 20 children with SLI (mean age = 4.9 years), and 17 boys…

  18. The Behavioural Phenotype of Cornelia de Lange Syndrome: A Study of 56 Individuals

    Science.gov (United States)

    Basile, Emanuele; Villa, L.; Selicorni, A.; Molteni, M.

    2007-01-01

    Background: Few studies have investigated functional and behavioural variables of Cornelia de Lange Syndrome (CdLS) in a large sample of individuals. The aim of this study is to provide greater insight into the clinical, behavioural and cognitive characteristics that are associated with CdLS. Methods: In total, 56 individuals with CdLS…

  19. Autosomal recessive ichthyosis with hypotrichosis syndrome: further delineation of the phenotype

    NARCIS (Netherlands)

    Avrahami, L.; Maas, S.; Pasmanik-Chor, M.; Rainshtein, L.; Magal, N.; Smitt, J. H. S.; van Marle, J.; Shohat, M.; Basel-Vanagaite, L.

    2008-01-01

    Autosomal recessive ichthyosis with hypotrichosis (ARIH) syndrome, which is characterized by congenital ichthyosis, abnormal hair and corneal involvement, has recently been shown in one consanguineous Israeli Arab family to be caused by a mutation in the ST14 gene, which encodes serine protease

  20. Phenotype-Environment Interactions in Genetic Syndromes Associated with Severe or Profound Intellectual Disability

    Science.gov (United States)

    Tunnicliffe, Penny; Oliver, Chris

    2011-01-01

    The research literature notes both biological and operant theories of behavior disorder in individuals with intellectual disabilities. These two theories of genetic predisposition and operant reinforcement remain quite distinct; neither theory on its own is sufficient to explain challenging behavior in genetic syndromes and an integrated approach…

  1. Hypersociability in the behavioral phenotype of 17q21.31 microdeletion syndrome

    NARCIS (Netherlands)

    Egger, J.I.M.; Wingbermühle, P.A.M.; Verhoeven, W.M.A.; Dijkman, M.W.; Radke, S.; Bruijn, E.R.A. de; Vries, B. de; Kessels, R.P.C.; Koolen, D.A.

    2013-01-01

    The 17q21.31 microdeletion syndrome with its characteristic features including developmental delay, moderate intellectual disability, facial dysmorphisms, and anomalies of the brain and multiple organ systems was recently described. As to its behavioral profile, scarce data from clinical

  2. Changing facial phenotype in Cohen syndrome : towards clues for an earlier diagnosis

    NARCIS (Netherlands)

    El Chehadeh-Djebbar, Salima; Blair, Edward; Holder-Espinasse, Muriel; Moncla, Anne; Frances, Anne-Marie; Rio, Marlene; Debray, Francois-Guillaume; Rump, Patrick; Masurel-Paulet, Alice; Gigot, Nadege; Callier, Patrick; Duplomb, Laurence; Aral, Bernard; Huet, Frederic; Thauvin-Robinet, Christel; Faivre, Laurence

    Cohen syndrome (CS) is a rare autosomal recessive condition caused by mutations and/or large rearrangements in the VPS13B gene. CS clinical features, including developmental delay, the typical facial gestalt, chorioretinal dystrophy (CRD) and neutropenia, are well described. CS diagnosis is

  3. Further phenotypic expansion of 15q11.2 BP1-BP2 microdeletion (Burnside-Butler) syndrome.

    Science.gov (United States)

    Jerkovich, Adria M; Butler, Merlin G

    2014-01-01

    We report a 10-year-old Caucasian male identified with copy number variation detected by microarray analysis including a maternally inherited 15q11.2 microdeletion involving 4 genes, paternally inherited 13q12.2 microdeletion with 10 genes, and a de novo 2q14.3 duplication involving 4 genes. He had a history of speech delay, cognitive deficits, attention deficit hyperactivity disorder and a posterior lenticonus cataract removed at 5 yr of age. The genes on chromosomes 2 and 13 are not known to be involved with cataract formation, which lends further support of the role of the 15q11.2 region and additional evidence for phenotypic expansion of the 15q11.2 BP1-BP2 microdeletion (termed Burnside-Butler) syndrome.

  4. Vocalization patterns in young children with Down syndrome: Utilizing the language environment analysis (LENA) to inform behavioral phenotypes.

    Science.gov (United States)

    Parikh, Chandni; Mastergeorge, Ann M

    2017-01-01

    Children with Down syndrome (DS) are at higher risk for both delayed expressive language and poor speech intelligibility. The current study utilized the quantitative automated language environment analysis (LENA) to depict mother and child vocalizations and conversational patterns in the home of 43 children with DS, chronologically aged 24-64 months. Children with DS displayed fewer utterances than typically developing children; however, there was wide variability. Furthermore, children with DS did not show increased vocalization counts across their chronological ages. In contrast to previous findings, this study found that the mothers of children with DS had a reduced number of vocalizations. However, the vocalizations increased with age in comparison to mothers of typically developing children. Implications for targeted interventions that facilitate learning opportunities in bidirectional contexts for children with DS and their parents are discussed, with particular attention to quantify behavioral phenotypes utilizing a novel expressive language assessment tool.

  5. An unusual case of Cat-Eye syndrome phenotype and extragonadal mature teratoma: review of the literature.

    Science.gov (United States)

    Tzetis, Maria; Stefanaki, Kalliopi; Syrmou, Areti; Kosma, Konstantina; Leze, Eleni; Giannikou, Krinio; Oikonomakis, Vasilis; Sofocleous, Christalena; Choulakis, Michael; Kolialexi, Aggeliki; Makrythanasis, Periklis; Kitsiou-Tzeli, Sophia

    2012-07-01

    BACKGROUND Cat-Eye syndrome (CES) with teratoma has not been previously reported. We present the clinical and molecular findings of a 9-month-old girl with features of CES and also a palpable midline neck mass proved to be an extragonadal mature teratoma, additionally characterized by array comparative genomic hybridization (aCGH). RESULTS High resolution oligonucleotide-based aCGH confirmed that the supernumerary marker chromosome (SMC) derived from chromosome 22, as was indicated by molecular cytogenetic analysis with fluorescence in situ hybridization (FISH). Additionally, aCGH clarified the size, breakpoints, and gene content of the duplication (dup 22q11.1q11.21; size:1.6 Mb; breakpoints: 15,438,946-17,041,773; hg18). The teratoma tissue was also tested with aCGH, in which the CES duplication was not found, but the analysis revealed three aberrations: del Xp22.3 (108,864-2788,689; 2.7 Mb hg18), dup Yp11.2 (6688,491-7340,982; 0.65 Mb, hg18), and dup Yq11.2q11.23 (12,570,853-27,177,133; 14.61 Mb, hg18). These results indicated 46 XY (male) karyotype of the teratoma tissue, making this the second report of mature extragonadal teratoma in a female neonate, probably deriving from an included dizygotic twin of opposite sex (fetus in fetu). CONCLUSIONS Our findings extend the phenotypic spectrum of CES syndrome, a disorder with clinical variability, pointing out specific dosage-sensitive genes that might contribute to specific phenotypic features. Copyright © 2012 Wiley Periodicals, Inc.

  6. Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation

    Science.gov (United States)

    2011-01-01

    Background The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) (OMIM 225400) is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC 1.14.11.4) due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP) and hydroxylysyl pyridinoline (HP) crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal. Methods We describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome. Results Age at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial), independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients. Conclusion In view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity. PMID:21699693

  7. Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA: clinical, molecular and biochemical delineation

    Directory of Open Access Journals (Sweden)

    Kariminejad Ariana

    2011-06-01

    Full Text Available Abstract Background The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA (OMIM 225400 is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC 1.14.11.4 due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP and hydroxylysyl pyridinoline (HP crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal. Methods We describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome. Results Age at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial, independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients. Conclusion In view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity.

  8. Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.

    Science.gov (United States)

    Gripp, Karen W; Zand, Dina J; Demmer, Laurie; Anderson, Carol E; Dobyns, William B; Zackai, Elaine H; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L; Sol-Church, Katia

    2013-10-01

    Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis. Copyright © 2013 Wiley Periodicals, Inc.

  9. Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture.

    Directory of Open Access Journals (Sweden)

    Akira Shimamoto

    Full Text Available Werner syndrome (WS is a premature aging disorder characterized by chromosomal instability and cancer predisposition. Mutations in WRN are responsible for the disease and cause telomere dysfunction, resulting in accelerated aging. Recent studies have revealed that cells from WS patients can be successfully reprogrammed into induced pluripotent stem cells (iPSCs. In the present study, we describe the effects of long-term culture on WS iPSCs, which acquired and maintained infinite proliferative potential for self-renewal over 2 years. After long-term cultures, WS iPSCs exhibited stable undifferentiated states and differentiation capacity, and premature upregulation of senescence-associated genes in WS cells was completely suppressed in WS iPSCs despite WRN deficiency. WS iPSCs also showed recapitulation of the phenotypes during differentiation. Furthermore, karyotype analysis indicated that WS iPSCs were stable, and half of the descendant clones had chromosomal profiles that were similar to those of parental cells. These unexpected properties might be achieved by induced expression of endogenous telomerase gene during reprogramming, which trigger telomerase reactivation leading to suppression of both replicative senescence and telomere dysfunction in WS cells. These findings demonstrated that reprogramming suppressed premature senescence phenotypes in WS cells and WS iPSCs could lead to chromosomal stability over the long term. WS iPSCs will provide opportunities to identify affected lineages in WS and to develop a new strategy for the treatment of WS.

  10. Syndrome of extreme insulin resistance (Rabson-Mendenhall phenotype) with atrial septal defect: clinical presentation and treatment outcomes.

    Science.gov (United States)

    Dutta, Deep; Maisnam, Indira; Ghosh, Sujoy; Mukhopadhyay, Satinath; Chowdhury, Subhankar

    2013-01-01

    Syndrome of extreme insulin resistance (SEIR) is a rare spectrum disorder with a primary defect in insulin receptor signalling, noted primarily in children, and is often difficult to diagnose due to the clinical heterogeneity.SEIR was diagnosed in an adolescent girl with facial dysmorphism,exuberant scalp and body hair, severe acanthosis, lipoatrophy, dental abnormalities, and short stature (Rabson-Mendenhall phenotype). She had elevated fasting (422.95 pmol/L) and post-glucose insulin levels(>2083 pmol/L). Total body fat was decreased (11%; dual-energy X-ray absorptiometry). Basal growth hormone (GH) was increased (7.9 μg/L)with normal insuline-like growth factor 1 (37.6 nmol/L) suggestive of GH resistance. She had fatty liver and polycystic ovaries. Echocardiography revealed ostium secundum type atrial septal defect (ASD). Blood glucose normalized with pioglitazone (30 mg/day). Delayed development, severe insulin resistance, mild hyperglycemia, absence of ketosis, and remarkable response of hyperinsulinemia and hyperglycemia to pioglitazone which persisted even after 1 year of diagnosis are some of the notable features of this patient. This is perhaps the first report of occurrence of congenital heart disease (ASD) in a patient of SEIR (Rabson-Mendenhall phenotype). This report highlights the clinical features of SEIR and the role of insulin sensitizers like pioglitazone in the management of such patients.

  11. Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype

    Science.gov (United States)

    Martinelli, Simone; De Luca, Alessandro; Stellacci, Emilia; Rossi, Cesare; Checquolo, Saula; Lepri, Francesca; Caputo, Viviana; Silvano, Marianna; Buscherini, Francesco; Consoli, Federica; Ferrara, Grazia; Digilio, Maria C.; Cavaliere, Maria L.; van Hagen, Johanna M.; Zampino, Giuseppe; van der Burgt, Ineke; Ferrero, Giovanni B.; Mazzanti, Laura; Screpanti, Isabella; Yntema, Helger G.; Nillesen, Willy M.; Savarirayan, Ravi; Zenker, Martin; Dallapiccola, Bruno; Gelb, Bruce D.; Tartaglia, Marco

    2010-01-01

    RAS signaling plays a key role in controlling appropriate cell responses to extracellular stimuli and participates in early and late developmental processes. Although enhanced flow through this pathway has been established as a major contributor to oncogenesis, recent discoveries have revealed that aberrant RAS activation causes a group of clinically related developmental disorders characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, ectodermal and musculoskeletal anomalies, and increased risk for certain malignancies. Here, we report that heterozygous germline mutations in CBL, a tumor-suppressor gene that is mutated in myeloid malignancies and encodes a multivalent adaptor protein with E3 ubiquitin ligase activity, can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS), the most common condition of this disease family. Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes. Phenotypic heterogeneity and variable expressivity were documented. Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies. Mutations were shown to affect CBL-mediated receptor ubiquitylation and dysregulate signal flow through RAS. These findings document that germline mutations in CBL alter development to cause a clinically variable condition that resembles NS and that possibly predisposes to malignancies. PMID:20619386

  12. Genetic Reduction of the α1 Subunit of Na/K-ATPase Corrects Multiple Hippocampal Phenotypes in Angelman Syndrome

    Directory of Open Access Journals (Sweden)

    Hanoch Kaphzan

    2013-08-01

    Full Text Available Angelman syndrome (AS is associated with symptoms that include autism, intellectual disability, motor abnormalities, and epilepsy. We recently showed that AS model mice have increased expression of the alpha1 subunit of Na/K-ATPase (α1-NaKA in the hippocampus, which was correlated with increased expression of axon initial segment (AIS proteins. Our developmental analysis revealed that the increase in α1-NaKA expression preceded that of the AIS proteins. Therefore, we hypothesized that α1-NaKA overexpression drives AIS abnormalities and that by reducing its expression these and other phenotypes could be corrected in AS model mice. Herein, we report that the genetic normalization of α1-NaKA levels in AS model mice corrects multiple hippocampal phenotypes, including alterations in the AIS, aberrant intrinsic membrane properties, impaired synaptic plasticity, and memory deficits. These findings strongly suggest that increased expression of α1-NaKA plays an important role in a broad range of abnormalities in the hippocampus of AS model mice.

  13. Genetic reduction of the α1 subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in Angelman syndrome.

    Science.gov (United States)

    Kaphzan, Hanoch; Buffington, Shelly A; Ramaraj, Akila B; Lingrel, Jerry B; Rasband, Matthew N; Santini, Emanuela; Klann, Eric

    2013-08-15

    Angelman syndrome (AS) is associated with symptoms that include autism, intellectual disability, motor abnormalities, and epilepsy. We recently showed that AS model mice have increased expression of the alpha1 subunit of Na/K-ATPase (α1-NaKA) in the hippocampus, which was correlated with increased expression of axon initial segment (AIS) proteins. Our developmental analysis revealed that the increase in α1-NaKA expression preceded that of the AIS proteins. Therefore, we hypothesized that α1-NaKA overexpression drives AIS abnormalities and that by reducing its expression these and other phenotypes could be corrected in AS model mice. Herein, we report that the genetic normalization of α1-NaKA levels in AS model mice corrects multiple hippocampal phenotypes, including alterations in the AIS, aberrant intrinsic membrane properties, impaired synaptic plasticity, and memory deficits. These findings strongly suggest that increased expression of α1-NaKA plays an important role in a broad range of abnormalities in the hippocampus of AS model mice. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  14. The Social Behavioral Phenotype in Boys and Girls with an Extra X Chromosome (Klinefelter Syndrome and Trisomy X): A Comparison with Autism Spectrum Disorder

    Science.gov (United States)

    van Rijn, Sophie; Stockmann, Lex; Borghgraef, Martine; Bruining, Hilgo; van Ravenswaaij-Arts, Conny; Govaerts, Lutgarde; Hansson, Kerstin; Swaab, Hanna

    2014-01-01

    The present study aimed to gain more insight in the social behavioral phenotype, and related autistic symptomatology, of children with an extra X chromosome in comparison to children with ASD. Participants included 60 children with an extra X chromosome (34 boys with Klinefelter syndrome and 26 girls with Trisomy X), 58 children with ASD and 106…

  15. Irritable bowel syndrome-diarrhea: characterization of genotype by exome sequencing, and phenotypes of bile acid synthesis and colonic transit

    Science.gov (United States)

    Klee, Eric W.; Shin, Andrea; Carlson, Paula; Li, Ying; Grover, Madhusudan; Zinsmeister, Alan R.

    2013-01-01

    The study objectives were: to mine the complete exome to identify putative rare single nucleotide variants (SNVs) associated with irritable bowel syndrome (IBS)-diarrhea (IBS-D) phenotype, to assess genes that regulate bile acids in IBS-D, and to explore univariate associations of SNVs with symptom phenotype and quantitative traits in an independent IBS cohort. Using principal components analysis, we identified two groups of IBS-D (n = 16) with increased fecal bile acids: rapid colonic transit or high bile acids synthesis. DNA was sequenced in depth, analyzing SNVs in bile acid genes (ASBT, FXR, OSTα/β, FGF19, FGFR4, KLB, SHP, CYP7A1, LRH-1, and FABP6). Exome findings were compared with those of 50 similar ethnicity controls. We assessed univariate associations of each SNV with quantitative traits and a principal components analysis and associations between SNVs in KLB and FGFR4 and symptom phenotype in 405 IBS, 228 controls and colonic transit in 70 IBS-D, 71 IBS-constipation. Mining the complete exome did not reveal significant associations with IBS-D over controls. There were 54 SNVs in 10 of 11 bile acid-regulating genes, with no SNVs in FGF19; 15 nonsynonymous SNVs were identified in similar proportions of IBS-D and controls. Variations in KLB (rs1015450, downstream) and FGFR4 [rs434434 (intronic), rs1966265, and rs351855 (nonsynonymous)] were associated with colonic transit (rs1966265; P = 0.043), fecal bile acids (rs1015450; P = 0.064), and principal components analysis groups (all 3 FGFR4 SNVs; P transit (P = 0.066). Thus exome sequencing identified additional variants in KLB and FGFR4 associated with bile acids or colonic transit in IBS-D. PMID:24200957

  16. The impact of self-reported ethnicity versus genetic ancestry on phenotypic characteristics of polycystic ovary syndrome (PCOS).

    Science.gov (United States)

    Louwers, Y V; Lao, O; Fauser, B C J M; Kayser, M; Laven, J S E

    2014-10-01

    It is well established that ethnicity is associated with the phenotype of polycystic ovary syndrome (PCOS). Self-reported ethnicity was shown to be an inaccurate proxy for ethnic origin in other disease traits, and it remains unclear how in PCOS patients self-reported ethnicity compares with a biological proxy such as genetic ancestry. We compared the impact of self-reported ethnicity versus genetic ancestry on PCOS and tested which of these 2 classifications better predicts the variability in phenotypic characteristics of PCOS. A total of 1499 PCOS patients from The Netherlands, comprising 11 self-reported ethnic groups of European, African, American, and Asian descent were genotyped with the Illumina 610K Quad BeadChip and merged with the data genotyped with the Illumina HumanHap650K available for the reference panel collected by the Human Genome Diversity Project (HGDP), in a collaboration with the Centre Etude Polymorphism Humain (CEPH), including 53 populations for ancestry reference. Algorithms for inferring genetic relationships among individuals, including multidimensional scaling and ADMIXTURE, were applied to recover genetic ancestry for each individual. Regression analysis was used to determine the best predictor for the variability in PCOS characteristics. The association between self-reported ethnicity and genetic ancestry was moderate. For amenorrhea, total follicle count, body mass index, SHBG, dehydroepiandrosterone sulfate, and insulin, mainly genetic ancestry clusters ended up in the final models (P values ancestry. Self-reported ancestry is not a perfect proxy for genetic ancestry in patients with PCOS, emphasizing that by using genetic ancestry data instead of self-reported ethnicity, PCOS-relevant misclassification can be avoided. Moreover, because genetic ancestry explained a larger proportion of phenotypic variability associated with PCOS than self-reported ethnicity, future studies should focus on genetic ancestry verification of PCOS

  17. Defining constant versus variable phenotypic features of women with polycystic ovary syndrome using different ethnic groups and populations.

    Science.gov (United States)

    Welt, C K; Arason, G; Gudmundsson, J A; Adams, J; Palsdóttir, H; Gudlaugsdóttir, G; Ingadóttir, G; Crowley, W F

    2006-11-01

    The phenotype of women with polycystic ovary syndrome (PCOS) is variable, depending on the ethnic background. The phenotypes of women with PCOS in Iceland and Boston were compared. The study was observational with a parallel design. Subjects were studied in an outpatient setting. Women, aged 18-45 yr, with PCOS defined by hyperandrogenism and fewer than nine menses per year, were examined in Iceland (n = 105) and Boston (n = 262). PCOS subjects underwent a physical exam, fasting blood samples for androgens, gonadotropins, metabolic parameters, and a transvaginal ultrasound. The phenotype of women with PCOS was compared between Caucasian women in Iceland and Boston and among Caucasian, African-American, Hispanic, and Asian women in Boston. Androstenedione (4.0 +/- 1.3 vs. 3.5 +/- 1.2 ng/ml; P testosterone (54.0 +/- 25.7 vs. 66.2 +/- 35.6 ng/dl; P Caucasian Icelandic compared with Boston women with PCOS. There were no differences in fasting blood glucose, insulin, or homeostasis model assessment in body mass index-matched Caucasian subjects from Iceland or Boston or in different ethnic groups in Boston. Polycystic ovary morphology was demonstrated in 93-100% of women with PCOS in all ethnic groups. The data demonstrate differences in the reproductive features of PCOS without differences in glucose and insulin in body mass index-matched populations. These studies also suggest that measuring androstenedione is important for the documentation of hyperandrogenism in Icelandic women. Finally, polycystic ovary morphology by ultrasound is an almost universal finding in women with PCOS as defined by hyperandrogenism and irregular menses.

  18. Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype.

    Science.gov (United States)

    Bramswig, Nuria C; Caluseriu, O; Lüdecke, H-J; Bolduc, F V; Noel, N C L; Wieland, T; Surowy, H M; Christen, H-J; Engels, H; Strom, T M; Wieczorek, D

    2017-03-01

    Chromatin remodeling is a complex process shaping the nucleosome landscape, thereby regulating the accessibility of transcription factors to regulatory regions of target genes and ultimately managing gene expression. The SWI/SNF (switch/sucrose nonfermentable) complex remodels the nucleosome landscape in an ATP-dependent manner and is divided into the two major subclasses Brahma-associated factor (BAF) and Polybromo Brahma-associated factor (PBAF) complex. Somatic mutations in subunits of the SWI/SNF complex have been associated with different cancers, while germline mutations have been associated with autism spectrum disorder and the neurodevelopmental disorders Coffin-Siris (CSS) and Nicolaides-Baraitser syndromes (NCBRS). CSS is characterized by intellectual disability (ID), coarsening of the face and hypoplasia or absence of the fifth finger- and/or toenails. So far, variants in five of the SWI/SNF subunit-encoding genes ARID1B, SMARCA4, SMARCB1, ARID1A, and SMARCE1 as well as variants in the transcription factor-encoding gene SOX11 have been identified in CSS-affected individuals. ARID2 is a member of the PBAF subcomplex, which until recently had not been linked to any neurodevelopmental phenotypes. In 2015, mutations in the ARID2 gene were associated with intellectual disability. In this study, we report on two individuals with private de novo ARID2 frameshift mutations. Both individuals present with a CSS-like phenotype including ID, coarsening of facial features, other recognizable facial dysmorphisms and hypoplasia of the fifth toenails. Hence, this study identifies mutations in the ARID2 gene as a novel and rare cause for a CSS-like phenotype and enlarges the list of CSS-like genes.

  19. [Neuropsychiatric phenotype of Angelman syndrome and clinical care: report of seven cases].

    Science.gov (United States)

    Cote-Orozco, Juan E; Mera-Solarte, Paola Del Rocío; Espinosa-García, Eugenia

    2017-04-01

    Angelman syndrome is a neurogenetic disorder caused by a lack or reduction of expression of UBE3A located within chromosome 15, which codes for ubiquitin protein ligase E3A, which has a key role in synaptic development and neural plasticity. Its main features are developmental delay/intellectual disability, lack of speech, a characteristic behavioural profile, and epilepsy. We describe clinical features and management of seven cases with 15q11-13 deletion. Due to their life expectancy, knowing and managing its comorbidities is crucial to improve their quality of life. We review the diagnosis and long-term clinical care of patients with Angelman syndrome. Sociedad Argentina de Pediatría.

  20. Phenotypic aspects of oral strains of Candida albicans in children with down's syndrome

    Directory of Open Access Journals (Sweden)

    E. L. Ribeiro

    Full Text Available The aim of this article is to characterize the biological aspects of oral strains of C. albicans in children with Down's syndrome. These yeasts were analyzed as to their macromorphological and enzymatic aspects and were tested as to their in vitro susceptibility to antifungal drugs using broth microdilution to determine the minimum inhibitory concentration (MIC. The morphotyping revealed that all oral C. albicans isolates from children with Down's syndrome promoted the formation of fringes regardless of size, while the control group presented smaller fringes. All oral C. albicans strains produced proteinase, but those with phospholipolytic activity showed greater enzyme capacity in the test group. In vitro susceptibility showed that all oral C. albicans isolates were sensitive to the drugs used.

  1. Phenotypic discordance in a family with monozygotic twins and non-syndromic cleft lip and palate

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    Wyszynski, D.F. [Johns Hopkins Univ., Baltimore, MD (United States)]|[National Center for Human Genome Research, Bethesda, MD (United States); Lewanda, A.F. [Johnson Hopkins Hospital, Baltimore, MD (United States)]|[Children`s National Medical Center, Washington, DC (United States); Beaty, T.H. [Johns Hopkins Univ., Balitomre, MD (United States)

    1996-12-30

    Despite considerable research, the cause of non-syndromic cleft lip with or without cleft palate (NSCLP) is still an enigma. Case-control and cohort studies have searched for environmental factors that might influence the development of this common malformation, such as maternal cigarette smoking, periconceptional supplementation of folic acid and multivitamins, agricultural chemical use, and place of residence, among others. However, these studies are subject to numerous biases, and their results have often been contradictory and inconclusive. 41 refs., 1 fig.

  2. Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome.

    Science.gov (United States)

    Anderson, G; Berk, M; Maes, M

    2014-02-01

    Somatization is a symptom cluster characterized by 'psychosomatic' symptoms, that is, medically unexplained symptoms, and is a common component of other conditions, including depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This article reviews the data regarding the pathophysiological foundations of 'psychosomatic' symptoms and the implications that this has for conceptualization of what may more appropriately be termed physio-somatic symptoms. This narrative review used papers published in PubMed, Scopus, and Google Scholar electronic databases using the keywords: depression and chronic fatigue, depression and somatization, somatization and chronic fatigue syndrome, each combined with inflammation, inflammatory, tryptophan, and cell-mediated immune (CMI). The physio-somatic symptoms of depression, ME/CFS, and somatization are associated with specific biomarkers of inflammation and CMI activation, which are correlated with, and causally linked to, changes in the tryptophan catabolite (TRYCAT) pathway. Oxidative and nitrosative stress induces damage that increases neoepitopes and autoimmunity that contribute to the immuno-inflammatory processes. These pathways are all known to cause physio-somatic symptoms, including fatigue, malaise, autonomic symptoms, hyperalgesia, intestinal hypermotility, peripheral neuropathy, etc. Biological underpinnings, such as immune-inflammatory pathways, may explain, at least in part, the occurrence of physio-somatic symptoms in depression, somatization, or myalgic encephalomyelitis/chronic fatigue syndrome and thus the clinical overlap among these disorders. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Truncating mutation in the NHS gene: phenotypic heterogeneity of Nance-Horan syndrome in an asian Indian family.

