Noonan syndrome

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Roberts, Amy E; Allanson, Judith E; Tartaglia, Marco; Gelb, Bruce D

2013-01-01

Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding difficulties. Mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS–MAPK pathway, leading to pathway dysregulation. Management guidelines have been developed. Several clinically relevant genotype–phenotype correlations aid ris...

Noonan and LEOPARD syndrome in zebrafish : molecular mechanisms and cardiac development

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Bonetti, Monica; Paardekooper Overman, Jeroen

2014-01-01

This thesis describes the use of zebrafish to study Noonan-(NS) and LEOPARD syndromes (LS), two autosomal dominant disorders with overlapping symptoms, caused by mutations in protein-tyrosine phosphatase, non-receptor type 11 (PTPN11). Intriguingly, while NS mutations result in a more ‘active’ state

Noonan syndrome

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van der Burgt Ineke

2007-01-01

Full Text Available Abstract Noonan Syndrome (NS is characterised by short stature, typical facial dysmorphology and congenital heart defects. The incidence of NS is estimated to be between 1:1000 and 1:2500 live births. The main facial features of NS are hypertelorism with down-slanting palpebral fissures, ptosis and low-set posteriorly rotated ears with a thickened helix. The cardiovascular defects most commonly associated with this condition are pulmonary stenosis and hypertrophic cardiomyopathy. Other associated features are webbed neck, chest deformity, mild intellectual deficit, cryptorchidism, poor feeding in infancy, bleeding tendency and lymphatic dysplasias. The syndrome is transmitted as an autosomal dominant trait. In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. Recently, mutations in the KRAS gene have been identified in a small proportion of patients with NS. A DNA test for mutation analysis can be carried out on blood, chorionic villi and amniotic fluid samples. NS should be considered in all foetuses with polyhydramnion, pleural effusions, oedema and increased nuchal fluid with a normal karyotype. With special care and counselling, the majority of children with NS will grow up and function normally in the adult world. Management should address feeding problems in early childhood, evaluation of cardiac function and assessment of growth and motor development. Physiotherapy and/or speech therapy should be offered if indicated. A complete eye examination and hearing evaluation should be performed during the first few years of schooling. Preoperative coagulation studies are indicated. Signs and symptoms lessen with age and most adults with NS do not require special medical care.

Growth Hormone Deficiency in a Child with Neurofibromatosis-Noonan Syndrome.

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Vurallı, Doğuş; Gönç, Nazlı; Vidaud, Dominique; Özön, Alev; Alikaşifoğlu, Ayfer; Kandemir, Nurgün

2016-03-05

Neurofibromatosis-Noonan syndrome (NFNS) is a distinct entity which shows the features of both NF1 (neurofibromatosis 1) and Noonan syndrome (NS). While growth hormone deficiency (GHD) has been relatively frequently identified in NF1 and NS patients, there is limited experience in NFNS cases. The literature includes only one case report of a NFNS patient having GHD and that report primarily focuses on the dermatological lesions that accompany the syndrome and not on growth hormone (GH) treatment. Here, we present a 13-year-old girl who had clinical features of NFNS with a mutation in the NF1 gene. The case is the first NFNS patient reported in the literature who was diagnosed to have GHD and who received GH treatment until reaching final height. The findings in this patient show that short stature is a feature of NFNS and can be caused by GHD. Patients with NFNS who show poor growth should be evaluated for GHD.

Colobomata associated with Noonan's syndrome.

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Kleanthous, L.; Cruz, D.; D'Graham, E.; Efthimiou, J.

1987-01-01

A patient with Noonan's syndrome and fundal colobomata in both eyes is described. To our knowledge, this is the first report of the association of colobomata with Noonan's syndrome. Although the patient had poor sight since early childhood and dyspnea on exertion as a teenager, the diagnosis of Noonan's syndrome was not made until early adulthood. We hope this report will encourage recognition of this syndrome and its implications at an earlier stage.

Neurofibromatosis-Noonan Syndrome: A Possible Paradigm of the Combination of Genetic and Epigenetic Factors.

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Yapijakis, Christos; Pachis, Nikos; Voumvourakis, Costas

2017-01-01

Neurofibromatosis-Noonan syndrome (NFNS) is a clinical entity possessing traits of autosomal dominant disorders neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). Germline mutations that disrupt the RAS/MAPK pathway are involved in the pathogenesis of both NS and NF1. In light of a studied Greek family, a new theory for etiological pathogenesis of NFNS is suggested. The NFNS phenotype may be the final result of a combination of a genetic factor (a mutation in the NF1 gene) and an environmental factor with the epigenetic effects of muscle hypotonia (such as hydantoin in the reported Greek family), causing hypoplasia of the face and micrognathia.

Cognitive functioning of adults with Noonan syndrome: A case-control study

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Wingbermühle, P.A.M.; Roelofs, R.L.; Burgt, C.J.A.M. van der; Souren, P.M.; Verhoeven, W.M.A.; Kessels, R.P.C.; Egger, J.I.M.

2012-01-01

Noonan syndrome (NS) is a genetic disorder characterised by short stature, facial dysmorphia, congenital heart defects and mildly lowered intellectual abilities. Research has mainly focused on genetic and somatic aspects, while intellectual and cognitive functioning has been documented scarcely.

Noonan syndrome: An anesthesiologist′s perspective

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Aggarwal Vikram

2011-01-01

Full Text Available Noonan syndrome (NS is one of the most common non chromosomal syndrome presenting to the cardiac anesthesiologist for the management of various cardiac lesions, predominantly pulmonary stenosis (PS (80% and hypertrophic obstructive cardiomyopathy (HOCM (30%. The presence of HOCM in NS makes these children susceptible to acute congestive heart failure due to hemodynamic fluctuations, thus necessitating optimization of drug and fluid therapy, careful conduct of anesthesia and providing adequate analgesia in the perioperative period. We describe a case of four year old boy with NS who presented to us for the management of PS and HOCM. In our case, transesophageal echocardiography (TEE played a major role in confirmation of the preoperative findings, detection of any new anomalies missed during the preoperative evaluation, intraoperative monitoring and assessment of the adequacy of repair in the immediate postoperative period. TEE provided invaluable help in taking critical surgical decisions, resulting in a favorable outcome.

Perinatal features of the RASopathies: Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome.

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Myers, Angela; Bernstein, Jonathan A; Brennan, Marie-Luise; Curry, Cynthia; Esplin, Edward D; Fisher, Jamie; Homeyer, Margaret; Manning, Melanie A; Muller, Eric A; Niemi, Anna-Kaisa; Seaver, Laurie H; Hintz, Susan R; Hudgins, Louanne

2014-11-01

The RASopathies are a family of developmental disorders caused by heritable defects of the RAS/MAPK signaling pathway. While the postnatal presentation of this group of disorders is well known, the prenatal and neonatal findings are less widely recognized. We report on the perinatal presentation of 10 patients with Noonan syndrome (NS), nine with Cardiofaciocutaneous syndrome (CFCS) and three with Costello syndrome (CS), in conjunction with the results of a comprehensive literature review. The majority of perinatal findings in NS, CS, and CFCS are shared: polyhydramnios; prematurity; lymphatic dysplasia; macrosomia; relative macrocephaly; respiratory distress; hypotonia, as well as cardiac and renal anomalies. In contrast, fetal arrhythmia and neonatal hypoglycemia are relatively specific to CS. NS, CS, and CFCS should all be considered as a possible diagnosis in pregnancies with a normal karyotype and ultrasound findings of a RASopathy. Recognition of the common perinatal findings of these disorders should facilitate both their prenatal and neonatal diagnosis. © 2014 Wiley Periodicals, Inc.

Alexithymia, emotion perception, and social assertiveness in adult women with Noonan and Turner syndromes

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Roelofs, R.L.; Wingbermühle, P.A.M.; Freriks, K.; Verhaak, C.M.; Kessels, R.P.C.; Egger, J.I.M.

2015-01-01

Noonan syndrome (NS) and Turner syndrome (TS) are associated with cognitive problems and difficulties in affective information processing. While both phenotypes include short stature, facial dysmorphisms, and a webbed neck, genetic etiology and neuropsychological phenotype differ significantly. The

Alexithymia, Emotion Perception, and Social Assertiveness in Adult Women with Noonan and Turner Syndromes

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Roelofs, R.L.; Wingbermühle, P.A.M.; Freriks, K.; Verhaak, C.M.; Kessels, R.P.C.; Egger, J.I.M.

2015-01-01

Noonan syndrome (NS) and Turner syndrome (TS) are associated with cognitive problems and difficulties in affective information processing. While both phenotypes include short stature, facial dysmorphisms, and a webbed neck, genetic etiology and neuropsychological phenotype differ significantly. The

The Language Phenotype of Children and Adolescents with Noonan Syndrome

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Pierpont, Elizabeth I.; Weismer, Susan Ellis; Roberts, Amy E.; Tworog-Dube, Erica; Pierpont, Mary Ella; Mendelsohn, Nancy J.; Seidenberg, Mark S.

2010-01-01

Purpose: This study presents an analysis of language skills in individuals with Noonan syndrome (NS), an autosomal dominant genetic disorder. We investigated whether the language impairments affecting some individuals arise from deficits specifically within the linguistic system or whether they are associated with cognitive, perceptual, and motor…

Cerebral arteriovenous malformation in Noonan's syndrome.

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Schon, F.; Bowler, J.; Baraitser, M.

1992-01-01

Noonan's syndrome involves the association of multiple congenital abnormalities including neck webbing, pectus excavatum, facial anomalies with a variety of cardiac defects. In this paper the association of Noonan's syndrome with a large cerebral arteriovenous malformation is reported. Congenital cerebrovascular abnormalities are not a recognized feature of the syndrome. The paper also reviews previous reports of neurological associations with Noonan's syndrome, the commonest being mild intel...

Prolapse of all cardiac valves in Noonan syndrome

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Otikunta, Adikesava Naidu; Subbareddy, Y V; Polamuri, Praneeth; Thakkar, Ashok

2015-01-01

Noonan syndrome is an autosomal dominant disorder with genetically heterogeneous inheritance. The incidence of cardiac abnormalities is higher in patients with Noonan syndrome and approximately 80% patients with Noonan syndrome are reported to have cardiac abnormalities during their lifetimes. However, polyvalvular disease in Noonan syndrome is rare. In this case-report, we describe a case of a young man whose features were strongly suggestive of Noonan syndrome and who was diagnosed with pro...

PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice

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Paardekooper Overman, Jeroen; Yi, Jae-Sung; Bonetti, Monica; Soulsby, Matthew; Preisinger, Christian; Stokes, Matthew P; Hui, Li; Silva, Jeffrey C; Overvoorde, John; Giansanti, Piero; Heck, Albert J R; Kontaridis, Maria I; den Hertog, Jeroen; Bennett, Anton M

Noonan syndrome (NS) is an autosomal dominant disorder caused by activating mutations in the PTPN11 gene encoding Shp2, which manifests in congenital heart disease, short stature, and facial dysmorphia. The complexity of Shp2 signaling is exemplified by the observation that LEOPARD syndrome (LS)

Craniosynostosis and Noonan syndrome with KRAS mutations: Expanding the phenotype with a case report and review of the literature.

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Addissie, Yonit A; Kotecha, Udhaya; Hart, Rachel A; Martinez, Ariel F; Kruszka, Paul; Muenke, Maximilian

2015-11-01

Noonan syndrome (NS) is a multiple congenital anomaly syndrome caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase (RAS-MAPK) pathway. Features include short stature, characteristic facies, congenital heart anomalies, and developmental delay. While there is considerable clinical heterogeneity in NS, craniosynostosis is not a common feature of the condition. Here, we report on a 2 month-old girl with Noonan syndrome associated with a de novo mutation in KRAS (p.P34Q) and premature closure of the sagittal suture. We provide a review of the literature of germline KRAS mutations and find that approximately 10% of published cases have craniosynostosis. Our findings expand on the NS phenotype and suggest that germline mutations in the KRAS gene are causally involved in craniosynostosis, supporting the role of the RAS-MAPK pathway as a mediator of aberrant bone growth in cranial sutures. The inclusion of craniosynostosis as a possible phenotype in KRAS-associated Noonan Syndrome has implications in the differential diagnosis and surgical management of individuals with craniosynostosis. © 2015 Wiley Periodicals, Inc.

Phosphoproteomics-mediated identification of Fer kinase as a target of mutant Shp2 in Noonan and LEOPARD syndrome

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Paardekooper Overman, Jeroen; Preisinger, Christian; Prummel, Karin; Bonetti, Monica; Giansanti, Piero; Heck, Albert; den Hertog, Jeroen

2014-01-01

Noonan syndrome (NS) and LEOPARD syndrome (LS) cause congenital afflictions such as short stature, hypertelorism and heart defects. More than 50% of NS and almost all of LS cases are caused by activating and inactivating mutations of the phosphatase Shp2, respectively. How these biochemically

Noonan Syndrome and Stroke: A Case Report

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Ebru Nur Mıhçı

2012-03-01

Full Text Available Noonan syndrome is an autosomal dominant genetic disease characterized by short stature, webbed neck, typical facial appearance and congenital heart disease. Here we report a 24 year old woman patient with the diagnosis of Noonan syndrome who admitted to our clinic with ischemic stroke caused by atrial fibrillation secondary to hypertrophic cardiomyopathy. Noonan syndrome patients with stroke due to vascular malformations have been reported, but non-obstructive hypertrophic cardiomyopathy is a rare cause for stroke in patients with Noonan syndrome. Our aim of presenting the case emphasize that Noonan syndrome should be thought as a differential diagnosis in patients with stroke at a young age and dysmorphic facial appearance

Noonan Syndrome and Stroke: A Case Report

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Ebru Nur Mıhçı

2012-03-01

Full Text Available Noonan syndrome is an autosomal dominant genetic disease characterized by short stature, webbed neck, typical facial appearance and congenital heart disease. Here we report a 24 year old woman patient with the diagnosis of Noonan syndrome who admitted to our clinic with ischemic stroke caused by atrial fibrillation secondary to hypertrophic cardiomyopathy. Noonan syndrome patients with stroke due to vascular malformations have been reported, but non-obstructive hypertrophic cardiomyopathy is a rare cause for stroke in patients with Noonan syndrome. Our aim of presenting the case emphasize that Noonan syndrome should be thought as a differential diagnosis in patients with stroke at a young age and dysmorphic facial appearance.

Genetics Home Reference: Noonan syndrome

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... growth spurt that results in shortened stature. Most males with Noonan syndrome have undescended testes (cryptorchidism), which may contribute to infertility (inability to father a child) later in life. Females with Noonan syndrome can experience delayed puberty but ...

Bone mineral density and body composition in Noonan's syndrome: effects of growth hormone treatment

NARCIS (Netherlands)

Noordam, C.; Span, J.; van Rijn, R. R.; Gomes-Jardin, E.; van Kuijk, C.; Otten, B. J.

2002-01-01

We assessed bone mineral density (BMD) and body composition in children with Noonan's syndrome (NS) before and during growth hormone (GH) treatment. Sixteen children (12 boys, 4 girls) with NS aged 5.8-14.2 (mean 10.0) years were studied for 2 years. Anthropometry, BMD measurements by radiographic

Noonan syndrome in diverse populations.

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Kruszka, Paul; Porras, Antonio R; Addissie, Yonit A; Moresco, Angélica; Medrano, Sofia; Mok, Gary T K; Leung, Gordon K C; Tekendo-Ngongang, Cedrik; Uwineza, Annette; Thong, Meow-Keong; Muthukumarasamy, Premala; Honey, Engela; Ekure, Ekanem N; Sokunbi, Ogochukwu J; Kalu, Nnenna; Jones, Kelly L; Kaplan, Julie D; Abdul-Rahman, Omar A; Vincent, Lisa M; Love, Amber; Belhassan, Khadija; Ouldim, Karim; El Bouchikhi, Ihssane; Shukla, Anju; Girisha, Katta M; Patil, Siddaramappa J; Sirisena, Nirmala D; Dissanayake, Vajira H W; Paththinige, C Sampath; Mishra, Rupesh; Klein-Zighelboim, Eva; Gallardo Jugo, Bertha E; Chávez Pastor, Miguel; Abarca-Barriga, Hugo H; Skinner, Steven A; Prijoles, Eloise J; Badoe, Eben; Gill, Ashleigh D; Shotelersuk, Vorasuk; Smpokou, Patroula; Kisling, Monisha S; Ferreira, Carlos R; Mutesa, Leon; Megarbane, Andre; Kline, Antonie D; Kimball, Amy; Okello, Emmy; Lwabi, Peter; Aliku, Twalib; Tenywa, Emmanuel; Boonchooduang, Nonglak; Tanpaiboon, Pranoot; Richieri-Costa, Antonio; Wonkam, Ambroise; Chung, Brian H Y; Stevenson, Roger E; Summar, Marshall; Mandal, Kausik; Phadke, Shubha R; Obregon, María G; Linguraru, Marius G; Muenke, Maximilian

2017-09-01

Noonan syndrome (NS) is a common genetic syndrome associated with gain of function variants in genes in the Ras/MAPK pathway. The phenotype of NS has been well characterized in populations of European descent with less attention given to other groups. In this study, individuals from diverse populations with NS were evaluated clinically and by facial analysis technology. Clinical data and images from 125 individuals with NS were obtained from 20 countries with an average age of 8 years and female composition of 46%. Individuals were grouped into categories of African descent (African), Asian, Latin American, and additional/other. Across these different population groups, NS was phenotypically similar with only 2 of 21 clinical elements showing a statistically significant difference. The most common clinical characteristics found in all population groups included widely spaced eyes and low-set ears in 80% or greater of participants, short stature in more than 70%, and pulmonary stenosis in roughly half of study individuals. Using facial analysis technology, we compared 161 Caucasian, African, Asian, and Latin American individuals with NS with 161 gender and age matched controls and found that sensitivity was equal to or greater than 94% for all groups, and specificity was equal to or greater than 90%. In summary, we present consistent clinical findings from global populations with NS and additionally demonstrate how facial analysis technology can support clinicians in making accurate NS diagnoses. This work will assist in earlier detection and in increasing recognition of NS throughout the world. © 2017 Wiley Periodicals, Inc.

Hematological findings in Noonan syndrome

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Bertola Débora R.

2003-01-01

Full Text Available OBJECTIVE: Noonan syndrome is a multiple congenital anomaly syndrome, and bleeding diathesis is considered part of the clinical findings. The purpose of this study was to determine the frequency of hemostatic abnormalities in a group of Noonan syndrome patients. METHOD: We studied 30 patients with clinical diagnosis of Noonan syndrome regarding their hemostatic status consisting of bleeding time, prothrombin time, activated partial thromboplastin time and thrombin time tests, a platelet count, and a quantitative determination of factor XI. RESULTS: An abnormal laboratory result was observed in 9 patients (30%. Although coagulation-factor deficiencies, especially factor XI deficiency, were the most common hematological findings, we also observed abnormalities of platelet count and function in our screening. CONCLUSIONS: Hemostatic abnormalities are found with some frequency in Noonan syndrome patients (30% in our sample. Therefore, we emphasize the importance of a more extensive hematological investigation in these patients, especially prior to an invasive procedure, which is required with some frequency in this disorder.

Prolapse of all cardiac valves in Noonan syndrome.

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Otikunta, Adikesava Naidu; Subbareddy, Y V; Polamuri, Praneeth; Thakkar, Ashok

2015-02-25

Noonan syndrome is an autosomal dominant disorder with genetically heterogeneous inheritance. The incidence of cardiac abnormalities is higher in patients with Noonan syndrome and approximately 80% patients with Noonan syndrome are reported to have cardiac abnormalities during their lifetimes. However, polyvalvular disease in Noonan syndrome is rare. In this case-report, we describe a case of a young man whose features were strongly suggestive of Noonan syndrome and who was diagnosed with prolapse of all four cardiac valves after 22 years of uneventful survival. 2015 BMJ Publishing Group Ltd.

Mutational Analysis of PTPN11 Gene in Taiwanese Children with Noonan Syndrome

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Chia-Sui Hung

2007-01-01

Full Text Available Noonan syndrome (NS is an autosomal dominant disorder presenting with characteristic facies, short stature, skeletal anomalies, and congenital heart defects. Mutations in protein-tyrosine phosphatase, nonreceptor-type 11 (PTPN11, encoding SHP-2, account for 33-50% of NS. This study screened for mutations in the PTPN11 gene in 34 Taiwanese patients with NS. Mutation analysis of the 15 coding exons and exon/intron boundaries was performed by polymerase chain reaction and direct sequencing of the PTPN11 gene. We identified 10 different missense mutations in 13 (38% patients, including a novel missense mutation (855T > G, F285L. These mutations were clustered in exon 3 (n = 6 encoding the N-SH2 domain, exon 4 (n = 2 encoding the C-SH2 domain, and in exons 8 (n = 2 and 13 (n = 3 encoding the PTP domain. In conclusion, this study provides further support that PTPN11 mutations are responsible for Noonan syndrome in Taiwanese patients. [J Formos Med Assoc 2007;106(2:169-172

Clinical Heterogeneity in two patients with Noonan-like Syndrome associated with the same SHOC2 mutation.

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Capalbo, Donatella; Scala, Maria Giuseppa; Melis, Daniela; Minopoli, Giorgia; Improda, Nicola; Palamaro, Loredana; Pignata, Claudio; Salerno, Mariacarolina

2012-09-20

Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM #607721) has been recently related to the invariant c.4A > G missense change in SHOC2. It is characterized by features reminiscent of Noonan syndrome. Ectodermal involvement, short stature associated to growth hormone (GH) deficiency (GHD), and cognitive deficits are common features. We compare in two patients with molecularly confirmed NS/LAH diagnosis, the clinical phenotype and pathogenetic mechanism underlying short stature. In particular, while both the patients exhibited a severe short stature, GH/IGFI axis functional evaluation revealed a different pathogenetic alteration, suggesting in one patient an upstream alteration (typical GHD) and in the other one a peripheral GH insensitivity.

[A patient with Noonan syndrome].

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Bins, A; Gortzak, R A Th

2013-12-01

Noonan syndrome is a relatively common autosomal dominant genetic disorder which is characterised by typical facial features, congenital heart diseases and small stature. In 50% of the cases the syndrome is caused by a mutation on the PTPN11-gen. The expression of symptoms associated with Noonan syndrome can be very mild in nature and facial features usually become less pronounced with age, which can sometimes make a correct diagnosis more difficult. Despite a wide range of associated symptoms most adults with Noonan syndrome can be self-sustaining, with a good quality of life. It is important that the dentist is well-informed about this syndrome due to the heart diseases and bleeding disorders which can be present with these patients and may influence a dentist's choice of therapy when invasive treatment is indicated.

Noonan's syndrome with keratoconus and optic disc coloboma.

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Ascaso, F J; Del Buey, M A; Huerva, V; Latre, B; Palomar, A

1993-01-01

We report the case of a 14-year-old girl with multiple findings characteristic of Noonan's syndrome, including short stature, mild mental retardation, facial, skeletal and renal abnormalities. In addition, ophthalmic examination revealed a keratoconus in the left eye and a right optic disc coloboma. To date, only two cases of Noonan's syndrome with keratoconus have been reported, and this is the second case of this syndrome with optic disc coloboma. To our knowledge, this is the first report of Noonan's syndrome associated with unilateral keratoconus and contralateral optic disc coloboma. In view of the large number of patients with Noonan's syndrome reported to date and the rarity of these ocular abnormalities, it is most likely that this association is fortuitous. Ocular findings reported in patients with Noonan's syndrome are reviewed.

Are ECG abnormalities in Noonan syndrome characteristic for the syndrome?

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Raaijmakers, R; Noordam, C; Noonan, J A; Croonen, E A; van der Burgt, C J A M; Draaisma, J M T

2008-12-01

Of all patients with Noonan syndrome, 50-90% have one or more congenital heart defects. The most frequent occurring are pulmonary stenosis (PS) and hypertrophic cardiomyopathy. The electrocardiogram (ECG) of a patient with Noonan syndrome often shows a characteristic pattern, with a left axis deviation, abnormal R/S ratio over the left precordium, and an abnormal Q wave. The objective of this study was to determine if these ECG characteristics are an independent feature of the Noonan syndrome or if they are related to the congenital heart defect. A cohort study was performed with 118 patients from two university hospitals in the United States and in The Netherlands. All patients were diagnosed with definite Noonan syndrome and had had an ECG and echocardiography. Sixty-nine patients (58%) had characteristic abnormalities of the ECG. In the patient group without a cardiac defect (n = 21), ten patients had a characteristic ECG abnormality. There was no statistical relationship between the presence of a characteristic ECG abnormality and the presence of a cardiac defect (p = 0.33). Patients with hypertrophic cardiomyopathy had more ECG abnormalities in total (p = 0.05), without correlation with a specific ECG abnormality. We conclude that the ECG features in patients with Noonan syndrome are characteristic for the syndrome and are not related to a specific cardiac defect. An ECG is very useful in the diagnosis of Noonan syndrome; every child with a Noonan phenotype should have an ECG and echocardiogram for evaluation.

Mutational analysis of the PTPN11 gene in Egyptian patients with Noonan syndrome.

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Essawi, Mona L; Ismail, Manal F; Afifi, Hanan H; Kobesiy, Maha M; El Kotoury, Ahmed; Barakat, Maged M

2013-11-01

Noonan syndrome (NS) is inherited as an autosomal dominant disorder with dysmorphic facies, short stature, and cardiac defects, which can be caused by missense mutations in the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) gene, which encodes src homology region 2 domain containing tyrosine phosphatase-2 (SHP-2), a protein tyrosine phosphatase that acts in signal transduction downstream to growth factors and cytokines. The current study aimed to study the molecular characterization of the PTPN11 gene among Egyptian patients with Noonan syndrome. Eleven exons of the PTPN11 gene were amplified and screened by single stranded conformational polymorphism (SSCP). DNA samples showing band shift in SSCP were subjected to sequencing. Mutational analysis of the PTPN11 gene revealed T→C transition at position 854 in exon 8, predicting Phe285Ser substitution within PTP domain of SHP-2 protein, in one NS patient and -21C→T polymorphism in intron 7 in four other cases. Knowing that NS is phenotypically heterogeneous, molecular characterization of the PTPN11 gene should serve to establish NS diagnosis in patients with atypical features, although lack of a mutation does not exclude the possibility of NS. Copyright © 2012. Published by Elsevier B.V.

Coarctation of the aorta in Noonan-like syndrome with loose anagen hair.

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Zmolikova, Michaela; Puchmajerova, Alena; Hecht, Petr; Lebl, Jan; Trkova, Marie; Krepelova, Anna

2014-05-01

Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721) due to a missense mutation c.4A>G in SHOC2 predicting p.Ser2Gly has been described recently. This condition is characterized by facial features similar to Noonan syndrome, reduced growth, cardiac defects, and typical abnormal hair. We report on a patient with molecularly confirmed NS/LAH with coarctation of the aorta. The girl was precipitously born at 37 weeks of gestation at home and required a 3-min resuscitation. Increased nuchal translucency and aortic coarctation with a small ventricular septal defect were described prenatally, hypertrophic cardiomyopathy was detected postnatally. The patient presented with facial dysmorphism typical of NS with redundant skin over the nape and on the back. Short stature, relative macrocephaly, failure-to-thrive together with dystrophic appearance, developmental delay mainly in motor milestones and very thin, sparse, slow-growing hair occurred a few weeks after birth. Endocrine evaluation revealed low IGF-1 levels and borderline growth hormone deficiency. Growth hormone therapy started at 16 months had a partial effect and prevented further growth deterioration. Coarctation of the aorta is not a typical heart defect among individuals with NS/LAH, therefore our observation extends the phenotypic spectrum of this disorder. © 2014 Wiley Periodicals, Inc.

Noonan syndrome: an update on growth and development.

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Yart, Armelle; Edouard, Thomas

2018-02-01

To provide an update on recent developments on Noonan syndrome with a special focus on endocrinology, bone, and metabolism aspects. The key issues still to be resolved and the future therapeutic perspectives will be discussed. The discovery of the molecular genetic causes of Noonan syndrome and Noonan-syndrome-related disorders has permitted us to better understand the mechanisms underlying the different symptoms of these diseases and to establish genotype-phenotype correlations (in growth patterns for example). In addition to the classical clinical hallmarks of Noonan syndrome, new important aspects include decreased fertility in men, lean phenotype with increased energy expenditure and possible impact on carbohydrate metabolism/insulin sensitivity, and impaired bone health. Further clinical studies are needed to investigate the long-term impact of these findings and their possible interconnections. Finally, the understanding of the crucial role of RAS/mitogen-activated protein kinases dysregulation in the pathophysiology of Noonan syndrome allows us to devise new therapeutic approaches. Some agents are currently undergoing clinical trials in Noonan syndrome patients. On the last 10 years, our knowledge of the molecular basis and the pathophysiology of Noonan syndrome has greatly advanced allowing us to gain insight in all the aspects of this disease and to devise new specific therapeutic strategies.

Germline KRAS mutations cause Noonan syndrome.

NARCIS (Netherlands)

Schubbert, S.; Zenker, M.; Rowe, S.L.; Boll, S.; Klein, C.; Bollag, G.; Burgt, I. van der; Musante, L.; Kalscheuer, V.M.M.; Wehner, L.E.; Nguyen, H.; West, B.; Zhang, K.Y.; Sistermans, E.A.; Rauch, A.; Niemeyer, C.M.; Shannon, K.; Kratz, C.P.

2006-01-01

Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approximately 50% of cases of Noonan syndrome. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream

PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.

NARCIS (Netherlands)

Tartaglia, M.; Kalidas, K.; Shaw, A.; Song, X.; Musat, D.L.; Burgt, C.J.A.M. van der; Brunner, H.G.; Bertola, D.R.; Crosby, A.; Ion, A.; Kucherlapati, R.S.; Jeffery, S.; Patton, M.A.; Gelb, B.D.

2002-01-01

Noonan syndrome (NS) is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects, and skeletal malformations. We recently demonstrated that mutations in PTPN11, the gene encoding the non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain

Radiological features of late-onset lymphoedema in Noonan's syndrome

International Nuclear Information System (INIS)

Ho, Wan-Ling; Wang, Jou-Kou; Li, Yiu-Wah

2003-01-01

Noonan's syndrome is a multiple congenital anomaly syndrome with diverse manifestations. Lymphatic abnormalities occur in less than 20% of patients. We report a 14-year-old boy who presented with swollen lower limbs and dysmorphic features characteristic of Noonan's syndrome. The radiological features of this unusual case of late-onset lymphoedema in association with Noonan's syndrome are presented. (orig.)

Radiological features of late-onset lymphoedema in Noonan's syndrome.

Science.gov (United States)

Ho, Wan-Ling; Wang, Jou-Kou; Li, Yiu-Wah

2003-03-01

Noonan's syndrome is a multiple congenital anomaly syndrome with diverse manifestations. Lymphatic abnormalities occur in less than 20% of patients. We report a 14-year-old boy who presented with swollen lower limbs and dysmorphic features characteristic of Noonan's syndrome. The radiological features of this unusual case of late-onset lymphoedema in association with Noonan's syndrome are presented.

Exclusion of 22q11 deletion in Noonan syndrome with Tetralogy of Fallot

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Digilio, M.C.; Marino, B.; Giannotti, A. [Bambino Gesu Hospital, Rome (Italy); Dallapiccola, B. [Univ. of Tor Vergata, Rome (Italy)]|[Casa Sollievo Sofferenza Hospital, San Giovanni Rotondo (Italy)

1996-04-24

We read with interest the report of Robin et al. [1995] published in recent issue of the Journal. The authors described 6 patients with Noonan syndrome (NS) who underwent molecular evaluation for submicroscopic deletion of chromosome band 22q11. None of those patients presented with conotruncal heart defects. Evidence for 22q11 hemizygosity was demonstrated in only one patient. This patient had NS-like manifestations without clinical manifestations of DiGeorge (DG) or velo-cardio-facial (VCF) syndromes. The molecular results obtained in the other 5 patients led the authors to conclude that classical NS is not due to del(22)(q11), even if some patients with del(22)(q11) may present NS-like manifestations. 12 refs., 1 tab.

OROFACIAL FINDINGS IN NOONAN SYNDROME: A CASE REPORT

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Raluca Maria MOCANU

2013-06-01

Full Text Available Noonan syndrome is an autosomal dominant multisys‐ tem disorder, associated with cardiac anomalies and a dis‐ tinctive facial appearance, characterized by genetic heterogeneity. Noonan syndrome affects both females and males, and has an estimated incidence of 1 per 1,000‐2,500 live births. The present report aims at presenting the cranio‐dento‐facial findings in a case of Noonan syndrome in a 6 year‐old male.

A Rare Cause of Pheochromocytoma; Neurofibromatosis Type 1-Noonan Syndrome

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Mazhar Müslüm Tuna

2014-09-01

Full Text Available Neurofibromatosis (NF Type 1 (NF-1 is an autosomal dominant disease with a prevalence of about 1/3000. NF-1 is a neurocutaneous syndrome characterized by cafe au lait macules, neurofibroma, optic glioma, lisch nodules, and symptoms involving other systems. Noonan syndrome (NS is a clinically heterogeneous disorder predominantly characterized by dysmorphic facial features, congenital heart disease, proportionate post-natal short stature, neck abnormalities, and chest deformities. NF-NS is a very rare overlapping syndrome sharing many features of both syndromes. Coexistence of pheochromocytoma, which can be life-threatening if not treated properly, is also a very rare complication of this disorder. Here, we report a patient who was admitted with a mass in the right upper quadrant and was diagnosed with pheochromocytoma and NFNS. (The Me­di­cal Bul­le­tin of Ha­se­ki 2014; 52: 227-31

Coronary artery ectasia in Noonan syndrome: Report of an individual with SOS1 mutation and literature review.