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    Ramprasad, Vedam Lakshmi; Thool, Alka; Murugan, Sakthivel; Nancarrow, Derek; Vyas, Prateep; Rao, Srinivas Kamalakar; Vidhya, Authiappan; Ravishankar, Krishnamoorthy; Kumaramanickavel, Govindasamy

    2005-01-01

    A four-generation family containing eight affected males who inherited X-linked developmental lens opacity and microcornea was studied. Some members in the family had mild to moderate nonocular clinical features suggestive of Nance-Horan syndrome. The purpose of the study was to map genetically the gene in the large 57-live-member Asian-Indian pedigree. PCR-based genotyping was performed on the X-chromosome, by using fluorescent microsatellite markers (10-cM intervals). Parametric linkage analysis was performed by using two disease models, assuming either recessive or dominant X-linked transmission by the MLINK/ILINK and FASTLINK (version 4.1P) programs (http:www.hgmp.mrc.ac.uk/; provided in the public domain by the Human Genome Mapping Project Resources Centre, Cambridge, UK). The NHS gene at the linked region was screened for mutation. By fine mapping, the disease gene was localized to Xp22.13. Multipoint analysis placed the peak LOD of 4.46 at DSX987. The NHS gene mapped to this region. Mutational screening in all the affected males and carrier females (heterozygous form) revealed a truncating mutation 115C-->T in exon 1, resulting in conversion of glutamine to stop codon (Q39X), but was not observed in unaffected individuals and control subjects. conclusions. A family with X-linked Nance-Horan syndrome had severe ocular, but mild to moderate nonocular, features. The clinical phenotype of the truncating mutation (Q39X) in the NHS gene suggests allelic heterogeneity at the NHS locus or the presence of modifier genes. X-linked families with cataract should be carefully examined for both ocular and nonocular features, to exclude Nance-Horan syndrome. RT-PCR analysis did not suggest nonsense-mediated mRNA decay as the possible mechanism for clinical heterogeneity.

  4. 46, XY, del (3) (pter-->p25) syndrome: further delineation of the clinical phenotype.

    Science.gov (United States)

    Benini, D; Vino, L; Vecchini, S; Fanos, V

    1999-12-01

    A boy with monosomy for the distal part of the short arm of chromosome 3 is described. The clinical features this patient has in common with the previously reported cases include pre- and post-natal growth delay, microcephaly, craniofacial dysmorphism and mental retardation. In addition, minor abnormalities not previously reported were observed, such as snapping thumbs, dorsiflected big toes, connecting anterior and posterior fontanelles at birth, nasolacrimal duct stenosis and double urethral meatus. Conclusion These five new clinical findings may help in further delineation of the syndrome and allow its early recognition. A complete revision of clinical findings published in literature is reported.

  5. Searching for Tourette’s syndrome gene. Part 1. Heterogeneity of clinical phenotypes

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    Anna Kowalska

    2012-02-01

    Full Text Available The French neuropsychiatrist Georges Gilles de la Tourette described in 1885 the “Maladie des Tics” which later was named after him, as Gilles de la Tourette syndrome (GTS. Gilles de la Tourette syndrome is a neurodevelopmental disorder characterized by simple and complex motor and vocal tics with multiple neuropsychiatric comorbidities. GTS is often concurrent with obsessive-compulsive disorder (OCD and attention deficit hyperactivity disorder (ADHD. There are several clinical GTS subtypes: GTS only, GTS OCD, and GTS OCD ADHD. Additional clinical aspects of the disorder include occurrence of anger episodes, anxiety and mood disorders, and learning and sleeping disturbances. The genetics of GTS is complex and remains unclear. So far, no causative candidate genes have been identified. However, segregation studies in families and twins with GTS provide strong evidence for the existence of a genetic background associated with a multifactorial mode of inheritance. Progress in studies on genome variability among patients with GTS is necessary to improve pharmacotherapeutic strategies of the disorder.

  6. Genotype-Phenotype Characterization of Wolf-Hirschhorn Syndrome Confirmed by FISH: Case Reports

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    F. Sheth

    2012-01-01

    Full Text Available The Wolf-Hirschhorn syndrome (WHS is a multiple malformation and contiguous gene syndrome resulting from the deletion encompassing a 4p16.3 region. A microscopically visible terminal deletion on chromosome 4p (4p16→pter was detected in Case 1 with full blown features of WHS. The second case which had an interstitial microdeletion encompassing WHSC 1 and WHSC 2 genes at 4p16.3 presented with less striking clinical features of WHS and had an apparently “normal” karyotype. The severity of the clinical presentation was as a result of haploinsufficiency and interaction with surrounding genes as well as mutations in modifier genes located outside the WHSCR regions. The study emphasized that an individual with a strong clinical suspicion of chromosomal abnormality and a normal conventional cytogenetic study should be further investigated using molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH or array-comparative genomic hybridization (a-CGH.

  7. Waardenburg syndrome type I: Dental phenotypes and genetic analysis of an extended family

    Science.gov (United States)

    de Aquino, Sibele-Nascimento; Paranaíba, Lívia-Maris-R.; Gomes, Andreia; dos-Santos-Neto, Pedro; Coletta, Ricardo-D.; Cardoso, Aline-Francoise; Frota, Ana-Cláudia; Martelli-Júnior, Hercílio

    2016-01-01

    Background The aim of this study was to describe the pattern of inheritance and the clinical features in a large family with Waardenburg syndrome type I (WS1), detailing the dental abnormalities and screening for PAX3 mutations. Material and Methods To characterize the pattern of inheritance and clinical features, 29 family members were evaluated by dermatologic, ophthalmologic, otorhinolaryngologic and orofacial examination. Molecular analysis of the PAX3 gene was performed. Results The pedigree of the family,including the last four generations, was constructed and revealed non-consanguineous marriages. Out of 29 descendants, 16 family members showed features of WS1, with 9 members showing two major criteria indicative of WS1. Five patients showed white forelock and iris hypopigmentation, and four showed dystopia canthorum and iris hypopigmentation. Two patients had hearing loss. Dental abnormalities were identified in three family members, including dental agenesis, conical teeth and taurodontism. Sequencing analysis failed to identify mutations in the PAX3 gene. Conclusions These results confirm that WS1 was transmitted in this family in an autosomal dominant pattern with variable expressivity and high penetrance. The presence of dental manifestations, especially tooth agenesis and conical teeth which resulted in considerable aesthetic impact on affected individuals was a major clinical feature. Clinical relevance: This article reveals the presence of well-defined dental changes associated with WS1 and tries to establish a possible association between these two entities showing a new spectrum of WS1. Key words:Waardenburg syndrome, hearing loss, oral manifestations, mutation. PMID:27031059

  8. Kenny Caffey syndrome with severe respiratory and gastrointestinal involvement: expanding the clinical phenotype.

    Science.gov (United States)

    Christodoulou, Loucas; Krishnaiah, Anil; Spyridou, Christina; Salpietro, Vincenzo; Hannan, Siobhan; Saggar, Anand; Mankad, Kshitij; Deep, Akash; Kinali, Maria

    2015-06-01

    Kenny Caffey syndrome (KCS) is a rare syndrome reported almost exclusively in Middle Eastern populations. It is characterized by severe growth retardation-short stature, dysmorphic features, episodic hypocalcaemia, hypoparathyroidism, seizures, and medullary stenosis of long bones with thickened cortices. We report a 10-year-old boy with KCS with an unusually severe respiratory and gastrointestinal system involvement-features not previously described in the literature. He had severe psychomotor retardation and regressed developmentally from walking unaided to sitting with support. MRI brain showed bilateral hippocampal sclerosis, marked supra-tentorial volume loss and numerous calcifications. A 12 bp deletion of exon 2 of tubulin-specific chaperone E (TBCE) gene was identified and the diagnosis of KCS was confirmed. Hypercarbia following a sleep study warranted nocturnal continuous positive airway pressure (CPAP) when aged 6. When boy aged 8, persistent hypercarbia with increasing oxygen requirement and increased frequency and severity of lower respiratory tract infections led to progressive respiratory failure. He became fully dependent on non-invasive ventilation and by 9 years he had a tracheotomy and was established on long-term ventilation. He developed retching, vomiting and diarrhea. Chest CT showed changes consistent with chronic aspiration, but no interstitial pulmonary fibrosis. He died aged 10 from respiratory complications.

  9. B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies.

    Science.gov (United States)

    Maroofian, Reza; Riemersma, Moniek; Jae, Lucas T; Zhianabed, Narges; Willemsen, Marjolein H; Wissink-Lindhout, Willemijn M; Willemsen, Michèl A; de Brouwer, Arjan P M; Mehrjardi, Mohammad Yahya Vahidi; Ashrafi, Mahmoud Reza; Kusters, Benno; Kleefstra, Tjitske; Jamshidi, Yalda; Nasseri, Mojila; Pfundt, Rolph; Brummelkamp, Thijn R; Abbaszadegan, Mohammad Reza; Lefeber, Dirk J; van Bokhoven, Hans

    2017-12-22

    The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of α-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular dystrophy without neural involvement. However, muscular dystrophy is invariably found across the spectrum of MDDG patients. Using linkage mapping and whole-exome sequencing in two families with an unexplained neurodevelopmental disorder, we have identified homozygous and compound heterozygous mutations in B3GALNT2. The first family comprises two brothers of Dutch non-consanguineous parents presenting with mild ID and behavioral problems. Immunohistochemical analysis of muscle biopsy revealed no significant aberrations, in line with the absence of a muscular phenotype in the affected siblings. The second family includes five affected individuals from an Iranian consanguineous kindred with mild-to-moderate intellectual disability (ID) and epilepsy without any notable neuroimaging, muscle, or eye abnormalities. Complementation assays of the compound heterozygous mutations identified in the two brothers had a comparable effect on the O-glycosylation of α-dystroglycan as previously reported mutations that are associated with severe muscular phenotypes. In conclusion, we show that mutations in B3GALNT2 can give rise to a novel MDDG syndrome presentation, characterized by ID associated variably with seizure, but without any apparent muscular involvement. Importantly, B3GALNT2 activity does not fully correlate with the severity of the phenotype as assessed by the complementation assay.

  10. Wernicke-Korsakoff syndrome as a rare phenotype of sporadic Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Bielewicz, Joanna; Szczepańska-Szerej, Anna; Ogórek, Magdalena; Dropko, Piotr; Wojtal, Katarzyna; Rejdak, Konrad

    2018-02-09

    We reported the case of a patient with Wernicke-Korsakoff syndrome (WKs) as an early clinical manifestation of sporadic Creutzfeld-Jakob disease (sCJD). The 66-year-old female complained of dizziness and imbalance which mostly occurred while walking. A neurological examination revealed a triad of symptoms characteristic for WKs such as gaze paresis, ataxia of limbs and trunk as well as memory disturbances with confabulations. The disturbances increased during the course of the disease, which led to the death of the patient four months after the appearance of the signs. The patient was finally diagnosed with sCJD disease. The most useful ancillary examination results supporting sCJD diagnosis were brain diffusion DWI MRI (diffusion weighted magnetic resonance imaging) and the presence of 14-3-3 protein in CSF (cerebrospinal fluid). Since that manifestation of sCJD is very unique other causes should be taken into consideration while making a final diagnosis.

  11. The cellular phenotype of Roberts syndrome fibroblasts as revealed by ectopic expression of ESCO2.

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    Petra van der Lelij

    Full Text Available Cohesion between sister chromatids is essential for faithful chromosome segregation. In budding yeast, the acetyltransferase Eco1/Ctf7 establishes cohesion during DNA replication in S phase and in response to DNA double strand breaks in G2/M phase. In humans two Eco1 orthologs exist: ESCO1 and ESCO2. Both proteins are required for proper sister chromatid cohesion, but their exact function is unclear at present. Since ESCO2 has been identified as the gene defective in the rare autosomal recessive cohesinopathy Roberts syndrome (RBS, cells from RBS patients can be used to elucidate the role of ESCO2. We investigated for the first time RBS cells in comparison to isogenic controls that stably express V5- or GFP-tagged ESCO2. We show that the sister chromatid cohesion defect in the transfected cell lines is rescued and suggest that ESCO2 is regulated by proteasomal degradation in a cell cycle-dependent manner. In comparison to the corrected cells RBS cells were hypersensitive to the DNA-damaging agents mitomycin C, camptothecin and etoposide, while no particular sensitivity to UV, ionizing radiation, hydroxyurea or aphidicolin was found. The cohesion defect of RBS cells and their hypersensitivity to DNA-damaging agents were not corrected by a patient-derived ESCO2 acetyltransferase mutant (W539G, indicating that the acetyltransferase activity of ESCO2 is essential for its function. In contrast to a previous study on cells from patients with Cornelia de Lange syndrome, another cohesinopathy, RBS cells failed to exhibit excessive chromosome aberrations after irradiation in G2 phase of the cell cycle. Our results point at an S phase-specific role for ESCO2 in the maintenance of genome stability.

  12. Recessive inheritance of population-specific intronic LINE-1 insertion causes a rotor syndrome phenotype.

    Science.gov (United States)

    Kagawa, Tatehiro; Oka, Akira; Kobayashi, Yoshinao; Hiasa, Yoichi; Kitamura, Tsuneo; Sakugawa, Hiroshi; Adachi, Yukihiko; Anzai, Kazuya; Tsuruya, Kota; Arase, Yoshitaka; Hirose, Shunji; Shiraishi, Koichi; Shiina, Takashi; Sato, Tadayuki; Wang, Ting; Tanaka, Masayuki; Hayashi, Hideki; Kawabe, Noboru; Robinson, Peter N; Zemojtel, Tomasz; Mine, Tetsuya

    2015-03-01

    Sequences of long-interspersed elements (LINE-1, L1) make up ∼17% of the human genome. De novo insertions of retrotransposition-active L1s can result in genetic diseases. It has been recently shown that the homozygous inactivation of two adjacent genes SLCO1B1 and SLCO1B3 encoding organic anion transporting polypeptides OATP1B1 and OATP1B3 causes a benign recessive disease presenting with conjugated hyperbilirubinemia, Rotor syndrome. Here, we examined SLCO1B1 and SLCO1B3 genes in six Japanese diagnosed with Rotor syndrome on the basis of laboratory data and laparoscopy. All six Japanese patients were homozygous for the c.1738C>T nonsense mutation in SLCO1B1 and homozygous for the insertion of a ∼6.1-kbp L1 retrotransposon in intron 5 of SLCO1B3, which altogether make up a Japanese-specific haplotype. RNA analysis revealed that the L1 insertion induced deleterious splicing resulting in SLCO1B3 transcripts lacking exon 5 or exons 5-7 and containing premature stop codons. The expression of OATP1B1 and OATP1B3 proteins was not detected in liver tissues. This is the first documented case of a population-specific polymorphic intronic L1 transposon insertion contributing to molecular etiology of recessive genetic disease. Since L1 activity in human genomes is currently seen as a major source of individual genetic variation, further investigations are warranted to determine whether this phenomenon results in other autosomal-recessive diseases. © 2014 WILEY PERIODICALS, INC.

  13. Small mosaic deletion encompassing the snoRNAs and SNURF-SNRPN results in an atypical Prader-Willi syndrome phenotype.

    Science.gov (United States)

    Anderlid, Britt-Marie; Lundin, Johanna; Malmgren, Helena; Lehtihet, Mikael; Nordgren, Ann

    2014-02-01

    Genetic analyses were performed in a male patient with suspected Prader-Willi syndrome who presented with hypogonadism, excessive eating, central obesity, small hands and feet and cognition within the low normal range. However, he had no neonatal hypotonia or feeding problems during infancy. Chromosome analysis showed a normal male karyotype. Further analysis with array-CGH identified a mosaic 847 kb deletion in 15q11-q13, including SNURF-SNRPN, the snoRNA gene clusters SNORD116 (HBII-85), SNORD115, (HBII-52), SNORD109 A and B (HBII-438A and B), SNORD64 (HBII-13), and NPAP1 (C15ORF2). MLPA confirmed the deletion and the results were compatible with a paternal origin. Metaphase-FISH verified the mosaicism with the deletion present in 58% of leukocytes analyzed. Three smaller deletions in this region have previously been reported in patients with Prader-Willi syndrome phenotype. All three deletions included SNORD116, but only two encompassed parts of SNURF-SNRPN, implicating SNORD116 as the major contributor to the Prader-Willi phenotype. Our case adds further information about genotype-phenotype correlation and supports the hypothesis that SNORD116 plays a major role in the pathogenesis of Prader-Willi syndrome. Furthermore, it examplifies diagnostic difficulties in atypical cases and illustrates the need for additional testing methods when Prader-Willi syndrome is suspected. © 2013 Wiley Periodicals, Inc.

  14. [Anthropometric indices to identify metabolic syndrome and hypertriglyceridemic waist phenotype: a comparison between the three stages of adolescence].

    Science.gov (United States)

    Pereira, Patrícia Feliciano; Faria, Franciane Rocha de; Faria, Eliane Rodrigues de; Hermsdorff, Helen Hermana Miranda; Peluzio, Maria do Carmo Gouveia; Franceschini, Sylvia do Carmo Castro; Priore, Silvia Eloiza

    2015-01-01

    To determine the prevalence of metabolic syndrome (MS) and the hypertriglyceridemic waist phenotype (HW) in a representative adolescent sample; as well as to establish which anthropometric indicator better identifies MS and HW, according to gender and adolescent age. This cross sectional study had the participation of 800 adolescents (414 girls) from 10-19 years old. Anthropometric indicators (body mass index, waist perimeter, waist/stature ratio, waist/hip ratio, and central/peripheral skinfolds) were determined by standard protocols. For diagnosis of MS, the criteria proposed by de Ferranti et al. (2004) were used. HW was defined by the simultaneous presence of increased waist perimeter (>75th percentile for age and sex) and high triglycerides (>100mg/dL). The ability of anthropometric indicators was evaluated by Receiver Operating Characteristic curve. The prevalence of MS was identical to HW (6.4%), without differences between genders and the adolescence phases. The waist perimeter showed higher area under the curve for the diagnosis of MS, except for boys with 17-19 years old, for whom the waist/stature ratio exhibited better performance. For diagnosing HW, waist perimeter also showed higher area under the curve, except for boys in initial and final phases, in which the waist/stature ratio obtained larger area under the curve. The central/peripheral skinfolds had the lowest area under the curve for the presence of both MS and HW phenotype. The waist perimeter and the waist/stature showed a better performance to identify MS and HW in both genders and in all three phases of adolescence. Copyright © 2015 Associação de Pediatria de São Paulo. Publicado por Elsevier Editora Ltda. All rights reserved.

  15. Generational association studies of dopaminergic genes in reward deficiency syndrome (RDS) subjects: selecting appropriate phenotypes for reward dependence behaviors.

    Science.gov (United States)

    Blum, Kenneth; Chen, Amanda L C; Oscar-Berman, Marlene; Chen, Thomas J H; Lubar, Joel; White, Nancy; Lubar, Judith; Bowirrat, Abdalla; Braverman, Eric; Schoolfield, John; Waite, Roger L; Downs, Bernard W; Madigan, Margaret; Comings, David E; Davis, Caroline; Kerner, Mallory M; Knopf, Jennifer; Palomo, Tomas; Giordano, John J; Morse, Siobhan A; Fornari, Frank; Barh, Debmalya; Femino, John; Bailey, John A

    2011-12-01

    Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the "brain reward cascade," a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific "reward" phenotype may be a paradigm shift in future association

  16. Fully-Automated μMRI Morphometric Phenotyping of the Tc1 Mouse Model of Down Syndrome.

    Directory of Open Access Journals (Sweden)

    Nick M Powell

    Full Text Available We describe a fully automated pipeline for the morphometric phenotyping of mouse brains from μMRI data, and show its application to the Tc1 mouse model of Down syndrome, to identify new morphological phenotypes in the brain of this first transchromosomic animal carrying human chromosome 21. We incorporate an accessible approach for simultaneously scanning multiple ex vivo brains, requiring only a 3D-printed brain holder, and novel image processing steps for their separation and orientation. We employ clinically established multi-atlas techniques-superior to single-atlas methods-together with publicly-available atlas databases for automatic skull-stripping and tissue segmentation, providing high-quality, subject-specific tissue maps. We follow these steps with group-wise registration, structural parcellation and both Voxel- and Tensor-Based Morphometry-advantageous for their ability to highlight morphological differences without the laborious delineation of regions of interest. We show the application of freely available open-source software developed for clinical MRI analysis to mouse brain data: NiftySeg for segmentation and NiftyReg for registration, and discuss atlases and parameters suitable for the preclinical paradigm. We used this pipeline to compare 29 Tc1 brains with 26 wild-type littermate controls, imaged ex vivo at 9.4T. We show an unexpected increase in Tc1 total intracranial volume and, controlling for this, local volume and grey matter density reductions in the Tc1 brain compared to the wild-types, most prominently in the cerebellum, in agreement with human DS and previous histological findings.

  17. Th1 and Th17 Cells and Associated Cytokines Discriminate among Clinically Isolated Syndrome and Multiple Sclerosis Phenotypes.

    Science.gov (United States)

    Arellano, Gabriel; Acuña, Eric; Reyes, Lilian I; Ottum, Payton A; De Sarno, Patrizia; Villarroel, Luis; Ciampi, Ethel; Uribe-San Martín, Reinaldo; Cárcamo, Claudia; Naves, Rodrigo

    2017-01-01

    Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the central nervous system. It is a heterogeneous pathology that can follow different clinical courses, and the mechanisms that underlie the progression of the immune response across MS subtypes remain incompletely understood. Here, we aimed to determine differences in the immunological status among different MS clinical subtypes. Blood samples from untreated patients diagnosed with clinically isolated syndrome (CIS) ( n  = 21), different clinical forms of MS ( n  = 62) [relapsing-remitting (RRMS), secondary progressive, and primary progressive], and healthy controls (HCs) ( n  = 17) were tested for plasma levels of interferon (IFN)-γ, IL-10, TGF-β, IL-17A, and IL-17F by immunoanalysis. Th1 and Th17 lymphocyte frequencies were determined by flow cytometry. Our results showed that IFN-γ levels and the IFN-γ/IL-10 ratio were higher in CIS patients than in RRMS patients and HC. Th1 cell frequencies were higher in CIS and RRMS than in progressive MS, and RRMS had a higher Th17 frequency than CIS. The Th1/Th17 cell ratio was skewed toward Th1 in CIS compared to MS phenotypes and HC. Receiver operating characteristic statistical analysis determined that IFN-γ, the IFN-γ/IL-10 ratio, Th1 cell frequency, and the Th1/Th17 cell ratio discriminated among CIS and MS subtypes. A subanalysis among patients expressing high IL-17F levels showed that IL-17F and the IFN-γ/IL-17F ratio discriminated between disease subtypes. Overall, our data showed that CIS and MS phenotypes displayed distinct Th1- and Th17-related cytokines and cell profiles and that these immune parameters discriminated between clinical forms. Upon validation, these parameters might be useful as biomarkers to predict disease progression.

  18. Definition of 5q11.2 Microdeletion Syndrome Reveals Overlap with CHARGE Syndrome and 22q11 Deletion Syndrome Phenotypes

    NARCIS (Netherlands)

    Blok, Charlotte Snijders; Corsten-Janssen, Nicole; FitzPatrick, David R.; Romano, Corrado; Fichera, Marco; Vitello, Girolamo Aurelio; Willemsen, Marjolein H.; Schoots, Jeroen; Pfundt, Rolph; van Ravenswaaij-Arts, Conny M. A.; Hoefsloot, Lies; Kleefstra, Tjitske

    2014-01-01

    Microdeletions of the 5q11.2 region are rare; in literature only two patients with a deletion in this region have been reported so far. In this study, we describe four additional patients and further define this new 5q11.2 microdeletion syndrome. A comparison of the features observed in all six

  19. Adrenocortical steroid response to ACTH in different phenotypes of non-obese polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Cinar Nese

    2012-12-01

    Full Text Available Abstract Background Adrenal androgen excess is frequently observed in PCOS. The aim of the study was to determine whether adrenal gland function varies among PCOS phenotypes, women with hyperandrogenism (H only and healthy women. Methods The study included 119 non-obese patients with PCOS (age: 22.2 ± 4.1y, BMI:22.5 ± 3.1 kg/m2, 24 women with H only and 39 age and BMI- matched controls. Among women with PCOS, 50 had H, oligo-anovulation (O, and polycystic ovaries (P (PHO, 32 had O and H (OH, 23 had P and H (PH, and 14 had P and O (PO. Total testosterone (T, SHBG and DHEAS levels at basal and serum 17-hydroxprogesterone (17-OHP, androstenedione (A4, DHEA and cortisol levels after ACTH stimulation were measured. Results T, FAI and DHEAS, and basal and AUC values for 17-OHP and A4 were significantly and similarly higher in PCOS and H groups than controls (p  Conclusion PCOS patients and women with H only have similar and higher basal and stimulated adrenal androgen levels than controls. All three hyperandrogenic subphenotypes of PCOS exhibit similar and higher basal and stimulated adrenal androgen secretion patterns compared to non-hyperandrogenic subphenotype.

  20. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort.

    Science.gov (United States)

    Masciari, Serena; Dillon, Deborah A; Rath, Michelle; Robson, Mark; Weitzel, Jeffrey N; Balmana, Judith; Gruber, Stephen B; Ford, James M; Euhus, David; Lebensohn, Alexandra; Telli, Melinda; Pochebit, Stephen M; Lypas, Georgios; Garber, Judy E

    2012-06-01

    Breast cancer is the most common tumor in women with Li-Fraumeni Syndrome (LFS), an inherited cancer syndrome associated with germline mutations in the TP53 tumor suppressor gene. Their lifetime breast cancer risk is 49% by age 60. Breast cancers in TP53 mutation carriers recently have more often been reported to be hormone receptor and HER-2 positive by immunohistochemistry and FISH in small series. We seek to complement the existing small literature with this report of a histopathologic analysis of breast cancers from women with documented LFS. Unstained slides and paraffin-embedded tumor blocks from breast cancers from 39 germline TP53 mutation carriers were assembled from investigators in the LFS consortium. Central histology review was performed on 93% of the specimens by a single breast pathologist from a major university hospital. Histology, grade, and hormone receptor status were assessed by immunohistochemistry; HER-2 status was defined by immunohistochemistry and/or FISH. The 43 tumors from 39 women comprise 32 invasive ductal carcinomas and 11 ductal carcinomas in situ (DCIS). No other histologies were observed. The median age at diagnosis was 32 years (range 22-46). Of the invasive cancers, 84% were positive for ER and/or PR; and 81% were high grade. Sixty three percent of invasive and 73% of in situ carcinomas were positive for Her2/neu (IHC 3+ or FISH amplified). Of the invasive tumors, 53% were positive for both ER and HER2+; other ER/PR/HER2 combinations were observed. The DCIS were positive for ER and HER2 in 27% of the cases. This report of the phenotype of breast cancers from women with LFS nearly doubles the literature on this topic. Most DCIS and invasive ductal carcinomas in LFS are hormone receptor positive and/or HER-2 positive. These findings suggest that modern treatments may result in improved outcomes for women with LFS-associated breast cancer.

  1. Phenotypic comparison of Caucasian and Asian women with polycystic ovary syndrome: a cross-sectional study.

    Science.gov (United States)

    Wang, Erica T; Kao, Chia-Ning; Shinkai, Kanade; Pasch, Lauri; Cedars, Marcelle I; Huddleston, Heather G

    2013-07-01

    To determine whether manifestations of polycystic ovary syndrome (PCOS), particularly androgen excess, differ between Caucasian and Asian women in the San Francisco Bay Area. Cross-sectional study. Multidisciplinary PCOS clinic at a tertiary academic center. 121 Caucasian and 28 Asian women, aged 18-44, examined between 2006 and 2011 with PCOS verified by a reproductive endocrinologist and dermatologist according to the Rotterdam criteria. Transvaginal ultrasounds, comprehensive dermatologic exams, and serum testing. Hirsutism defined as a modified Ferriman-Gallwey (mFG) score ≥ 8, acne, androgenic alopecia, and biochemical hyperandrogenism. Caucasian and Asian women had a similar prevalence of all measures of androgen excess. Both groups had similar total mFG scores and site-specific mFG scores, except Asian women had a lower site-specific mFG score for the chest. Although Asian women were more likely to use laser hair removal, the results were unchanged when the women with a history of laser hair removal were excluded. Caucasian and Asian women with PCOS living in the same geographic region had a similar prevalence of hirsutism as well as other markers for androgen excess. Further studies are necessary to evaluate the need for ethnic-specific mFG scores in women with PCOS. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  2. Effect of the Antioxidant Lipoic Acid in Aortic Phenotype in a Marfan Syndrome Mouse Model

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    Maria C. Guido

    2018-01-01

    Full Text Available Marfan syndrome (MFS cardiovascular manifestations such as aortic aneurysms and cardiomyopathy carry substantial morbidity/mortality. We investigated the effects of lipoic acid, an antioxidant, on ROS production and aortic remodeling in a MFS mgΔloxPneo mouse model. MFS and WT (wild-type 1-month-old mice were allocated to 3 groups: untreated, treated with losartan, and treated with lipoic acid. At 6 months old, echocardiography, ROS production, and morphological analysis of aortas were performed. Aortic ROS generation in 6-month-old MFS animals was higher at advanced stages of disease in MFS. An unprecedented finding in MFS mice analyzed by OCT was the occurrence of focal inhomogeneous regions in the aortic arch, either collagen-rich extremely thickened or collagen-poor hypotrophic regions. MFS animals treated with lipoic acid showed markedly reduced ROS production and lower ERK1/2 phosphorylation; meanwhile, aortic dilation and elastic fiber breakdown were unaltered. Of note, lipoic acid treatment associated with the absence of focal inhomogeneous regions in MFS animals. Losartan reduced aortic dilation and elastic fiber breakdown despite no change in ROS generation. In conclusion, oxidant generation by itself seems neutral with respect to aneurysm progression in MFS; however, lipoic acid-mediated reduction of inhomogeneous regions may potentially associate with less anisotropy and reduced chance of dissection/rupture.