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Calcagni, Giulio; Baban, Anwar; De Luca, Enrica; Leonardi, Benedetta; Pongiglione, Giacomo; Digilio, Maria Cristina

2016-03-01

Noonan syndrome (NS) is the second most frequent hereditary syndrome with cardiac involvement. Pulmonary valve stenosis and hypertrophic cardiomyopathy are the most prevalent cardiovascular abnormalities. We report on a 14-year-old girl with NS due to SOS1 mutation with pulmonary stenosis and idiopathic coronary ectasia. To the best of our knowledge, this is the first report describing coronary ectasia in a patient with NS secondary to a SOS1 mutation. We include a literature review of this rare association. © 2015 Wiley Periodicals, Inc.

Moyamoya syndrome in a patient with Noonan-like syndrome with loose anagen hair.

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Choi, Jin-Ho; Oh, Moon-Yeon; Yum, Mi-Sun; Lee, Beom Hee; Kim, Gu-Hwan; Yoo, Han-Wook

2015-03-01

Noonan-like syndrome with loose anagen hair is one of the RASopathies characterized by Noonan syndrome-like features with unique ectodermal abnormalities. This syndrome is caused by mutations in the SHOC2 gene. We encountered a patient with moyamoya syndrome associated with Noonan-like syndrome with loose anagen hair presenting with transient ischemic attacks. A 6-year-old girl was diagnosed with Noonan-like syndrome with loose anagen hair because of profound short stature and ectodermal anomalies such as sparse and easily pluckable hair. A heterozygous mutation of c.4A>G (p.S2G) in the SHOC2 gene was identified, and recombinant human growth hormone therapy was initiated at 8 years of age. At age 10, she manifested recurrent left hemiplegia. Moreover, cerebrovascular imaging revealed occlusion or narrowing of both internal carotid arteries and both middle cerebral arteries with distal moyamoya-like vessels. She is treated with aspirin and calcium channel blocker. We describe the first case of Noonan-like syndrome with loose anagen hair associated with moyamoya syndrome, although it has been reported to be associated with a few cases of other RASopathies, including Noonan, cardiofaciocutaneous, and Costello syndromes. This report emphasizes the associations between cerebrovascular anomalies and Noonan-like syndrome with loose anagen hair. Copyright © 2015 Elsevier Inc. All rights reserved.

Occurrence of DNET and other brain tumors in Noonan syndrome warrants caution with growth hormone therapy.

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McWilliams, Geoffrey D; SantaCruz, Karen; Hart, Blaine; Clericuzio, Carol

2016-01-01

Noonan syndrome (NS) is an autosomal dominant developmental disorder caused by mutations in the RAS-MAPK signaling pathway that is well known for its relationship with oncogenesis. An 8.1-fold increased risk of cancer in Noonan syndrome has been reported, including childhood leukemia and solid tumors. The same study found a patient with a dysembryoplastic neuroepithelial tumor (DNET) and suggested that DNET tumors are associated with NS. Herein we report an 8-year-old boy with genetically confirmed NS and a DNET. Literature review identified eight other reports, supporting the association between NS and DNETs. The review also ascertained 13 non-DNET brain tumors in individuals with NS, bringing to 22 the total number of NS patients with brain tumors. Tumor growth while receiving growth hormone (GH) occurred in our patient and one other patient. It is unknown whether the development or progression of tumors is augmented by GH therapy, however there is concern based on epidemiological, animal and in vitro studies. This issue was addressed in a 2015 Pediatric Endocrine Society report noting there is not enough data available to assess the safety of GH therapy in children with neoplasia-predisposition syndromes. The authors recommend that GH use in children with such disorders, including NS, be undertaken with appropriate surveillance for malignancies. Our case report and literature review underscore the association of NS with CNS tumors, particularly DNET, and call attention to the recommendation that clinicians treating NS patients with GH do so with awareness of the possibility of increased neoplasia risk. © 2015 Wiley Periodicals, Inc.

Vaginal rhabdomyosarcoma in a patient with Noonan syndrome.

OpenAIRE

Khan, S; McDowell, H; Upadhyaya, M; Fryer, A

1995-01-01

This is the first report of a Noonan syndrome patient who has had a vaginal rhabdomyosarcoma. Recent reports of Noonan syndrome patients with leukaemia have prompted speculation that there may be a slightly increased malignancy risk associated with this syndrome.

Motor performance in children with Noonan syndrome

NARCIS (Netherlands)

Croonen, E.A.; Essink, M.; Burgt, I. van der; Draaisma, J.M.; Noordam, C.; Nijhuis-Van der Sanden, M.W.G.

2017-01-01

Although problems with motor performance in daily life are frequently mentioned in Noonan syndrome, the motor performance profile has never been systematically investigated. The aim of this study was to examine whether a specific profile in motor performance in children with Noonan syndrome was seen

Case report: Noonan-like multiple central giant cell granuloma syndrome.

Science.gov (United States)

Bitton, Natalie; Alexander, Stanley; Ruggiero, Salvatore; Parameswaran, Ashish; Russo, Antonino; Ferguson, Fred

2012-01-01

The purpose of this report was to: summarize the care of a child between the ages of 12 to 16 years old born with Noonan-like central giant cell syndrome and unrelated common variable immune deficiency; provide information on the dental management of patients with Noonan's syndrome; and present a brief discussion of the recent associated genetic findings. A review of the common features of Noonan syndrome and Noonan-like central giant cell syndrome is also provided.

Abnormal Auditory Brainstem Response (ABR Findings in a Near-Normal Hearing Child with Noonan Syndrome

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Bahram Jalaei

2017-01-01

Full Text Available Introduction: Noonan syndrome (NS is a heterogeneous genetic disease that affects many parts of the body. It was named after Dr. Jacqueline Anne Noonan, a paediatric cardiologist.Case Report: We report audiological tests and auditory brainstem response (ABR findings in a 5-year old Malay boy with NS. Despite showing the marked signs of NS, the child could only produce a few meaningful words. Audiological tests found him to have bilateral mild conductive hearing loss at low frequencies. In ABR testing, despite having good waveform morphology, the results were atypical. Absolute latency of wave V was normal but interpeak latencies of wave’s I-V, I-II, II-III were prolonged. Interestingly, interpeak latency of waves III-V was abnormally shorter.Conclusion:Abnormal ABR results are possibly due to abnormal anatomical condition of brainstem and might contribute to speech delay.

Anesthetic Approach to a Child with Noonan's Syndrome

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Zehra Hatipoglu

2015-03-01

Full Text Available Noonan syndrome is characterized by fascial and physical features along with congenital heart disease. In these patients, fascial features include short webbed neck, micrognathia, limited mouth opening and high arched palate. Pulmonary stenosis and hypertrophic obstructive cardiomyopathy are highly prevalent in Noonan's syndrome. The anesthetic management is important because of difficult airway and severe cardiac abnormalities. We reported that anesthetic management of a child with Noonan's syndrome. [Cukurova Med J 2015; 40(Suppl 1: 47-50

Are ECG abnormalities in Noonan syndrome characteristic for the syndrome?

NARCIS (Netherlands)

Raaijmakers, R.; Noordam, C.; Noonan, J.A.; Croonen, E.A.; Burgt, C.J.A.M. van der; Draaisma, J.M.T.

2008-01-01

Of all patients with Noonan syndrome, 50-90% have one or more congenital heart defects. The most frequent occurring are pulmonary stenosis (PS) and hypertrophic cardiomyopathy. The electrocardiogram (ECG) of a patient with Noonan syndrome often shows a characteristic pattern, with a left axis

Intellectual development in Noonan syndrome: a longitudinal study.

Science.gov (United States)

Roelofs, Renée L; Janssen, Nikki; Wingbermühle, Ellen; Kessels, Roy P C; Egger, Jos I M

2016-07-01

Although cognitive impairments in adults with Noonan syndrome seem to be limited to a low-average intelligence and slower processing speed, studies in children with Noonan syndrome have demonstrated more extensive cognitive problems. These include deficits in language skills, memory, attention, and executive functioning. This longitudinal study is the first to investigate intellectual development in a group of individuals with Noonan syndrome. Sixteen patients with Noonan syndrome underwent intelligence assessment both in childhood and in adulthood, using Wechsler's intelligence scales. IQ scores and Wechsler standard scores achieved in childhood and adulthood were compared. Subsequently, verbal and performance IQ in childhood were used as predictors for adult IQ and index scores. Compared with childhood scores, adult full-scale IQ and performance IQ significantly increased. Adult performance IQ was higher than verbal IQ. Childhood performance IQ and verbal IQ together predicted all adult IQ and index scores, except for the processing speed index. Childhood IQ was a significant predictor of adult intelligence in patients with Noonan syndrome. Performance IQ advanced to a normal level in adulthood, while verbal IQ did not develop proportionately, resulting in a discrepancy between adult performance IQ and verbal IQ. This finding could suggest a delay in the development of executive functioning in patients with Noonan syndrome, which seems to be outgrown in adulthood.

[RIT1: a novel gene associated with Noonan syndrome].

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Arroyo-Carrera, I; Solo de Zaldivar-Tristancho, M; Martin-Fernandez, R; Vera-Torres, M; Gonzalez de Buitrago-Amigo, J F; Botet-Rodriguez, J

2016-10-16

Noonan syndrome is the most frequent of the congenital group of malformation syndromes caused by germline mutations that encode components of the RAS/MAPK pathway, termed RASopathies, one of the most frequent congenital genetic disorders in the clinical practice. Recently RIT1 mutations have been reported in patients with Noonan syndrome. A 7 years-old girl with a clinical diagnosis of Noonan syndrome, and with a hypertrophic cardiomyopathy included in her clinical manifestations, where a de novo heterozygous, probably pathogenic, novel mutation in RIT1, c.295T>C (p.Phe99Leu), has been identified. RIT1 shares homology with other RAS proteins and the expression of mutant alleles demonstrates a gain-of-function effect supporting a causative role in Noonan syndrome pathogenesis. Data suggest that the frequency of RIT1 mutations can be estimated as 3-5% in Noonan syndrome patients. These cases compared with Noonan patients harboring mutations in other genes are characterized by high frequency of prenatal abnormalities and hypertrophic cardiomyopathy, and lower frequencies of short stature and pectus abnormalities. We emphasize the importance of the novel identified genes in order to be included in the diagnostic panels.

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.

A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype.

Science.gov (United States)

Edwards, Jonathan J; Martinelli, Simone; Pannone, Luca; Lo, Ivan Fai-Man; Shi, Lisong; Edelmann, Lisa; Tartaglia, Marco; Luk, Ho-Ming; Gelb, Bruce D

2014-09-01

The RASopathies are a relatively common group of phenotypically similar and genetically related autosomal dominant genetic syndromes caused by missense mutations affecting genes participating in the RAS/mitogen-activated protein kinase (MAPK) pathway that include Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML, formerly LEOPARD syndrome). NS and NSML can be difficult to differentiate during infancy, but the presence of multiple lentigines, café au lait spots, and specific cardiac defects facilitate the diagnosis. Furthermore, individual PTPN11 missense mutations are highly specific to each syndrome and engender opposite biochemical alterations on the function of SHP-2, the protein product of that gene. Here, we report on a 5-year-old male with two de novo PTPN11 mutations in cis, c.1471C>T (p.Pro491Ser), and c.1492C>T (p.Arg498Trp), which are associated with NS and NSML, respectively. This boy's phenotype is intermediate between NS and NSML with facial dysmorphism, short stature, mild global developmental delay, pulmonic stenosis, and deafness but absence of café au lait spots or lentigines. The double-mutant SHP-2 was found to be catalytically impaired. This raises the question of whether clinical differences between NS and NSML can be ascribed solely to the relative SHP-2 catalytic activity. © 2014 Wiley Periodicals, Inc.

Constitutional bone impairment in Noonan syndrome.

Science.gov (United States)

Baldassarre, Giuseppina; Mussa, Alessandro; Carli, Diana; Molinatto, Cristina; Ferrero, Giovanni Battista

2017-03-01

Noonan syndrome (NS) is an autosomal dominant trait characterized by genotypic and phenotypic variability. It belongs to the Ras/MAPK pathway disorders collectively named Rasopathies or neurocardiofaciocutaneous syndromes. Phenotype is characterized by short stature, congenital heart defects, facial dysmorphisms, skeletal and ectodermal anomalies, cryptorchidism, mild to moderate developmental delay/learning disability, and tumor predisposition. Short stature and skeletal dysmorphisms are almost constant and several studies hypothesized a role for the RAS pathway in regulating bone metabolism. In this study, we investigated the bone quality assessed by phalangeal quantitative ultrasound (QUS) and the metabolic bone profiling in a group of patients with NS, to determine whether low bone mineralization is primary or secondary to NS characteristics. Thirty-five patients were enrolled, including 20 males (55.6%) and 15 females (44.5%) aged 1.0-17.8 years (mean 6.4 ± 4.5, median 4.9 years). Each patients was submitted to clinical examination, estimation of the bone age, laboratory assays, and QUS assessment. Twenty-five percent of the cohort shows reduced QUS values for their age based on bone transmission time. Bone measurement were adjusted for multiple factors frequently observed in NS patients, such as growth retardation, delayed bone age, retarded puberty, and reduced body mass index, potentially affecting bone quality or its appraisal. In spite of the correction attempts, QUS measurement indicates that bone impairment persists in nearly 15% of the cohort studied. Our results indicate that bone impairment in NS is likely primary and not secondary to any of the phenotypic traits of NS, nor consistent with metabolic disturbances. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Noonan syndrome and chylothorax

International Nuclear Information System (INIS)

Martinez-Leon, M. I.; Ceres-Ruiz, L.; Solbes-Vila, R.; Valls-Moreno, E.

2001-01-01

Chylothorax during childhood usually develops as a result of posto-perative complications following cardiothoracic surgery. It is rarely due to the malformations of the lymphatic system associated with dysmorphic syndrome. We report two cases of Noonan syndrome involving neonatal development of chylothorax. In children with the Noonan phenotype who develop pleural effusion during the neonatal period in the absence of obstetric trauma, it is advisable to rule out the presence of congenital lymphatic malformation and study the pleural effusion, initially introducing conservative treatment with dietary therapy. Chest radiography, ultrasound and computed tomography reveal the presence of the pleural effusion and parenchymal pattern compatible with chloroethoxy and lymphangiectasis. (Author) 15 refs

Noonan syndrome and chylothorax; Sindrome de Noonan y quilotorax

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Martinez-Leon, M. I.; Ceres-Ruiz, L.; Solbes-Vila, R.; Valls-Moreno, E. [Hospital Infantil del C.H.U. Carlos Haya. Malaga (Spain)

2001-07-01

Chylothorax during childhood usually develops as a result of posto-perative complications following cardiothoracic surgery. It is rarely due to the malformations of the lymphatic system associated with dysmorphic syndrome. We report two cases of Noonan syndrome involving neonatal development of chylothorax. In children with the Noonan phenotype who develop pleural effusion during the neonatal period in the absence of obstetric trauma, it is advisable to rule out the presence of congenital lymphatic malformation and study the pleural effusion, initially introducing conservative treatment with dietary therapy. Chest radiography, ultrasound and computed tomography reveal the presence of the pleural effusion and parenchymal pattern compatible with chloroethoxy and lymphangiectasis. (Author) 15 refs.

Intellectual development in Noonan syndrome: A longitudinal study

NARCIS (Netherlands)

Roelofs, R.L.; Janssen, N.; Wingbermühle, P.A.M.; Kessels, R.P.C.; Egger, J.I.M.

2016-01-01

INTRODUCTION: Although cognitive impairments in adults with Noonan syndrome seem to be limited to a low-average intelligence and slower processing speed, studies in children with Noonan syndrome have demonstrated more extensive cognitive problems. These include deficits in language skills, memory,

Tegumentary manifestations of Noonan and Noonan-related syndromes

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Caio Robledo D'Angioli Costa Quaio

2013-01-01

Full Text Available OBJECTIVES: Noonan and Noonan-related syndromes are common autosomal dominant disorders with neuro-cardio-facial-cutaneous and developmental involvement. The objective of this article is to describe the most relevant tegumentary findings in a cohort of 41 patients with Noonan or Noonan-related syndromes and to detail certain aspects of the molecular mechanisms underlying ectodermal involvement. METHODS: A standard questionnaire was administered. A focused physical examination and a systematic review of clinical records was performed on all patients to verify the presence of tegumentary alterations. The molecular analysis of this cohort included sequencing of the following genes in all patients: PTPN1, SOS1, RAF1, KRAS, SHOC2 and BRAF. RESULTS: The most frequent tegumentary alterations were xeroderma (46%, photosensitivity (29%, excessive hair loss (24%, recurrent oral ulcers (22%, curly hair (20%, nevi (17%, markedly increased palmar and plantar creases (12%, follicular hyperkeratosis (12%, palmoplantar hyperkeratosis (10%, café-au-lait spots (10% and sparse eyebrows (7%. Patients with mutations in PTPN11 had lower frequencies of palmar and plantar creases and palmar/plantar hyperkeratosis compared with the other patients. CONCLUSIONS: We observed that patients with mutations in genes directly involved in cell proliferation kinase cascades (SOS1, BRAF, KRAS and RAF1 had a higher frequency of hyperkeratotic lesions compared with patients with mutations in genes that have a more complex interaction with and modulation of cell proliferation kinase cascades (PTPN11.

Noonans syndrom kan diagnosticere sklinisk og molekylærgenetisk

DEFF Research Database (Denmark)

Krab Henningsen, Marie; Jelsig, Anne Marie; Andersen, Helle

2015-01-01

Noonan syndrome is part of the group of RASopathies caused by germ line mutations in genes involved in the RAS/MAPK pathway. There is substantial phenotypic overlap among the RASopathies. Diagnosis of Noonan syndrome is often based on clinical features including dysmorphic facial features, short...... stature and congenital heart disease. Rapid advances in sequencing technology have made molecular genetic analyses a helpful tool in diagnosing and distinguishing Noonan syndrome from other RASopathies....

Noonan Syndrome Complicated by Primary Pulmonary Lymphangiectasia.

Science.gov (United States)

Ford, Jaclyn Jo; Trotter, Carol W

2015-01-01

Noonan syndrome is a genetic disorder that has several features common to other conditions, making diagnosis a challenge. This column summarizes the case of a neonate with an atypical presentation of Noonan syndrome involving a fatal type of lymphangiectasia resulting in persistent pleural effusions. Radiographic features of this condition are presented along with the complexities of diagnosis and treatment.

Noonan syndrome: Severe phenotype and PTPN11 mutations.

Science.gov (United States)

Carrasco Salas, Pilar; Gómez-Molina, Gertrudis; Carreto-Alba, Páxedes; Granell-Escobar, Reyes; Vázquez-Rico, Ignacio; León-Justel, Antonio

2018-04-24

Noonan syndrome (NS) is a genetic disorder characterized by a wide range of distinctive features and health problems. It caused in 50% of cases by missense mutations in PTPN11 gene. It has been postulated that it is possible to predict the disease course based into the impact of mutations on the protein. We report two cases of severe NS phenotype including hydrops fetalis. PTPN11 gene was studied in germinal cells of both patients by sequencing. Two different mutations (p.Gly503Arg and p.Met504Val) was detected in PTPN11 gene. These mutations have been reported previously, and when they were germinal variants, patients presented classic NS, NS with other malignancies and recently, p.Gly503Arg has been also observed in a patient with severe NS and hydrops fetalis, as our cases. Therefore, these observations shade light on that it is not always possibly to determine the genotype-phenotype relation based into the impact of mutations on the protein in NS patients with PTPN11 mutations. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

Noonan's and DiGeorge syndromes with monosomy 22q11.

OpenAIRE

Wilson, D I; Britton, S B; McKeown, C; Kelly, D; Cross, I E; Strobel, S; Scambler, P J

1993-01-01

A boy with the dysmorphic features of Noonan's syndrome and pulmonary valve stenosis who had evidence of hypoparathyroidism and abnormal T lymphocyte numbers in the neonatal period is reported. He had a normal karyotype but molecular analysis revealed a submicroscopic deletion within chromosome 22q11, the region deleted in DiGeorge syndrome. Thus this child has both Noonan's syndrome and DiGeorge syndrome; 22q11 is a candidate region for a gene defective in Noonan's syndrome.

Management of moyamoya syndrome in patients with Noonan syndrome.

Science.gov (United States)

Gupta, Mihir; Choudhri, Omar A; Feroze, Abdullah H; Do, Huy M; Grant, Gerald A; Steinberg, Gary K

2016-06-01

A few isolated reports have described an association between Noonan syndrome and cerebrovascular abnormalities, including moyamoya syndrome. These reports have been limited to pediatric patients presenting with recurrent transient ischemic attacks (TIA) or headaches. Management has primarily been pharmacologic, with only one prior report of surgical revascularization to our knowledge. We report four cases of Noonan syndrome patients presenting with headaches and/or sensorimotor strokes in childhood that caused unilateral sensorimotor impairment. Cerebral angiography and MRI revealed bilateral moyamoya syndrome. All patients underwent successful bilateral extracranial-to-intracranial revascularization. The first patient was a 10-year-old girl who presented following a hemorrhagic stroke and recovered well after indirect bypass. The second patient was an adult with a history of childhood stroke whose symptoms progressed in adulthood. She underwent a direct bypass and improved, but continued to experience TIA at her 4 year follow-up. The third patient was a 7-year-old girl with headaches and a new onset TIA who failed pharmacological therapy and subsequently underwent bilateral indirect bypass. The fourth patient was a 24-year-old woman with worsening headaches and an occluded left middle cerebral artery from unilateral moyamoya syndrome. A left sided direct bypass was completed given delayed MRI perfusion with poor augmentation. To our knowledge these are the first reported surgical cases of combined Noonan and moyamoya syndrome. These cases highlight the need to recognize moyamoya syndrome in patients with Noonan syndrome. Early surgical revascularization should be pursued in order to prevent symptom progression. Copyright © 2015 Elsevier Ltd. All rights reserved.

A unique association of Noonan syndrome and 47,XYY syndrome in a male presenting with failure to thrive.

Science.gov (United States)

Bellfield, Edward J; Shad, Zohra

2017-09-01

We describe a 24-month-old male patient who presented to our Genetics-Endocrinology Clinic with a history of failure to thrive, short stature and cryptorchidism. Soon after birth he was diagnosed with 47,XYY syndrome, but due unusual facial features had further diagnostic workup which revealed Noonan syndrome (NS) as well. This report illustrates significant phenotypic-cytogenetic variability within the clinical presentation of NS and 47,XYY syndrome, as well as the need to investigate patients for other genetic defects when phenotype does not correlate with genotype. Furthermore, in this case, the cellular pathways attenuating growth via PTPN11 mutation appear to supersede the SHOX overdosage-an observation that can lead to further research in genetic mechanisms of growth physiology.

Cardiomyopathies in Noonan syndrome and the other RASopathies

Science.gov (United States)

Gelb, Bruce D.; Roberts, Amy E.; Tartaglia, Marco

2015-01-01

Noonan syndrome and related disorders (Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with loose anagen hair, and other related traits) are autosomal dominant traits. Mutations causing these disorders alter proteins relevant for signaling through RAS. Thus, these traits are now collectively called the RASopathies. While the RASopathies have pleiomorphic features, this review will focus on the hypertrophic cardiomyopathy observed in varying percentages of all of these traits. In addition, inherited abnormalities in one pathway gene, RAF1, cause pediatric-onset dilated cardiomyopathy. The pathogeneses for the RASopathy-associated cardiomyopathies are being elucidated, principally using animal models, leading to genotype-specific insights into how signal transduction is perturbed. Based on those findings, small molecule therapies seem possible for RASopathy-associated cardiomyopathies. PMID:26380542

Transnodal lymphangiography and post-CT for protein-losing enteropathy in Noonan syndrome.

Science.gov (United States)

Matsumoto, Tomohiro; Kudo, Takahiro; Endo, Jun; Hashida, Kazunobu; Tachibana, Nao; Murakoshi, Takatsugu; Hasebe, Terumitsu

2015-01-01

Noonan syndrome, which is a multiple congenital disorder, may be associated with lymphatic abnormalities. Protein-losing enteropathy (PLE) developing in Noonan syndrome is rare. We performed transnodal lymphangiography by directly accessing bilateral inguinal nodes under ultrasound guidance in a 17-year-old female with PLE developing in Noonan syndrome to assess detailed anatomical findings regarding lymphatic vessels. There have been no reports on transnodal lymphangiography for Noonan syndrome. Post-lymphangiographic CT images revealed multiple lymphatic abnormalities and lipiodol extravasation into the duodenum and the proximal jejunum. Transnodal lymphangiography was easy and safe for PLE developing in Noonan syndrome, and post-lymphangiographic CT provided invaluable information.

Radiological features of late-onset lymphoedema in Noonan's syndrome

Energy Technology Data Exchange (ETDEWEB)

Ho, Wan-Ling; Wang, Jou-Kou [Department of Pediatrics, National Taiwan University Hospital, Taipei (Taiwan); Li, Yiu-Wah [Department of Radiology, National Taiwan University Hospital, Taipei (Taiwan)

2003-03-01

Noonan's syndrome is a multiple congenital anomaly syndrome with diverse manifestations. Lymphatic abnormalities occur in less than 20% of patients. We report a 14-year-old boy who presented with swollen lower limbs and dysmorphic features characteristic of Noonan's syndrome. The radiological features of this unusual case of late-onset lymphoedema in association with Noonan's syndrome are presented. (orig.)

Targeted/exome sequencing identified mutations in ten Chinese patients diagnosed with Noonan syndrome and related disorders

Directory of Open Access Journals (Sweden)

Shanshan Xu

2017-10-01

Full Text Available Abstract Background Noonan syndrome (NS and Noonan syndrome with multiple lentigines (NSML are autosomal dominant developmental disorders. NS and NSML are caused by abnormalities in genes that encode proteins related to the RAS-MAPK pathway, including PTPN11, RAF1, BRAF, and MAP2K. In this study, we diagnosed ten NS or NSML patients via targeted sequencing or whole exome sequencing (TS/WES. Methods TS/WES was performed to identify mutations in ten Chinese patients who exhibited the following manifestations: potential facial dysmorphisms, short stature, congenital heart defects, and developmental delay. Sanger sequencing was used to confirm the suspected pathological variants in the patients and their family members. Results TS/WES revealed three mutations in the PTPN11 gene, three mutations in RAF1 gene, and four mutations in BRAF gene in the NS and NSML patients who were previously diagnosed based on the abovementioned clinical features. All the identified mutations were determined to be de novo mutations. However, two patients who carried the same mutation in the RAF1 gene presented different clinical features. One patient with multiple lentigines was diagnosed with NSML, while the other patient without lentigines was diagnosed with NS. In addition, a patient who carried a hotspot mutation in the BRAF gene was diagnosed with NS instead of cardiofaciocutaneous syndrome (CFCS. Conclusions TS/WES has emerged as a useful tool for definitive diagnosis and accurate genetic counseling of atypical cases. In this study, we analyzed ten Chinese patients diagnosed with NS and related disorders and identified their correspondingPTPN11, RAF1, and BRAF mutations. Among the target genes, BRAF showed the same degree of correlation with NS incidence as that of PTPN11 or RAF1.

Hemostatic abnormalities in Noonan syndrome.

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Artoni, Andrea; Selicorni, Angelo; Passamonti, Serena M; Lecchi, Anna; Bucciarelli, Paolo; Cerutti, Marta; Cianci, Paola; Gianniello, Francesca; Martinelli, Ida

2014-05-01

A bleeding diathesis is a common feature of Noonan syndrome, and various coagulation abnormalities have been reported. Platelet function has never been carefully investigated. The degree of bleeding diathesis in a cohort of patients with Noonan syndrome was evaluated by a validated bleeding score and investigated with coagulation and platelet function tests. If ratios of prothrombin time and/or activated partial thromboplastin time were prolonged, the activity of clotting factors was measured. Individuals with no history of bleeding formed the control group. The study population included 39 patients and 28 controls. Bleeding score was ≥2 (ie, suggestive of a moderate bleeding diathesis) in 15 patients (38.5%) and ≥4 (ie, suggestive of a severe bleeding diathesis) in 7 (17.9%). Abnormal coagulation and/or platelet function tests were found in 14 patients with bleeding score ≥2 (93.3%) but also in 21 (87.5%) of those with bleeding score Noonan syndrome had a bleeding diathesis and >90% of them had platelet function and/or coagulation abnormalities. Results of these tests should be taken into account in the management of bleeding or invasive procedures in these patients. Copyright © 2014 by the American Academy of Pediatrics.

Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects

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Vincent Runtuwene

2011-05-01

Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras–mitogen-activated-protein-kinase (MAPK signaling pathway. Recently, two mutations in NRAS were reported to be associated with Noonan syndrome, T50I and G60E. Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that we identified in an individual bearing typical Noonan syndrome features. The I24N mutation activates N-Ras, resulting in enhanced downstream signaling. Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient to induce developmental disorders. The defects in zebrafish embryos are reminiscent of symptoms in individuals with Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes induce in zebrafish embryos. MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling. In conclusion, mutations in NRAS from individuals with Noonan syndrome activated N-Ras signaling and induced developmental defects in zebrafish embryos, indicating that activating mutations in NRAS cause Noonan syndrome.

Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects

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Runtuwene, Vincent; van Eekelen, Mark; Overvoorde, John; Rehmann, Holger; Yntema, Helger G.; Nillesen, Willy M.; van Haeringen, Arie; van der Burgt, Ineke; Burgering, Boudewijn; den Hertog, Jeroen

2011-01-01

SUMMARY Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras–mitogen-activated-protein-kinase (MAPK) signaling pathway. Recently, two mutations in NRAS were reported to be associated with Noonan syndrome, T50I and G60E. Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that we identified in an individual bearing typical Noonan syndrome features. The I24N mutation activates N-Ras, resulting in enhanced downstream signaling. Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient to induce developmental disorders. The defects in zebrafish embryos are reminiscent of symptoms in individuals with Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes induce in zebrafish embryos. MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling. In conclusion, mutations in NRAS from individuals with Noonan syndrome activated N-Ras signaling and induced developmental defects in zebrafish embryos, indicating that activating mutations in NRAS cause Noonan syndrome. PMID:21263000

Cardiac findings in 31 patients with Noonan's syndrome

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Bertola Débora Romeo

2000-01-01

Full Text Available OBJECTIVE: To evaluate cardiac findings in 31 Noonan syndrome patients. METHODS: Thirty-one (18 males and 13 femalespatients from 26 families affected with Noonan's syndrome were evaluated from the cardiac point of view with electrocardiography and echodopplercardiography. RESULTS: Twenty patients had some type of cardiac abnormality. The most frequent was pulmonary valve stenosis followed by hypertrophic myocardiopathy, commonly associated with valve defects. Upper deviation of the QRS axis was observed in 80% of these patients. CONCLUSION: In view of the high frequency and diversity of cardiac abnormalities present in Noonan syndrome, cardiac evaluation with electrocardiography and echocardiography should be performed in all patients diagnostically suspected of having this disease.

[Cardiofaciocutaneous syndrome, a Noonan syndrome related disorder: clinical and molecular findings in 11 patients].

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Carcavilla, Atilano; García-Miñaúr, Sixto; Pérez-Aytés, Antonio; Vendrell, Teresa; Pinto, Isabel; Guillén-Navarro, Encarna; González-Meneses, Antonio; Aoki, Yoko; Grinberg, Daniel; Ezquieta, Begoña

2015-01-20

To describe 11 patients with cardiofaciocutaneous syndrome (CFC) and compare them with 130 patients with other RAS-MAPK syndromes (111 Noonan syndrome patients [NS] and 19 patients with LEOPARD syndrome). Clinical data from patients submitted for genetic analysis were collected. Bidirectional sequencing analysis of PTPN11, SOS1, RAF1, BRAF, and MAP2K1 focused on exons carrying recurrent mutations, and of all KRAS exons were performed. Six different mutations in BRAF were identified in 9 patients, as well as 2 MAP2K1 mutations. Short stature, developmental delay, language difficulties and ectodermal anomalies were more frequent in CFC patients when compared with other neuro-cardio-faciocutaneous syndromes (P<.05). In at least 2 cases molecular testing helped reconsider the diagnosis. CFC patients showed a rather severe phenotype but at least one patient with BRAF mutation showed no developmental delay, which illustrates the variability of the phenotypic spectrum caused by BRAF mutations. Molecular genetic testing is a valuable tool for differential diagnosis of CFC and NS related disorders. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Constitutional NRAS mutations are rare among patients with Noonan syndrome or juvenile myelomonocytic leukemia.

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Kraoua, Lilia; Journel, Hubert; Bonnet, Philippe; Amiel, Jeanne; Pouvreau, Nathalie; Baumann, Clarisse; Verloes, Alain; Cavé, Hélène

2012-10-01

Recently, germline mutations of NRAS have been shown to be associated with Noonan syndrome (NS), a relatively common developmental disorder characterized by short stature, congenital heart disease, and distinctive facial features. We report on the mutational analysis of NRAS in a cohort of 125 French patients with NS and no known mutation for PTPN11, KRAS, SOS1, MEK1, MEK2, RAF1, BRAF, and SHOC2. The c.179G>A (p.G60E) mutation was identified in two patients with typical NS, confirming that NRAS germline mutations are a rare cause of this syndrome. We also screened our cohort of 95 patients with juvenile myelomonocytic leukemia (JMML). Among 17 patients with NRAS-mutated JMML, none had clinical features suggestive of NS. None of the 11 JMML patients for which germline DNA was available had a constitutional NRAS mutation. Copyright © 2012 Wiley Periodicals, Inc.