  3. Germline PRKACA amplification leads to Cushing syndrome caused by 3 adrenocortical pathologic phenotypes.

    Science.gov (United States)

    Carney, J Aidan; Lyssikatos, Charalampos; Lodish, Maya B; Stratakis, Constantine A

    2015-01-01

    We describe the pathology of 5 patients with germline PRKACA copy number gain and Cushing syndrome: 4 males and 1 female, aged 2 to 43 years, including a mother and son. Imaging showed normal or slightly enlarged adrenal glands in 4 patients and a unilateral mass in the fifth. Biochemically, the patients had corticotropin-independent hypercortisolism. Four underwent bilateral adrenalectomy; unilateral adrenalectomy was performed in the patient with the adrenal mass. Pathologically, 3 patients, including the 1 with the tumor (adenoma), had primary pigmented nodular adrenocortical disease with extranodular cortical atrophy and mild intracapsular and extracapsular extension of cortical cells. The other 2 patients had cortical hyperplasia and prominent capsular and extracapsular micronodular cortical hyperplasia. Immunoperoxidase staining revealed differences for synaptophysin, inhibin-A, and Ki-67 (nuclei) in the atrophic cortices (patients 1, 2, and 3) and hyperplastic cortices (patients 4 and 5) and for Ki-67 (nuclei) and vimentin in the extracortical nodules in the 2 groups of patients. β-Catenin stained the cell membrane, cytoplasm, and nuclei of the adenoma. The patients were well at follow-up (1-23 years); 24-hour urinary cortisol excretion was elevated in the patient who had unilateral adrenalectomy. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping.

    Science.gov (United States)

    Amos, J S; Huang, L; Thevenon, J; Kariminedjad, A; Beaulieu, C L; Masurel-Paulet, A; Najmabadi, H; Fattahi, Z; Beheshtian, M; Tonekaboni, S H; Tang, S; Helbig, K L; Alcaraz, W; Rivière, J-B; Faivre, L; Innes, A M; Lebel, R R; Boycott, K M

    2017-01-01

    THOC6 is a part of the THO complex, which is involved in coordinating mRNA processing with export. The THO complex interacts with additional components to form the larger TREX complex (transcription export complex). Previously, a homozygous missense mutation in THOC6 in the Hutterite population was reported in association with syndromic intellectual disability. Using exome sequencing, we identified three unrelated patients with bi-allelic mutations in THOC6 associated with intellectual disability and additional clinical features. Two of the patients were compound heterozygous for a stop and a missense mutation, and the third was homozygous for a missense mutation; the missense mutations were predicted to be pathogenic by in silico analysis and modeling. Clinical features of the three newly identified patients and those previously reported are reviewed; intellectual disability is moderate to severe, and malformations are variable including renal and heart defects, cleft palate, microcephaly, and corpus callosum dysgenesis. Facial features are variable and include tall forehead, short upslanting palpebral fissures +/- deep set eyes, and a long nose with overhanging columella. These subtle facial features render the diagnosis difficult to make in isolation with certainty. Our results expand the mutational and clinical spectrum of this rare disease, confirm that THOC6 is an intellectual disability causing gene, while providing insight into the importance of the THO complex in neurodevelopment. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Genetic and phenotypic heterogeneity in Chinese patients with Waardenburg syndrome type II.

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    Shuzhi Yang

    Full Text Available Waardenburg Syndrome (WS is an autosomal-dominant disorder characterized by sensorineural hearing loss and pigmentary abnormalities of the eyes, hair, and skin. Microphthalmia-associated transcription factor (MITF gene mutations account for about 15% of WS type II (WS2 cases. To date, fewer than 40 different MITF gene mutations have been identified in human WS2 patients, and few of these were of Chinese descent. In this study, we report clinical findings and mutation identification in the MITF gene of 20 Chinese WS2 patients from 14 families. A high level of clinical variability was identified. Sensorineural hearing loss (17/20, 85.0% and heterochromia iridum (20/20, 100.0% were the most commonly observed clinical features in Chinese WS2 patients. Five affected individuals (5/20, 25.0% had numerous brown freckles on the face, trunk, and limb extremities. Mutation screening of the MITF gene identified five mutations: c.20A>G, c.332C>T, c.647_649delGAA, c.649A>G, and c.763C>T. The total mutational frequency of the MITF gene was 21.4% (3/14, which is significantly higher than the 15.0% observed in the fair-skinned WS2 population. Our results indicate that MITF mutations are relatively common among Chinese WS2 patients.

  6. Genetic and phenotypic heterogeneity in Chinese patients with Waardenburg syndrome type II.

    Science.gov (United States)

    Yang, Shuzhi; Dai, Pu; Liu, Xin; Kang, Dongyang; Zhang, Xin; Yang, Weiyan; Zhou, Chengyong; Yang, Shiming; Yuan, Huijun

    2013-01-01

    Waardenburg Syndrome (WS) is an autosomal-dominant disorder characterized by sensorineural hearing loss and pigmentary abnormalities of the eyes, hair, and skin. Microphthalmia-associated transcription factor (MITF) gene mutations account for about 15% of WS type II (WS2) cases. To date, fewer than 40 different MITF gene mutations have been identified in human WS2 patients, and few of these were of Chinese descent. In this study, we report clinical findings and mutation identification in the MITF gene of 20 Chinese WS2 patients from 14 families. A high level of clinical variability was identified. Sensorineural hearing loss (17/20, 85.0%) and heterochromia iridum (20/20, 100.0%) were the most commonly observed clinical features in Chinese WS2 patients. Five affected individuals (5/20, 25.0%) had numerous brown freckles on the face, trunk, and limb extremities. Mutation screening of the MITF gene identified five mutations: c.20A>G, c.332C>T, c.647_649delGAA, c.649A>G, and c.763C>T. The total mutational frequency of the MITF gene was 21.4% (3/14), which is significantly higher than the 15.0% observed in the fair-skinned WS2 population. Our results indicate that MITF mutations are relatively common among Chinese WS2 patients.

  7. Cataract as a phenotypic marker for a mutation in WFS1, the Wolfram syndrome gene.

    Science.gov (United States)

    Titah, Salah Mohamed Cherif; Meunier, Isabelle; Blanchet, Catherine; Lopez, Severine; Rondouin, Gerard; Lenaers, Guy; Amati-Bonneau, Patrizia; Reynier, Pascal; Paquis-Flucklinger, Veronique; Hamel, Christian P

    2012-01-01

    Wolfram syndrome (WS) or diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD) (OMIM 222300) is an inherited neurodegenerative disease characterized by diabetes mellitus and optic atrophy as the 2 major criteria, followed later in life by deafness, diabetes insipidus, and various signs of neurologic impairment. The presence of a cataract has been variably mentioned in WS. Two members of a family had thorough ophthalmic examination and their DNA was screened for mutations in mitochondrial DNA, WFS1, OPA1, and OPA3 genes. We report a patient who first had surgery for bilateral cataract at age 5 and who subsequently presented typical signs of WS, i.e., diabetes mellitus, optic atrophy with reduced visual acuity at 20/400 on both eyes at age 22, and mild deafness. The patient was found to be a compound heterozygote for 2 truncating mutations in WFS1, the major WS gene. She carried the previously reported c.1231_1233 delCT and a novel c.2431_2465dup35 mutation. She also was heterozygote for a novel OPA1 sequence variant, c.929A>G in exon 9, whose pathogenicity remains uncertain. The patient's mother was a heterozygous carrier of the c.2431_2465dup35 mutation. She did not have diabetes mellitus or optic atrophy but had bilateral polar cataract. She did not carry the OPA1 sequence variant. Cataract could be a marker for the WFS1 heterozygosity in this family, namely the c.2431_2465dup35 mutation.

  8. Genetic and Phenotypic Heterogeneity in Chinese Patients with Waardenburg Syndrome Type II

    Science.gov (United States)

    Yang, Shuzhi; Dai, Pu; Liu, Xin; Kang, Dongyang; Zhang, Xin; Yang, Weiyan; Zhou, Chengyong; Yang, Shiming; Yuan, Huijun

    2013-01-01

    Waardenburg Syndrome (WS) is an autosomal-dominant disorder characterized by sensorineural hearing loss and pigmentary abnormalities of the eyes, hair, and skin. Microphthalmia-associated transcription factor (MITF) gene mutations account for about 15% of WS type II (WS2) cases. To date, fewer than 40 different MITF gene mutations have been identified in human WS2 patients, and few of these were of Chinese descent. In this study, we report clinical findings and mutation identification in the MITF gene of 20 Chinese WS2 patients from 14 families. A high level of clinical variability was identified. Sensorineural hearing loss (17/20, 85.0%) and heterochromia iridum (20/20, 100.0%) were the most commonly observed clinical features in Chinese WS2 patients. Five affected individuals (5/20, 25.0%) had numerous brown freckles on the face, trunk, and limb extremities. Mutation screening of the MITF gene identified five mutations: c.20A>G, c.332C>T, c.647_649delGAA, c.649A>G, and c.763C>T. The total mutational frequency of the MITF gene was 21.4% (3/14), which is significantly higher than the 15.0% observed in the fair-skinned WS2 population. Our results indicate that MITF mutations are relatively common among Chinese WS2 patients. PMID:24194866

  9. Extending the phenotypic spectrum of keratitis-ichthyosis-deafness syndrome: report of a patient with GJB2 (G12R) Connexin 26 mutation and unusual clinical findings.

    Science.gov (United States)

    Lazic, Tamara; Li, Qiaoli; Frank, Michael; Uitto, Jouni; Zhou, Linda H

    2012-01-01

    Keratitis-ichthyosis-deafness (KID) syndrome is a rare ectodermal dysplasia, characterized mainly by the presence of hyperkeratotic skin lesions, neurosensory hearing loss, and vascularizing keratitis. Most mutations that have been discovered as a cause of KID syndrome are autosomal dominant, found in exon 2 of the Connexin (Cx) 26 gene. A G12R (p.Gly12Arg) is a GJB2 mutation reported in only two patients with KID syndrome to date. This article describes a patient with the G12R mutation and KID syndrome with interesting additional features, which include a porokeratotic eccrine ostial and dermal duct nevus, follicular occlusion triad, and unusual persistent oral mucosal papules. We compare this patient's phenotype with the only two other patients described with the same (G12R) mutation. The phenotypic heterogeneity of KID syndrome, inexplicable according to our current understanding of these proteins, speaks to the complexity of the connexin system and its overlapping expression patterns in different tissues. © 2011 Wiley Periodicals, Inc.

  10. Hypothalamic transcriptional expression of the kisspeptin system and sex steroid receptors differs among polycystic ovary syndrome rat models with different endocrine phenotypes.

    Science.gov (United States)

    Marcondes, Rodrigo Rodrigues; Carvalho, Kátia Cândido; Giannocco, Gisele; Duarte, Daniele Coelho; Garcia, Natália; Soares-Junior, José Maria; da Silva, Ismael Dale Cotrim Guerreiro; Maliqueo, Manuel; Baracat, Edmund Chada; Maciel, Gustavo Arantes Rosa

    2017-08-01

    Polycystic ovary syndrome is a heterogeneous endocrine disorder that affects reproductive-age women. The mechanisms underlying the endocrine heterogeneity and neuroendocrinology of polycystic ovary syndrome are still unclear. In this study, we investigated the expression of the kisspeptin system and gonadotropin-releasing hormone pulse regulators in the hypothalamus as well as factors related to luteinizing hormone secretion in the pituitary of polycystic ovary syndrome rat models induced by testosterone or estradiol. A single injection of testosterone propionate (1.25 mg) (n=10) or estradiol benzoate (0.5 mg) (n=10) was administered to female rats at 2 days of age to induce experimental polycystic ovary syndrome. Controls were injected with a vehicle (n=10). Animals were euthanized at 90-94 days of age, and the hypothalamus and pituitary gland were used for gene expression analysis. Rats exposed to testosterone exhibited increased transcriptional expression of the androgen receptor and estrogen receptor-β and reduced expression of kisspeptin in the hypothalamus. However, rats exposed to estradiol did not show any significant changes in hormone levels relative to controls but exhibited hypothalamic downregulation of kisspeptin, tachykinin 3 and estrogen receptor-α genes and upregulation of the gene that encodes the kisspeptin receptor. Testosterone- and estradiol-exposed rats with different endocrine phenotypes showed differential transcriptional expression of members of the kisspeptin system and sex steroid receptors in the hypothalamus. These differences might account for the different endocrine phenotypes found in testosterone- and estradiol-induced polycystic ovary syndrome rats.

  11. Clinical Phenotyping Does Not Differentiate Hunner Lesion Subtype of Interstitial Cystitis/Bladder Pain Syndrome: A Relook at the Role of Cystoscopy.

    Science.gov (United States)

    Doiron, R Christopher; Tolls, Victoria; Irvine-Bird, Karen; Kelly, Kerri-Lynn; Nickel, J Curtis

    2016-10-01

    Identifying Hunner lesions in patients with interstitial cystitis/bladder pain syndrome presents an opportunity for objective classification into Hunner lesion interstitial cystitis/bladder pain syndrome (classic interstitial cystitis) and nonHunner lesion bladder pain syndrome. While currently the former diagnosis requires cystoscopy, limited data suggest that these subtypes can be distinguished without endoscopy based on the degree of bladder focused centricity and the infrequent association with generalized pain conditions. Patients in a prospective, single center database of interstitial cystitis/bladder pain syndrome who had documented cystoscopic findings were categorized with Hunner lesion interstitial cystitis/bladder pain syndrome or nonHunner lesion bladder pain syndrome. Demographics, pain and symptom scores, voiding symptoms, irritable bowel syndrome and clinical UPOINT (urinary, psychosocial, organ specific, infection, neurological and tenderness) scoring were comparatively analyzed. We reviewed the records of 469 patients, including 359 with documented local anesthetic cystoscopic findings, 44 (12.3%) with Hunner lesion interstitial cystitis/bladder pain syndrome and 315 (87.7%) with nonHunner bladder pain syndrome. Patients with Hunner lesions were older (p = 0.004) and had greater urinary frequency (p = 0.013), more nocturia (p = 0.0004) and higher ICSI (Interstitial Cystitis Symptom Index) scores (p = 0.017). Hunner lesion prevalence was significantly lower in those younger than 50 years vs those 50 years old or older (7.8% vs 14.9%, p = 0.0095). There was no difference in the number of UPOINT phenotype domains reported, overall UPOINT scores or the prevalence of irritable bowel syndrome between the groups. A subtype of interstitial cystitis with Hunner lesions has worse bladder centric symptoms but did not show a distinct bladder centric phenotype. Given the management implications of distinguishing classic interstitial cystitis from non

  12. Targeted next-generation sequencing makes new molecular diagnoses and expands genotype-phenotype relationship in Ehlers-Danlos syndrome.

    Science.gov (United States)

    Weerakkody, Ruwan A; Vandrovcova, Jana; Kanonidou, Christina; Mueller, Michael; Gampawar, Piyush; Ibrahim, Yousef; Norsworthy, Penny; Biggs, Jennifer; Abdullah, Abdulshakur; Ross, David; Black, Holly A; Ferguson, David; Cheshire, Nicholas J; Kazkaz, Hanadi; Grahame, Rodney; Ghali, Neeti; Vandersteen, Anthony; Pope, F Michael; Aitman, Timothy J

    2016-11-01

    Ehlers-Danlos syndrome (EDS) comprises a group of overlapping hereditary disorders of connective tissue with significant morbidity and mortality, including major vascular complications. We sought to identify the diagnostic utility of a next-generation sequencing (NGS) panel in a mixed EDS cohort. We developed and applied PCR-based NGS assays for targeted, unbiased sequencing of 12 collagen and aortopathy genes to a cohort of 177 unrelated EDS patients. Variants were scored blind to previous genetic testing and then compared with results of previous Sanger sequencing. Twenty-eight pathogenic variants in COL5A1/2, COL3A1, FBN1, and COL1A1 and four likely pathogenic variants in COL1A1, TGFBR1/2, and SMAD3 were identified by the NGS assays. These included all previously detected single-nucleotide and other short pathogenic variants in these genes, and seven newly detected pathogenic or likely pathogenic variants leading to clinically significant diagnostic revisions. Twenty-two variants of uncertain significance were identified, seven of which were in aortopathy genes and required clinical follow-up. Unbiased NGS-based sequencing made new molecular diagnoses outside the expected EDS genotype-phenotype relationship and identified previously undetected clinically actionable variants in aortopathy susceptibility genes. These data may be of value in guiding future clinical pathways for genetic diagnosis in EDS.Genet Med 18 11, 1119-1127.

  13. Further delineation of the oculoauricular syndrome phenotype: A new family with a novel truncating HMX1 mutation.

    Science.gov (United States)

    Abdel-Salam, Ghada M H; Abdel-Hamid, Mohamed S; Mehrez, Mennat I; Kamal, Ahmad M; Taher, Mohamed B; Afifi, Hanan H

    2018-04-01

    Biallelic HMX1 mutations cause a very rare autosomal recessive genetic disorder termed as oculoauricular syndrome (OAS) because it is characterized only by the combination of eye and ear anomalies. We identified a new family bringing to three the total families reported with this disorder. Our proband presented with anteriorly protruded ears and malformed ear pinnae in association with microphthalmia, congenital cataract, microcornea, and iris and optic disc colobomata. Additionally, he had high and broad forehead with asymmetry giving a recognizable facial gestalt. Further, short left mandibular ramus and bifid cingulum in the boy and short right mandibular ramus in his father were observed. Mutation analysis revealed a novel homozygous nonsense mutation c.487G>T in the second exon of the HMX1 that predicted to introduce a premature stop codon at position 163 (p.E163*). Parents showed the heterozygous state of the detected mutation. Investigations in a process as complex as craniofacial development suggest that there are still additional, as yet unidentified, genes that play in orchestrate to determine the final phenotype.

  14. Motor Neuron Syndrome as a New Phenotypic Manifestation of Mutation 9185T>C in Gene MTATP6

    Directory of Open Access Journals (Sweden)

    Marisa Brum

    2014-01-01

    Full Text Available Background. The mutation 9185T>C in ATP6 gene, associated with Leigh syndrome, was reported in only few families. Motor neuron disease (MND, both clinically and electrophysiologically, was not previously described in association with this mutation. Case Report. 33-year-old male, with family history of mitochondrial disease, presented with cognitive impairment, exercise intolerance, and progressive muscle weakness. Examination revealed global hypotonia, and proximal tetraparesis, without atrophy or fasciculation, pyramidal signs, or sensory symptoms. The laboratory findings revealed an increase of lactate and lactate/pyruvate ratio; electromyogram showed chronic neurogenic compromise; muscle biopsy was suggestive of spinal muscular atrophy and mitochondriopathy; genetic study of SMN1 was negative but detected a homoplasmic mutation 9185T>C in ATP6 gene. His younger sister, with the same mutation, had cognitive impairment, ataxia, and muscle weakness. EMG showed axonal peripheral neuropathy. Conclusion. This case is unique because of the benignity and the coexistence of clinical, neurophysiological, and pathological findings suggestive of MND that, although described in mitochondrial disease, have not yet been reported in association with 9185T>C mutation. The present case contributes to the expansion of the phenotypic expressions of this particular mutation.

  15. Array-based FMR1 sequencing and deletion analysis in patients with a fragile X syndrome-like phenotype.

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    Stephen C Collins

    2010-03-01

    Full Text Available Fragile X syndrome (FXS is caused by loss of function mutations in the FMR1 gene. Trinucleotide CGG-repeat expansions, resulting in FMR1 gene silencing, are the most common mutations observed at this locus. Even though the repeat expansion mutation is a functional null mutation, few conventional mutations have been identified at this locus, largely due to the clinical laboratory focus on the repeat tract.To more thoroughly evaluate the frequency of conventional mutations in FXS-like patients, we used an array-based method to sequence FMR1 in 51 unrelated males exhibiting several features characteristic of FXS but with normal CGG-repeat tracts of FMR1. One patient was identified with a deletion in FMR1, but none of the patients were found to have other conventional mutations.These data suggest that missense mutations in FMR1 are not a common cause of the FXS phenotype in patients who have normal-length CGG-repeat tracts. However, screening for small deletions of FMR1 may be of clinically utility.

  16. Novel CDKL5 Mutations in Czech Patients with Phenotypes of Atypical Rett Syndrome and Early-Onset Epileptic Encephalopathy.

    Science.gov (United States)

    Záhoráková, D; Langová, M; Brožová, K; Laštůvková, J; Kalina, Z; Rennerová, L; Martásek, P

    2016-01-01

    The X-linked CDKL5 gene, which encodes cyclin-dependent kinase-like 5 protein, has been implicated in early-onset encephalopathy and atypical Rett syndrome with early-onset seizures. The CDKL5 protein is a kinase required for neuronal development and morphogenesis, but its precise functions are still largely unexplored. Individuals with CDKL5 mutations present with severe global developmental delay, intractable epilepsy, and Rett-like features. A clear genotype-phenotype correlation has not been established due to an insufficient number of reported cases. The aim of this study was to analyse the CDKL5 gene in Czech patients with early-onset seizures and Rett-like features. We performed mutation screening in a cohort of 83 individuals using high-resolution melting analysis, DNA sequencing and multiplex ligation- dependent probe amplification. Molecular analyses revealed heterozygous pathogenic mutations in three girls with severe intellectual disability and intractable epilepsy starting at the age of two months. All three identified mutations, c.637G>A, c.902_977+29del105, and c.1757_1758delCT, are novel, thus significantly extending the growing spectrum of known pathogenic CDKL5 sequence variants. Our results support the importance of genetic testing of the CDKL5 gene in patients with early-onset epileptic encephalopathy and Rett-like features with early-onset seizures. This is the first study referring to molecular defects of CDKL5 in Czech cases.

  17. Oral phenotype and scoring of vascular Ehlers–Danlos syndrome: a case–control study

    Science.gov (United States)

    Frank, Michael; Gogly, Bruno; Golmard, Lisa; Naveau, Adrien; Chérifi, Hafida; Emmerich, Joseph; Gaultier, Frédérick; Berdal, Ariane; Jeunemaitre, Xavier; Fournier, Benjamin P J

    2012-01-01

    Objective Vascular Ehlers–Danlos syndrome (vEDS) is a rare genetic condition related to mutations in the COL3A1 gene, responsible of vascular, digestive and uterine accidents. Difficulty of clinical diagnosis has led to the design of diagnostic criteria, summarised in the Villefranche classification. The goal was to assess oral features of vEDS. Gingival recession is the only oral sign recognised as a minor diagnostic criterion. The authors aimed to check this assumption since bibliographical search related to gingival recession in vEDS proved scarce. Design Prospective case–control study. Setting Dental surgery department in a French tertiary hospital. Participants 17 consecutive patients with genetically proven vEDS, aged 19–55 years, were compared with 46 age- and sex-matched controls. Observations Complete oral examination (clinical and radiological) with standardised assessment of periodontal structure, temporomandibular joint function and dental characteristics were performed. COL3A1 mutations were identified by direct sequencing of genomic or complementary DNA. Results Prevalence of gingival recession was low among patients with vEDS, as for periodontitis. Conversely, patients showed marked gingival fragility, temporomandibular disorders, dentin formation defects, molar root fusion and increased root length. After logistic regression, three variables remained significantly associated to vEDS. These variables were integrated in a diagnostic oral score with 87.5% and 97% sensitivity and specificity, respectively. Conclusions Gingival recession is an inappropriate diagnostic criterion for vEDS. Several new specific oral signs of the disease were identified, whose combination may be of greater value in diagnosing vEDS. PMID:22492385

  18. Hepatic Transporter Expression in Metabolic Syndrome: Phenotype, Serum Metabolic Hormones, and Transcription Factor Expression.

    Science.gov (United States)

    Donepudi, Ajay C; Cheng, Qiuqiong; Lu, Zhenqiang James; Cherrington, Nathan J; Slitt, Angela L

    2016-04-01

    Metabolic syndrome is a multifactorial disease associated with obesity, insulin resistance, diabetes, and the alteration of multiple metabolic hormones. Obesity rates have been rising worldwide, which increases our need to understand how this population will respond to drugs and exposure to other chemicals. The purpose of this study was to determine in lean and obese mice the ontogeny of clinical biomarkers such as serum hormone and blood glucose levels as well as the physiologic markers that correlate with nuclear receptor- and transporter-related pathways. Livers from male and female wild-type (WT) (C57BL/6) and ob/ob mice littermates were collected before, during, and after the onset of obesity. Serum hormone and mRNA levels were analyzed. Physiologic changes and gene expression during maturation and progression to obesity were performed and correlation analysis was performed using canonical correlations. Significant ontogenic changes in both WT and ob/ob mice were observed and these ontogenic changes differ in ob/ob mice with the development of obesity. In males and females, the ontogenic pattern of the expression of genes such as Abcc3, 4, Abcg2, Cyp2b10, and 4a14 started to differ from week 3, and became significant at weeks 4 and 8 in ob/ob mice compared with WT mice. In obese males, serum resistin, glucagon, and glucose levels correlated with the expression of most hepatic ATP-binding cassette (Abc) transporters, whereas in obese females, serum glucagon-like peptide 1 levels were correlated with most hepatic uptake transporters and P450 enzymes. Overall, the correlation between physiologic changes and gene expression indicate that metabolism-related hormones may play a role in regulating the genes involved in drug metabolism and transport. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  19. 12q14 microdeletion syndrome: A family with short stature and Silver-Russell syndrome (SRS)-like phenotype and review of the literature.

    Science.gov (United States)

    Heldt, Frederik; Wallaschek, Hannah; Ripperger, Tim; Morlot, Susanne; Illig, Thomas; Eggermann, Thomas; Schlegelberger, Brigitte; Scholz, Caroline; Steinemann, Doris

    2018-03-01

    We report here on the first family with short stature and Silver-Russell-like phenotype due to a microdeletion in 12q14.3. The Netchine-Harbison clinical scoring system was used for the clinical diagnosis of Silver-Russell syndrome (SRS). The three affected first-degree relatives (index patient, mother and brother) presented with prenatal and postnatal growth retardation, feeding difficulties, a prominent forehead and a failure to thrive, but did not show relative macrocephaly. In addition, our index patient showed dysmorphic facial features, periodically increased sweating, and scoliosis. Learning problems and cardiac arrhythmia presented as additional features of her brother. Using high-resolution array-CGH, heterozygosity for a 1.67 Mb deletion in 12q14.3 was detected in the index patient. The heterozygous loss was confirmed by MLPA in the index patient and the other two affected family members. The deletion includes the genes HMGA2, LLPH, TMBIM4, IRAK3, HELB, GRIP1, and the pseudogene RPSAP52. We conclude from these results and from the data of other patients reported in the literature that haploinsufficiency of HMGA2 leads to the short stature in this family. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  20. Deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in twins with a Rett syndrome-like phenotype

    Science.gov (United States)

    Williamson, Sarah L; Ellaway, Carolyn J; Peters, Greg B; Pelka, Gregory J; Tam, Patrick PL; Christodoulou, John

    2015-01-01

    Rett syndrome (RTT), a neurodevelopmental disorder that predominantly affects females, is primarily caused by variants in MECP2. Variants in other genes such as CDKL5 and FOXG1 are usually associated with individuals who manifest distinct phenotypes that may overlap with RTT. Individuals with phenotypes suggestive of RTT are typically screened for variants in MECP2 and then subsequently the other genes dependent on the specific phenotype. Even with this screening strategy, there are individuals in whom no causative variant can be identified, suggesting that there are other novel genes that contribute to the RTT phenotype. Here we report a de novo deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in identical twins with a RTT-like phenotype. We also demonstrate the reduced expression of Ptpn4 in a Mecp2 null mouse model of RTT, as well as the activation of the PTPN4 promoter by MeCP2. Our findings suggest that PTPN4 should be considered for addition to the growing list of genes that warrant screening in individuals with a RTT-like phenotype. PMID:25424712

  1. Is it the resistance training itself or the combined associated weight loss that improves the metabolic syndrome-related phenotypes in postmenopausal women?