Multifocal tenosynovial giant cell tumors in a child with Noonan syndrome

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Meyers, Arthur B. [Children' s Hospital of Wisconsin, Department of Radiology, Milwaukee, WI (United States); Nemours Children' s Health System/Nemours Children' s Hospital, Department of Radiology, Orlando, FL (United States); Awomolo, Agboola O. [Children' s Hospital of Wisconsin, Department of Radiology, Milwaukee, WI (United States); Szabo, Sara [Medical College of Wisconsin and Children' s Hospital of Wisconsin, Department of Pathology, Milwaukee, WI (United States); Cincinnati Children' s Hospital Medical Center, Division of Pathology and Laboratory Medicine, Cincinnati, OH (United States)

2017-03-15

Noonan syndrome is a genetic disorder with variable expression of distinctive facial features, webbed neck, chest deformity, short stature, cryptorchidism and congenital heart disease. The association of Noonan syndrome and giant cell granulomas of the mandible is widely reported. However, Noonan syndrome may also be associated with single or multifocal tenosynovial giant cell tumors, also referred to as pigmented villonodular synovitis. We report a child with Noonan syndrome, giant cell granulomas of the mandible and synovial and tenosynovial giant cell tumors involving multiple joints and tendon sheaths who was initially misdiagnosed with juvenile idiopathic arthritis. It is important for radiologists to be aware of the association of Noonan syndrome and multifocal giant cell lesions, which can range from the more commonly described giant cell granulomas of the mandible to isolated or multifocal intra- or extra-articular tenosynovial giant cell tumors or a combination of all of these lesions. (orig.)

Multifocal tenosynovial giant cell tumors in a child with Noonan syndrome.

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Meyers, Arthur B; Awomolo, Agboola O; Szabo, Sara

2017-03-01

Noonan syndrome is a genetic disorder with variable expression of distinctive facial features, webbed neck, chest deformity, short stature, cryptorchidism and congenital heart disease. The association of Noonan syndrome and giant cell granulomas of the mandible is widely reported. However, Noonan syndrome may also be associated with single or multifocal tenosynovial giant cell tumors, also referred to as pigmented villonodular synovitis. We report a child with Noonan syndrome, giant cell granulomas of the mandible and synovial and tenosynovial giant cell tumors involving multiple joints and tendon sheaths who was initially misdiagnosed with juvenile idiopathic arthritis. It is important for radiologists to be aware of the association of Noonan syndrome and multifocal giant cell lesions, which can range from the more commonly described giant cell granulomas of the mandible to isolated or multifocal intra- or extra-articular tenosynovial giant cell tumors or a combination of all of these lesions.

Multifocal tenosynovial giant cell tumors in a child with Noonan syndrome

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Meyers, Arthur B.; Awomolo, Agboola O.; Szabo, Sara

2017-01-01

Noonan syndrome is a genetic disorder with variable expression of distinctive facial features, webbed neck, chest deformity, short stature, cryptorchidism and congenital heart disease. The association of Noonan syndrome and giant cell granulomas of the mandible is widely reported. However, Noonan syndrome may also be associated with single or multifocal tenosynovial giant cell tumors, also referred to as pigmented villonodular synovitis. We report a child with Noonan syndrome, giant cell granulomas of the mandible and synovial and tenosynovial giant cell tumors involving multiple joints and tendon sheaths who was initially misdiagnosed with juvenile idiopathic arthritis. It is important for radiologists to be aware of the association of Noonan syndrome and multifocal giant cell lesions, which can range from the more commonly described giant cell granulomas of the mandible to isolated or multifocal intra- or extra-articular tenosynovial giant cell tumors or a combination of all of these lesions. (orig.)

Noonan's Syndrome and Autoimmune Thyroiditis

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Vesterhus, Per; Aarskog, Dagfinn

1973-01-01

Thyroid abnormalities were studies in seven boys and three girls, 4- to 17-years-old, with Noonan's syndrome, characterized by mental retardation, ocular anomalies (wide spaced eyes, drooped eye lids, or strabismus), heart lesions, characteristics of Turner's syndrome, and normal karyotypes (chromosome arrangement). (MC)

Noonan syndrome: A case report

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Asokan S

2007-09-01

Full Text Available Noonan syndrome is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects and skeletal malformations. It may be sporadic or inherited as an autosomal dominant or recessive trait and occurs, one in 1000-2500 children. This is a case report of a 13 year-old girl who was referred by a general dental practitioner to a pediatric dentist for management. Full mouth dental rehabilitation was done and the child was brought to a dental institution for correction of orofacial and occlusal defects. Multidisciplinary treatment is the key to success in managing children with Noonan syndrome and the pediatric dentists play an important position to lead the health team.

Hotspots in PTPN11 Gene Among Indian Children With Noonan Syndrome.

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Narayanan, Dhanya Lakshmi; Pandey, Himani; Moirangthem, Amita; Mandal, Kausik; Gupta, Rekha; Puri, Ratna Dua; Patil, S J; Phadke, Shubha R

2017-08-15

To test for PTPN11 mutations in clinically diagnosed cases of Noonan syndrome. 17 individuals with clinical diagnosis of Noonan syndrome were included in the study. Sanger sequencing of all the 15 exons of PTPN11 was done. A genotype-phenotype correlation was attempted. Mutation in PTPN11 was detected in 11 out of 17 (64.7%) patients with Noonan syndrome; 72% had mutation in exon 3 and 27 % had mutation in exon 13. PTPN11 mutation accounts for 64.7% of cases with clinical features of Noonan syndrome in India. Majority of the mutations are in exon 3 and exon 13 of PTPN11, making them the hotspots in Indian population.

K-RasV14I recapitulates Noonan syndrome in mice

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Hernández-Porras, Isabel; Fabbiano, Salvatore; Schuhmacher, Alberto J.; Aicher, Alexandra; Cañamero, Marta; Cámara, Juan Antonio; Cussó, Lorena; Desco, Manuel; Heeschen, Christopher; Mulero, Francisca; Bustelo, Xosé R.; Guerra, Carmen; Barbacid, Mariano

2014-01-01

Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. NS also is associated with a risk for developing myeloproliferative disorders (MPD), including juvenile myelomonocytic leukemia (JMML). Mutations responsible for NS occur in at least 11 different loci including KRAS. Here we describe a mouse model for NS induced by K-RasV14I, a recurrent KRAS mutation in NS patients. K-RasV14I–mutant mice displayed multiple NS-associated developmental defects such as growth delay, craniofacial dysmorphia, cardiac defects, and hematologic abnormalities including a severe form of MPD that resembles human JMML. Homozygous animals had perinatal lethality whose penetrance varied with genetic background. Exposure of pregnant mothers to a MEK inhibitor rescued perinatal lethality and prevented craniofacial dysmorphia and cardiac defects. However, Mek inhibition was not sufficient to correct these defects when mice were treated after weaning. Interestingly, Mek inhibition did not correct the neoplastic MPD characteristic of these mutant mice, regardless of the timing at which the mice were treated, thus suggesting that MPD is driven by additional signaling pathways. These genetically engineered K-RasV14I–mutant mice offer an experimental tool for studying the molecular mechanisms underlying the clinical manifestations of NS. Perhaps more importantly, they should be useful as a preclinical model to test new therapies aimed at preventing or ameliorating those deficits associated with this syndrome. PMID:25359213

[Noonan syndrome can be diagnosed clinically and through molecular genetic analyses].

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Henningsen, Marie Krab; Jelsig, Anne Marie; Andersen, Helle; Brusgaard, Klaus; Ousager, Lilian Bomme; Hertz, Jens Michael

2015-08-03

Noonan syndrome is part of the group of RASopathies caused by germ line mutations in genes involved in the RAS/MAPK pathway. There is substantial phenotypic overlap among the RASopathies. Diagnosis of Noonan syndrome is often based on clinical features including dysmorphic facial features, short stature and congenital heart disease. Rapid advances in sequencing technology have made molecular genetic analyses a helpful tool in diagnosing and distinguishing Noonan syndrome from other RASopathies.

Bleeding diathesis in Noonan syndrome

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Staudt, Joost M.; van der Horst, Chantal M. A. M.; Peters, Marjolijn; Melis, Paris

2005-01-01

An 18-year-old girl with Noonan syndrome was operated on for prominent ears. Subcutaneous haematomas developed on both sides, and coagulation tests reported a bleeding diathesis. This is seldom mentioned in descriptions of the syndrome, but it has been shown that one-third of all patients with the

Electrocardiography in Noonan syndrome PTPN11 gene mutation--phenotype characterization.

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Croonen, E.A.; Burgt, I. van der; Kapusta, L.; Draaisma, J.M.T.

2008-01-01

Noonan syndrome is a developmental disorder with distinctive facial features, short stature and cardiac abnormalities. In this cross-sectional study, we evaluated characteristic electrocardiographic (ECG) findings and cardiac abnormalities in 84 patients with Noonan syndrome, 56 (67%) of who were

Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome.

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Aoki, Yoko; Niihori, Tetsuya; Banjo, Toshihiro; Okamoto, Nobuhiko; Mizuno, Seiji; Kurosawa, Kenji; Ogata, Tsutomu; Takada, Fumio; Yano, Michihiro; Ando, Toru; Hoshika, Tadataka; Barnett, Christopher; Ohashi, Hirofumi; Kawame, Hiroshi; Hasegawa, Tomonobu; Okutani, Takahiro; Nagashima, Tatsuo; Hasegawa, Satoshi; Funayama, Ryo; Nagashima, Takeshi; Nakayama, Keiko; Inoue, Shin-Ichi; Watanabe, Yusuke; Ogura, Toshihiko; Matsubara, Yoichi

2013-07-11

RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Alexithymia, emotion perception, and social assertiveness in adult women with Noonan and Turner syndromes.

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Roelofs, Renée L; Wingbermühle, Ellen; Freriks, Kim; Verhaak, Chris M; Kessels, Roy P C; Egger, Jos I M

2015-04-01

Noonan syndrome (NS) and Turner syndrome (TS) are associated with cognitive problems and difficulties in affective information processing. While both phenotypes include short stature, facial dysmorphisms, and a webbed neck, genetic etiology and neuropsychological phenotype differ significantly. The present study examines putative differences in affective information processing and social assertiveness between adult women with NS and TS. Twenty-six women with NS, 40 women with TS, and 40 female controls were matched on age and intelligence, and subsequently compared on (1) alexithymia, measured by the Bermond-Vorst Alexithymia Questionnaire, (2) emotion perception, evaluated by the Emotion Recognition Task, and (3) social assertiveness and social discomfort, assessed by the Scale for Interpersonal Behavior. Women with TS showed higher levels of alexithymia than women with NS and controls (P-values assertiveness and the level of social discomfort. Women with NS and TS demonstrated different patterns of impairment in affective information processing, in terms of alexithymia and emotion perception. The present findings suggest neuropsychological phenotyping to be helpful for the diagnosis of specific cognitive-affective deficits in genetic syndromes, for the enhancement of genetic counseling, and for the development of personalized treatment plans. © 2015 Wiley Periodicals, Inc.

NOONAN SYNDROME – CASE REPORT

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Milena Vujanović

2014-06-01

Full Text Available Noonan Syndrome is a rare, autosomal dominant disorder characterized by short stature, facial abnormalities, congenital heart defects and urogenital malformations. Ocular changes occur in 95% of patients and usually include hypertelorism, ptosis, refractive errors, strabismus, amblyopia, rarely nystagmus, colobomas, cataracts, optic nerve drusen. Case report: We present a case of a boy, 10 months old, referred by the pediatrician because of strabismus. During the general examination of the head and face, we noted that the ears were low-set, and the lower jaw was slightly smaller. Ophthalmological examination revealed hypertelorism, left eye esotropia, hyperopia, and optic disc pit. Other associated malformations were: dilatation of both pyelons, cryptorchidism, pulmonary stenosis. Genetic analysis confirmed the diagnosis of Noonan syndrome. The variety of clinical manifestations of this syndrome indicates that a multidisciplinary approach is necessary for diagnosis, treatment, and follow-up of these patients.

A case of Noonan`s syndrome with terminal renal failure and neoplasmic disease; Przypadek zespolu Noonan z niewydolnoscia nerek i rozrostem nowotworowym

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Wierzbowska-Lange, B.; Sieniawska, M.; Polanski, J.; Kisiel, M. [Akademia Medyczna, Warsaw (Poland)

1993-12-31

A 16 year old boy with Noonan syndrome diagnosed in the 3rd month of life was treated for renal insufficiency and hepatic tumor. Hemodialisis was started in preparation for surgery. Exacerbation of renal insufficiency occurred after surgical removal of the hepatic tumor together with the right hepatic lobe. Histopathologic examination showed adenoma hepatocellulare. Cysts in the extraperitoneal space appeared in the following months and were identified as cystes dysontogenetici benigni ``hamartia``. Renal function deteriorated during this time to end stage renal disease. The authors emphasize the possibility of good mental development in a patients with Noonan syndrome as well as the presence of urinary tract abnormalities and renal insufficiency of unknown origin - a phenomenon that has not yet been reported in other cases of Noonan syndrome. (author) 11 refs, 1 fig

Psychopathological features in Noonan syndrome.

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Perrino, Francesca; Licchelli, Serena; Serra, Giulia; Piccini, Giorgia; Caciolo, Cristina; Pasqualetti, Patrizio; Cirillo, Flavia; Leoni, Chiara; Digilio, Maria Cristina; Zampino, Giuseppe; Tartaglia, Marco; Alfieri, Paolo; Vicari, Stefano

2018-01-01

Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, skeletal and haematological/lymphatic defects, distinctive facies, cryptorchidism, and a wide spectrum of congenital heart defects. Recurrent features also include variable cognitive deficits and behavioural problems. Recent research has been focused on the assessment of prevalence, age of onset and characterization of psychiatric features in this disorder. Herein, we evaluated the prevalence of attention deficit and hyperactivity disorder (ADHD), anxiety and depressive symptoms and syndromes in a cohort of individuals with clinical and molecular diagnosis of NS. The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS PL) has been used for the assessment of psychiatric disorders according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Multidimensional Anxiety Scale for Children (MASC) and the Children's Depression Inventory (CDI) have been assessed for the evaluation of anxiety and depressive symptoms and syndromes, whereas Conners Teacher and Parent Rating Scales-long version (CRS-R) have been used to evaluate ADHD. The study included 27 individuals (67% males) with an average age of 10.4 years (range 6-18 years) receiving molecular diagnosis of NS or a clinically related condition, evaluated and treated at the Neuropsychiatric Unit of Children's Hospital Bambino Gesù and at the Center for Rare Diseases of Fondazione Policlinico Universitario Agostino Gemelli, in Rome. Twenty individuals showed mutations in PTPN11, five in SOS1 and two in SHOC2. The mean IQ was 94 (Standard Deviation = 17, min = 56, max = 130). Seventy percent of the individuals (n = 19; 95% Confidence Interval = 52-85%) showed ADHD features, with six individuals reaching DSM-IV-TR criteria for ADHD disorder, and thirteen showing subsyndromal traits. Symptoms or syndrome of anxiety were present in 37% of the cohort

Central xanthoma of the jaw in association with Noonan syndrome.

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Olson, Nicholas J; Addante, Rocco R; de Abreu, Francine B; Memoli, Vincent A

2018-05-01

Xanthomas are histiocytic lesions of the skin, soft tissue and bone and are generally considered to be reactive in nature. When they arise in the bones of the jaw, they are referred to as central xanthomas. New evidence supports the hypothesis that central xanthomas are a separate and distinct entity from their extragnathic counterparts. Noonan syndrome (NS) is an autosomal dominant disorder that has been associated with giant cell lesions which also commonly occur in the jaw. We present a case of a 15year-old-male with NS who presented with a radiolucent lesion of the mandible that on excision, was found to be a central xanthoma. Although giant cell lesions have been well described in NS, xanthomas of the jaw have not been reported. We will also discuss the entities that must be excluded prior to making a diagnosis of central xanthoma, as this can affect both treatment and follow up. Copyright © 2018. Published by Elsevier Inc.

Chronic pain in Noonan Syndrome: A previously unreported but common symptom.

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Vegunta, Sravanthi; Cotugno, Richard; Williamson, Amber; Grebe, Theresa A

2015-12-01

Noonan syndrome (NS) is a multiple malformation syndrome characterized by pulmonic stenosis, cardiomyopathy, short stature, lymphatic dysplasia, craniofacial anomalies, cryptorchidism, clotting disorders, and learning disabilities. Eight genes in the RAS/MAPK signaling pathway are implicated in NS. Chronic pain is an uncommon feature. To investigate the prevalence of pain in NS, we distributed a two-part questionnaire about pain among NS individuals at the Third International Meeting on Genetic Syndromes of the Ras/MAPK Pathway. The first part of the questionnaire queried demographic information among all NS participants. The second part was completed by individuals with chronic pain. Questions included musculoskeletal problems and clinical features of pain. Forty-five questionnaires were analyzed; 53% of subjects were female. Mean age was 17 (2-48) years; 47% had a PTPN11 mutation. Sixty-two percent (28/45) of individuals with NS experienced chronic pain. There was a significant relationship between prevalence of pain and residing in a cold climate (P = 0.004). Pain occurred commonly in extremities/joints and head/trunk, but more commonly in extremities/joints (P = 0.066). Subjects with hypermobile joints were more likely to have pain (P = 0.052). Human growth hormone treatment was not statistically significant among subjects without chronic pain (P = 0.607). We conclude that pain is a frequent and under-recognized clinical feature of NS. Chronic pain may be associated with joint hypermobility and aggravated by colder climate. Our study is a preliminary investigation that should raise awareness about pain as a common symptom in children and adults with NS. © 2015 Wiley Periodicals, Inc.