    Directory of Open Access Journals (Sweden)

    Soyluk O

    2015-10-01

    Full Text Available Ozlem Soyluk,1 Gulistan Bahat21Division of Endocrinology and Metabolism, Department of Internal Medicine, Istanbul Medical School, Istanbul University, Capa, Istanbul, Turkey; 2Division of Geriatrics, Department of Internal Medicine, Istanbul Medical School, Istanbul University, Capa, Istanbul, TurkeyWe read the article entitled “Resistance training improves isokinetic strength and metabolic syndrome-related phenotypes in postmenopausal women” by Oliveira et al1 with great interest. In the study, the authors examined the effects of 12 weeks of resistance training (RT on metabolic syndrome-related phenotypes in postmenopausal women. They reported that total cholesterol, low-density lipoprotein cholesterol levels, total cholesterol/high-density lipoprotein cholesterol ratio, blood glucose, basal insulin, and homeostatic model assessment of insulin resistance were all significantly reduced with RT (P<0.01. Accordingly, they concluded that a 12-week progressive RT program induces beneficial alterations on metabolic syndrome-related phenotypes in postmenopausal women. View original paper by Oliveira and colleagues.

  2. High-resolution mapping of genotype-phenotype relationships in cri du chat syndrome using array comparative genomic hybridization.

    Science.gov (United States)

    Zhang, Xiaoxiao; Snijders, Antoine; Segraves, Richard; Zhang, Xiuqing; Niebuhr, Anita; Albertson, Donna; Yang, Huanming; Gray, Joe; Niebuhr, Erik; Bolund, Lars; Pinkel, Dan

    2005-02-01

    We have used array comparative genomic hybridization to map DNA copy-number changes in 94 patients with cri du chat syndrome who had been carefully evaluated for the presence of the characteristic cry, speech delay, facial dysmorphology, and level of mental retardation (MR). Most subjects had simple deletions involving 5p (67 terminal and 12 interstitial). Genotype-phenotype correlations localized the region associated with the cry to 1.5 Mb in distal 5p15.31, between bacterial artificial chromosomes (BACs) containing markers D5S2054 and D5S676; speech delay to 3.2 Mb in 5p15.32-15.33, between BACs containing D5S417 and D5S635; and the region associated with facial dysmorphology to 2.4 Mb in 5p15.2-15.31, between BACs containing D5S208 and D5S2887. These results overlap and refine those reported in previous publications. MR depended approximately on the 5p deletion size and location, but there were many cases in which the retardation was disproportionately severe, given the 5p deletion. All 15 of these cases, approximately two-thirds of the severely retarded patients, were found to have copy-number aberrations in addition to the 5p deletion. Restriction of consideration to patients with only 5p deletions clarified the effect of such deletions and suggested the presence of three regions, MRI-III, with differing effect on retardation. Deletions including MRI, a 1.2-Mb region overlapping the previously defined cri du chat critical region but not including MRII and MRIII, produced a moderate level of retardation. Deletions restricted to MRII, located just proximal to MRI, produced a milder level of retardation, whereas deletions restricted to the still-more proximal MRIII produced no discernible phenotype. However, MR increased as deletions that included MRI extended progressively into MRII and MRIII, and MR became profound when all three regions were deleted.

  3. High-resolution mapping of genotype-phenotype relationships in cridu chat syndrome using array comparative genomic hybridization

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Xiaoxiao; Snijders, Antoine; Segraves, Richard; Zhang,Xiuqing; Niebuhr, Anita; Albertson, Donna; Yang, Huanming; Gray, Joe; Niebuhr, Erik; Bolund, Lars; Pinkel, Dan

    2007-07-03

    We have used array comparative genomic hybridization to map DNA copy-number changes in 94 patients with cri du chat syndrome who had been carefully evaluated for the presence of the characteristic cry, speech delay, facial dysmorphology, and level of mental retardation (MR). Most subjects had simple deletions involving 5p (67 terminal and 12 interstitial). Genotype-phenotype correlations localized the region associated with the cry to 1.5 Mb in distal 5p15.31, between bacterial artificial chromosomes (BACs) containing markers D5S2054 and D5S676; speech delay to 3.2 Mb in 5p15.32-15.33, between BACs containing D5S417 and D5S635; and the region associated with facial dysmorphology to 2.4 Mb in 5p15.2-15.31, between BACs containing D5S208 and D5S2887. These results overlap and refine those reported in previous publications. MR depended approximately on the 5p deletion size and location, but there were many cases in which the retardation was disproportionately severe, given the 5p deletion. All 15 of these cases, approximately two-thirds of the severely retarded patients, were found to have copy-number aberrations in addition to the 5p deletion. Restriction of consideration to patients with only 5p deletions clarified the effect of such deletions and suggested the presence of three regions, MRI-III, with differing effect on retardation. Deletions including MRI, a 1.2-Mb region overlapping the previously defined cri du chat critical region but not including MRII and MRIII, produced a moderate level of retardation. Deletions restricted to MRII, located just proximal to MRI, produced a milder level of retardation, whereas deletions restricted to the still-more proximal MRIII produced no discernible phenotype. However, MR increased as deletions that included MRI extended progressively into MRII and MRIII, and MR became profound when all three regions were deleted.

  4. Tourette syndrome in a longitudinal perspective. Clinical course of tics and comorbidities, coexisting psychopathologies, phenotypes and predictors.

    Science.gov (United States)

    Groth, Camilla

    2018-04-01

    Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder characterised by motor and vocal tics and frequent associated comorbidities. The developmental trajectory of tic shows tic-onset in the age of 4-6, peak in the age of 10-12 and decline during adolescence, although only few and small longitudinal studies form the basis of this evidence. Recent studies suggest that comorbid obsessive-compulsive disorder (OCD), attention deficit-hyperactivity disorder (ADHD) and coexisting psychopathologies tend to persist and become more dominant in adolescence. This large prospective follow-up study want to examine the clinical course of TS: tic and comorbidities during adolescence, the prevalence of coexisting psychopathologies, the tic-related impairment, development in phenotype expression and find predictors for the expected course of TS. 
Method: This study is examining a large clinical cohort recruited at the Danish National Tourette Clinic during the period 2005-2007 and 2011-2013. At baseline, 314 participants aged 5-19 years were included and at follow-up 6 years later 227 participated, aged 11-26. All participants were uniformly clinically examined at basis and follow-up with a clinical interview and validated measurements to assess comorbidities. The Yale Global Tic Severity Scale was used to asses tic severity and tic-related impairment. At follow-up a cross-sectional diagnostic evaluation was made with the Development and Well-Being Assessment to assess coexisting psychopathologies.
 Results: A significant decline in tic and the most frequent comorbidities OCD and ADHD was found although some variation existed and some subclinical and partial remissions persisted. Tic-related impairment was not reflected in the tic-decline as expected but influenced by several parameters. The phenotype expression was found to be dynamic but overall changed toward TS without comorbidities. Several predictors were found to predict the clinical course of TS in

  5. Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

    Directory of Open Access Journals (Sweden)

    Frank Fornari

    2011-11-01

    Full Text Available Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS. RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic. Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]. Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms. Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015 more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32 and 47.8% of Family B subjects (11 of 23. No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific

  6. Novel rearrangement of chromosome band 22q11.2 causing 22q11 microdeletion syndrome-like phenotype and rhabdoid tumor of the kidney.

    Science.gov (United States)

    Wieser, R; Fritz, B; Ullmann, R; Müller, I; Galhuber, M; Storlazzi, C T; Ramaswamy, A; Christiansen, H; Shimizu, N; Rehder, H

    2005-08-01

    The 22q11.2 microdeletion syndrome is the most frequent microdeletion syndrome in humans, yet its genetic basis is complex and is still not fully understood. Most patients harbor a 3-Mb deletion (typically deleted region [TDR]), but occasionally patients with atypical deletions, some of which do not overlap with each other and/or the TDR, have been described. Microduplication of the TDR leads to a phenotype similar, albeit not identical, to the deletion of this region. Here we present a child initially suspected of having 22q11 microdeletion syndrome, who in addition developed a fatal malignant rhabdoid tumor of the kidney. Detailed cytogenetic and molecular analyses revealed a complex de novo rearrangement of band q11 of the paternally derived chromosome 22. This aberration exhibited two novel features. First, a microduplication of the 22q11 TDR was associated with an atypical 22q11 microdeletion immediately telomeric of the duplicated region. Second, this deletion was considerably larger than previously reported atypical 22q11 deletions, spanning 2.8 Mb and extending beyond the SMARCB1/SNF5/INI1 tumor suppressor gene, whose second allele harbored a somatic frameshift-causing sequence alteration in the patient's tumor. Two nonallelic homologous recombination events between low-copy repeats (LCRs) could explain the emergence of this novel and complex mutation associated with the phenotype of 22q11 microdeletion syndrome. (c) 2005 Wiley-Liss, Inc.

  7. Symptom patterns and phenotypic subgrouping of women with polycystic ovary syndrome: association between endocrine characteristics and metabolic aberrations.

    Science.gov (United States)

    Huang, Chu-Chun; Tien, Yin-Jing; Chen, Mei-Jou; Chen, Chun-Houh; Ho, Hong-Nerng; Yang, Yu-Shih

    2015-04-01

    What are the potential endocrine characteristics related to risk and severity of metabolic disturbances in women with polycystic ovary syndrome (PCOS)? Women with PCOS could be subtyped into four subgroups according to heterogeneous endocrine characteristics and the major predictive endocrine factors for metabolic aberrations among different subgroups were free androgen index (FAI) and luteinizing hormone (LH) levels. Women diagnosed with PCOS present with highly heterogeneous phenotypes, including endocrine and metabolic aberrations. Different strategies have been proposed to predict the metabolic outcomes but whether the endocrine factors can solely predict the metabolic aberrations is still inconclusive. A cross-sectional study including 460 patients recruited from a reproductive endocrinology outpatient clinic of a tertiary medical center. Patients with PCOS diagnosed according to the 2003 Rotterdam criteria were studied. Clinical history recorded by questionnaires, anthropometric measurements, biochemistry tests after an overnight fast, and pelvic ultrasonography were collected from all patients. Applying a matrix visualization and clustering approach (generalized association plots), the patients were divided into four distinct clusters according to the correlation with four endocrine parameters. Each cluster exhibited specific endocrine characteristics and the prevalence of metabolic syndrome (MS) was significantly different among the clusters (P characteristic of these two metabolically unhealthy clusters was relatively lower LH level. Contrarily, higher LH level (≧15 mIU/ml) during early follicular phase was found to be the best indicator of the metabolically healthy cluster (cluster 1). While high FAI level did correlate with more severe metabolic aberrations, high LH level showed better predictive value than low FAI level to become a metabolically healthy cluster. The results should be applied to other populations with caution due to racial or

  8. Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL).

    Science.gov (United States)

    Elouej, Sahar; Beleza-Meireles, Ana; Caswell, Richard; Colclough, Kevin; Ellard, Sian; Desvignes, Jean Pierre; Béroud, Christophe; Lévy, Nicolas; Mohammed, Shehla; De Sandre-Giovannoli, Annachiara

    2017-06-01

    Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance and metabolic abnormalities. This syndrome is caused by heterozygous de novo mutations in the POLD1 gene. To date, 19 patients with MDPL have been reported in the literature and among them 14 patients have been characterized at the molecular level. Twelve unrelated patients carried a recurrent in-frame deletion of a single codon (p.Ser605del) and two other patients carried a novel heterozygous mutation in exon 13 (p.Arg507Cys). Additionally and interestingly, germline mutations of the same gene have been involved in familial polyposis and colorectal cancer (CRC) predisposition. We describe a male and a female patient with MDPL respectively affected with mild and severe phenotypes. Both of them showed mandibular hypoplasia, a beaked nose with bird-like facies, prominent eyes, a small mouth, growth retardation, muscle and skin atrophy, but the female patient showed such a severe and early phenotype that a first working diagnosis of Hutchinson-Gilford Progeria was made. The exploration was performed by direct sequencing of POLD1 gene exon 15 in the male patient with a classical MDPL phenotype and by whole exome sequencing in the female patient and her unaffected parents. Exome sequencing identified in the latter patient a de novo heterozygous undescribed mutation in the POLD1 gene (NM_002691.3: c.3209T>A), predicted to cause the missense change p.Ile1070Asn in the ZnF2 (Zinc Finger 2) domain of the protein. This mutation was not reported in the 1000 Genome Project, dbSNP and Exome sequencing databases. Furthermore, the Isoleucine1070 residue of POLD1 is highly conserved among various species, suggesting that this substitution may cause a major impairment of POLD1 activity. For the second patient, affected with a typical MDPL phenotype, direct sequencing

  9. Cancer predisposition in children: genetics, phenotypes & screening

    NARCIS (Netherlands)

    Hopman, S.M.J.

    2014-01-01

    This thesis describes the genetic, phenotypic and screening aspects of tumor predisposition syndromes in childhood cancer patients. In tumor predisposition syndromes, the same constitutional molecular defects that lead to the clinical phenotype predispose the patient to develop specific cancers.

  10. Brittle cornea syndrome ZNF469 mutation carrier phenotype and segregation analysis of rare ZNF469 variants in familial keratoconus.

    Science.gov (United States)

    Davidson, Alice E; Borasio, Edmondo; Liskova, Petra; Khan, Arif O; Hassan, Hala; Cheetham, Michael E; Plagnol, Vincent; Alkuraya, Fowzan S; Tuft, Stephen J; Hardcastle, Alison J

    2015-01-06

    Brittle cornea syndrome 1 (BCS1) is a rare recessive condition characterized by extreme thinning of the cornea and sclera, caused by mutations in ZNF469. Keratoconus is a relatively common disease characterized by progressive thinning and ectasia of the cornea. The etiology of keratoconus is complex and not yet understood, but rare ZNF469 variants have recently been associated with disease. We investigated the phenotype of BCS1 carriers with known pathogenic ZNF469 mutations, and recruited families in which aggregation of keratoconus was observed to establish if rare variants in ZNF469 segregated with disease. Patients and family members were recruited and underwent comprehensive anterior segment examination, including corneal topography. Blood samples were donated and genomic DNA was extracted. The coding sequence and splice sites of ZNF469 were PCR amplified and Sanger sequenced. Four carriers of three BCS1-associated ZNF469 loss-of-function mutations (p.[Glu1392Ter], p.[Gln1930Argfs*6], p.[Gln1930fs*133]) were examined and none had keratoconus. One carrier had partially penetrant features of BCS1, including joint hypermobility. ZNF469 sequencing in 11 keratoconus families identified 9 rare (minor allele frequency [MAF] ≤ 0.025) variants predicted to be potentially damaging. However, in each instance the rare variant(s) identified, including two previously reported as potentially keratoconus-associated, did not segregate with the disease. The presence of heterozygous loss-of-function alleles in the ZNF469 gene did not cause keratoconus in the individuals examined. None of the rare nonsynonymous ZNF469 variants identified in the familial cohort conferred a high risk of keratoconus; therefore, genetic variants contributing to disease pathogenesis in these 11 families remain to be identified. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

  11. Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a cross‐sectional study

    Science.gov (United States)

    Mensah, F.; Bansal, A.; Berkovitz, S.; Sharma, A.; Reddy, V.; Leandro, M. J.

    2016-01-01

    Summary Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous condition of unknown aetiology characterized by multiple symptoms including fatigue, post‐exertional malaise and cognitive impairment, lasting for at least 6 months. Recently, two clinical trials of B cell depletion therapy with rituximab (anti‐CD20) reported convincing improvement in symptoms. A possible but undefined role for B cells has therefore been proposed. Studies of the relative percentages of B cell subsets in patients with ME/CFS have not revealed any reproducible differences from healthy controls (HC). In order to explore whether more subtle alterations in B cell subsets related to B cell differentiation exist in ME/CFS patients we used flow cytometry to immunophenotype CD19+ B cells. The panel utilized immunoglobulin (Ig)D, CD27 and CD38 (classical B cell subsets) together with additional markers. A total of 38 patients fulfilling Canadian, Centre for Disease Control and Fukuda ME/CFS criteria and 32 age‐ and sex‐matched HC were included. We found no difference in percentages of classical subsets between ME/CFS patients and HC. However, we observed an increase in frequency (P 20%) was associated with the presence of ME/CFS [odds ratio: 3·47 (1·15–10·46); P = 0·03] compared with HC, and there was a negative correlation with disease duration. In conclusion, we identified possible changes in B cell phenotype in patients with ME/CFS. These may reflect altered B cell function and, if confirmed in other patient cohorts, could provide a platform for studies based on clinical course or responsiveness to rituximab therapy. PMID:26646713

  12. Of mothers and myelin: Aberrant myelination phenotypes in mouse model of Angelman syndrome are dependent on maternal and dietary influences.

    Science.gov (United States)

    Grier, Mark D; Carson, Robert P; Lagrange, Andre H

    2015-09-15

    Angelman syndrome (AS) is a neurodevelopmental disorder characterized by a number of neurological problems, including developmental delay, movement disorders, and epilepsy. AS results from the loss of UBE3A (an imprinted gene) expressed from the maternal chromosome in neurons. Given the ubiquitous expression of Ube3a and the devastating nature of AS, the role of environmental and maternal effects has been largely ignored. Severe ataxia, anxiety-like behaviors and learning deficits are well-documented in patients and AS mice. More recently, clinical imaging studies of AS patients suggest myelination may be delayed or reduced. Utilizing a mouse model of AS, we found disrupted expression of cortical myelin proteins, the magnitude of which is influenced by maternal status, in that the aberrant myelination in the AS pups of AS affected mothers were more pronounced than those seen in AS pups raised by unaffected (Ube3a (m+/p-)) Carrier mothers. Furthermore, feeding the breeding mothers a higher fat (11% vs 5%) diet normalizes these myelin defects. These effects are not limited to myelin proteins. Since AS mice have abnormal stress responses, including altered glucocorticoid receptor (GR) expression, we measured GR expression in pups from Carrier and affected AS mothers. AS pups had higher GR expression than their WT littermates. However, we also found an effect of maternal status, with reduced GR levels in pups from affected mothers compared to genotypically identical pups raised by unaffected Carrier mothers. Taken together, our findings suggest that the phenotypes observed in AS mice may be modulated by factors independent of Ube3a genotype. Published by Elsevier B.V.

  13. Mandibulofacial dysostosis (Treacher-Collins syndrome) in the fetus: novel association with Pectus carinatum in a molecularly confirmed case and review of the fetal phenotype.

    Science.gov (United States)

    Konstantinidou, Anastasia E; Tasoulas, Jason; Kallipolitis, Georgios; Gasparatos, Spyros; Velissariou, Voula; Paraskevakou, Helen

    2013-12-01

    Treacher Collins syndrome is the most common mandibulofacial dysostosis of autosomal dominant or, rarely, recessive inheritance. Affected fetuses may be identified by prenatal ultrasound or diagnosed at autopsy in case of perinatal death or pregnancy termination. We describe the ultrasonographic, autopsy, and molecular findings in a 25-week-gestation affected fetus, and review the clinical, prenatal, and postmortem findings in 15 previously reported fetal and perinatal cases. A nearly complete spectrum of the typical facial characteristics can be present by the early second trimester of gestation, including subtle defects such as lower eyelid colobomas. Mandibular hypoplasia and bilateral auricle defects were constant findings in the affected fetal population. Downslanting palpebral fissures were the second more common feature, followed by midface hypoplasia, polyhydramnios, and ocular defects. Association with Pierre Robin sequence was common (38%) in the reviewed series. Previously unreported pectus carinatum was noted in our case bearing a heterozygous TCOF1 mutation. Other unique reported findings include salivary gland hyperplasia, single umbilical artery, and tracheo-esophageal fistula, all in molecularly unconfirmed cases. Treacher Collins syndrome can be prenatally detected by ultrasound and should be included in the wide range of genetic syndromes that can be diagnosed at perinatal autopsy. Affected fetuses tend to have a more severe phenotype than living patients. The reported association of Treacher Collins syndrome type 1 with pectus carinatum expands the phenotype, provides information on genotype-phenotype correlation, and suggests possible pathogenetic interactions between neural crest cell disorders and the formation of the sternum that merit investigation. Copyright © 2013 Wiley Periodicals, Inc.

  14. Two novel heterozygous mutations of EVC2 cause a mild phenotype of Ellis-van Creveld syndrome in a Chinese family.

    Science.gov (United States)

    Shen, Wenjing; Han, Dong; Zhang, Jin; Zhao, Hongshan; Feng, Hailan

    2011-09-01

    Ellis-van Creveld syndrome (EvC, chondroectodermal dysplasia; OMIM 225500) is an autosomal recessive skeletal dysplasia with associated multisystem involvement. The syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails, and abnormal teeth. Congenital heart defects occur in 50-60% of cases. In this study, we report EvC in a 6-year-old Chinese girl with hypodontia and polydactyly, mild short stature, and abnormalities of the knee joints. No signs of short ribs, narrow thorax, or congenital heart defects were found in this patient. The EvC phenotype shares some similarity with Weyers acrofacial dysostosis (Weyer; OMIM 193530), an autosomal dominant disorder clinically characterized by mild short stature, postaxial polydactyly, nail dystrophy, and dysplastic teeth. Mutations in EVC or EVC2 are associated with both EvC syndrome and Weyers acrodental dysostosis, but the two conditions differ in the severity of the phenotype and their pattern of inheritance. In this study, two novel heterozygous EVC2 mutations, IVS5-2A > G and c.2653C > T (Arg885X), were identified in the patient. The IVS5-2A > G mutation was inherited from the patient's mother and the c.2653C > T from her father. Her parents have no phenotypic symptoms similar to those of the patient. These findings extend the mutation spectrum of this malformation syndrome and provide the possibility of prenatal diagnosis for future offspring in this family. Copyright © 2011 Wiley-Liss, Inc.

  15. Bannayan-Riley-Ruvalcaba syndrome: further delineation of the phenotype and management of PTEN mutation-positive cases.

    NARCIS (Netherlands)

    Hendriks, Y.M.; Verhallen, J.T.; Smagt, J.J. van der; Kant, S.; Hilhorst, Y.; Hoefsloot, L.H.; Hansson, K.B.; Straaten, P.J. van der; Boutkan, H.; Breuning, M.H.; Vasen, H.F.; Brocker-Vriends, A.H.

    2003-01-01

    Bannayan-Riley-Ruvalcaba syndrome (BRRS) is characterised by macrocephaly, intestinal hamartomatous polyps, lipomas, pigmented maculae of the glans penis, developmental delay and mental retardation. The syndrome follows an autosomal dominant pattern of inheritance. In 1997 reports on two BRRS

  16. Neuropsychological phenotype and psychopathology in seven adult patients with Phelan-McDermid syndrome : implications for treatment strategy

    NARCIS (Netherlands)

    Egger, J. I. M.; Zwanenburg, R. J.; van Ravenswaaij-Arts, C. M. A.; Kleefstra, T.; Verhoeven, W. M. A.

    Phelan-McDermid syndrome presents with specific deficits in neurocognition, cerebellar regulatory functioning and enhanced vulnerability for the development of atypical bipolar disorder. Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is characterized by a variable degree of intellectual

  17. Next generation phenotyping in Emanuel and Pallister-Killian syndrome using computer-aided facial dysmorphology analysis of 2D photos.

    Science.gov (United States)

    Liehr, T; Acquarola, N; Pyle, K; St-Pierre, S; Rinholm, M; Bar, O; Wilhelm, K; Schreyer, I

    2018-02-01

    High throughput approaches are continuously progressing and have become a major part of clinical diagnostics. Still, the critical process of detailed phenotyping and gathering clinical information has not changed much in the last decades. Forms of next generation phenotyping (NGP) are needed to increase further the value of any kind of genetic approaches, including timely consideration of (molecular) cytogenetics during the diagnostic quest. As NGP we used in this study the facial dysmorphology novel analysis (FDNA) technology to automatically identify facial phenotypes associated with Emanuel (ES) and Pallister-Killian Syndrome (PKS) from 2D facial photos. The comparison between ES or PKS and normal individuals expressed a full separation between the cohorts. Our results show that NPG is able to help in the clinic, and could reduce the time patients spend in diagnostic odyssey. It also helps to differentiate ES or PKS from each other and other patients with small supernumerary marker chromosomes, especially in countries with no access to more sophisticated genetic approaches apart from banding cytogenetics. Inclusion of more facial pictures of patient with sSMC, like isochromosome-18p-, cat-eye-syndrome or others may contribute to higher detection rates in future. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Hypothalamic transcriptional expression of the kisspeptin system and sex steroid receptors differs among polycystic ovary syndrome rat models with different endocrine phenotypes

    Directory of Open Access Journals (Sweden)

    Rodrigo Rodrigues Marcondes

    Full Text Available OBJECTIVES: Polycystic ovary syndrome is a heterogeneous endocrine disorder that affects reproductive-age women. The mechanisms underlying the endocrine heterogeneity and neuroendocrinology of polycystic ovary syndrome are still unclear. In this study, we investigated the expression of the kisspeptin system and gonadotropin-releasing hormone pulse regulators in the hypothalamus as well as factors related to luteinizing hormone secretion in the pituitary of polycystic ovary syndrome rat models induced by testosterone or estradiol. METHODS: A single injection of testosterone propionate (1.25 mg (n=10 or estradiol benzoate (0.5 mg (n=10 was administered to female rats at 2 days of age to induce experimental polycystic ovary syndrome. Controls were injected with a vehicle (n=10. Animals were euthanized at 90-94 days of age, and the hypothalamus and pituitary gland were used for gene expression analysis. RESULTS: Rats exposed to testosterone exhibited increased transcriptional expression of the androgen receptor and estrogen receptor-β and reduced expression of kisspeptin in the hypothalamus. However, rats exposed to estradiol did not show any significant changes in hormone levels relative to controls but exhibited hypothalamic downregulation of kisspeptin, tachykinin 3 and estrogen receptor-α genes and upregulation of the gene that encodes the kisspeptin receptor. CONCLUSIONS: Testosterone- and estradiol-exposed rats with different endocrine phenotypes showed differential transcriptional expression of members of the kisspeptin system and sex steroid receptors in the hypothalamus. These differences might account for the different endocrine phenotypes found in testosterone- and estradiol-induced polycystic ovary syndrome rats.

  19. 1031-1034delTAAC (Leu125Stop: a novel familial UBE3A mutation causing Angelman syndrome in two siblings showing distinct phenotypes

    Directory of Open Access Journals (Sweden)

    De Molfetta Greice Andreotti

    2012-12-01

    Full Text Available Abstract Background More than 50 mutations in the UBE3A gene (E6-AP ubiquitin protein ligase gene have been found in Angelman syndrome patients with no deletion, no uniparental disomy, and no imprinting defect. Case Presentation We here describe a novel UBE3A frameshift mutation in two siblings who have inherited it from their asymptomatic mother. Despite carrying the same UBE3A mutation, the proband shows a more severe phenotype whereas his sister shows a milder phenotype presenting the typical AS features. Conclusions We hypothesized that the mutation Leu125Stop causes both severe and milder phenotypes. Potential mechanisms include: i maybe the proband has an additional problem (genetic or environmental besides the UBE3A mutation; ii since the two siblings have different fathers, the UBE3A mutation is interacting with a different genetic variant in the proband that, by itself, does not cause problems but in combination with the UBE3A mutation causes the severe phenotype; iii this UBE3A mutation alone can cause either typical AS or the severe clinical picture seen in the proband.