Ocular Manifestations of Noonan Syndrome: A Prospective Clinical and Genetic Study of 25 Patients.

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van Trier, Dorothée C; Vos, Anna M C; Draaijer, Renske W; van der Burgt, Ineke; Draaisma, Jos M Th; Cruysberg, Johannes R M

2016-10-01

To determine the full spectrum of ocular manifestations in patients with Noonan syndrome (NS). Prospective cross-sectional clinical and genetic study in a tertiary referral center. Twenty-five patients with NS (mean age, 14 years; range, 8 months-25 years) clinically diagnosed by validated criteria. All patients were examined by the same team following a detailed study protocol. Genetic analyses were performed in 23 patients. Ocular abnormalities of vision and refraction, external ocular features, ocular position and motility, anterior segment, posterior segment, and intraocular pressure. Ocular features of vision and refraction were amblyopia (32%), myopia (40%), and astigmatism (52%). External ocular features were epicanthic folds (84%), hypertelorism (68%), ptosis (56%), high upper eyelid crease (64%), lower eyelid retraction (60%), abnormal upward slanting palpebral fissures (36%), downward slanting palpebral fissures (32%), and lagophthalmos (28%). Orthoptic abnormalities included strabismus (40%), abnormal stereopsis (44%), and limited ocular motility (40%). Anterior segment abnormalities included prominent corneal nerves (72%) and posterior embryotoxon (32%). Additional ocular features were found, including nonglaucomatous optic disc excavation (20%), relatively low (Noonan syndrome is a clinical diagnosis with multiple genetic bases associated with an extensive variety of congenital ocular abnormalities. Ocular features of NS are characterized by 1 or more developmental anomalies of the eyelids (involving the position, opening, and closure) associated with various other ocular abnormalities in childhood, including amblyopia, myopia, astigmatism, strabismus, limited ocular motility, prominent corneal nerves, and posterior embryotoxon. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Phosphoproteomics-mediated identification of Fer kinase as a target of mutant Shp2 in Noonan and LEOPARD syndrome.

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Jeroen Paardekooper Overman

Full Text Available Noonan syndrome (NS and LEOPARD syndrome (LS cause congenital afflictions such as short stature, hypertelorism and heart defects. More than 50% of NS and almost all of LS cases are caused by activating and inactivating mutations of the phosphatase Shp2, respectively. How these biochemically opposing mutations lead to similar clinical outcomes is not clear. Using zebrafish models of NS and LS and mass spectrometry-based phosphotyrosine proteomics, we identified a down-regulated peptide of Fer kinase in both NS and LS. Further investigation showed a role for Fer during development, where morpholino-based knockdown caused craniofacial defects, heart edema and short stature. During gastrulation, loss of Fer caused convergence and extension defects without affecting cell fate. Moreover, Fer knockdown cooperated with NS and LS, but not wild type Shp2 to induce developmental defects, suggesting a role for Fer in the pathogenesis of both NS and LS.

Preoperative Detailed Coagulation Tests Are Required in Patients With Noonan Syndrome.

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Morice, Anne; Harroche, Annie; Cairet, Pascale; Khonsari, Roman H

2017-12-29

Patients with Noonan syndrome often require surgery at young ages. They are at high risk of perioperative bleeding from coagulation defects that might not have been detected by routine screening. These risks are rarely described in the oral and maxillofacial surgery (OMS) literature. The aim of this study was to evaluate the perioperative bleeding risks associated with Noonan syndrome and to propose preoperative guidelines. This report describes a retrospective case series of patients with Noonan syndrome who underwent OMS procedures during a continuous observational period (2013 through 2016) in the authors' center. Clinical data, blood screening test results, and perioperative bleeding were analyzed. Five patients (age, 4 to 20 yr) with Noonan syndrome who underwent OMS procedures were included in this study. One patient presented a spontaneous bleeding tendency (epistaxis requiring cauterization). Blood screening showed clotting defects in 3 patients. One patient presented abnormal perioperative bleeding owing to a mild defect in factor XI. Patients with Noonan syndrome must be referred to a hematologist for specific preoperative investigations and for adapted perioperative management. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Unique cerebrovascular anomalies in Noonan syndrome with RAF1 mutation.

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Zarate, Yuri A; Lichty, Angie W; Champion, Kristen J; Clarkson, L Kate; Holden, Kenton R; Matheus, M Gisele

2014-08-01

Noonan syndrome is a common autosomal dominant neurodevelopmental disorder caused by gain-of-function germline mutations affecting components of the Ras-MAPK pathway. The authors present the case of a 6-year-old male with Noonan syndrome, Chiari malformation type I, shunted benign external hydrocephalus in infancy, and unique cerebrovascular changes. A de novo heterozygous change in the RAF1 gene was identified. The patient underwent brain magnetic resonance imaging, computed tomography angiography, and magnetic resonance angiography to further clarify the nature of his abnormal brain vasculature. The authors compared his findings to the few cases of Noonan syndrome reported with cerebrovascular pathology. © The Author(s) 2013.

Noonan syndrome-causing genes: Molecular update and an assessment of the mutation rate

Directory of Open Access Journals (Sweden)

Ihssane El Bouchikhi

2016-12-01

Full Text Available Noonan syndrome is a common autosomal dominant disorder characterized by short stature, congenital heart disease and facial dysmorphia with an incidence of 1/1000 to 2500 live births. Up to now, several genes have been proven to be involved in the disturbance of the transduction signal through the RAS-MAP Kinase pathway and the manifestation of Noonan syndrome. The first gene described was PTPN11, followed by SOS1, RAF1, KRAS, BRAF, NRAS, MAP2K1, and RIT1, and recently SOS2, LZTR1, and A2ML1, among others. Progressively, the physiopathology and molecular etiology of most signs of Noonan syndrome have been demonstrated, and inheritance patterns as well as genetic counseling have been established. In this review, we summarize the data concerning clinical features frequently observed in Noonan syndrome, and then, we describe the molecular etiology as well as the physiopathology of most Noonan syndrome-causing genes. In the second part of this review, we assess the mutational rate of Noonan syndrome-causing genes reported up to now in most screening studies. This review should give clinicians as well as geneticists a full view of the molecular aspects of Noonan syndrome and the authentic prevalence of the mutational events of its causing-genes. It will also facilitate laying the groundwork for future molecular diagnosis research, and the development of novel treatment strategies.

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

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Johnston, Jennifer J; van der Smagt, Jasper J; Rosenfeld, Jill A; Pagnamenta, Alistair T; Alswaid, Abdulrahman; Baker, Eva H; Blair, Edward; Borck, Guntram; Brinkmann, Julia; Craigen, William; Dung, Vu Chi; Emrick, Lisa; Everman, David B; van Gassen, Koen L; Gulsuner, Suleyman; Harr, Margaret H; Jain, Mahim; Kuechler, Alma; Leppig, Kathleen A; McDonald-McGinn, Donna M; Can, Ngoc Thi Bich; Peleg, Amir; Roeder, Elizabeth R; Rogers, R Curtis; Sagi-Dain, Lena; Sapp, Julie C; Schäffer, Alejandro A; Schanze, Denny; Stewart, Helen; Taylor, Jenny C; Verbeek, Nienke E; Walkiewicz, Magdalena A; Zackai, Elaine H; Zweier, Christiane; Zenker, Martin; Lee, Brendan; Biesecker, Leslie G

2018-02-22

PurposeTo characterize the molecular genetics of autosomal recessive Noonan syndrome.MethodsFamilies underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.ResultsTwelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.ConclusionThese clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.Genet Med advance online publication, 22 February 2018; doi:10.1038/gim.2017.249.

Otolaryngologic manifestations of Noonan syndrome.

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Geelan-Hansen, Katie; Anne, Samantha

2015-09-01

Noonan syndrome is an autosomal dominant disorder with associated anomalies that include short stature, congenital heart defects, developmental delay, and characteristic facial features among other abnormalities. Articulation deficiency and language delay are often present and require speech therapy. Otitis media and hearing loss have been reported to be common in these patients. We performed a retrospective chart review of pediatric patients who were diagnosed with Noonan syndrome at our tertiary care center from January 1979 through December 2009. We found 19 such patients. Of these, 8 had received single-specialty care at our hospital; it is not known if they had received otolaryngologic care from an outside provider. These 8 patients were not included in our study. The remaining 11 patients-6 boys and 5 girls, aged 1 to 19 years (mean: 9.2)-had all received multidisciplinary care at our institution; 9 of them had received care from an otolaryngologist at our center. Of this group, 7 had history of feeding difficulty, 6 had experienced speech delay that required speech therapy, 6 had undergone placement of a pressure equalization tube, 4 had undergone adenoidectomy with or without tonsillectomy, and 1 had been treated with endoscopic sinus surgery. Although this study is limited by our small number of patients, our results suggest that early otolaryngologist involvement must be considered in the care of children with Noonan syndrome because many have evidence of eustachian tube dysfunction, hearing loss, and speech delay.

DRESS syndrome with thrombotic microangiopathy revealing a Noonan syndrome

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Bobot, Mickaël; Coen, Matteo; Simon, Clémentine; Daniel, Laurent; Habib, Gilbert; Serratrice, Jacques

2018-01-01

Abstract Rationale: The life-threatening drug rash with eosinophilia and systemic symptoms (DRESS) syndrome occurs most commonly after exposure to drugs, clinical features mimic those found with other serious systemic disorders. It is rarely associated with thrombotic microangiopathy. Patient concerns: We describe the unique case of a 44-year-old man who simultaneously experienced DRESS syndrome with thrombotic microangiopathy (TMA) after a 5 days treatment with fluindione. Diagnoses: Clinical evaluation leads to the discovery of an underlying lymphangiomatosis, due to a Noonan syndrome. Intervetions: The anticoagulant was withdrawn, and corticosteroids (1 mg/kg/day) and acenocoumarol were started. Outcomes: Clinical improvement ensued. At follow-up the patient is well. Lessons: The association of DRESS with TMA is a rare condition; we believe that the presence of the underlying Noonan syndrome could have been the trigger. Moreover, we speculate about the potential interrelations between these entities. PMID:29642153

Prolonged thrombocytopenia in a child with severe neonatal alloimmune reaction and Noonan syndrome.

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Salva, Inês; Batalha, Sara; Maia, Raquel; Kjollerstrom, Paula

2016-06-01

Fetomaternal alloimmune thrombocytopenia (FMAIT) caused by maternal antibodies is the leading cause of severe neonatal thrombocytopenia. A 1-month-old Caucasian girl was referred to our Hematology Clinic for persistent thrombocytopenia diagnosed after a bleeding episode. Diagnostic tests suggested FMAIT. Mild thrombocytopenia persisted for 18 months, and subsequent findings of dysmorphic facies, short stature and mild pulmonary stenosis led to the hypothesis of Noonan syndrome (NS), which was confirmed by genetic test. Other hematological abnormalities were excluded and she had no further bleeding episodes. This case illustrates the possibility of different diagnoses with the same clinical manifestations. The persistence of thrombocytopenia longer than expected associated with typical physical features led to the diagnosis of NS.

First-year growth in children with Noonan syndrome: Associated with feeding problems?

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Croonen, Ellen A; Draaisma, Jos M T; van der Burgt, Ineke; Roeleveld, Nel; Noordam, Cees

2018-04-01

Children with Noonan syndrome show rapid decline of growth in the first year of life and feeding problems are present in over 50%. The aim of this study was to explore whether growth decelerates because of feeding problems or other Noonan syndrome-related factors. We performed a retrospective, longitudinal cohort study of clinically and genetically diagnosed subjects with Noonan syndrome (n = 143). Questionnaires about the phenotypic-genotypic profile and reported feeding problems were sent to eligible subjects. Data on first-year growth was obtained from growth charts. Ninety-one participants were excluded because of different criteria. A total of 52 subjects with Noonan syndrome were included. The largest decline in weight and length standard deviation score (SDS) occurred in the first 2.5 months after birth (-1.93 and -1.15, respectively), with feeding problems causing a decline of 0.57 SDS in the remaining months. At 1 year, children with feeding problems were on average 290 g lighter and 0.8 cm shorter than children without feeding problems. Weight gain was also negatively influenced by having a PTPN11 mutation (n = 39) and a higher gestational age, whereas children of parents with Noonan syndrome and with a higher birth weight gained more weight. Growth in length was reduced by having cardiac surgery and a higher gestational age, but positively influenced by birth length and maternal height. Growth in children with Noonan syndrome is impaired right after birth and only partially associated with feeding problems. In addition, several specific Noonan syndrome-related factors seem to influence growth in the first year. © 2018 Wiley Periodicals, Inc.

Noonan syndrome: crossed fused ectopic kidneys and focal segmental glomerulosclerosis-a rare association.

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Gupta, Ankur; Khaira, Ambar; Lal, Charanjit; Mahajan, Sandeep; Tiwari, Suresh C

2009-10-01

Noonan syndrome is characterised by short stature, typical facial dysmorphology and congenital heart defects. Urogenital abnormalities are reported in 10% of the cases. We present a 14-year-old girl with characteristic features of Noonan syndrome and nephrotic-range proteinuria. She had crossed fused ectopic kidneys. Renal biopsy showed focal segmental glomerulosclerosis. Oral steroids were instituted and she responded well. The case highlights this novel renal presentation of Noonan syndrome.

A new nonsense mutation in the NF1 gene with neurofibromatosis-Noonan syndrome phenotype.

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Yimenicioğlu, Sevgi; Yakut, Ayten; Karaer, Kadri; Zenker, Martin; Ekici, Arzu; Carman, Kürşat Bora

2012-12-01

Neurofibromatosis-Noonan syndrome is a rare autosomal dominant disorder which combines neurofibromatosis type 1 (NF1) features with Noonan syndrome. NF1 gene mutations are reported in the majority of these patients. Sequence analysis of the established genes for Noonan syndrome revealed no mutation; a heterozygous NF1 point mutation c.7549C>T in exon 51, creating a premature stop codon (p.R2517X), had been demonstrated. Neurofibromatosis-Noonan syndrome recently has been considered a subtype of NF1 and caused by different NF1 mutations. We report the case of a 14-year-old boy with neurofibromatosis type 1 with Noonan-like features, who complained of headache with triventricular hydrocephaly and a heterozygous NF1 point mutation c.7549C>T in exon 51.

Effects of Germline Mutations in the Ras/MAPK Signaling Pathway on Adaptive Behavior: Cardiofaciocutaneous Syndrome and Noonan Syndrome

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Pierpont, Elizabeth I.; Pierpont, Mary Ella; Mendelsohn, Nancy J.; Roberts, Amy E.; Tworog-Dube, Erica; Rauen, Katherine A.; Seidenberg, Mark S.

2011-01-01

Cardiofaciocutaneous syndrome (CFC) and Noonan syndrome (NS) are two phenotypically overlapping genetic disorders whose underlying molecular etiologies affect a common signaling pathway. Mutations in the BRAF, MEK1 and MEK2 genes cause most cases of CFC and mutations in PTPN11, SOS1, KRAS and RAF1 typically cause NS. Although both syndromes are associated with developmental delays of varying severity, the extent to which the behavioral profiles differ may shed light on the different roles these respective genes play in development of skills necessary for everyday functioning. In this study, profiles of adaptive behavior of individuals with CFC and NS who had confirmed pathogenic mutations in Ras/MAPK pathway genes were investigated. Patterns of strengths and weaknesses, age-related differences, and risk factors for difficulties in adaptive skills were assessed. Although genes acting more downstream in the Ras/MAPK pathway were associated with more difficulties in adaptive functioning than genes more upstream in the pathway, several inconsistencies highlight the wide spectrum of possible developmental courses in CFC and NS. Along with clinical and genetic factors, variables such as chronological age, gestational age at birth and parental education levels accounted for significant variance in adaptive skills. Results indicate that there is wide heterogeneity in adaptive ability in CFC and NS, but that these abilities are correlated to some extent with the specific disease-causing genes. PMID:20186801

Perceived motor problems in daily life: Focus group interviews with people with Noonan syndrome and their relatives.

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Croonen, Ellen A; Harmsen, Mirjam; Van der Burgt, Ineke; Draaisma, Jos M; Noordam, Kees; Essink, Marlou; Nijhuis-van der Sanden, Maria W G

2016-09-01

Studies from a patient perspective on motor performance problems in Noonan syndrome in daily life are lacking. The aims of this study were to provide insight into the motor performance problems that people with Noonan syndrome and/or their relatives experienced, the major consequences they suffered, the benefits of interventions they experienced, and the experiences with healthcare professionals they mentioned. We interviewed 10 adults with Noonan syndrome (two were joined by their parent), and 23 mothers (five of whom had Noonan syndrome), nine fathers (one of whom had Noonan syndrome) and one cousin who reported on 28 children with Noonan syndrome. People with Noonan syndrome reported particular problems related to pain, decreased muscle strength, fatigue, and clumsiness, which had an evident impact on functioning in daily life. Most participants believed that problems with motor performance improved with exercise, appropriate physiotherapy guidance, and other supportive interventions. Nevertheless, people with Noonan syndrome and/or their relatives did not feel heard and supported and experienced no understanding of their problems by healthcare professionals. This was the first study from a patient perspective that described the motor performance problems in people with Noonan syndrome, the major consequences in daily life, the positive experiences of interventions and the miscommunication with healthcare professionals. To achieve optimal support, healthcare professionals, as well as people with Noonan syndrome and/or their relatives themselves, should be aware of these frequently presented problems with motor performance. Research on these different aspects is needed to better understand and support people with Noonan syndrome.© 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Anesthetic implications of emergent Cesarean section in a parturient with Noonan syndrome and bacterial endocarditis.