  20. A New COL3A1 Mutation in Ehlers-Danlos Syndrome Vascular Type With Different Phenotypes in the Same Family.

    Science.gov (United States)

    Cortini, Francesca; Marinelli, Barbara; Romi, Silvia; Seresini, Agostino; Pesatori, Angela Cecilia; Seia, Manuela; Montano, Nicola; Bassotti, Alessandra

    2017-04-01

    Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe connective tissue disorder caused by mutations in the collagen type III alpha I chain ( COL3A1) gene. We describe a pathogenetic heterozygous COL3A1 mutation c.3140 G>A, p. Gly1047Asp, identified using next-generation sequencing, in a 40-year-old Italian female. The genetic test performed on her relatives, which present different clinical phenotypes, confirmed that they carry the same mutation in heterozygous state. This finding confirms that mutations causing vEDS have an incomplete penetrance.

  1. A SMARCA2 Mutation in the First Case Report of Nicolaides-Baraitser Syndrome in Latin America: Genotype-Phenotype Correlation

    Directory of Open Access Journals (Sweden)

    Ana Isabel Sánchez

    2017-01-01

    Full Text Available Nicolaides-Baraitser syndrome (NCBRS is a rare and well-recognized entity that was first described in 1993, with a prevalence that is currently not known. It is recognized as a distinctive entity, with some variability in its signs and symptoms. The most important characteristics include intellectual disability, peculiar facial features including sparse scalp hair, coarse facial features, low frontal hairline, and microcephaly, and seizures. Additional features may include epicanthic folds, thin upper lip vermilion with thick lower lip vermilion, skeletal abnormalities, and severe language impairment. The disorder is inherited in an autosomal dominant manner caused by de novo mutations in the SMARCA2 gene, with most being missense mutations. We report a young adult patient with NCBRS and, to our knowledge, the first case report of the syndrome in Latin America with a confirmed molecular diagnosis and a mild-to-moderate phenotype.

  2. Phenotypic expression of mitochondrial genotypes in cultured skin fibroblasts and in Epstein-Barr virus-transformed lymphocytes in Pearson syndrome.

    Science.gov (United States)

    Rötig, A; Bourgeron, T; Rustin, P; Munnich, A

    1995-01-01

    Pearson syndrome is a fatal disorder involving the hematopoietic system and exocrine pancreas. Mitochondrial respiratory chain deficiencies and/or rearrangements of the mitochondrial DNA were consistently observed in all patients. We report here on the variant phenotypic expression of mitochondrial genotypes in cultured cells from a patient with Pearson syndrome. Skin fibroblasts and lymphocytes harbored, respectively, 60% and 80% of deleted mtDNA molecules initially and displayed defective respiratory chain activities. In both cases, there was a progressive recovery of respiratory chain activities during in vitro cell proliferation due to the loss of deleted mtDNA molecules in cultured skin fibroblasts and to an increase in the mtRNA translation efficiency in Epstein-Barr virus-transformed lymphocytes. The present study suggests that various cellular responses to abnormal mitochondrial genotypes might contribute to the tissue-specific expression of mitochondrial disorders in vivo.

  3. Genotype-Phenotype Correlation of SCN5A Mutation for the Clinical and Electrocardiographic Characteristics of Probands With Brugada Syndrome: A Japanese Multicenter Registry.

    Science.gov (United States)

    Yamagata, Kenichiro; Horie, Minoru; Aiba, Takeshi; Ogawa, Satoshi; Aizawa, Yoshifusa; Ohe, Tohru; Yamagishi, Masakazu; Makita, Naomasa; Sakurada, Harumizu; Tanaka, Toshihiro; Shimizu, Akihiko; Hagiwara, Nobuhisa; Kishi, Ryoji; Nakano, Yukiko; Takagi, Masahiko; Makiyama, Takeru; Ohno, Seiko; Fukuda, Keiichi; Watanabe, Hiroshi; Morita, Hiroshi; Hayashi, Kenshi; Kusano, Kengo; Kamakura, Shiro; Yasuda, Satoshi; Ogawa, Hisao; Miyamoto, Yoshihiro; Kapplinger, Jamie D; Ackerman, Michael J; Shimizu, Wataru

    2017-06-06

    The genotype-phenotype correlation of SCN5A mutations as a predictor of cardiac events in Brugada syndrome remains controversial. We aimed to establish a registry limited to probands, with a long follow-up period, so that the genotype-phenotype correlation of SCN5A mutations in Brugada syndrome can be examined without patient selection bias. This multicenter registry enrolled 415 probands (n=403; men, 97%; age, 46±14 years) diagnosed with Brugada syndrome whose SCN5A gene was analyzed for mutations. During a mean follow-up period of 72 months, the overall cardiac event rate was 2.5%/y. In comparison with probands without mutations ( SCN5A (-), n=355), probands with SCN5A mutations ( SCN5A (+), n=60) experienced their first cardiac event at a younger age (34 versus 42 years, P =0.013), had a higher positive rate of late potentials (89% versus 73%, P =0.016), exhibited longer P-wave, PQ, and QRS durations, and had a higher rate of cardiac events ( P =0.017 by log-rank). Multivariate analysis indicated that only SCN5A mutation and history of aborted cardiac arrest were significant predictors of cardiac events ( SCN5A (+) versus SCN5A (-): hazard ratio, 2.0 and P =0.045; history of aborted cardiac arrest versus no such history: hazard ratio, 6.5 and P syndrome patients with SCN5A mutations exhibit more conduction abnormalities on ECG and have higher risk for cardiac events. © 2017 American Heart Association, Inc.

  4. An Angiotensin I Converting Enzyme Polymorphism Is Associated with Clinical Phenotype When Using Differentiation-Syndrome to Categorize Korean Bronchial Asthma Patients

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    Sung-ki Jung

    2011-01-01

    Full Text Available In this study, genetic analysis was conducted to investigate the association of angiotensin I converting enzyme (ACE gene polymorphism with clinical phenotype based on differentiation-syndrome of bronchial asthma patients. Differentiation-syndrome is a traditional Korean medicine (TKM theory in which patients are classified into a Deficiency Syndrome Group (DSG and an Excess Syndrome Group (ESG according to their symptomatic classification. For this study, 110 participants were evaluated by pulmonary function test. Among them, 39 patients were excluded because they refused genotyping. Of the remaining patients, 52 with DSG of asthma (DSGA and 29 with ESG of asthma (ESGA, as determined by the differentiation-syndrome techniques were assessed by genetic analysis. ACE insertion/deletion (I/D polymorphism analysis was conducted using polymerase chain reaction (PCR. Student's t, chi-square, Fisher and Hardy-Weinberg equilibrium tests were used to compare groups. No significant differences in pulmonary function were observed between DSGA and ESGA. The genotypic frequency of ACE I/D polymorphism was found to differ slightly between DSGA and ESGA (P = .0495. However, there were no significant differences in allelic frequency observed between DSGA and ESGA (P = .7006, OR = 1.1223. Interestingly, the allelic (P = .0043, OR = 3.4545 and genotypic (P = .0126 frequencies of the ACE I/D polymorphism in female patients differed significantly between DSGA and ESGA. Taken together, the results presented here indicate that the symptomatic classification of DSGA and ESGA by differentiation-syndrome in Korean asthma patients could be useful in evaluation of the pathogenesis of bronchial asthma.

  5. Low-level hyperinsulinism with hypoglycemic spells in an infant with mosaic Turner syndrome and mild Kabuki-like phenotype: a case report and review of the literature.

    Science.gov (United States)

    Pietzner, Vera; Weigel, Johannes F W; Wand, Dorothea; Merkenschlager, Andreas; Bernhard, Matthias K

    2014-01-01

    Impaired glucose tolerance and type 2 diabetes are well-known features in patients with Turner syndrome. To the best of our knowledge, there is only one reported case of hyperinsulinemic hypoglycemia associated with a complex mosaic Turner syndrome available in the current literature. We report on the case of a 13-month-old girl with a complex mosaic Turner genotype and mild hyperinsulinemic hypoglycemia responsive to diazoxide therapy. Cytogenetic analyses showed two or possibly three cell lines. Sixty percent of the cell lines had a 45,X genotype and the rest had 46,XX with a marker ring chromosome. Diagnosis of a mosaic Turner syndrome and mild Kabuki-like phenotype was confirmed. Despite the rareness of this case, clinicians should be aware of the possibility of hyperinsulinemic hypoglycemia in patients with Turner syndrome to prevent further brain damage caused by hypoglycemic episodes and seizures. Although the mechanism leading to hyperinsulinism in this condition is still unknown, the present report discusses this rare presentation and gives an overview on the current literature regarding this case.

  6. Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2.

    Science.gov (United States)

    Zollino, Marcella; Lecce, Rosetta; Fischetto, Rita; Murdolo, Marina; Faravelli, Francesca; Selicorni, Angelo; Buttè, Cinzia; Memo, Luigi; Capovilla, Giuseppe; Neri, Giovanni

    2003-03-01

    In an attempt to define the distinctive Wolf-Hirschhorn syndrome (WHS) phenotype, and to map its specific clinical manifestations, a total of eight patients carrying a 4p16.3 microdeletion were analyzed for their clinical phenotype and their respective genotypes. The extent of each individual deletion was established by fluorescence in situ hybridization, with a cosmid contig spanning the genomic region from MSX1 (distal half of 4p16.1) to the subtelomeric locus D4S3359. The deletions were 1.9-3.5 Mb, and all were terminal. All the patients presented with a mild phenotype, in which major malformations were usually absent. It is worth noting that head circumference was normal for height in two patients (those with the smallest deletions [1.9 and 2.2 Mb]). The currently accepted WHS critical region (WHSCR) was fully preserved in the patient with the 1.9-Mb deletion, in spite of a typical WHS phenotype. The deletion in this patient spanned the chromosome region from D4S3327 (190 b4 cosmid clone included) to the telomere. From a clinical point of view, the distinctive WHS phenotype is defined by the presence of typical facial appearance, mental retardation, growth delay, congenital hypotonia, and seizures. These signs represent the minimal diagnostic criteria for WHS. This basic phenotype maps distal to the currently accepted WHSCR. Here, we propose a new critical region for WHS, and we refer to this region as "WHSCR-2." It falls within a 300-600-kb interval in 4p16.3, between the loci D4S3327 and D4S98-D4S168. Among the candidate genes already described for WHS, LETM1 (leucine zipper/EF-hand-containing transmembrane) is likely to be pathogenetically involved in seizures. On the basis of genotype-phenotype correlation analysis, dividing the WHS phenotype into two distinct clinical entities, a "classical" and a "mild" form, is recommended for the purpose of proper genetic counseling.

  7. THE KABUKI (NIIKAWA-KUROKI) SYNDROME - FURTHER DELINEATION OF THE PHENOTYPE IN 29 NON-JAPANESE PATIENTS

    NARCIS (Netherlands)

    SCHRANDERSTUMPEL, C; MEINECKE, P; WILSON, G; GILLESSENKAESBACH, G; TINSCHERT, S; KONIG, R; PHILIP, N; RIZZO, R; SCHRANDER, J; PFEIFFER, L; MAATKIEVIT, A; VANDERBURGT, [No Value; VANESSEN, T; LATTA, E; HILLIG, U; VERLOES, A; JOURNEL, H; FRYNS, JP

    The Kabuki (Niikawa-Kuroki) syndrome was reported in 1981 by Niikawa et al. [19] and Kuroki et al. [15] in a total of ten unrelated Japanese children with a characteristic array of multiple congenital anomalies and mental retardation. The syndrome is characterized by a distinct face, mild to

  8. GENERAL OVERGROWTH IN THE FRAGILE-X SYNDROME - VARIABILITY IN THE PHENOTYPIC-EXPRESSION OF THE FMR1 GENE MUTATION

    NARCIS (Netherlands)

    DEVRIES, BBA; ROBINSON, H; STOLTEDIJKSTRA, [No Value; GI, CVTP; DIJKSTRA, PF; VANDOOM, J; HALLEY, DJJ; OOSTRA, BA; TURNER, G; NIERMEIJER, MF

    1995-01-01

    The fragile X syndrome, which often presents in childhood with overgrowth, may in some cases show some diagnostic overlap with classical Sotos syndrome. We describe four fragile X patients with general overgrowth, all of whom are from families with other affected relatives who show the classic

  9. Mother-Child Interaction as a Window to a Unique Social Phenotype in 22q11.2 Deletion Syndrome and in Williams Syndrome

    Science.gov (United States)

    Weisman, Omri; Feldman, Ruth; Burg-Malki, Merav; Keren, Miri; Geva, Ronny; Diesendruck, Gil; Gothelf, Doron

    2015-01-01

    Mother-child interactions in 22q11.2 Deletion syndrome (22q11.2DS) and Williams syndrome (WS) were coded for maternal sensitivity/intrusiveness, child's expression of affect, levels of engagement, and dyadic reciprocity. WS children were found to express more positive emotions towards their mothers compared to 22q11.2DS children and those with…

  10. GAPO syndrome : a new case of this rare syndrome and a review of the relative importance of different phenotypic features in diagnosis

    NARCIS (Netherlands)

    Bacon, W; Hall, RK; Roset, JP; Boukari, A; Tenenbaum, H; Walter, B

    1999-01-01

    The case of GAPO syndrome reported here is the 24th recorded case, 23 cases having been published previously. The 29-year-old male under discussion presents all the typical features of the syndrome, having short stature, dysmorphic craniofacial features. total alopecia and pseudoanodontia. Orally,

  11. Potter syndrome

    Science.gov (United States)

    Potter phenotype ... In Potter syndrome, the primary problem is kidney failure. The kidneys fail to develop properly as the baby is ... kidneys normally produce the amniotic fluid (as urine). Potter phenotype refers to a typical facial appearance that ...

  12. Phenotype of Usher syndrome type II assosiated with compound missense mutations of c.721 C>T and c.1969 C>T in MYO7A in a Chinese Usher syndrome family

    Directory of Open Access Journals (Sweden)

    Wei Zhai

    2015-08-01

    Full Text Available AIM:To identify the pathogenic mutations in a Chinese pedigree affected with Usher syndrome type II (USH2.METHODS:The ophthalmic examinations and audiometric tests were performed to ascertain the phenotype of the family. To detect the genetic defect, exons of 103 known RDs -associated genes including 12 Usher syndrome (USH genes of the proband were captured and sequencing analysis was performed to exclude known genetic defects and find potential pathogenic mutations. Subsequently, candidate mutations were validated in his pedigree and 100 normal controls using polymerase chain reaction (PCR and Sanger sequencing.RESULTS:The patient in the family occurred hearing loss (HL and retinitis pigmentosa (RP without vestibular dysfunction, which were consistent with standards of classification for USH2. He carried the compound heterozygous mutations, c.721 C>T and c.1969 C>T, in the MYO7A gene and the unaffected members carried only one of the two mutations. The mutations were not present in the 100 normal controls.CONCLUSION:We suggested that the compound heterozygous mutations of the MYO7A could lead to USH2, which had revealed distinguished clinical phenotypes associated with MYO7A and expanded the spectrum of clinical phenotypes of the MYO7A mutations.

  13. A comparative study of the neuropsychiatric and neurocognitive phenotype in two microdeletion syndromes: velocardiofacial (22q11.2 deletion) and Williams (7q11.23 deletion) syndromes.

    Science.gov (United States)

    Zarchi, O; Diamond, A; Weinberger, R; Abbott, D; Carmel, M; Frisch, A; Michaelovsky, E; Gruber, R; Green, T; Weizman, A; Gothelf, D

    2014-05-01

    22q11.2 deletion syndrome (22q11.2DS) and Williams syndrome (WS) are common neurogenetic microdeletion syndromes. The aim of the present study was to compare the neuropsychiatric and neurocognitive phenotypes of 22q11.2DS and WS. Forty-five individuals with 22q11.2DS, 24 with WS, 22 with idiopathic developmental disability (DD) and 22 typically developing (TD) controls were compared for the rates of psychiatric disorders as well as cognitive executive and visuospatial functions. We found that while anxiety, mood and disruptive disorders had an equally high prevalence among individuals with 22q11.2DS, WS and DDs, the 22q11.2DS group had the highest rates of psychotic disorders and the WS group had the highest rates of specific phobia. We also found that the WS group demonstrated more severe impairments in both executive and visuospatial functions than the other groups. WS and 22q11.2DS subjects had worse Performance-IQ than Verbal-IQ, a feature typical of non-verbal learning disorders. These findings offer a wide perspective on unique versus common phenotypes in 22q11.2DS and WS. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  14. A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression.

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    Bruno L Lima

    2010-11-01

    Full Text Available Marfan syndrome is an autosomal dominant disease of connective tissue caused by mutations in the fibrillin-1 encoding gene FBN1. Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mgΔloxPneo, carrying the same internal deletion of exons 19-24 as the mgΔ mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. Finally, we show a strong negative correlation between overall levels of Fbn1 expression and the severity of the phenotypes, corroborating the suggested protective role of normal fibrillin-1 in MFS pathogenesis, and supporting the development of therapies based on increasing Fbn1 expression.

  15. Expanding the phenotype of alopecia-contractures-dwarfism mental retardation syndrome (ACD syndrome): description of an additional case and review of the literature.

    Science.gov (United States)

    Schell-Apacik, Chayim; Hardt, Michael; Ertl-Wagner, Birgit; Klopocki, Eva; Möhrenschlager, Matthias; Heinrich, Uwe; von Voss, Hubertus

    2008-09-01

    Alopecia-contractures-dwarfism mental retardation syndrome (ACD syndrome; OMIM 203550) is a very rare genetic disorder with distinct features. To our knowledge, there have been four cases documented to date. In addition, another three patients, previously described as having IFAP syndrome (OMIM %308205), may also have ACD syndrome. We report on one patient with short stature, total alopecia, ichthyosis, photophobia, seizures, ectrodactyly, vertebral anomalies, scoliosis, multiple contractures, mental retardation, and striking facial and other features (e.g. microdolichocephaly, missing eyebrows and eyelashes, long nose, large ears) consistent with ACD syndrome. Results of laboratory testing in the literature case reports were normal, although in none of them, array-CGH (microarray-based comparative genomic hybridization) analysis was performed. In conclusion, the combination of specific features, including total alopecia, ichthyosis, mental retardation, and skeletal anomalies are suggestive of ACD syndrome. We propose that children with this syndrome undergo a certain social pediatric protocol including EEG diagnostics, ophthalmological investigation, psychological testing, management of dermatologic and orthopedic problems, and genetic counseling.

  16. A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs.

    Directory of Open Access Journals (Sweden)

    Mia Olsson

    2011-03-01

    Full Text Available Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA signal for susceptibility to the periodic fever syndrome (p(raw = 2.3 × 10⁻⁶, p(genome = 0.01. Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2 gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA, a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p < 0.0001. When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.

  17. A molecular deletion of distal chromosome 4p in two families with a satellited chromosome 4 lacking the Wolf-Hirschhorn syndrome phenotype.

    Science.gov (United States)

    Estabrooks, L L; Lamb, A N; Kirkman, H N; Callanan, N P; Rao, K W

    1992-11-01

    We report two families with a satellited chromosome 4 short arm (4ps). Satellites and stalks normally occur on the short arms of acrocentric chromosomes; however, the literature cites several reports of satellited nonacrocentric chromosomes, which presumably result from a translocation with an acrocentric chromosome. This is the first report of 4ps chromosomes. Our families are remarkable in that both unaffected and affected individuals carry the 4ps chromosome. The phenotypes observed in affected individuals, although dissimilar, were sufficient to encourage a search for a deletion of chromosome 4p. By Southern blot analysis and fluorescence in situ hybridization, a deletion of material mapping approximately 150 kb from chromosome 4pter was discovered. This deletion is notable because it does not result in the Wolf-Hirschhorn syndrome and can result in an apparently normal phenotype. We speculate that homology between subterminal repeat sequences on 4p and sequences on the acrocentric short arms may explain the origin of the rearrangement and that position effect may play a role in the expression of the abnormal phenotype.

  18. Early Retinal Defects in Fmr1−/y Mice: Toward a Critical Role of Visual Dys-Sensitivity in the Fragile X Syndrome Phenotype?

    Directory of Open Access Journals (Sweden)

    Olivier Perche

    2018-04-01

    Full Text Available Fragile X Syndrome (FXS is caused by a deficiency in Fragile X Mental Retardation Protein (FMRP leading to global sensorial abnormalities, among which visual defects represent a critical part. These visual defects are associated with cerebral neuron immaturity especially in the primary visual cortex. However, we recently demonstrated that retinas of adult Fmr1−/y mice, the FXS murine model, present molecular, cellular and functional alterations. However, no data are currently available on the evolution pattern of such defects. As retinal stimulation through Eye Opening (EO is a crucial signal for the cerebral visual system maturation, we questioned the precocity of molecular and functional retinal phenotype. To answer this question, we studied the retinal molecular phenotype of Fmr1−/y mice before EO until adult age and the consequences of the retinal loss of Fmrp on retinal function in young and adult mice. We showed that retinal molecular defects are present before EO and remain stable at adult age, leading to electrophysiological impairments without any underlying structural changes. We underlined that loss of Fmrp leads to a wide range of defects in the retina, settled even before EO. Our work demonstrates a critical role of the sensorial dysfunction in the Fmr1−/y mice overall phenotype, and provides evidence that altered peripheral perception is a component of the sensory processing defect in FXS conditions.

  19. Early Retinal Defects in Fmr1-/y Mice: Toward a Critical Role of Visual Dys-Sensitivity in the Fragile X Syndrome Phenotype?

    Science.gov (United States)

    Perche, Olivier; Felgerolle, Chloé; Ardourel, Maryvonne; Bazinet, Audrey; Pâris, Arnaud; Rossignol, Rafaëlle; Meyer-Dilhet, Géraldine; Mausset-Bonnefont, Anne-Laure; Hébert, Betty; Laurenceau, David; Montécot-Dubourg, Céline; Menuet, Arnaud; Bizot, Jean-Charles; Pichon, Jacques; Ranchon-Cole, Isabelle; Briault, Sylvain

    2018-01-01

    Fragile X Syndrome (FXS) is caused by a deficiency in Fragile X Mental Retardation Protein (FMRP) leading to global sensorial abnormalities, among which visual defects represent a critical part. These visual defects are associated with cerebral neuron immaturity especially in the primary visual cortex. However, we recently demonstrated that retinas of adult Fmr1 -/y mice, the FXS murine model, present molecular, cellular and functional alterations. However, no data are currently available on the evolution pattern of such defects. As retinal stimulation through Eye Opening (EO) is a crucial signal for the cerebral visual system maturation, we questioned the precocity of molecular and functional retinal phenotype. To answer this question, we studied the retinal molecular phenotype of Fmr1 -/y mice before EO until adult age and the consequences of the retinal loss of Fmrp on retinal function in young and adult mice. We showed that retinal molecular defects are present before EO and remain stable at adult age, leading to electrophysiological impairments without any underlying structural changes. We underlined that loss of Fmrp leads to a wide range of defects in the retina, settled even before EO. Our work demonstrates a critical role of the sensorial dysfunction in the Fmr1 -/y mice overall phenotype, and provides evidence that altered peripheral perception is a component of the sensory processing defect in FXS conditions.

  20. Early Retinal Defects in Fmr1−/y Mice: Toward a Critical Role of Visual Dys-Sensitivity in the Fragile X Syndrome Phenotype?

    Science.gov (United States)

    Perche, Olivier; Felgerolle, Chloé; Ardourel, Maryvonne; Bazinet, Audrey; Pâris, Arnaud; Rossignol, Rafaëlle; Meyer-Dilhet, Géraldine; Mausset-Bonnefont, Anne-Laure; Hébert, Betty; Laurenceau, David; Montécot-Dubourg, Céline; Menuet, Arnaud; Bizot, Jean-Charles; Pichon, Jacques; Ranchon-Cole, Isabelle; Briault, Sylvain

    2018-01-01

    Fragile X Syndrome (FXS) is caused by a deficiency in Fragile X Mental Retardation Protein (FMRP) leading to global sensorial abnormalities, among which visual defects represent a critical part. These visual defects are associated with cerebral neuron immaturity especially in the primary visual cortex. However, we recently demonstrated that retinas of adult Fmr1−/y mice, the FXS murine model, present molecular, cellular and functional alterations. However, no data are currently available on the evolution pattern of such defects. As retinal stimulation through Eye Opening (EO) is a crucial signal for the cerebral visual system maturation, we questioned the precocity of molecular and functional retinal phenotype. To answer this question, we studied the retinal molecular phenotype of Fmr1−/y mice before EO until adult age and the consequences of the retinal loss of Fmrp on retinal function in young and adult mice. We showed that retinal molecular defects are present before EO and remain stable at adult age, leading to electrophysiological impairments without any underlying structural changes. We underlined that loss of Fmrp leads to a wide range of defects in the retina, settled even before EO. Our work demonstrates a critical role of the sensorial dysfunction in the Fmr1−/y mice overall phenotype, and provides evidence that altered peripheral perception is a component of the sensory processing defect in FXS conditions. PMID:29681800

  1. Association of Calpain (CAPN) 10 (UCSNP-43, rs3792267) gene polymorphism with elevated serum androgens in young women with the most severe phenotype of polycystic ovary syndrome (PCOS).

    Science.gov (United States)

    Anastasia, Karela; Koika, Vasiliki; Roupas, Nikolaos D; Armeni, Anastasia; Marioli, Dimitra; Panidis, Dimitrios; George, Adonakis; Georgopoulos, Neoklis A

    2015-01-01

    To highlight a possible association of Calpain (CAPN 10) gene UCSNP-43 polymorphism with hormonal and metabolic traits of young women with different phenotypes of polycystic ovary syndrome (PCOS). PCOS women were genotyped for the CAPN 10 gene UCSNP-43 polymorphism. A comparison of clinical and biochemical features of women with PCOS stratified on the basis of the CAPN 10 gene UCSNP-43 variants was assessed. Anthropometric, hormonal and biochemical measurements were carried out in 668 PCOS women and 200 healthy controls. Subjects were also genotyped for the CAPN 10 gene UCSNP-43 polymorphism. The genotype frequency distributions between groups and controls were compared using the chi-square test. The association of the polymorphism with the clinical and biochemical features of the study cohort was estimated as well. No association of the frequency of CAPN 10 gene UCSNP-43 polymorphism with PCOS was detected. No association of the polymorphism with the anthropometric, biochemical and hormonal features was detected both in PCOS and control women. The polymorphism was associated with serum Δ4 androstenedione (p = 0.018), as well as with 17-OH progesterone (17-hydroxyprogesterone) among women with PCOS phenotype A (p = 0.012). CAPN 10 gene polymorphism UCSNP-43 is deprived of a metabolic contribution to cardiovascular disease (CVD). However, due to its association with androgen excess in phenotype A, CAPN 10 gene polymorphism UCSNP-43 could be used as a genetic marker for CVD in young PCOS women.

  2. The Attenuation Phenotype of a Ribavirin-Resistant Porcine Reproductive and Respiratory Syndrome Virus Is Maintained during Sequential Passages in Pigs

    Science.gov (United States)

    Khatun, Amina; Shabir, Nadeem; Seo, Byoung-Joo; Kim, Bum-Seok; Yoon, Kyoung-Jin

    2016-01-01

    ABSTRACT In a previous study, ribavirin-resistant porcine reproductive and respiratory syndrome virus (PRRSV) mutants (RVRp13 and RVRp22) were selected, and their resistance against random mutation was shown in cultured cells. In the present study, these ribavirin-resistant mutants were evaluated in terms of their genetic and phenotypic stability during three pig-to-pig passages in comparison with modified live virus (MLV) (Ingelvac PRRS MLV). Pigs challenged with RVRp22 had significantly lower (P PRRS; however, there have been serious concerns regarding the use of MLV as a vaccine virus due to the rapid reversion to virulence during replication in pigs. As previously reported, ribavirin is an effective antiviral drug against many RNA viruses. Ribavirin-resistant mutants reemerged by escaping lethal mutagenesis when the treatment concentration was sublethal, and those mutants were genetically more stable than parental viruses. In a previous study, two ribavirin-resistant PRRSV mutants (RVRp13 and RVRp22) were selected, and their higher genetic stability was shown in vitro. Consequently, in the present study, both of the ribavirin-resistant mutants were evaluated in terms of their genetic and phenotypic stability in vivo. RVRp22 was found to exhibit higher genetic and phenotypic stability than MLV, and nine unique mutations were identified in the RVRp22 genome based on a full-length sequence comparison with the RVRp13, VR2332, and MLV genomes. PMID:26889041

  3. Characterization of isolates of Flavobacterium psychrophilum associated with coldwater disease or rainbow trout fry syndrome I : phenotypic and genomic studies

    DEFF Research Database (Denmark)

    Lorenzen, Ellen; Dalsgaard, Inger; Bernardet, Jean-Francois

    1997-01-01

    Isolates of Flavobacterium psychrophilum (formerly Cytophaga psychrophila and Flexibacter psychrophilus) mainly originating from clinical outbreaks of either coldwater disease (CWD) or rainbow trout fry syndrome (RTFS) were studied for selected biochemical, physiological, morphological and genomic...

  4. New or Progressive Multiple Organ Dysfunction Syndrome in Pediatric Severe Sepsis: A Sepsis Phenotype With Higher Morbidity and Mortality

    NARCIS (Netherlands)

    Lin, J.C.; Spinella, P.C.; Fitzgerald, J.C.; Tucci, M.; Bush, J.L.; Nadkarni, V.M.; Thomas, N.J.; Weiss, S.L.; Lemson, J.; Sherring, C.; Bushell, T.

    2017-01-01

    OBJECTIVES: To describe the epidemiology, morbidity, and mortality of new or progressive multiple organ dysfunction syndrome in children with severe sepsis. DESIGN: Secondary analysis of a prospective, cross-sectional, point prevalence study. SETTING: International, multicenter PICUs. PATIENTS:

  5. Análisis genotípico de 11 pacientes colombianos son síndrome de Apert

    Directory of Open Access Journals (Sweden)

    Harvy M. Velasco

    2013-01-01

    Full Text Available Antecedentes. El síndrome de Apert (SA es una de las craneosinostosissindrómicas más severas que afecta el neuro yviscerocraneo y además presenta alteraciones multisistémicascon repercusiones en aspectos físicos (aspecto generaly talla baja, sensoriales (hipoacusia y trastornos visuales,cognoscitivos (retardo mental o trastornos del aprendizaje yde inclusión laboral (sindactilia severa en manos y pies. Suetiología es la mutación del receptor 2 del factor de crecimientofibroblástico (FGFR2 y se hereda de forma autosómicadominante.Materiales y métodos. Se analizaron clínica y molecularmente11 pacientes con sospecha de SA. Se realizó estudiomutacional mediante RFLP para el gen FGFR2.Resultados. Se confirmaron molecularmente los 11 pacientescon SA, cuyas edades oscilaron desde los 0 a 32 años. Todoslos pacientes presentaron el fenotipo clásico. Se encontró un63.6% de pacientes con la mutación S252W y 36.4% conP253R.Discusión. De los pacientes analizados, llamo la atención lapresencia de talla baja y RM/RGD en algunos de ellos. Desdeel punto de vista genotípico, las frecuencias mutacionales paraS252W y P253R no mostraron diferencias con relación a loreportado mundialmente. Aunque no se disponen de datos de laincidencia de esta patología a nivel local, este estudio podría serel primer acercamiento para fines epidemiológicos en Colombia.

  6. Elevated serum androstenedione is associated with a more severe phenotype in women with polycystic ovary syndrome (PCOS).

    Science.gov (United States)

    Georgopoulos, Neoklis A; Papadakis, Efstathios; Armeni, Anastasia K; Katsikis, Ilias; Roupas, Nikolaos D; Panidis, Dimitrios

    2014-01-01

    To evaluate the impact of elevated serum Δ4A levels on the hormonal and metabolic features of the different phenotypes of PCOS. 1276 women with PCOS according to the Rotterdam criteria were included, in whom serum hormonal levels were determined. In PCOS women as a whole, as well as in patients presenting clinical and/or biochemical hyperandrogenemia (phenotypes I and II), Δ4A levels >3.8 ng/ml were positively related to LH, LH/FSH ratio, T, DHEAS, 17 OH progesterone and FAI and negatively related to T/Δ4A ratio. In the milder phenotype III, a positive correlation between Δ4A levels >3.8 ng/ml and T, DHEAS, 17 OH progesterone and FAI and a negative one between increased Δ4A and T/Δ4A ratio were reported. In the whole PCOS group with androstenedione >3.8 ng/ml, an increased ovarian volume was observed, while a greater mean follicular number was found only in phenotypes I and II. Increased serum Δ4A levels, which are associated with more severe PCOS phenotypes, possibly contribute to the worsening of PCOS features and therefore could be a valuable marker of biochemical hyperandrogenemia.

  7. A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions.

    Science.gov (United States)

    Rouzier, Cécile; Moore, David; Delorme, Cécile; Lacas-Gervais, Sandra; Ait-El-Mkadem, Samira; Fragaki, Konstantina; Burté, Florence; Serre, Valérie; Bannwarth, Sylvie; Chaussenot, Annabelle; Catala, Martin; Yu-Wai-Man, Patrick; Paquis-Flucklinger, Véronique

    2017-05-01

    Wolfram syndrome (WS) is a progressive neurodegenerative disease characterized by early-onset optic atrophy and diabetes mellitus, which can be associated with more extensive central nervous system and endocrine complications. The majority of patients harbour pathogenic WFS1 mutations, but recessive mutations in a second gene, CISD2, have been described in a small number of families with Wolfram syndrome type 2 (WFS2). The defining diagnostic criteria for WFS2 also consist of optic atrophy and diabetes mellitus, but unlike WFS1, this phenotypic subgroup has been associated with peptic ulcer disease and an increased bleeding tendency. Here, we report on a novel homozygous CISD2 mutation (c.215A > G; p.Asn72Ser) in a Moroccan patient with an overlapping phenotype suggesting that Wolfram syndrome type 1 and type 2 form a continuous clinical spectrum with genetic heterogeneity. The present study provides strong evidence that this particular CISD2 mutation disturbs cellular Ca2+ homeostasis with enhanced Ca2+ flux from the ER to mitochondria and cytosolic Ca2+ abnormalities in patient-derived fibroblasts. This Ca2+ dysregulation was associated with increased ER-mitochondria contact, a swollen ER lumen and a hyperfused mitochondrial network in the absence of overt ER stress. Although there was no marked alteration in mitochondrial bioenergetics under basal conditions, culture of patient-derived fibroblasts in glucose-free galactose medium revealed a respiratory chain defect in complexes I and II, and a trend towards decreased ATP levels. Our results provide important novel insight into the potential disease mechanisms underlying the neurodegenerative consequences of CISD2 mutations and the subsequent development of multisystemic disease. © The Author 2017. Published by Oxford University Press.

  8. Apert Syndrome: Molecularly Confirmed C.758C>G (P.Pro253Arg) in FGFR2

    Energy Technology Data Exchange (ETDEWEB)

    Cha Gon, Lee, E-mail: leechagon@eulji.ac.kr [Department of Pediatrics, Eulji General Hospital, College of Medicine, Eulji University, 68 Hangeulbiseok-ro, Nowon-gu, Seoul 139-711 (Korea, Republic of)

    2016-03-21

    A 5-day-old girl was referred to our clinic for evaluation of congenital malformations. She was identified with a pathogenic mutation c.758C>G (p.Pro253Arg) in FGFR2 gene using targeted exome sequencing. The de novo mutation was confirmed with Sanger sequencing in the patient and her parents. She showed occipital plagiocephaly with frontal bossing (Figure A and B). Skull frontal and lateral radiography revealed fusion of most of the sutures except coronal suture, with convolutional markings (Figure D and E). She had complete cleft palate (Figure C). Her fused bilateral hands showed type II syndactyly with complete syndactyly between the ring and the little fingers (Figure F1-F3). Both toes were simple syndactyly with side-to-side fusion of skin (Figure G1-)

  9. Apert Syndrome: Molecularly Confirmed C.758C>G (P.Pro253Arg) in FGFR2

    International Nuclear Information System (INIS)

    Cha Gon, Lee

    2016-01-01

    A 5-day-old girl was referred to our clinic for evaluation of congenital malformations. She was identified with a pathogenic mutation c.758C>G (p.Pro253Arg) in FGFR2 gene using targeted exome sequencing. The de novo mutation was confirmed with Sanger sequencing in the patient and her parents. She showed occipital plagiocephaly with frontal bossing (Figure A and B). Skull frontal and lateral radiography revealed fusion of most of the sutures except coronal suture, with convolutional markings (Figure D and E). She had complete cleft palate (Figure C). Her fused bilateral hands showed type II syndactyly with complete syndactyly between the ring and the little fingers (Figure F1-F3). Both toes were simple syndactyly with side-to-side fusion of skin (Figure G1-)

  10. A hypoplastic atlas and long odontoid process in a girl manifesting phenotypic features resembling spondyloepimetaphyseal dysplasia joint laxity syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Al Kaissi, Ali [Hanusch Hospital, Ludwig Boltzmann Institute of Osteology, Vienna (Austria); Hanusch Hospital, AUVA Trauma Centre Meidling, 4th Medical Department, Vienna (Austria); Children' s Hospital, Orthopaedic Paediatric Surgery, Tunis Jabari (Tunisia); Orthopaedic Hospital of Speising, Paediatric Department, Vienna (Austria); Ben Chehida, Farid [Ibn Zohr Institute of Radiology, Tunis (Tunisia); Ben Ghachem, Maher [Children' s Hospital, Orthopaedic Paediatric Surgery, Tunis Jabari (Tunisia); Klaushofer, Klaus [Hanusch Hospital, Ludwig Boltzmann Institute of Osteology, Vienna (Austria); Hanusch Hospital, AUVA Trauma Centre Meidling, 4th Medical Department, Vienna (Austria); Grill, Franz [Orthopaedic Hospital of Speising, Paediatric Department, Vienna (Austria)

    2008-05-15

    Phenotypic features consistent but not completely diagnostic for spondyloepimetaphyseal dysplasia joint laxity (SEMDJL) were encountered in a 7-year-old-girl. Additional tomographic features of a hypoplastic atlas (assimilation of the posterior arch of the atlas) and unduly long odontoid process were seen. We report what might be a novel type of SEMDJL. (orig.)

  11. De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes

    DEFF Research Database (Denmark)

    Gil-Rodríguez, María Concepción; Deardorff, Matthew A; Ansari, Morad

    2015-01-01

    LS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive...

  12. No significant effect of monosomy for distal 21q22. 3 on the Down syndrom phenotype in mirror' duplications of chromosome 21

    Energy Technology Data Exchange (ETDEWEB)

    Pangalos, C.; Prieur, M.; Rethore, M.O.; Lejeune, J. (Institut de Progenese, Paris (France)); Theophile, D.; Sinet, P.M.; Chettouh, Z.; Delabar, J.M. (Hopital Necker Enfants Malades, Paris (France)); Marks, A. (Univ. of Toronto, Ontario (Canada)); Stamboulieh-Abazis, D. (Diagnostic Genetic Center, Athens (Greece)); Verellen, C. (Centre de Genetique Humaine, Brussels (Belgium))

    1992-12-01

    Three Down syndrome patients for whom karyotypic analysis showed a mirror' (reverse tandem) duplication of chromosome 21 were studied by phenotypic, cytogenetic, and molecular methods. On high-resolution R-banding analysis performed in two cases, the size of the fusion 21q22.3 band was apparently less than twice the size of the normal 21q22.3, suggesting a partial deletion of distal 21q. The evaluation of eight chromosome 21 single-copy sequences of the 21q22 region - namely, SOD1, D21S15, D21S42, CRYA1, PFKL, CD18, COL6A1, and S100B - by a slot blot method showed in all three cases a partial deletion of 21q22.3 and partial monosomy. The translocation breakpoints were different in each patient, and in two cases the rearranged chromosome was found to be asymmetrical. The molecular definition of the monosomy 21 in each patient was, respectively, COL6A1-S100B, CD18-S100B, and PFKL-S100B. DNA polymorphism analysis indicated in all cases a homozygosity of the duplicated material. The duplicated region was maternal in two patients and paternal in one patient. These data suggest that the reverse tandem chromosomes did not result from a telomeric fusion between chromosomes 21 but from a translocation between sister chromatids. The phenotypes of these patients did not differ significantly from that of individuals with full trisomy 21, except in one case with large ears with an unfolded helix. The fact that monosomy of distal 21q22.3 in these patients resulted in a phenotype very similar to Down syndrome suggests that the duplication of the genes located in this part of chromosome 21 is not necessary for the pathogenesis of the Down syndrome features observed in these patients, including most of the facial and hand features, muscular hypotonia, cardiopathy of the Fallot tetralogy type, and part of the mental retardation. 54 refs., 5 figs., 3 tabs.

  13. Coexpression network analysis in abdominal and gluteal adipose tissue reveals regulatory genetic loci for metabolic syndrome and related phenotypes

    DEFF Research Database (Denmark)

    Min, Josine L; Nicholson, George; Halgrimsdottir, Ingileif

    2012-01-01

    Metabolic Syndrome (MetS) is highly prevalent and has considerable public health impact, but its underlying genetic factors remain elusive. To identify gene networks involved in MetS, we conducted whole-genome expression and genotype profiling on abdominal (ABD) and gluteal (GLU) adipose tissue, ...

  14. De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes

    NARCIS (Netherlands)

    Gil-Rodríguez, María Concepción; Deardorff, Matthew A.; Ansari, Morad; Tan, Christopher A.; Parenti, Ilaria; Baquero-Montoya, Carolina; Ousager, Lilian B.; Puisac, Beatriz; Hernández-Marcos, María; Teresa-Rodrigo, María Esperanza; Marcos-Alcalde, Iñigo; Wesselink, Jan-Jaap; Lusa-Bernal, Silvia; Bijlsma, Emilia K.; Braunholz, Diana; Bueno-Martinez, Inés; Clark, Dinah; Cooper, Nicola S.; Curry, Cynthia J.; Fisher, Richard; Fryer, Alan; Ganesh, Jaya; Gervasini, Cristina; Gillessen-Kaesbach, Gabriele; Guo, Yiran; Hakonarson, Hakon; Hopkin, Robert J.; Kaur, Maninder; Keating, Brendan J.; Kibaek, María; Kinning, Esther; Kleefstra, Tjitske; Kline, Antonie D.; Kuchinskaya, Ekaterina; Larizza, Lidia; Li, Yun R.; Liu, Xuanzhu; Mariani, Milena; Picker, Jonathan D.; Pié, Ángeles; Pozojevic, Jelena; Queralt, Ethel; Richer, Julie; Roeder, Elizabeth; Sinha, Anubha; Scott, Richard H.; So, Joyce; Wusik, Katherine A.; Wilson, Louise; Zhang, Jianguo; Gómez-Puertas, Paulino; Casale, César H.; Ström, Lena; Selicorni, Angelo; Ramos, Feliciano J.; Jackson, Laird G.; Krantz, Ian D.; Das, Soma; Hennekam, Raoul C. M.; Kaiser, Frank J.; Fitzpatrick, David R.; Pié, Juan

    2015-01-01

    Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for

  15. Carbohydrate-deficient glycoprotein syndrome type 1a: a variant phenotype with borderline cognitive dysfunction, cerebellar hypoplasia, and coagulation disturbances

    NARCIS (Netherlands)

    van Ommen, C. H.; Peters, M.; Barth, P. G.; Vreken, P.; Wanders, R. J.; Jaeken, J.

    2000-01-01

    An 8-year-old boy is described with borderline cognitive impairment, cerebellar hypoplasia, a stroke-like episode, and venous thrombosis of the left leg after a period of immobilization. The pattern of multiple abnormalities in blood coagulation suggested carbohydrate-deficient glycoprotein syndrome

  16. Whole blood microarray analysis of pigs showing extreme phenotypes after a porcine reproductive and respiratory syndrome virus infection

    Science.gov (United States)

    Background Observed variability in pig response to Porcine Reproductive and Respiratory Syndrome virus (PRRSv) infection, and recently demonstrated genetic control of such responses, suggest that it may be possible to reduce the economic impact of this disease by selecting more disease-resistant pig...

  17. The phenotype of Floating-Harbor syndrome: Clinical characterization of 52 individuals with mutations in exon 34 of SRCAP

    NARCIS (Netherlands)

    S.M. Nikkel (Sarah); A. Dauber (Andrew); S. de Munnik (Sonja); M. Connolly (Meghan); R.L. Hood (Rebecca L); O. Caluseriu (Oana); J.A. Hurst (Jane); U. Kini (Usha); M.J.M. Nowaczyk; A. Afenjar (Alexandra); B. Albrecht; J.E. Allanson (Judith); P. Balestri (Paolo); T. Ben-Omran (Tawfeg); F. Brancati (Fred); I. Cordeiro (Isabel); B.S. Da Cunha (Bruna Santos); P.F. Delaney (Peter); A. Destrée (Anne); D.R. Fitzpatrick (David); F. Forzano (Francesca); N. Ghali (Neeti); G. Gillies (Greta); J. Harwood; Y. Hendriks; D. Héron (Delphine); A. Hoischen (Alex); E.M. Honey (Engela Magdalena); E.H. Hoefsloot (Lies); J. Ibrahim (Jennifer); C. Jacob (Claire); S.G. Kant (Sarina); C.A. Kim (Chong); E.P. Kirk (Edwin P); N.V.A.M. Knoers (Nine); D. Lacombe (Denis); C. van der Lee (Christiaan); I.F.M. Lo (Ivan F M); L.S. Lucas (Luiza S); F. Mari (Francesca); V. Mericq (Veronica); J.S. Moilanen (Jukka S); S.T. Møller (Sanne Traasdahl); S. Moortgat (Stephanie); D.T. Pilz (Daniela); K. Pope (Kate); S. Price (Susan); A. Renieri (Alessandra); J. Sá (Joaquim); J. Schoots (Jeroen); E.L. Silveira (Elizabeth L); M.E.H. Simon (Marleen); A. Slavotinek (Anne); I.K. Temple; I. van der Burgt (Ineke); B.B.A. de Vries (Bert); J.D. Weisfeld-Adams (James D); M.L. Whiteford (Margo L); D. Wierczorek (Dagmar); J.M. Wit (Jan); C.F.O. Yee (Connie Fung On); P. Beaulieu (Patrick); S.M. White (Sue M); B. Bulman; E. Bongers (Ernie); H. Brunner (Han); M. Feingold (Murray); K.M. Boycott (Kym)

    2013-01-01

    textabstractBackground: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA

  18. Genetic polymorphisms of the glucocorticoid receptor may affect the phenotype of women with anovulatory polycystic ovary syndrome

    NARCIS (Netherlands)

    Valkenburg, O.; Uitterlinden, A. G.; Themmen, A. P.; de Jong, F. H.; Hofman, A.; Fauser, B. C. J. M.; Laven, J. S. E.

    2011-01-01

    BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by ovarian dysfunction. The association with obesity and insulin resistance is well established. Steroid hormones play a central role in the regulation of both ovarian function and body composition. This study aims to assess the influence

  19. Proteomics, ultrastructure, and physiology of hippocampal synapses in a fragile X syndrome mouse model reveal presynaptic phenotype

    NARCIS (Netherlands)

    Klemmer, P.; Meredith, R.M.; Holmgren, C.D.; Klychnikov, O.I.; Stahl-Zeng, J.; Loos, M.; van der Schors, R.C.; Wortel, J.; de Wit, H.; Spijker, S.; Rotaru, D.C.; Mansvelder, H.D.; Smit, A.B.; Li, K.W.

    2011-01-01

    Fragile X syndrome (FXS), the most common form of hereditary mental retardation, is caused by a loss-of-function mutation of the Fmr1 gene, which encodes fragile X mental retardation protein (FMRP). FMRP affects dendritic protein synthesis, thereby causing synaptic abnormalities. Here, we used a

  20. Increase in central striatal dopamine transporters in patients with Shwachman-Diamond syndrome: additional evidence of a brain phenotype

    NARCIS (Netherlands)

    Booij, Jan; Reneman, Liesbeth; Alders, Marielle; Kuijpers, Taco W.

    2013-01-01

    Patients with Shwachman-Diamond syndrome (SDS) do not only experience well-described physical features like skeletal abnormalities and hematological dysfunctions, but recent studies also suggested attention and working memory deficits in SDS. Indeed, a recent structural magnetic resonance imaging

  1. Phenotype and natural history in 101 individuals with Pitt-Hopkins syndrome through an internet questionnaire system

    NARCIS (Netherlands)

    de Winter, Channa F.; Baas, Melanie; Bijlsma, Emilia K.; van Heukelingen, John; Routledge, Sue; Hennekam, Raoul C. M.

    2016-01-01

    Pitt-Hopkins syndrome (PTHS; MIM# 610954) is a genetically determined entity mainly caused by mutations in TransCription Factor 4 (TCF4). We have developed a new way to collect information on (ultra-)rare disorders through a web-based database which we call 'waihonapedia' (waihona [meaning treasure

  2. A Novel Frameshift Mutation (c.5387_5388insTT) in NIPBL in Cornelia de Lange Syndrome with Severe Phenotype.

    Science.gov (United States)

    Kang, Min Jae; Ahn, Soo Min; Hwang, Il Tae

    2018-01-01

    Cornelia de Lange syndrome (CdLS) is a developmental disorder which is characterized by typical facial features, upper extremity malformations, and growth and cognitive delays. The genes involved in CdLS encode the cohesin complex and its associated proteins; and NIPBL mutations, which account for half of the cases, result in severe CdLS phenotypes. We describe a girl with CdLS, presenting with typical facial dysmorphism, cleft palate, hypertrichosis, upper limb hypertonicity, flexion contracture of elbows, micromelia, bilateral hearing loss, gastroesophageal reflux, and severe pyloric stenosis. We detected a heterozygous frameshift mutation in NIPBL (c.5387_5388ins(TT), p.Leu1796Phefs*8) which is a novel mutation. © 2018 by the Association of Clinical Scientists, Inc.

  3. Additional case of Marden-Walker syndrome: support for the autosomal-recessive inheritance adn refinement of phenotype in a surviving patient.

    Science.gov (United States)

    Orrico, A; Galli, L; Zappella, M; Orsi, A; Hayek, G

    2001-02-01

    In this report, we present a 14-year-old girl, born to consanguineous parents, who presented with severe mental retardation, hypotonia, short stature, and congenital joint contractures. The craniofacial features were scaphocephaly, thin/long and immobile face, marked hypoplasia of the midface, temporal narrowness, blepharophimosis, palpebral ptosis, and strabismus. The combination of such a distinctive craniofacial appearance and psychomotor retardation allows us to recognize a new case of the Marden-Walker syndrome. Our patient represents one of the rare cases in which consanguineous mating supports the autosomal-recessive pattern of inheritance of this condition. Furthermore, through refining the phenotype of a surviving patient, this report may contribute to a better recognition of this disorder in older affected children.

  4. Delineation of 2q32q35 Deletion Phenotypes: Two Apparent “Proximal” and “Distal” Syndromes

    Directory of Open Access Journals (Sweden)

    Adrian Mc Cormack

    2013-01-01

    Full Text Available We report on three patients with interstitial deletions of the long arm of chromosome 2 involving bands 2q32.1–q35. They presented with wide-ranging phenotypic variation including facial dysmorphisms, cleft palate, learning difficulties, behavioural issues and severe heart defects. Microarray analysis confirmed an 8.6 Mb deletion in patients 1 and 2 and a 24.7 Mb deletion in patient 3. We discuss the genes involved in the deleted regions including MYO1B, GLS, FRZB, SATB2, and CPS1 and compare the phenotype with those reported in the literature. Taken together, these data suggest that there is a spectrum of disease severity such that patients with deletions encompassing the region of 2q32.1q32.2, which includes the FRZB gene, show an apparently milder phenotype compared to those that lie further distal in 2q32.3q35 that encompasses the SATB2 gene.

  5. Shwachman-Diamond syndrome presenting with early ichthyosis, associated dermal and epidermal intracellular lipid droplets, hypoglycemia, and later distinctive clinical SDS phenotype.

    Science.gov (United States)

    Scalais, Emmanuel; Connerotte, Anne-Catherine; Despontin, Karine; Biver, Armand; Ceuterick-de Groote, Chantal; Alders, Marielle; Kolivras, Athanassios; Hachem, Jean-Pierre; De Meirleir, Linda

    2016-07-01

    Shwachman-Diamond syndrome (SDS) is a recessive ribosomopathy, characterized by bone marrow failure and exocrine pancreatic insufficiency (ePI) often associated with neurodevelopmental and skeletal abnormalities. The aim of this report is to describe a SDS patient with early ichthyosis associated with dermal and epidermal intracellular lipid droplets (iLDs), hypoglycemia and later a distinctive clinical SDS phenotype. At 3 months of age, she had ichthyosis, growth retardation, and failure to thrive. She had not cytopenia. Ultrasonography (US) showed pancreatic diffuse high echogenicity. Subsequently fasting hypoketotic hypoglycemia occurred without permanent hepatomegaly or hyperlipidemia. Continuous gavage feeding was followed by clinical improvement including ichthyosis and hypoglycemia. After 14 months of age, she developed persistent neutropenia and ePI consistent with SDS. The ichthyotic skin biopsy, performed at 5 months of age, disclosed iLDs in all epidermal layers, in melanocytes, eccrine sweat glands, Schwann cells and dermal fibroblasts. These iLDs were reminiscent of those described in Dorfman-Chanarin syndrome (DCS) or Wolman's disease. Both LIPA and CGI-58 analysis did not revealed pathogenic mutation. By sequencing SBDS, a compound heterozygous for a previously reported gene mutation (c.258 + 2T>C) and a novel mutation (c.284T>G) were found. Defective SBDS may hypothetically interfere as in DCS, with neutral lipid metabolism and play a role in the SDS phenotype such as ichthyosis with dermal and epidermal iLDs and hypoglycemia. This interference with neutral lipid metabolism must most likely occur in the cytoplasm compartment as in DCS and not in the lysosomal compartment as in Wolman's disease. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  6. Phenotypic characterization of an older adult male with late-onset epilepsy and a novel mutation in ASXL3 shows overlap with the associated Bainbridge-Ropers syndrome

    Directory of Open Access Journals (Sweden)

    Verhoeven W

    2018-03-01

    Full Text Available Willem Verhoeven,1,2 Jos Egger,1,3 Emmy Räkers,4 Arjen van Erkelens,5 Rolph Pfundt,5 Marjolein H Willemsen5 1Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Venray, the Netherlands; 2Department of Psychiatry, Erasmus University Medical Centre, Rotterdam, the Netherlands; 3Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands; 4ASVZ, Centre for People with Intellectual Disabilities, Sliedrecht, the Netherlands; 5Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands Abstract: The additional sex combs like 3 gene is considered to be causative for the rare Bainbridge-Ropers syndrome (BRPS, which is characterized by severe intellectual disability, neonatal hypotonia, nearly absent development of speech and language as well as several facial dysmorphisms. Apart from disruptive autistiform behaviors, sleep disturbances and epileptic phenomena may be present. Here, a 47-year-old severely intellectually disabled male is described in whom exome sequencing disclosed a novel heterozygous frameshift mutation in the ASXL3 gene leading to a premature stopcodon in the last part of the last exon. Mutations in this very end 3' of the gene have not been reported before in BRPS. The phenotypical presentation of the patient including partially therapy-resistant epilepsy starting in later adulthood shows overlap with BRPS, and it was therefore concluded that the phenotype is likely explained by the identified mutation in ASXL3. Keywords: Bainbridge-Ropers syndrome, ASLX3, frameshift mutation, epilepsy, intellectual disability, array analysis, whole exome sequencing, autism spectrum disorder

  7. Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A.

    Science.gov (United States)

    Kosho, Tomoki; Okamoto, Nobuhiko

    2014-09-01

    Coffin-Siris syndrome (CSS) is a rare congenital malformation syndrome, recently found to be caused by mutations in several genes encoding components of the BAF complex. To date, 109 patients have been reported with their mutations: SMARCB1 (12%), SMARCA4 (11%), SMARCE1 (2%), ARID1A (7%), ARID1B (65%), and PHF6 (2%). We review genotype-phenotype correlation of all previously reported patients with mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A through reassessment of their clinical and molecular findings. Cardinal features of CSS included variable degrees of intellectual disability (ID) predominantly affecting speech, sucking/feeding difficulty, and craniofacial (thick eyebrows, long eyelashes), digital (hypoplastic 5th fingers or toes, hypoplastic 5th fingernails or toenails), and other characteristics (hypertrichosis). In addition, patients with SMARCB1 mutations had severe neurodevelopmental deficits including severe ID, seizures, CNS structural abnormalities, and no expressive words as well as scoliosis. Especially, those with a recurrent mutation "p.Lys364del" represented strikingly similar phenotypes including characteristic facial coarseness. Patients with SMARCA4 mutations had less coarse craniofacial appearances and behavioral abnormalities. Patients with SMARCE1 mutations had a wide spectrum of manifestations from severe to moderate ID. Patients with ARID1A also had a wide spectrum of manifestations from severe ID and serous internal complications that could result in early death to mild ID. Mutations in SMARCB1, SMARCA4, and SMARCE1 are expected to exert dominant-negative or gain-of-function effects, whereas those in ARID1A are expected to exert loss-of-function effects. © 2014 Wiley Periodicals, Inc.