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Chase, Charles J; Holak, Elena J; Pagel, Paul S

2013-08-01

Noonan syndrome is a relatively common genetically transmitted disorder characterized by facial, cardiac, and musculoskeletal abnormalities. The management of a 27 year old woman with Noonan syndrome at 23 weeks' gestation, presenting with premature labor, who required an emergent Cesarean section for placental abruption, is discussed. In addition to Noonan syndrome, this patient had bacterial endocarditis involving the mitral and aortic valves. The anesthetic implications of Noonan syndrome and endocarditis during pregnancy are presented. © 2013 Elsevier Inc. All rights reserved.

Motor performance in children with Noonan syndrome.

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Croonen, Ellen A; Essink, Marlou; van der Burgt, Ineke; Draaisma, Jos M; Noordam, Cees; Nijhuis-van der Sanden, Maria W G

2017-09-01

Although problems with motor performance in daily life are frequently mentioned in Noonan syndrome, the motor performance profile has never been systematically investigated. The aim of this study was to examine whether a specific profile in motor performance in children with Noonan syndrome was seen using valid norm-referenced tests. The study assessed motor performance in 19 children with Noonan syndrome (12 females, mean age 9 years 4 months, range 6 years 1 month to 11 years and 11 months, SDS 1 year and 11 months). More than 60% of the parents of the children reported pain, decreased muscle strength, reduced endurance, and/or clumsiness in daily functioning. The mean standard scores on the Visual Motor Integration (VMI) test and Movement Assessment Battery for Children 2, Dutch version (MABC-2-NL) items differed significantly from the reference scores. Grip strength, muscle force, and 6 min Walking Test (6 MWT) walking distance were significantly lower, and the presence of generalized hypermobility was significantly higher. All MABC-2-NL scores (except manual dexterity) correlated significantly with almost all muscle strength tests, VMI total score, and VMI visual perception score. The 6 MWT was only significantly correlated to grip strength. This is the first study that confirms that motor performance, strength, and endurance are significantly impaired in children with Noonan syndrome. Decreased functional motor performance seems to be related to decreased visual perception and reduced muscle strength. Research on causal relationships and the effectiveness of interventions is needed. Physical and/or occupational therapy guidance should be considered to enhance participation in daily life. © 2017 Wiley Periodicals, Inc.

Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome.

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Ekvall, Sara; Sjörs, Kerstin; Jonzon, Anders; Vihinen, Mauno; Annerén, Göran; Bondeson, Marie-Louise

2014-03-01

Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present. © 2013 Wiley Periodicals, Inc.

Improved growth velocity of a patient with Noonan-like syndrome with loose anagen hair (NS/LAH) without growth hormone deficiency by low-dose growth hormone therapy.

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Takasawa, Kei; Takishima, Shigeru; Morioka, Chikako; Nishioka, Masato; Ohashi, Hirofumi; Aoki, Yoko; Shimohira, Masayuki; Kashimada, Kenichi; Morio, Tomohiro

2015-10-01

Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721) is caused by a heterozygous c.4A>G mutation in SHOC2. Most cases exhibit both growth hormone deficiency (GHD) and growth hormone insensitivity (GHI) and thus require a high dose of growth hormone (GH) therapy (e.g., 35-40 µg/kg/day). We report on a genetically diagnosed NS/LAH patient manifesting severe short stature (-3.85 SDs) with low serum level of IGF1, 30 ng/ml. The peak levels of GH stimulation tests were within the normal range, and GHI was not observed in the IGF1 generation test. However, with low-dose GH therapy (25 µg/kg/day) for two years, IGF1 level and height were remarkably improved (IGF1: 117 ng/ml, height SDs: -2.20 SDs). Further, catch-up of motor development and improvement of the proportion of extending limbs to trunk were observed (the Developmental Quotient score increased from 68 to 98 points, and the relative sitting height ratio decreased from 0.62 to 0.57). Our results suggest that endocrinological causes for short stature are variable in NS/LAH and that GH therapy should be considered as a possible treatment for delayed development in NS/LAH. © 2015 Wiley Periodicals, Inc.

Noonan syndrome and related disorders: alterations in growth and puberty.

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Noonan, Jacqueline A

2006-12-01

Noonan syndrome is a relatively common multiple malformation syndrome with characteristic facies, short stature and congenital heart disease, most commonly pulmonary stenosis (Noonan, Clin Pediatr, 33:548-555, 1994). Recently, a mutation in the PTPN11 gene (Tartaglia, Mehler, Goldberg, Zampino, Brunner, Kremer et al., Nat Genet, 29:465-468, 2001) was found to be present in about 50% of individuals with Noonan syndrome. The phenotype noted in Noonan syndrome is also found in a number of other syndromes which include LEOPARD (Gorlin, Anderson, Blaw, Am J Dis Child, 17:652-662, 1969), Cardio-facio-cutaneous syndrome (Reynolds, Neri, Hermann, Blumberg, Coldwell, Miles et al., Am J Med Genet, 28:413-427, 1986) and Costello syndrome (Hennekam, Am J Med Genet, 117C(1):42-48, 2003). All three of these syndromes share similar cardiac defects and all have postnatal short stature. Very recently, HRAS mutations (Aoki, Niihori, Kawame, Kurosawa, Ohashi, Tanaka et al., Nat Genet, 37:1038-1040, 2005) have been found in the Costello syndrome and germline mutations in KRAS and BRAF genes (Rodriguez-Viciana, Tetsu, Tidyman, Estep, Conger, Santa Cruz et al., Nat Genet, 2006; Niihori, Aoki, Narumi, Neri, Cave, Verloes et al., Nat Genet, 38:294-296, 2006) in the Cardio-facio-cutaneous syndrome. Phenotypic overlap between these genetic disorders can now be explained since each is caused by germline mutations that are major components of the RAS-MAPK pathway. This pathway plays an important role in growth factor and cytokine signaling as well as cancer pathogenesis.

A novel heterozygous RIT1 mutation in a patient with Noonan syndrome, leukopenia, and transient myeloproliferation-a review of the literature.

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Nemcikova, Michaela; Vejvalkova, Sarka; Fencl, Filip; Sukova, Martina; Krepelova, Anna

2016-04-01

Noonan syndrome (NS) is a genetic condition presenting with typical facies, cardiac defects, short stature, variable developmental deficit, cryptorchidism, skeletal, and other abnormalities. Germline mutations in genes involved in the RAS/MAPK signaling have been discovered to underlie NS. Recently, missense mutations in RIT1 have been reported as causative for individuals with clinical signs of NS. We report on a 2.5-year-old boy with NS phenotype with a novel heterozygous change in the RIT1 gene. The patient was born prematurely from pregnancy monitored for polyhydramnios. At 7 months of age, non-immune neutropenia and splenomegaly have been observed. During the severe pneumonia at 10 months, significant progression of hepatosplenomegaly, leukopenia with monocytosis (15-29 %), and thrombocytopenia occurred. Bone marrow evaluation showed myeloid hyperplasia and monocytosis, suggestive of myeloproliferative syndrome. Clinical phenotype (facial dysmorphism, soft hair, short neck, broad chest, widely spaced nipples, mild pectus carinatum, deep palmar creases, unilateral cryptorchidism), and moderate pulmonary valve stenosis with mild psychomotor delay were indicative of NS. DNA analysis identified a de novo heterozygous variant c.69A >T, p.(Lys23Asn) in exon 2 of the RIT1 gene, presumed to be causative. We present a patient with a clinical suspicion of NS carrying a novel substitution in RIT1 and hematologic findings not being observed in RIT1 positive patients to date. Thus, the case broadens variability of hematologic symptoms in RIT1 positive NS individuals. • Noonan syndrome is a common genetically heterogeneous disorder of autosomal dominant inheritance characterized by craniofacial dysmorphism, short stature, congenital heart defects, variable cognitive deficit, and other anomalies. What is new: • We report on a 2.5-year-old male patient with clinical signs of NS and hematologic abnormalities, in whom a novel heterozygous substitution in RIT1 with probable

Aberrant lymphatic development in euploid fetuses with increased nuchal translucency including Noonan syndrome.

NARCIS (Netherlands)

Mooij, Y.M. de; Akker, N.M. van den; Bekker, M.N.; Bartelings, M.M.; Vugt, J.M.G. van; Gittenberger-de Groot, A.C.

2011-01-01

OBJECTIVE: Increased nuchal translucency in the human fetus is associated with aneuploidy, structural malformations and several syndromes such as Noonan syndrome. In 60-70% of the Noonan syndrome cases, a gene mutation can be demonstrated. Previous research showed that aneuploid fetuses with

Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects

NARCIS (Netherlands)

Runtuwene, V.J.; van Eekelen, M.J.L.; Overvoorde, J.; Rehmann, H.; Yntema, H.G.; Nillesen, W.M.; van Haeringen, A.; van der Burgt, I.; Burgering, B.; den Hertog, J.

2011-01-01

Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras-mitogen-activated-protein-kinase (MAPK) signaling pathway. Recently, two mutations in NRAS

Attention skills and executive functioning in children with Noonan syndrome and their unaffected siblings.

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Pierpont, Elizabeth I; Tworog-Dube, Erica; Roberts, Amy E

2015-04-01

Emerging research indicates that gene mutations within the RAS-MAPK signaling cascade, which cause Noonan syndrome and related disorders, affect neurophysiologic activity in brain regions underlying attention and executive functions. The present study examined whether children with Noonan syndrome are at heightened risk for symptoms of attention-deficit-hyperactivity disorder (ADHD) and executive dysfunction relative to an unaffected sibling comparison group, and investigated three key aspects of behavioral attention: auditory attention, sustained attention, and response inhibition. Children and adolescents with Noonan syndrome (n=32, 17 males, 15 females, mean age 11y 3mo, SD 3y) and their unaffected siblings (n=16, eight males, eight females, mean age 11y, SD 3y 6mo) were administered standardized tests of intellectual functioning and clinic-based measures of behavioral attention. Parent ratings of ADHD symptoms, executive functioning, and behavior were also obtained. Children with Noonan syndrome demonstrated higher rates of past ADHD diagnosis, as well as reduced performance compared with unaffected siblings on behavioral attention measures. Parent-rated functional impairments in attention, social skills, working memory, and self-monitoring were more prevalent in the Noonan syndrome group. The relationship between attention regulation skills (sustained attention and inhibitory control) and intellectual test performance was significantly stronger in the Noonan syndrome group than the comparison group. Clinical screening/evaluation for ADHD and executive dysfunction in Noonan syndrome is recommended to facilitate appropriate intervention and to address functional impact on daily life activities. © 2014 Mac Keith Press.

Anesthetic management in a pediatric patient with Noonan syndrome, hypopituitarism and hypothyroidism: A case report

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Abdulkadir Yektaş

2013-06-01

Full Text Available Noonan syndrome is a genetically transmitted autosomaldominant disorder characterized by various anatomicanomalies and pathophysiologic derangements. Associatedanomalies include hyperthelorism, ptosis, micrognathia,downward sloping palpebral fissures, low-set ears,abnormal helix of ear, deeply grooved philtrum, short and/or webbed neck, low hairline and cervical vertebral anomalies.Patients with Noonan syndrome are known to presentwith challenging airways. Tracheal intubation can bedifficult because of airway and cervical vertebral anomaliesand bag mask ventilation may be difficult because ofasymmetrical face. We present a case of anesthetic managementfor Noonan syndrome. J Clin Exp Invest 2013;4 (2: 238-241Key words: Anesthesia, general, noonan syndrome, airwaymanagement

Síndrome de Noonan: relato de caso Noonan's syndrome: case report

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Vanderson Glerian Dias

2004-08-01

Full Text Available Os autores apresentam um caso de síndrome de Noonan em criança de 14 anos de idade, diagnosticada por meio de exame genético-clínico, demonstrando alterações oftalmológicas como hipertelorismo, alterações da fenda palpebral, hipotropia direita com pequena anisotropia em V, nistagmo, ptose palpebral bilateral e ambliopia do olho direito. Discute-se a importância do oftalmologista para esta síndrome e a necessidade do acompanhamento por equipe médica multidisciplinar.The authors present the case of a 14-year-old child with Noonan´s syndrome, diagnosed by clinical genetic examination, demonstrating ophthalmologic alterations such as: hypertelorism, eyelid fissue changes, right hypotropia with a small V anisotropy, nystagmus, bilateral eyelid ptosis and amblyopia in right eye. The importance of the ophthalmologist in this syndrome and the need for a follow-up by a multidisciplinary medical group are discussed.

DRESS syndrome with thrombotic microangiopathy revealing a Noonan syndrome: Case report.

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Bobot, Mickaël; Coen, Matteo; Simon, Clémentine; Daniel, Laurent; Habib, Gilbert; Serratrice, Jacques

2018-04-01

The life-threatening drug rash with eosinophilia and systemic symptoms (DRESS) syndrome occurs most commonly after exposure to drugs, clinical features mimic those found with other serious systemic disorders. It is rarely associated with thrombotic microangiopathy. We describe the unique case of a 44-year-old man who simultaneously experienced DRESS syndrome with thrombotic microangiopathy (TMA) after a 5 days treatment with fluindione. Clinical evaluation leads to the discovery of an underlying lymphangiomatosis, due to a Noonan syndrome. The anticoagulant was withdrawn, and corticosteroids (1 mg/kg/day) and acenocoumarol were started. Clinical improvement ensued. At follow-up the patient is well. The association of DRESS with TMA is a rare condition; we believe that the presence of the underlying Noonan syndrome could have been the trigger. Moreover, we speculate about the potential interrelations between these entities.

Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies

NARCIS (Netherlands)

Komatsuzaki, Shoko; Aoki, Yoko; Niihori, Tetsuya; Okamoto, Nobuhiko; Hennekam, Raoul C. M.; Hopman, Saskia; Ohashi, Hirofumi; Mizuno, Seiji; Watanabe, Yoriko; Kamasaki, Hotaka; Kondo, Ikuko; Moriyama, Nobuko; Kurosawa, Kenji; Kawame, Hiroshi; Okuyama, Ryuhei; Imaizumi, Masue; Rikiishi, Takeshi; Tsuchiya, Shigeru; Kure, Shigeo; Matsubara, Yoichi

2010-01-01

Noonan syndrome is an autosomal dominant disease characterized by dysmorphic features, webbed neck, cardiac anomalies, short stature and cryptorchidism. It shows phenotypic overlap with Costello syndrome and cardio-facio-cutaneous (CFC) syndrome. Noonan syndrome and related disorders are caused by

Giant cell lesions with a Noonan-like phenotype: a case report.

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Cancino, Claudia Marcela H; Gaião, Léonilson; Sant'Ana Filho, Manoel; Oliveira, Flavio Augusto Marsiaj

2007-05-01

The purpose of this article is to describe a case of multiple giant cell lesions of the mandible that occurred in a 14-year-old girl with phenotypic characteristics associated with Noonan Syndrome (NS). NS is a dysmorphic disorder characterized by hypertelorism, short stature, congenital heart defects, short and webbed neck, skeletal anomalies, and bleeding diathesis. A 14-year-old girl with a previous diagnosis of NS (sporadic case) presented with multiple radiolucent lesions in the body and ramus of her mandible. In terms of clinical behavior and the described radiographic characteristics, giant cells lesions with Noonan-like phenotype can be considered a form of cherubism. Therefore, surgical intervention is not necessary, but radiographic follow-up and observation is very important during the control and gradual regression of the lesions.

Zespół Noonan u 8-letniej pacjentki – opis przypadku = 8 - year - old patient with Noonan syndrome - case report

Directory of Open Access Journals (Sweden)

Aleksandra Grabiec

2016-12-01

Kierownik: dr hab. n. med. prof. nadzw. Anna Janas-Naze               Adres do korespondencji: Aleksandra Szczepkowska Zakład Chirurgii Stomatologicznej UM w Łodzi 92-213 Łódź, ul. Pomorska 251 e-mail: aleksandra.szczepkowska@gmail.com tel. 42 675 75 71           Praca finansowana przez Uniwersytet Medyczny w Łodzi w ramach działalności statutowej nr 503/2-163-01/503-21-001       Streszczenie: W poniższej pracy opisano przypadek zespołu Noonan u 8- letniej dziewczynki.   Słowa kluczowe: zespół Noonan, rzadkie choroby genetyczne, znieczulenia ogólne     Abstract: The article presents the case of 7 year old girl with Noonan syndrome.   Key words: Noonan syndrome, rare genetic diseases, general anesthesia

Hashimoto thyroiditis with an unusual presentation of cardiac tamponade in Noonan syndrome.