  8. Involvement of lipoprotein(a) phenotypes in the etiology of cerebral white matter lesion seen in the elderly with geriatric syndrome

    International Nuclear Information System (INIS)

    Nakai, Toshiki; Koyama, Syun-ichi; Kanetaka, Hidekazu; Iwamoto, Toshihiko; Arai, Hisayuki

    2009-01-01

    Lipoprotein(a) [Lp(a)], an apolipoprotein(a) combined with apoB100 protein and low-density lipoprotein (LDL) cholesterol, has a variety of phenotypes, mainly due to the number of kringle 4 type 2 within the apolipoprotein(a), and kringle 4 type 2 is extremely similar to plasminogen. Lp(a) is well-known as a risk factor for atherosclerosis, however, the association between Lp(a) phenotypes and the etiology of cerebral white matter lesion, so-called leukoaraiosis seen commonly in the elderly, remains unclear. We therefore conducted a study in 113 elderly patients with geriatric syndrome by assessing MR images and determining the Lp(a) phenotypes. They were divided into 4 groups according to the Fazekas scale for grading leukoaraiosis, and we compared the distribution of Lp(a) phenotypes and background factors in each group. Factors related to severe leuko-araiosis were also studied by multivariate analysis. There were no significant differences in age or gender among groups. Alzheimer disease and cardioembolic stroke were frequently seen in groups without leukoaraiosis or with mild leukoaraiosis, whereas the frequencies of vascular risks, previous history of stroke and vascular dementia were high in group with severe leukoaraiosis. Multivariate analysis showed strong association of S4 homozygote of the Lp(a) phenotype to severe leukoaraiosis, indicating the S4 homozygote as an independent factor for severe leukoaraiosis as well as hypertension, a high level of Lp(a) of 40 mg/dl or more. Among all patients, a high Lp(a) level and S4 homozygote, showing a low level of Lp(a), were seen in 20.4%, respectively. This contradictory finding that high levels of Lp(a) and S4 homozygote were both associated with severe leukoaraiosis indicated the possibility of different mechanisms for developing white matter lesions; a high level of Lp(a) (LDL cholesterol and apoB100 protein rich) promotes atherosclerosis of major arteries such as the carotid artery, while S4 homozygote [low

  9. Rectus muscle excyclorotation and V-pattern strabismus: a quantitative appraisal of clinical relevance in syndromic craniosynostosis.

    Science.gov (United States)

    Dagi, Linda R; MacKinnon, Sarah; Zurakowski, David; Prabhu, Sanjay P

    2017-11-01

    V-pattern strabismus observed with syndromic craniosynostosis has been attributed to disparate causes. We compared severity of V pattern with degree of excyclorotation of rectus muscles to appraise significance of this proposed aetiology. 43 patients with Apert, Crouzon or Pfeiffer syndrome referred to Boston Children's Hospital Department of Ophthalmology were identified. 28 met inclusion criteria for retrospective cohort study, specifically: (1) sensorimotor measurements in minimum of seven cardinal gazes, (2) quantified fundus torsion and (3) orbital CT imaging sufficient to measure rectus muscle cyclorotation in coronal and quasicoronal planes, posteriorly (near orbital apex) and anteriorly (near pulleys). Patients were placed in one of four V-pattern severity groups. The most severe group demonstrated inability to elevate abducted eye above midline with characteristic 'seesaw' misalignment during horizontal saccades. Rectus muscle cyclorotation was measured by paediatric neuroradiologist blinded to group placement. Primary outcome was correlation of severity of V pattern with degree of excyclorotation. Secondary outcome was correlation of severity with craniosynostosis syndrome. Increasing severity of V pattern correlated with greater excyclorotation in anterior coronal (p=0.009), anterior quasicoronal (p=0.021), posterior coronal (p=0.014) and posterior quasicoronal (p=0.040) planes for moderate-to-severe V pattern. Even greater excyclorotation was associated with seesaw V pattern in anterior quasicoronal (p=0.004) and posterior quasicoronal (p=0.001) views. Highly significant association was found between Apert syndrome and severity of V pattern (p=0.004). Severity of V pattern is associated with magnitude of excyclorotation. More severe V pattern and seesaw strabismus noted with Apert syndrome may relate to distinctive orbital morphology. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please

  10. Comparison of periodontal parameters in individuals with syndromic craniosynostosis

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    Paula Simões Múfalo

    2009-02-01

    Full Text Available Craniosynostosis syndromes are characterized by premature closure of one or more cranial sutures, associated with other malformations, the most frequent of which are the Crouzon and Apert syndromes. Few studies in the literature have addressed the oral health of these individuals. The purpose of this study was to compare the periodontal status of individuals with Apert, Crouzon, Pfeiffer and Saethre-Chotzen syndromes before toothbrushing and compare the efficiency of plaque removal before and after mechanical toothbrushing. The probing depth, plaque index (according to Löe and O'Leary, clinical attachment level, gingival index (according to Silness and Löe and amount of keratinized mucosa were evaluated before toothbrushing, and the O'Leary plaque index was assessed before and immediately after toothbrushing, on the same day, in 27 individuals aged 11 to 36 years. There was statistically significant difference in the mean probing depth and clinical attachment level among regions (p=0.00; p=0.01, respectively. The gingival index did not reveal statistically significant differences. With regard to the plaque index, the left region exhibited higher plaque index values than the right and anterior regions. No significant results were found in the analysis of keratinized mucosa. Comparison of the O'Leary plaque index before and after toothbrushing revealed statistically significant difference for all syndromes except for the Pfeiffer syndrome (p<0.05. In conclusion, there was no difference in the periodontal status among individuals with syndromic craniosynostosis. The posterior region was more affected than the anterior region as to the presence of plaque, loss of insertion and probing depth. Individuals with Pfeiffer syndrome exhibited greater toothbrushing efficiency than individuals with the other craniosynostosis syndromes.

  11. Prenatal detection of a de novo terminal inverted duplication 4p in a fetus with the Wolf-Hirschhorn syndrome phenotype.

    Science.gov (United States)

    Beaujard, M-P; Jouannic, J-M; Bessières, B; Borie, C; Martin-Luis, I; Fallet-Bianco, C; Portnoï, M-F

    2005-06-01

    To present the prenatal diagnosis of a de novo terminal inversion duplication of the short arm of chromosome 4 and a review of the literature. An amniocentesis for chromosome analysis was performed at 33 weeks' gestation because ultrasound examination showed a female fetus with multiple abnormalities consisting of severe intrauterine growth retardation, microcephaly, a cleft lip and renal hypoplasia. Cytogenetic analysis and FISH studies of the cultured amniocytes revealed a de novo terminal inversion duplication of the short arm of chromosome 4 characterized by a duplication of 4p14-p16.1 chromosome region concomitant with a terminal deletion 4p16.1-pter. The karyotype was thus: 46,XX, inv dup del (4)(:p14-->p16.1::p16.1-->qter). The parents opted to terminate the pregnancy. Fetopathological examination showed dysmorphic features and abnormalities consistent with a Wolf-Hirschhorn syndrome (WHS) diagnosis, clinical manifestations of partial 4p trisomy being mild. Although relatively rare, inverted duplications have been reported repeatedly in an increasing number of chromosomes. Only two previous cases with de novo inv dup del (4p) and one with tandem dup 4p have been reported, all of them associated with a 4pter deletion. We report the first case diagnosed prenatally. Breakpoints are variable, resulting in different abnormal phenotype. In our case, clinical manifestations resulted in a WHS phenotype.

  12. miR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes

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    Keita Tsujimura

    2015-09-01

    Full Text Available Rett syndrome (RTT is a neurodevelopmental disorder caused by MECP2 mutations. Although emerging evidence suggests that MeCP2 deficiency is associated with dysregulation of mechanistic target of rapamycin (mTOR, which functions as a hub for various signaling pathways, the mechanism underlying this association and the molecular pathophysiology of RTT remain elusive. We show here that MeCP2 promotes the posttranscriptional processing of particular microRNAs (miRNAs as a component of the microprocessor Drosha complex. Among the MeCP2-regulated miRNAs, we found that miR-199a positively controls mTOR signaling by targeting inhibitors for mTOR signaling. miR-199a and its targets have opposite effects on mTOR activity, ameliorating and inducing RTT neuronal phenotypes, respectively. Furthermore, genetic deletion of miR-199a-2 led to a reduction of mTOR activity in the brain and recapitulated numerous RTT phenotypes in mice. Together, these findings establish miR-199a as a critical downstream target of MeCP2 in RTT pathogenesis by linking MeCP2 with mTOR signaling.

  13. Pharmacogenetic Inhibition of eIF4E-Dependent Mmp9 mRNA Translation Reverses Fragile X Syndrome-like Phenotypes

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    Christos G. Gkogkas

    2014-12-01

    Full Text Available Fragile X syndrome (FXS is the leading genetic cause of autism. Mutations in Fmr1 (fragile X mental retardation 1 gene engender exaggerated translation resulting in dendritic spine dysmorphogenesis, synaptic plasticity alterations, and behavioral deficits in mice, which are reminiscent of FXS phenotypes. Using postmortem brains from FXS patients and Fmr1 knockout mice (Fmr1−/y, we show that phosphorylation of the mRNA 5′ cap binding protein, eukaryotic initiation factor 4E (eIF4E, is elevated concomitant with increased expression of matrix metalloproteinase 9 (MMP-9 protein. Genetic or pharmacological reduction of eIF4E phosphorylation rescued core behavioral deficits, synaptic plasticity alterations, and dendritic spine morphology defects via reducing exaggerated translation of Mmp9 mRNA in Fmr1−/y mice, whereas MMP-9 overexpression produced several FXS-like phenotypes. These results uncover a mechanism of regulation of synaptic function by translational control of Mmp-9 in FXS, which opens the possibility of new treatment avenues for the diverse neurological and psychiatric aspects of FXS.

  14. Phenotypic variability in Waardenburg syndrome resulting from a 22q12.3-q13.1 microdeletion involving SOX10.

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    Jelena, Brezo; Christina, Lam; Eric, Vilain; Fabiola, Quintero-Rivera

    2014-06-01

    Waardenburg syndrome (WS) is a neurocristopathy characterized by pigmentation abnormalities of the skin, hair, and iris, as well as sensorineural hearing loss. Contiguous gene deletions encompassing SOX10 are rare, which limits conclusions about genotype-phenotype correlation regarding patient prognosis and management. This study adds to the existing body of knowledge by characterizing a 2.4 Mb deletion [arr[hg19] 22q12.3-q13.1 (36467502-38878207)x1] encompassing SOX10 and 53 additional RefSeq genes in a 15-year-old female with atypical WS. The patient presented with developmental delay, profound bilateral sensorineural hearing loss, heterochromia iridis, hypotonia, and bilateral finger contractures. Published genomic and phenotypic profiles of patients with SOX10-encompassing deletions point toward several plausible candidate gene that could account for the considerable clinical heterogeneity. These studies suggest the existence of modifiers among the co-deleted, dosage-sensitive genes (e.g., MYH9) and among genes whose effect may depend on the unmasking of recessive mutations (e.g., PLA2G6). Finally, we highlight evidence illustrating extensive interconnectivity of SOX10-hypothesizing that haploinsufficiency of SOX10 may "unmask" subtler effects on expression or epistasis associated with variants in SOX10 targets (e.g., DHH), in its partners (e.g., PAX3, EGR2), and in genes with functional overlap (e.g., SOX8, SOX9). © 2014 Wiley Periodicals, Inc.

  15. Co-existence of other copy number variations with 22q11.2 deletion or duplication: a modifier for variable phenotypes of the syndrome?

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    Li Deling

    2012-04-01

    Full Text Available Abstract Background The phenotype in patients with a 22q11.2 deletion or duplication can be extremely variable, and the causes of such as variations are not well known. Results We observed additional copy number variations (CNVs in 2 of 15 cases with a 22q11.2 deletion or duplication. Both cases were newborn babies referred for severe congenital heart defects. The first case had a deletion with a size of approximately 1.56 Mb involving multiple genes including STS in the Xp22.31 region along with a 22q11.2 deletion. The second case had a duplication of 605 kb in the 15q13.3 region encompassing CHRNA7 and a deletion of 209 kb involving the RBFOX1 gene in the 16p13.2 region, in addition to 22q11.2 duplication. Discussion Our observations have shown that additional CNVs are not rare (2/15, 13% in patients with a 22q11.2 deletion or duplication. We speculate that these CNVs may contribute to phenotype variations of 22q11.2 microdeletion/duplication syndromes as genomic modifiers.

  16. Genetic characterization of Italian patients with Bardet-Biedl syndrome and correlation to ocular, renal and audio-vestibular phenotype: identification of eleven novel pathogenic sequence variants.

    Science.gov (United States)

    Esposito, Gabriella; Testa, Francesco; Zacchia, Miriam; Crispo, Anna Alessia; Di Iorio, Valentina; Capolongo, Giovanna; Rinaldi, Luca; D'Antonio, Marcella; Fioretti, Tiziana; Iadicicco, Pasquale; Rossi, Settimio; Franzè, Annamaria; Marciano, Elio; Capasso, Giovanbattista; Simonelli, Francesca; Salvatore, Francesco

    2017-02-01

    Bardet-Biedl syndrome (BBS) is a rare genetic disorder that features retinal degeneration, obesity, polydactyly, learning disabilities and renal abnormalities. The diagnosis is often missed at birth, the median age at diagnosis being 9 years. In the attempt to shed light on BBS and improve its diagnosis and treatment, we evaluated the genotype-phenotype relationship in patients with a molecular diagnosis of BBS. We analyzed three common BBS genes, BBS1, BBS10 and BBS2, in 25 Italian patients fulfilling the clinical criteria of BBS. In 12 patients, we identified gene-specific biallelic variants and thus correlated genotype to the ophthalmic, renal and audio-vestibular phenotypes. At least one sequence variant was found in 60% of patients. The most common mutated gene was BBS1 followed by BBS10. Of the 17 sequence variants we found, 11 have not previously been associated with BBS. In 12 patients, we identified biallelic pathogenic variants; they had retinitis pigmentosa with early onset of visual impairment. However, retinal dystrophy was less severe in patients with BBS1 than in those with BBS10 variants. Overall, we found a high prevalence of renal dysmorphism and dysfunction. Notably, patients with BBS10 variants had the most severe renal impairment, which resulted in a critical decline in renal function. All the patients who underwent audio-vestibular evaluation had dysfunction of the cochlear outer hair cells, thus confirming the presence of hearing defects. BBS1, BBS2 and BBS10 are major causative genes in Italian BBS patients. BBS10 was associated with the worse outcome in terms of the renal, ocular and audiovestibular phenotypes. Cochlear dysfunction should be included among the hallmarks of BBS.

  17. Novel PIGT Variant in Two Brothers: Expansion of the Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 Phenotype

    OpenAIRE

    Skauli, Nadia; Wallace, Sean; Chiang, Samuel C. C.; Bar?y, Tuva; Holmgren, Asbj?rn; Stray-Pedersen, Asbj?rg; Bryceson, Yenan T.; Str?mme, Petter; Frengen, Eirik; Misceo, Doriana

    2016-01-01

    Biallelic PIGT variants were previously reported in seven patients from three families with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3), characterized by epileptic encephalopathy, hypotonia, global developmental delay/intellectual disability, cerebral and cerebellar atrophy, craniofacial dysmorphisms, and skeletal, ophthalmological, cardiac, and genitourinary abnormalities. We report a novel homozygous PIGT missense variant c.1079G>T (p.Gly360Val) in two brothers w...

  18. Prenatal Diagnosis of Arthrogryposis as a Phenotype of Pena-Shokeir Syndrome using Two- and Three-dimensional Ultrasonography

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    Eduardo Felix Martins Santana

    2014-01-01

    Full Text Available Pena-Shokeir syndrome is a rare autosomal recessive disease, characterized by facial anomalies, arthrogryposis, polyhydramnios, fetal growth restriction, and pulmonary hypoplasia. This report describes the findings of this anomaly with two and three-dimensional ultrasound in a female in her 28 th week of pregnancy, who was referred to us because the fetus presented arthrogryposis of unknown cause. These imaging methods allowed adequate evaluation of the fetal malformations and also enabled appropriate counseling of the couple.

  19. MECP2 mutations in Czech patients with Rett syndrome and Rett-like phenotypes: novel mutations, genotype-phenotype correlations and validation of high-resolution melting analysis for mutation scanning.

    Science.gov (United States)

    Zahorakova, Daniela; Lelkova, Petra; Gregor, Vladimir; Magner, Martin; Zeman, Jiri; Martasek, Pavel

    2016-07-01

    Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by developmental regression with loss of motor, communication and social skills, onset of stereotypic hand movements and often seizures. RTT is primarily caused by de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). We established a high-resolution melting (HRM) technique for mutation scanning of the MECP2 gene and performed analyses in Czech patients with RTT, autism spectrum conditions and intellectual disability with Rett-like features. In the cases with confirmed MECP2 mutations, we determined X-chromosome inactivation (XCI), examined the relationships between genotype and clinical severity and evaluated the modifying influence of XCI. Our results demonstrate that HRM analysis is a reliable method for the detection of point mutations, small deletions and duplications in the MECP2 gene. We identified 29 pathogenic mutations in 75 girls, including four novel mutations: c.155_1189del1035;909_932inv;insC, c.573delC, c.857_858dupAA and c.1163_1200del38. Skewed XCI (ratio >75%) was found in 19.3% of the girls, but no gross divergence in clinical severity was observed. Our findings confirm a high mutation frequency in classic RTT (92%) and a correlation between the MECP2 mutation type and clinical severity. We also demonstrate limitations of XCI in explaining all of the phenotypic differences in RTT.

  20. Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome

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    J. Hsiao

    2016-07-01

    Full Text Available Dravet syndrome is a devastating genetic brain disorder caused by heterozygous loss-of-function mutation in the voltage-gated sodium channel gene SCN1A. There are currently no treatments, but the upregulation of SCN1A healthy allele represents an appealing therapeutic strategy. In this study we identified a novel, evolutionary conserved mechanism controlling the expression of SCN1A that is mediated by an antisense non-coding RNA (SCN1ANAT. Using oligonucleotide-based compounds (AntagoNATs targeting SCN1ANAT we were able to induce specific upregulation of SCN1A both in vitro and in vivo, in the brain of Dravet knock-in mouse model and a non-human primate. AntagoNAT-mediated upregulation of Scn1a in postnatal Dravet mice led to significant improvements in seizure phenotype and excitability of hippocampal interneurons. These results further elucidate the pathophysiology of Dravet syndrome and outline a possible new approach for the treatment of this and other genetic disorders with similar etiology.

  1. A single nucleotide variant in the FMR1 CGG repeat results in a "Pseudodeletion" and is not associated with the fragile X syndrome phenotype.

    Science.gov (United States)

    Cecconi, Massimiliano; Forzano, Francesca; Rinaldi, Rosanna; Cappellacci, Sandra; Grammatico, Paola; Faravelli, Francesca; Dagna Bricarelli, Franca; Di Maria, Emilio; Grasso, Marina

    2008-05-01

    The molecular diagnosis of fragile X syndrome relies on the detection of the pathogenic CGG repeat expansion in the FMR1 gene. Deletions and point mutations have occasionally been reported. Rare polymorphisms might mimic a deletion by Southern blot analysis, leading to false-positive results. We describe a novel rare nucleotide substitution within the CGG repeat. The proband was a woman with a positive family history of mental retardation. Southern blot analysis showed an additional band consistent with a deletion in the region detected by the StB12.3 probe. Sequencing of this region revealed a G>C transversion that interrupts the CGG repeat and introduces an EagI site. The same variant was observed in both the healthy son and father of the proband, supporting the hypothesis that the nucleotide substitution is a silent polymorphism, the frequency of which we estimated to be less than 1% in the general population. These findings argue for a pathogenic role of nucleotide variants within the CGG repeat and suggest possible consequences of unexpected findings in the molecular diagnostics of fragile X syndrome. Thus, although the sequence context of a single nucleotide substitution may not predict possible effects on mRNA or protein function, a specific change in the higher order structures of DNA or mRNA may be functionally relevant in the pathological phenotype.

  2. A Single Nucleotide Variant in the FMR1 CGG Repeat Results in a “Pseudodeletion” and Is Not Associated with the Fragile X Syndrome Phenotype

    Science.gov (United States)

    Cecconi, Massimiliano; Forzano, Francesca; Rinaldi, Rosanna; Cappellacci, Sandra; Grammatico, Paola; Faravelli, Francesca; Dagna Bricarelli, Franca; Di Maria, Emilio; Grasso, Marina

    2008-01-01

    The molecular diagnosis of fragile X syndrome relies on the detection of the pathogenic CGG repeat expansion in the FMR1 gene. Deletions and point mutations have occasionally been reported. Rare polymorphisms might mimic a deletion by Southern blot analysis, leading to false-positive results. We describe a novel rare nucleotide substitution within the CGG repeat. The proband was a woman with a positive family history of mental retardation. Southern blot analysis showed an additional band consistent with a deletion in the region detected by the StB12.3 probe. Sequencing of this region revealed a G>C transversion that interrupts the CGG repeat and introduces an EagI site. The same variant was observed in both the healthy son and father of the proband, supporting the hypothesis that the nucleotide substitution is a silent polymorphism, the frequency of which we estimated to be less than 1% in the general population. These findings argue for a pathogenic role of nucleotide variants within the CGG repeat and suggest possible consequences of unexpected findings in the molecular diagnostics of fragile X syndrome. Thus, although the sequence context of a single nucleotide substitution may not predict possible effects on mRNA or protein function, a specific change in the higher order structures of DNA or mRNA may be functionally relevant in the pathological phenotype. PMID:18403614

  3. Analyses of Genotypes and Phenotypes of Ten Chinese Patients with Wolf-Hirschhorn Syndrome by Multiplex Ligation-dependent Probe Amplification and Array Comparative Genomic Hybridization.

    Science.gov (United States)

    Yang, Wen-Xu; Pan, Hong; Li, Lin; Wu, Hai-Rong; Wang, Song-Tao; Bao, Xin-Hua; Jiang, Yu-Wu; Qi, Yu

    2016-03-20

    Wolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome that is typically caused by a deletion of the distal portion of the short arm of chromosome 4. However, there are few reports about the features of Chinese WHS patients. This study aimed to characterize the clinical and molecular cytogenetic features of Chinese WHS patients using the combination of multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (array CGH). Clinical information was collected from ten patients with WHS. Genomic DNA was extracted from the peripheral blood of the patients. The deletions were analyzed by MLPA and array CGH. All patients exhibited the core clinical symptoms of WHS, including severe growth delay, a Greek warrior helmet facial appearance, differing degrees of intellectual disability, and epilepsy or electroencephalogram anomalies. The 4p deletions ranged from 2.62 Mb to 17.25 Mb in size and included LETM1, WHSC1, and FGFR3. The combined use of MLPA and array CGH is an effective and specific means to diagnose WHS and allows for the precise identification of the breakpoints and sizes of deletions. The deletion of genes in the WHS candidate region is closely correlated with the core WHS phenotype.

  4. Significant expressivity of Wolfram syndrome: phenotypic assessment of two known and one novel mutation in the WFS1 gene in three Iranian families.

    Science.gov (United States)

    Sobhani, Maryam; Tabatabaiefar, Mohammad Amin; Rajab, Asadollah; Kajbafzadeh, Abdol-Mohammad; Noori-Daloii, Mohammad Reza

    2014-11-01

    Wolfram syndrome also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness) is a rare neurodegenerative autosomal recessive disorder. There is evidence of variable expressivity both in patients and heterozygous carriers. In this study, we describe three Persian Wolfram syndrome families with differences in the age of onset, signs and symptoms of the disease. We clinically evaluated affected families for verifying WS clinical diagnosis. After linkage analysis via 5 STR markers, molecular analysis for WFS1 was performed by direct sequencing for patients and available family members. Three homozygous mutations were identified including c.1885 C>T, c.2205C>A both in exon 8 and c.460+1G>A in intron 4. The mutation c.2205C>A was found to be novel. We report interesting phenotype-genotype correlations: homozygous c.1885C>T and c.2205C>A variants were correlated with quite different disease severity and onset in the siblings. We report a rare case of WS with homozygous c.1885C>T who is married and has a healthy child. c.460+1G>A showed a possible partial dominant inheritance put forth by a heterozygous parent showing partial WS symptoms while her daughter displayed typical WS symptoms. Due to variable expressivity, detailed clinical examination and molecular diagnostics should be used to confirm WS and a more exact recurrence risk data.

  5. Novel mutations in the CDKL5 gene in complex genotypes associated with West syndrome with variable phenotype: First description of somatic mosaic state.

    Science.gov (United States)

    Jdila, Marwa Ben; Issa, Abir Ben; Khabou, Boudour; Rhouma, Bochra Ben; Kamoun, Fatma; Ammar-Keskes, Leila; Triki, Chahnez; Fakhfakh, Faiza

    2017-10-01

    West syndrome is a rare epileptic encephalopathy of early infancy, characterized by epileptic spasms, hypsarrhythmia, and psychomotor retardation beginning in the first year of life. The present study reports the clinical, molecular and bioinformatic investigation in the three studied West patients. The results revealed a complex genotype with more than one mutation in each patient including the known mutations c.1910C>G (P2, P3); c.2372A>C in P3 and c.2395C>G in P1 and novel variants including c.616G>A, shared by the three patients P1, P2 and P3; c.1403G>C shared by P2 and P3 and c.2288A>G in patient P1. All the mutations were at somatic mosaic state and were de novo in the patients except ones (c.2372A>C). To our knowledge; the somatic mosaic state is described for the first time in patients with West syndrome. Five identified mutations were located in the C-terminal domain of the protein, while the novel mutation (c.616G>A) was in the catalytic domain. Bioinformatic tools predicted that this latter is the most pathogenic substitution affecting 3D protein structure and the secondary mRNA structure. Complex genotype composed of different combinations of mutations in each patient seems to be related to the phenotype variability. Copyright © 2017. Published by Elsevier B.V.

  6. Characterization of women with elevated antimüllerian hormone levels (AMH): correlation of AMH with polycystic ovarian syndrome phenotypes and assisted reproductive technology outcomes.

    Science.gov (United States)

    Tal, Reshef; Seifer, David B; Khanimov, Moisey; Malter, Henry E; Grazi, Richard V; Leader, Ben

    2014-07-01

    Serum Antimüllerian hormone (AMH) levels are elevated in polycystic ovarian syndrome and have been shown to be useful in its diagnosis. However, the clinical significance of extremely high AMH levels is understudied. We aimed to characterize a population of women with elevated AMH (>5 ng/mL). This was a retrospective cohort study of 134 women presenting to our fertility clinic for infertility evaluation and treatment who were found to have random serum AMH over 5 ng/mL. Women were divided into 3 groups according to AMH: 5-10 ng/mL, >10-14 ng/mL, and >14 ng/mL. Endocrine characteristics, polycystic ovarian syndrome (PCOS) phenotypes, fertilization rate, implantation rate, clinical pregnancy, and multiple pregnancy rates were compared between groups. AMH ranged between 5 to 48 ng/mL. Greater than 97% of women with ultrahigh AMH (>10 ng/mL) had PCOS. In addition, women with AMH >10 ng/mL had greater prevalence of polycystic ovarian morphology and oligoamenorrhea than women with AMH 5-10 ng/mL. Moreover, serum AMH correlated positively with luteinizing hormone, total testosterone, and dehydroepiandrosterone sulfate. Furthermore, AMH showed strong predictive ability for the presence of amenorrhea (area under the curve, 0.87; 95% confidence interval, 0.80-0.92; P women with AMH >10 ng/mL showed higher rates of ovarian hyperstimulation syndrome and clinical pregnancy rates compared with women with AMH 5-10 ng/mL. These data characterize a population of women with elevated AMH levels, demonstrating that the vast majority of women with AMH >10 ng/mL have PCOS. Increased AMH levels correlated with PCOS severity and are associated with greater ovarian stimulation and higher clinical pregnancy rates following assisted reproductive technology. Copyright © 2014 Mosby, Inc. All rights reserved.

  7. Homozygosity and Heterozygosity for Null Col5a2 Alleles Produce Embryonic Lethality and a Novel Classic Ehlers-Danlos Syndrome-Related Phenotype.

    Science.gov (United States)

    Park, Arick C; Phillips, Charlotte L; Pfeiffer, Ferris M; Roenneburg, Drew A; Kernien, John F; Adams, Sheila M; Davidson, Jeffrey M; Birk, David E; Greenspan, Daniel S

    2015-07-01

    Null alleles for the COL5A1 gene and missense mutations for COL5A1 or the COL5A2 gene underlie cases of classic Ehlers-Danlos syndrome, characterized by fragile, hyperextensible skin and hypermobile joints. However, no classic Ehlers-Danlos syndrome case has yet been associated with COL5A2 null alleles, and phenotypes that might result from such alleles are unknown. We describe mice with null alleles for the Col5a2. Col5a2(-/-) homozygosity is embryonic lethal at approximately 12 days post conception. Unlike previously described mice null for Col5a1, which die at 10.5 days post conception and virtually lack collagen fibrils, Col5a2(-/-) embryos have readily detectable collagen fibrils, thicker than in wild-type controls. Differences in Col5a2(-/-) and Col5a1(-/-) fibril formation and embryonic survival suggest that α1(V)3 homotrimers, a rare collagen V isoform that occurs in the absence of sufficient levels of α2(V) chains, serve functional roles that partially compensate for loss of the most common collagen V isoform. Col5a2(+/-) adults have skin with marked hyperextensibility and reduced tensile strength at high strain but not at low strain. Col5a2(+/-) adults also have aortas with increased compliance and reduced tensile strength. Results thus suggest that COL5A2(+/-) humans, although unlikely to present with frank classic Ehlers-Danlos syndrome, are likely to have fragile connective tissues with increased susceptibility to trauma and certain chronic pathologic conditions. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  8. The new total Western diet for rodents does not induce an overweight phenotype or alter parameters of metabolic syndrome in mice.

    Science.gov (United States)

    Monsanto, Stephany P; Hintze, Korry J; Ward, Robert E; Larson, Deanna P; Lefevre, Michael; Benninghoff, Abby D

    2016-09-01

    In this study, we determined the impact of the total Western diet (TWD) for rodents and its macro- and micronutrient components on weight gain and biomarkers of metabolic function in mice compared to a 45% fat diet-induced obesity (DIO) diet and the standard AIN93G diet. We hypothesized that mice fed the TWD would have increased body fat with indicators of metabolic syndrome similar to mice consuming the DIO diet. As expected, DIO-fed mice acquired a metabolic syndrome phenotype typified by increased energy intake, increased body weight gain, increased fat mass, higher fasting glucose, impaired glucose tolerance, and higher plasma leptin relative to the AIN93G diet. Mice fed a macronutrient-modified (MM) diet (with standard vitamin and mineral composition) had a similar response, albeit to a lesser degree than mice fed the DIO diet. Mice fed a vitamin- and mineral-modified diet (with standard macronutrient composition) were not different from mice fed the AIN93G diet. Surprisingly, the TWD (with modified macronutrients, vitamins and minerals) did not significantly affect any of these parameters, despite the fact that the TWD macronutrient profile was identical to the MM diet. These data suggest that, in the context of the TWD, vitamin and mineral intakes in mice that reflect a Western dietary pattern inhibit the hyperphagia and resulting increased weight gain associated with the higher fat content of the TWD. In conclusion, these observations underscore the need to consider the influence of micronutrient intakes in pre-clinical models of obesity and metabolic syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. A novel single point mutation of the LYST gene in two siblings with different phenotypic features of Chediak Higashi syndrome.

    Science.gov (United States)

    Kaya, Zuhre; Ehl, Stephan; Albayrak, Meryem; Maul-Pavicic, Andrea; Schwarz, Klaus; Kocak, Ulker; Ergun, Mehmet Ali; Gursel, Turkiz

    2011-07-01

    Chediak Higashi syndrome (CHS) is an autosomal-recessive disorder characterized by oculocutaneous albinism, recurrent infections and a progressive primary neurological disease. Here, we describe two siblings with CHS due to a novel homozygous R1836X mutation in the LYST gene associated with loss of NK cell degranulation and cytotoxicity. While one sibling was born with fair skin and hair and died of hemophagocytic lymphohistiocytosis (HLH) at 5 months of age, the other sibling had dark black hair and skin and developed HLH at the age of 4 years. Copyright © 2011 Wiley-Liss, Inc.

  10. The evolution of sports participation guidelines and the influence of genotype-phenotype correlation in long QT syndrome.

    Science.gov (United States)

    Furst, Matthew L; Aziz, Peter F

    2016-11-01

    Congenital Long QT Syndrome (LQTS) results in abnormal ventricular repolarization in patients with otherwise structurally normal hearts. Following the initial clinical descriptions of LQTS, there has been a great deal of investigation into the genetic etiology and pathophysiology of these entities, with the goal of improved screening tools and understanding of associated risks. Through this work, heart rhythm experts continue to revise their recommendations regarding sports eligibility. We review the evolution of sports participation recommendations for LQTS. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Síndrome de Apert, una aproximación para un diagnóstico clínico. Reporte de caso

    Directory of Open Access Journals (Sweden)

    Diana Ramírez

    2010-01-01

    Full Text Available Introducción: El síndrome de Apert, o acrocefalosindactilia tipo I, es un síndrome caracterizado por craneosinostosis, acompañada de sindactilia simétrica en las cuatro extremidades, alteraciones maxilofaciales, cutáneas y retardo mental variable. Este síndrome se debe a una mutación en el gen del receptor 2 del factor del crecimiento fibroblástico (FGFR2, el cual se expresa de manera autosómica dominante (AD Caso clínico: Se presenta caso de recién nacido femenino, de 36 semanas de edad gestacional, con las características fenotípicas clásicas de este síndrome como la acrocefalia y la sindactilia en manos y pies. Discusión: El síndrome de Apert hace parte de lo que hoy se denomina un espectro de enfermedades causadas por la mutación en el gen FGFR2 que se caracterizan por anormalidades en el cráneo y las extremidades. Este gen es necesario para la osificación normal y también está implicado en la diferenciación neural. Sus mutaciones producen un receptor anormal que funciona aun sin la unión de su ligando "ganancia de función", lo que se traduce en una osificación temprana de los huesos, en grados variables, dependiendo del sitio exacto de la mutación.

  12. A Cross-Sectional Study of the Phenotypes of Obesity and Insulin Resistance in Adults with Down Syndrome

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    Diego Real de Asua

    2014-12-01

    Full Text Available BackgroundDespite the confluence of multiple cardiovascular risk factors, subclinical atherosclerotic damage and cardiovascular events remain extremely rare in adults with Down syndrome (DS. We aim to determine the prevalence of obesity and metabolic disorders in an adult cohort with DS and to compare our findings with adults without DS.MethodsCross-sectional study of 51 consecutively selected adults with DS living in the community and 51 healthy controls in an outpatient clinic of a tertiary care hospital in Madrid, Spain. Epidemiological data (age and gender, anthropometric data (body mass index and waist-to-height ratio, coexisting clinical conditions, and laboratory data (fasting glucose, insulin, glycated hemoglobin, creatinine, thyroid hormones, vitamins, and lipid profile were measured and compared between the groups.ResultsAdults with DS were significantly younger and more often men with a higher prevalence of overweight and obesity than controls. Their waist-to-height ratio was higher, and they more frequently had abdominal obesity. The results of an analysis adjusted for age and gender revealed no differences in fasting insulin levels, homeostatic model assessment indexes, or lipid profile between adults with DS and controls.ConclusionAdults with DS presented a high prevalence of overweight and obesity. However, we found no differences in lipid profile, prevalence of insulin resistance, or metabolic syndrome between adults with DS and controls.

  13. Novel PIGT Variant in Two Brothers: Expansion of the Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 Phenotype

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    Nadia Skauli

    2016-11-01

    Full Text Available Biallelic PIGT variants were previously reported in seven patients from three families with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3, characterized by epileptic encephalopathy, hypotonia, global developmental delay/intellectual disability, cerebral and cerebellar atrophy, craniofacial dysmorphisms, and skeletal, ophthalmological, cardiac, and genitourinary abnormalities. We report a novel homozygous PIGT missense variant c.1079G>T (p.Gly360Val in two brothers with several of the typical features of MCAHS3, but in addition, pyramidal tract neurological signs. Notably, they are the first patients with MCAHS3 without skeletal, cardiac, or genitourinary anomalies. PIGT encodes a crucial subunit of the glycosylphosphatidylinositol (GPI transamidase complex, which catalyzes the attachment of proteins to GPI-anchors, attaching the proteins to the cell membrane. In vitro studies in cells from the two brothers showed reduced levels of GPI-anchors and GPI-anchored proteins on the cell surface, supporting the pathogenicity of the novel PIGT variant.

  14. Combined Pulmonary Fibrosis and Emphysema Syndrome: A New Phenotype within the Spectrum of Smoking-Related Interstitial Lung Disease

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    Karina Portillo

    2012-01-01

    Full Text Available Combined pulmonary fibrosis and emphysema (CPFE is a recently defined syndrome, in which centrilobular and/or paraseptal emphysemas in upper lung zones coexist with pulmonary fibrosis in lower lobes in individuals. These patients have a characteristic lung function profile, with unexpected subnormal dynamic and static lung volumes, contrasting with a significant reduction of carbon monoxide transfer (DLco and exercise hypoxemia. Pulmonary hypertension is highly prevalent in CPFE and is the leading determinant of death. Tobacco smoking has been proposed as the main factor in its etiology, though the pathophysiology and its natural history remain to be determined. High-resolution computed axial tomography is the mandatory tool to confirm the diagnosis. Currently, there is no consensus about its treatment since those published to date on this issue are limited to well-characterised series of cases; hence, a better understanding of this entity may help in the development of future therapeutic approaches.

  15. Expanding the phenotypic profile of Kleefstra syndrome: A female with low-average intelligence and childhood apraxia of speech.

    Science.gov (United States)

    Samango-Sprouse, Carole; Lawson, Patrick; Sprouse, Courtney; Stapleton, Emily; Sadeghin, Teresa; Gropman, Andrea

    2016-05-01

    Kleefstra syndrome (KS) is a rare neurogenetic disorder most commonly caused by deletion in the 9q34.3 chromosomal region and is associated with intellectual disabilities, severe speech delay, and motor planning deficits. To our knowledge, this is the first patient (PQ, a 6-year-old female) with a 9q34.3 deletion who has near normal intelligence, and developmental dyspraxia with childhood apraxia of speech (CAS). At 6, the Wechsler Preschool and Primary Intelligence testing (WPPSI-III) revealed a Verbal IQ of 81 and Performance IQ of 79. The Beery Buktenica Test of Visual Motor Integration, 5th Edition (VMI) indicated severe visual motor deficits: VMI = 51; Visual Perception = 48; Motor Coordination speech delay and expressive language disorder. Further research is warranted on the impact of CAS on intelligence and behavioral outcome in KS. Therapeutic and prognostic implications are discussed. © 2016 Wiley Periodicals, Inc.

  16. Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

    Science.gov (United States)

    Kaiser, Frank J.; Ansari, Morad; Braunholz, Diana; Concepción Gil-Rodríguez, María; Decroos, Christophe; Wilde, Jonathan J.; Fincher, Christopher T.; Kaur, Maninder; Bando, Masashige; Amor, David J.; Atwal, Paldeep S.; Bahlo, Melanie; Bowman, Christine M.; Bradley, Jacquelyn J.; Brunner, Han G.; Clark, Dinah; Del Campo, Miguel; Di Donato, Nataliya; Diakumis, Peter; Dubbs, Holly; Dyment, David A.; Eckhold, Juliane; Ernst, Sarah; Ferreira, Jose C.; Francey, Lauren J.; Gehlken, Ulrike; Guillén-Navarro, Encarna; Gyftodimou, Yolanda; Hall, Bryan D.; Hennekam, Raoul; Hudgins, Louanne; Hullings, Melanie; Hunter, Jennifer M.; Yntema, Helger; Innes, A. Micheil; Kline, Antonie D.; Krumina, Zita; Lee, Hane; Leppig, Kathleen; Lynch, Sally Ann; Mallozzi, Mark B.; Mannini, Linda; Mckee, Shane; Mehta, Sarju G.; Micule, Ieva; Mohammed, Shehla; Moran, Ellen; Mortier, Geert R.; Moser, Joe-Ann S.; Noon, Sarah E.; Nozaki, Naohito; Nunes, Luis; Pappas, John G.; Penney, Lynette S.; Pérez-Aytés, Antonio; Petersen, Michael B.; Puisac, Beatriz; Revencu, Nicole; Roeder, Elizabeth; Saitta, Sulagna; Scheuerle, Angela E.; Schindeler, Karen L.; Siu, Victoria M.; Stark, Zornitza; Strom, Samuel P.; Thiese, Heidi; Vater, Inga; Willems, Patrick; Williamson, Kathleen; Wilson, Louise C.; Hakonarson, Hakon; Quintero-Rivera, Fabiola; Wierzba, Jolanta; Musio, Antonio; Gillessen-Kaesbach, Gabriele; Ramos, Feliciano J.; Jackson, Laird G.; Shirahige, Katsuhiko; Pié, Juan; Christianson, David W.; Krantz, Ian D.; Fitzpatrick, David R.; Deardorff, Matthew A.

    2014-01-01

    Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS. PMID:24403048

  17. The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers–Danlos syndrome

    Science.gov (United States)

    Frank, Michael; Albuisson, Juliette; Ranque, Brigitte; Golmard, Lisa; Mazzella, Jean-Michael; Bal-Theoleyre, Laurence; Fauret, Anne-Laure; Mirault, Tristan; Denarié, Nicolas; Mousseaux, Elie; Boutouyrie, Pierre; Fiessinger, Jean-Noël; Emmerich, Joseph; Messas, Emmanuel; Jeunemaitre, Xavier

    2015-01-01

    Vascular Ehlers–Danlos syndrome (vEDS) is a rare and severe autosomal dominant disorder caused by variants at the COL3A1 gene. Clinical characteristics and course of disease of 215 molecularly proven patients (146 index cases and 69 relatives) were analysed. We found 126 distincts variants that were divided into five groups: (1) Glycine substitutions (n=71), (2) splice-site and in-frame insertions–deletions (n=36), (3) variants leading to haplo-insufficiency (n=7), (4) non-glycine missense variants within the triple helix (n=4 variants), and (5) non-glycine missense variants or in-frame insertions–deletions, in the N- or C-terminal part of the protein (n=8). Overall, our cohort confirmed the severity of the disease with a median age at first complication of 29 years (IQR 22–39), the most frequent being arterial (48%) and digestive (24%) ruptures. Groups 2 and 1 were significantly more severe than groups 3–5, with extreme median ages at first major complication of 23–47 years. Patients of groups 3–5 had a less typical phenotype and remarkably absence of digestive events. The distribution of glycine-replacing amino acids was strongly biased towards more destabilizing residues of the collagen assembly. Thus the natural course of vEDS and the clinical phenotype of patients are influenced by the type of COL3A1 variant. This study also confirms that patients with variants located in the C- and N-termini or leading to haplo-insufficiency have milder course of the disease and less prevalent diagnostic criteria. These findings may help refine diagnostic strategy, genetic counselling and clinical care. PMID:25758994

  18. Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes.

    Science.gov (United States)

    Romei, Cristina; Mariotti, Stefano; Fugazzola, Laura; Taccaliti, Augusto; Pacini, Furio; Opocher, Giuseppe; Mian, Caterina; Castellano, Maurizio; degli Uberti, Ettore; Ceccherini, Isabella; Cremonini, Nadia; Seregni, Ettore; Orlandi, Fabio; Ferolla, Piero; Puxeddu, Efisio; Giorgino, Francesco; Colao, Annamaria; Loli, Paola; Bondi, Fabio; Cosci, Barbara; Bottici, Valeria; Cappai, Antonello; Pinna, Giovanni; Persani, Luca; Verga, Uberta; Uberta, Verga; Boscaro, Marco; Castagna, Maria Grazia; Cappelli, Carlo; Zatelli, Maria Chiara; Faggiano, Antongiulio; Francia, Giuseppe; Brandi, Maria Luisa; Falchetti, Alberto; Pinchera, Aldo; Elisei, Rossella

    2010-08-01

    Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disease characterized by medullary thyroid carcinoma (MTC) associated (MEN 2A and 2B) or not familial MTC (FMTC) with other endocrine neoplasia due to germline RET gene mutations. The prevalence of these rare genetic diseases and their corresponding RET mutations are unknown due to the small size of the study population. We collected data on germline RET mutations of 250 families with hereditary MTC followed in 20 different Italian centres. The most frequent RET amino acid substitution was Val804Met (19.6%) followed by Cys634Arg (13.6%). A total of 40 different germline RET mutations were present. Six families (2.4%) were negative for germline RET mutations. The comparison of the prevalence of RET germline mutations in the present study with those published by other European studies showed a higher prevalence of Val804Met and Ser891Ala mutations and a lower prevalence of Leu790Phe and Tyr791Phe (P<0.0001). A statistically significant higher prevalence of mutations affecting non-cysteine codons was also found (P<0.0001). Furthermore, the phenotype data collection showed an unexpected higher prevalence of FMTC (57.6%) with respect to other MEN 2 syndromes (34% MEN 2A and 6.8% of MEN 2B). In conclusion, we observed a statistically significant different pattern of RET mutations in Italian MEN 2 families with respect to other European studies and a higher prevalence of FMTC phenotype. The different ethnic origins of the patients and the particular attention given to analysing apparently sporadic MTC for RET germline mutations may explain these findings.

  19. Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features.

    Science.gov (United States)

    Miguet, Marguerite; Faivre, Laurence; Amiel, Jeanne; Nizon, Mathilde; Touraine, Renaud; Prieur, Fabienne; Pasquier, Laurent; Lefebvre, Mathilde; Thevenon, Julien; Dubourg, Christèle; Julia, Sophie; Sarret, Catherine; Remerand, Ganaëlle; Francannet, Christine; Laffargue, Fanny; Boespflug-Tanguy, Odile; David, Albert; Isidor, Bertrand; Vigneron, Jacqueline; Leheup, Bruno; Lambert, Laetitia; Philippe, Christophe; Béri-Dexheimer, Mylène; Cuisset, Jean-Marie; Andrieux, Joris; Plessis, Ghislaine; Toutain, Annick; Guibaud, Laurent; Cormier-Daire, Valérie; Rio, Marlene; Bonnefont, Jean-Paul; Echenne, Bernard; Journel, Hubert; Burglen, Lydie; Chantot-Bastaraud, Sandrine; Bienvenu, Thierry; Baumann, Clarisse; Perrin, Laurence; Drunat, Séverine; Jouk, Pierre-Simon; Dieterich, Klaus; Devillard, Françoise; Lacombe, Didier; Philip, Nicole; Sigaudy, Sabine; Moncla, Anne; Missirian, Chantal; Badens, Catherine; Perreton, Nathalie; Thauvin-Robinet, Christel; AChro-Puce, Réseau; Pedespan, Jean-Michel; Rooryck, Caroline; Goizet, Cyril; Vincent-Delorme, Catherine; Duban-Bedu, Bénédicte; Bahi-Buisson, Nadia; Afenjar, Alexandra; Maincent, Kim; Héron, Delphine; Alessandri, Jean-Luc; Martin-Coignard, Dominique; Lesca, Gaëtan; Rossi, Massimiliano; Raynaud, Martine; Callier, Patrick; Mosca-Boidron, Anne-Laure; Marle, Nathalie; Coutton, Charles; Satre, Véronique; Caignec, Cédric Le; Malan, Valérie; Romana, Serge; Keren, Boris; Tabet, Anne-Claude; Kremer, Valérie; Scheidecker, Sophie; Vigouroux, Adeline; Lackmy-Port-Lis, Marilyn; Sanlaville, Damien; Till, Marianne; Carneiro, Maryline; Gilbert-Dussardier, Brigitte; Willems, Marjolaine; Van Esch, Hilde; Portes, Vincent Des; El Chehadeh, Salima

    2018-04-04

    The Xq28 duplication involving the MECP2 gene ( MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  20. Síndrome de Aarskog: hallazgos fenotípicos en una cohorte de pacientes Aarskog syndrome: phenotypic findings in a cohort of patients

    Directory of Open Access Journals (Sweden)

    Iván Hernández García

    2008-12-01

    Full Text Available Se presentan los hallazgos fenotípicos de 7 pacientes diagnosticados de síndrome de Aarskog en el servicio de Genética del Hospital Pediátrico Docente «William Soler». Las características fenotípicas que estuvieron presentes en todos los pacientes fueron el pico de viuda, las extremidades cortas y la braquidactilia. Les siguieron en orden de frecuencia (85 % la nariz pequeña, el puente nasal ancho y el filtrum largo y ancho. Otras dismorfias faciales encontradas (71 % fueron la frente amplia, las narinas antevertidas, el hipertelorismo, el cuello corto y el surco simiano. Se discute la posibilidad de que exista algún sesgo de detección debido a que el examinador presta mayor atención a la cara que a otros segmentos corporales. La criptorquidia, que distingue y da nombre al síndrome, se encontró en un porcentaje menor de individuos (60 %. En dos casos se encontró hipoplasia renal, hallazgo ocasional en la literatura consultada. En ningún caso se constató retraso mental. Las diferencias fenotípicas halladas pudieran atribuirse a las diferencias moleculares reportadas en la literatura.The phenotypic fndings of 7 patients who were diagnosed Aarskog syndrome in the Service of Genetics of «William Soler» Pediatric Teaching Hospital were presented. The phenotypic characteristics appearing in all patients were widow's peak, short extremities and brachydactilia. They were followed in order of frequency (85 % by small nose, wide nasal bridge and long and wide filtrum. Other facial dismorphies (71 % were wide forehead, anteverted narines, hypertelorism, short neck and simian crease. It is discussed the possibility that there is some bias of detection due to the fact that the examiner pays more attention to the face than to other body segments. Criptorchydia, that distinguishes and gives name to the syndrome, was found in a lower percent of individuals (60 %. Renal hypoplasia, an occasional finding in the consulted literature, was

  1. Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism

    Science.gov (United States)

    Ansari, Morad; Poke, Gemma; Ferry, Quentin; Williamson, Kathleen; Aldridge, Roland; Meynert, Alison M; Bengani, Hemant; Chan, Cheng Yee; Kayserili, Hülya; Avci, Şahin; Hennekam, Raoul C M; Lampe, Anne K; Redeker, Egbert; Homfray, Tessa; Ross, Alison; Falkenberg Smeland, Marie; Mansour, Sahar; Parker, Michael J; Cook, Jacqueline A; Splitt, Miranda; Fisher, Richard B; Fryer, Alan; Magee, Alex C; Wilkie, Andrew; Barnicoat, Angela; Brady, Angela F; Cooper, Nicola S; Mercer, Catherine; Deshpande, Charu; Bennett, Christopher P; Pilz, Daniela T; Ruddy, Deborah; Cilliers, Deirdre; Johnson, Diana S; Josifova, Dragana; Rosser, Elisabeth; Thompson, Elizabeth M; Wakeling, Emma; Kinning, Esther; Stewart, Fiona; Flinter, Frances; Girisha, Katta M; Cox, Helen; Firth, Helen V; Kingston, Helen; Wee, Jamie S; Hurst, Jane A; Clayton-Smith, Jill; Tolmie, John; Vogt, Julie; Tatton–Brown, Katrina; Chandler, Kate; Prescott, Katrina; Wilson, Louise; Behnam, Mahdiyeh; McEntagart, Meriel; Davidson, Rosemarie; Lynch, Sally-Ann; Sisodiya, Sanjay; Mehta, Sarju G; McKee, Shane A; Mohammed, Shehla; Holden, Simon; Park, Soo-Mi; Holder, Susan E; Harrison, Victoria; McConnell, Vivienne; Lam, Wayne K; Green, Andrew J; Donnai, Dian; Bitner-Glindzicz, Maria; Donnelly, Deirdre E; Nellåker, Christoffer; Taylor, Martin S; FitzPatrick, David R

    2014-01-01

    Background Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. Methods We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. Results Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases. Conclusions Future diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues. PMID:25125236

  2. Wireless capsule endoscopy for evaluation of phenotypic expression of small-bowel polyps in patients with Peutz-Jeghers syndrome and in symptomatic first-degree relatives.

    Science.gov (United States)

    Soares, J; Lopes, L; Vilas Boas, G; Pinho, C

    2004-12-01

    Peutz-Jeghers syndrome (PJS) is an inherited gastrointestinal hamartomatous polyposis disorder. Small-bowel intussusception and bleeding are the most common complications, and malignancy may also occur. Survey of the gastrointestinal tract, particularly of the small bowel, is difficult and current recommendations for management syndrome are ambiguous. We evaluated the feasibility of capsule endoscopy for identifying phenotypic expression of small-bowel polyps in patients with full-blown PJS and a previous diagnosis of gastrointestinal polyposis, and in symptomatic kindred of PJS patients with no previous diagnosis of gastrointestinal polyposis. Two groups were studied: group A consisted of 14 patients with gastrointestinal polyposis, eight of whom had undergone previous small-intestine surgery; group B consisted of six symptomatic first-degree relatives of PJS patients; these patients had previous negative gastrointestinal endoscopic examinations. Numerous polyps were detected in all patients in group A. Most polyps were sessile, but the larger polyps tended to be pedunculated. Polyp density was highest in the jejunum (greater than in the ileum and duodenum). Seven patients had at least one large polyp (> 11 mm) and five of these patients subsequently underwent enteroscopy, which revealed that capsule endoscopy had correctly identified all the patients with large polyps, but had missed 20 % of the total number of large polyps in these patients. No polyps were detected by capsule endoscopy in group B patients, despite the excellent visualization of the small intestine. In all patients, the capsules were expelled within 24 hours, without complications, and the procedure was well tolerated. Capsule endoscopy is an effective and well-tolerated method for evaluating small-bowel pathology in patients with PJS.

  3. Absence of family history and phenotype-genotype correlation in pediatric Brugada syndrome: more burden to bear in clinical and genetic diagnosis.

    Science.gov (United States)

    Daimi, Houria; Khelil, Amel Haj; Ben Hamda, Khaldoun; Aranega, Amelia; Chibani, Jemni B E; Franco, Diego

    2015-06-01

    Brugada syndrome (BrS) is an autosomal-dominant genetic cardiac disorder caused in 18-30 % of the cases by SCN5A gene mutations and manifested by an atypical right bundle block pattern with ST segment elevation and T wave inversion in the right precordial leads. The syndrome is usually detected after puberty. The identification of BrS in pediatric patients is thus a rare occurrence, and most of the reported cases are unmasked after febrile episodes. Usually, having a family history of sudden death represents the first reason to perform an ECG in febrile children. However, this practice makes the sporadic cases of cardiac disease and specially the asymptomatic ones excluded from this diagnosis. Here, we report a sporadic case of a 2-month-old male patient presented with vaccination-related fever and ventricular tachycardia associated with short breathing, palpitation and cold sweating. ECG changes were consistent with type 1 BrS. SCN5A gene analysis of the proband and his family revealed a set of mutations and polymorphisms differentially distributed among family members, however, without any clear genotype-phenotype correlation. Based on our findings, we think that genetic testing should be pursued as a routine practice in symptomatic and asymptomatic pediatric cases of BrS, with or without family history of sudden cardiac death. Similarly, our study suggests that pediatrician should be encouraged to perform an ECG profiling in suspicious febrile children and quickly manage fever since it is the most important factor unmasking BrS in children.

  4. Association of Markers of Proinflammatory Phenotype and Beige Adipogenesis with Metabolic Syndrome in Chinese Centrally Obese Adults

    Directory of Open Access Journals (Sweden)

    Wilson K. C. Leung

    2018-01-01

    Full Text Available Background. Visceral adiposity is associated with higher productions of C-reactive protein (CRP and interleukin-6 (IL-6. Inflammation of obese adipose tissues could contribute to systemic metabolic dysregulation, especially thermogenic a