Science.gov (United States)

Lee, Mi Ji; Kim, Byung Young; Ma, Jae Sook; Choi, Young Earl; Kim, Young Ok; Cho, Hwa Jin; Kim, Chan Jong

2016-11-01

Noonan syndrome is an autosomal dominant, multisystem disorder. Autoimmune thyroiditis with hypothyroidism is an infrequent feature in patients with Noonan syndrome. A 16-year-old boy was admitted because of chest discomfort and dyspnea; an echocardiogram revealed pericardial effusion. Additional investigations led to a diagnosis of severe hypothyroidism due to Hashimoto thyroiditis. The patient was treated with L-thyroxine at 0.15 mg daily. However, during admission, he developed symptoms of cardiac tamponade. Closed pericardiostomy was performed, after which the patient's chest discomfort improved, and his vital signs stabilized. Herein, we report a case of an adolescent with Noonan syndrome, who was diagnosed with Hashimoto thyroiditis with an unusual presentation of cardiac tamponade.

Noonan syndrome: a clinical and genetic study of 31 patients

Directory of Open Access Journals (Sweden)

Bertola Débora Romeo

1999-01-01

Full Text Available Noonan syndrome is a multiple congenital anomaly syndrome, inherited in an autosomal dominant pattern. We studied 31 patients (18 males and 13 females affected by this disorder regarding their clinical and genetic characteristics. The most frequent clinical findings were short stature (71%; craniofacial dysmorphisms, especially hypertelorism, ptosis, downslanting of the palpebral fissures; short or webbed neck (87%; cardiac anomalies (65%, and fetal pads in fingers and toes (70%. After studying the probands' first-degree relatives, we made the diagnosis of Noonan syndrome in more than one family member in three families. Therefore, the majority of our cases were sporadic.

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

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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.

Noonan syndrome and clinically related disorders

Science.gov (United States)

Tartaglia, Marco; Gelb, Bruce D.; Zenker, Martin

2010-01-01

Noonan syndrome is a relatively common, clinically variable developmental disorder. Cardinal features include postnatally reduced growth, distinctive facial dysmorphism, congenital heart defects and hypertrophic cardiomyopathy, variable cognitive deficit and skeletal, ectodermal and hematologic anomalies. Noonan syndrome is transmitted as an autosomal dominant trait, and is genetically heterogeneous. So far, heterozygous mutations in nine genes (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 and CBL) have been documented to underlie this disorder or clinically related phenotypes. Based on these recent discoveries, the diagnosis can now be confirmed molecularly in approximately 75% of affected individuals. Affected genes encode for proteins participating in the RAS-mitogen-activated protein kinases (MAPK) signal transduction pathway, which is implicated in several developmental processes controlling morphology determination, organogenesis, synaptic plasticity and growth. Here, we provide an overview of clinical aspects of this disorder and closely related conditions, the molecular mechanisms underlying pathogenesis, and major genotype-phenotype correlations. PMID:21396583

SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions.

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Beneteau, Claire; Cavé, Hélène; Moncla, Anne; Dorison, Nathalie; Munnich, Arnold; Verloes, Alain; Leheup, Bruno

2009-10-01

We report five cases of multiple giant cell lesions in patients with typical Noonan syndrome. Such association has frequently been referred to as Noonan-like/multiple giant cell (NL/MGCL) syndrome before the molecular definition of Noonan syndrome. Two patients show mutations in PTPN11 (p.Tyr62Asp and p.Asn308Asp) and three in SOS1 (p.Arg552Ser and p.Arg552Thr). The latter are the first SOS1 mutations reported outside PTPN11 in NL/MGCL syndrome. MGCL lesions were observed in jaws ('cherubism') and joints ('pigmented villonodular synovitis'). We show through those patients that both types of MGCL are not PTPN11-specific, but rather represent a low penetrant (or perhaps overlooked) complication of the dysregulated RAS/MAPK signaling pathway. We recommend discarding NL/MGCL syndrome from the nosology, as this presentation is neither gene-nor allele-specific of Noonan syndrome; these patients should be described as Noonan syndrome with MGCL (of the mandible, the long bone...). The term cherubism should be used only when multiple giant cell lesions occur without any other clinical and molecular evidence of Noonan syndrome, with or without mutations of the SH3BP2 gene.

Aneurysmal sub-arachnoid haemorrhage in patients with Noonan syndrome: a report of two cases and review of neurovascular presentations in this syndrome

International Nuclear Information System (INIS)

Dineen, R.A.; Lenthall, R.K.

2004-01-01

To date, intracranial aneurysms have been reported in two patients with Noonan syndrome. We report two unrelated patients with Noonan syndrome who presented with sub-arachnoid haemorrhage secondary to intracranial aneurysms. These cases are discussed and other cerebrovascular abnormalities that have been described in association with Noonan syndrome are reviewed. Ultrastructural and genetic factors contributing to these associations are considered. (orig.)

Aneurysmal sub-arachnoid haemorrhage in patients with Noonan syndrome: a report of two cases and review of neurovascular presentations in this syndrome

Energy Technology Data Exchange (ETDEWEB)

Dineen, R.A.; Lenthall, R.K. [Department of Radiology, University Hospital, Queen' s Medical Centre, NG7 2UH, Nottingham (United Kingdom)

2004-04-01

To date, intracranial aneurysms have been reported in two patients with Noonan syndrome. We report two unrelated patients with Noonan syndrome who presented with sub-arachnoid haemorrhage secondary to intracranial aneurysms. These cases are discussed and other cerebrovascular abnormalities that have been described in association with Noonan syndrome are reviewed. Ultrastructural and genetic factors contributing to these associations are considered. (orig.)

Management of Cardiovascular Disorders in Patients with Noonan Syndrome: A Case Report

OpenAIRE

Mohammad Rafie Khorgami; Maryam Moradian; Negar Omidi; Mohammad Yousef Aarabi Moghadam

2018-01-01

The Noonan syndrome is a rare disorder, one of whose major complications is cardiovascular involvement. A wide spectrum of congenital heart diseases has been observed in this syndrome. The most common cardiac disorder is pulmonary valve stenosis, which has a progressive nature. Hypertrophic cardiomyopathy is less common, but its morbidity and mortality rates are high. We herein introduce a 12-year-old boy with the typical findings of the Noonan syndrome. His symptoms began from infancy, and t...

Cardiac findings in Noonan syndrome on long-term follow-up.

Science.gov (United States)

Colquitt, John L; Noonan, Jacqueline A

2014-01-01

Noonan syndrome (NS) is the second most common genetic syndrome associated with cardiac abnormalities, including, most notably, pulmonary stenosis (PS) and hypertrophic cardiomyopathy (HCM). Little is known about the natural history of heart disease in this unique subset of patients. We sought to contribute information on the natural history of NS by looking at how the cardiac disease progresses with time. This is a retrospective review of the medical records of patients with NS seen at our institution between 1963 and 2011. Records were available for 113 patients. Average length of follow-up was 14.16 years (2 months to 44 years, median 12.5 years). Sixty-six percent (75/113) of our patients had PS; within this subset, 57% (43) were classified as mild, 9% (7) moderate, and 33% (25) severe. None of the cases of mild PS worsened with time. All of the severe cases had an intervention, as did some moderate cases. Fourteen percent (16/113) of our patients had HCM; 56% (9/16) were mild, diagnosed at an average age of 3.8 years. Seven of these were stable with time, while one did progress. Forty-four percent (7/16) of cases were classified as severe, diagnosed at an average age of 4.2 months, and all were managed medically, surgically, or both. Our cohort had seven deaths (ages 6 months and 6, 10, 20, 40, 49, and 50 years). Mild PS in patients with NS is nonprogressive. Severe, and in some cases moderate, PS will invariably require a therapeutic intervention. It is uncommon for HCM to progress or have new onset beyond early childhood. Prognosis of heart disease in NS is influenced most by the findings on presentation. © 2013 Wiley Periodicals, Inc.

Ulerythema ophryogenes, a rarely reported cutaneous manifestation of noonan syndrome: case report and review of the literature.

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Li, Kayi; Ann Thomas, Mary; Haber, Richard M

2013-01-01

Ulerythema ophryogenes (also known as keratosis pilaris atrophicans faciei) is a rarely reported cutaneous manifestation of Noonan syndrome. Recognizing ulerythema ophryogenes as a cutaneous association in Noonan syndrome may aid in the diagnosis of this relatively common genetic condition. We present a case of a patient with Noonan syndrome and ulerythema ophryogenes associated with a SOS1 mutation and review the literature on this association. To the best of our knowledge, this is the second case of Noonan syndrome proven to be due to an SOS1 mutation in which ulerythema ophryogenes was clinically recognized and specifically diagnosed. The presence of ulerythema ophryogenes in a patient with Noonan syndrome increases the likelihood of a SOS1 mutation. Further reports by dermatologists and medical geneticists documenting ulerythema ophryogenes and not just descriptions of sparse or absent eyebrows will help support this genotype-phenotype correlation.

Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.

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Yamamoto, Guilherme Lopes; Aguena, Meire; Gos, Monika; Hung, Christina; Pilch, Jacek; Fahiminiya, Somayyeh; Abramowicz, Anna; Cristian, Ingrid; Buscarilli, Michelle; Naslavsky, Michel Satya; Malaquias, Alexsandra C; Zatz, Mayana; Bodamer, Olaf; Majewski, Jacek; Jorge, Alexander A L; Pereira, Alexandre C; Kim, Chong Ae; Passos-Bueno, Maria Rita; Bertola, Débora Romeo

2015-06-01

Noonan syndrome is an autosomal dominant, multisystemic disorder caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. Heterozygous, pathogenic variants in 11 known genes account for approximately 80% of cases. The identification of novel genes associated with Noonan syndrome has become increasingly challenging, since they might be responsible for very small fractions of the cases. A cohort of 50 Brazilian probands negative for pathogenic variants in the known genes associated with Noonan syndrome was tested through whole-exome sequencing along with the relatives in the familial cases. Families from the USA and Poland with mutations in the newly identified genes were included subsequently. We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands. SOS2 and LZTR1 variants were also found to segregate in one American and one Polish family. Notably, SOS2 variants were identified in patients with marked ectodermal involvement, similar to patients with SOS1 mutations. We identified two novel genes, SOS2 and LZTR1, associated with Noonan syndrome, thereby expanding the molecular spectrum of RASopathies. Mutations in these genes are responsible for approximately 3% of all patients with Noonan syndrome. While SOS2 is a natural candidate, because of its homology with SOS1, the functional role of LZTR1 in the RAS/MAPK pathway is not known, and it could not have been identified without the large pedigrees. Additional functional studies are needed to elucidate the role of LZTR1 in RAS/MAPK signalling and in the pathogenesis of Noonan syndrome. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

A case of Noonan's syndrome with terminal renal failure and neoplasmic disease

International Nuclear Information System (INIS)

Wierzbowska-Lange, B.; Sieniawska, M.; Polanski, J.; Kisiel, M.

1993-01-01

A 16 year old boy with Noonan syndrome diagnosed in the 3rd month of life was treated for renal insufficiency and hepatic tumor. Hemodialisis was started in preparation for surgery. Exacerbation of renal insufficiency occurred after surgical removal of the hepatic tumor together with the right hepatic lobe. Histopathologic examination showed adenoma hepatocellulare. Cysts in the extraperitoneal space appeared in the following months and were identified as cystes dysontogenetici benigni ''hamartia''. Renal function deteriorated during this time to end stage renal disease. The authors emphasize the possibility of good mental development in a patients with Noonan syndrome as well as the presence of urinary tract abnormalities and renal insufficiency of unknown origin - a phenomenon that has not yet been reported in other cases of Noonan syndrome. (author)

The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor.

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Harms, Frederike L; Alawi, Malik; Amor, David J; Tan, Tiong Y; Cuturilo, Goran; Lissewski, Christina; Brinkmann, Julia; Schanze, Denny; Kutsche, Kerstin; Zenker, Martin

2018-02-01

Noonan syndrome is characterized by typical craniofacial dysmorphism, postnatal growth retardation, congenital heart defect, and learning difficulties and belongs to the RASopathies, a group of neurodevelopmental disorders caused by germline mutations in genes encoding components of the RAS-MAPK pathway. Mutations in the RAF1 gene are associated with Noonan syndrome, with a high prevalence of hypertrophic cardiomyopathy (HCM). RAF1 mutations cluster in exons encoding the conserved region 2 (CR2), the kinase activation segment of the CR3 domain, and the C-terminus. We present two boys with Noonan syndrome and the identical de novo RAF1 missense variant c.1082G>C/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a RAF1 allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial-like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well-established association of NS with malignant tumors, especially childhood hemato-oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots. © 2017 Wiley Periodicals, Inc.

Mechanism and treatment for the learning and memory deficits associated with mouse models of Noonan syndrome

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Lee, Yong-Seok; Ehninger, Dan; Zhou, Miou; Oh, Jun-Young; Kang, Minkyung; Kwak, Chuljung; Ryu, Hyun-Hee; Butz, Delana; Araki, Toshiyuki; Cai, Ying; Balaji, J.; Sano, Yoshitake; Nam, Christine I.; Kim, Hyong Kyu; Kaang, Bong-Kiun; Burger, Corinna; Neel, Benjamin G.; Silva, Alcino J.

2015-01-01

In Noonan Syndrome (NS) 30% to 50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated Ptpn11 mutations show hippocampal-dependent spatial learning impairments and deficits in hippocampal long-term potentiation (LTP). In addition, viral overexpression of the PTPN11D61G in adult hippocampus results in increased baseline excitatory synaptic function, deficits in LTP and spatial learning, which can all be reversed by a MEK inhibitor. Furthermore, brief treatment with lovastatin reduces Ras-Erk activation in the brain, and normalizes the LTP and learning deficits in adult Ptpn11D61G/+ mice. Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS. PMID:25383899

Successful diuretics treatment of protein-losing enteropathy in Noonan syndrome.

Science.gov (United States)

Mizuochi, Tatsuki; Suda, Kenji; Seki, Yoshitaka; Yanagi, Tadahiro; Yoshimoto, Hironaga; Kudo, Yoshiyuki; Iemura, Motofumi; Tanikawa, Ken; Matsuishi, Toyojiro

2015-04-01

There are few reports on successful high-dose spironolactone treatment of refractory protein-losing enteropathy (PLE) caused by Fontan procedure. We report successful diuretics treatment with spironolactone and furosemide at standard dose, of refractory PLE in a patient with Noonan syndrome and repaired congenital heart disease. This is the first successful application of diuretics treatment in a patient with refractory PLE without Fontan procedure. This case illustrates that diuretics treatment can be the first-line treatment of PLE regardless of the causative physiology, and can be effective in refractory PLE with Noonan syndrome. © 2015 Japan Pediatric Society.

Twin infant with lymphatic dysplasia diagnosed with Noonan syndrome by molecular genetic testing.

Science.gov (United States)

Mathur, Deepan; Somashekar, Santhosh; Navarrete, Cristina; Rodriguez, Maria M

2014-08-01

Noonan Syndrome is an autosomal dominant disorder characterized by short stature, congenital heart defects, developmental delay, dysmorphic facial features and occasional lymphatic dysplasias. The features of Noonan Syndrome change with age and have variable expression. The diagnosis has historically been based on clinical grounds. We describe a child that was born with congenital refractory chylothorax and subcutaneous edema suspected to be secondary to pulmonary lymphangiectasis. The infant died of respiratory failure and anasarca at 80 days. The autopsy confirmed lymphatic dysplasia in lungs and mesentery. The baby had no dysmorphic facial features and was diagnosed postmortem with Noonan syndrome by genomic DNA sequence analysis as he had a heterozygous mutation for G503R in the PTPN11 gene.

The use of recombinant factor VIIa in a patient with Noonan syndrome and life-threatening bleeding.

Science.gov (United States)

Tofil, Nancy M; Winkler, Margaret K; Watts, Raymond G; Noonan, Jacqueline

2005-05-01

To present a case report of a patient with Noonan syndrome who developed life-threatening gastrointestinal bleeding shortly after cardiac surgery that was successfully treated with recombinant factor VIIa. Case report. Pediatric intensive care unit of a children's hospital. Ten-month-old with Noonan syndrome and massive gastrointestinal bleeding resulting in severe hypovolemic shock. Recombinant factor VIIa was used in this patient's severe bleeding associated with Noonan syndrome after no other supportive measures were successful. Recombinant Factor VIIa significantly decreased the patient's bleeding and allowed his hypovolemic shock to improve. Ultimately, the patient made a complete recovery. Noonan syndrome has a constellation of both cardiac and noncardiac malformations including an increased risk of bleeding, and recombinant factor VIIa is an important agent in the treatment of significant bleeding.

Genetics Home Reference: Noonan syndrome with multiple lentigines

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... of Noonan syndrome with multiple lentigines include brown skin spots called lentigines that are similar to freckles, heart ... individuals may have thousands of small dark brown skin spots by the time they reach puberty. Unlike freckles, ...

Noonan Syndrome: An Underestimated Cause of Severe to Profound Sensorineural Hearing Impairment. Which Clues to Suspect the Diagnosis?

Science.gov (United States)

Ziegler, Alban; Loundon, Natalie; Jonard, Laurence; Cavé, Hélène; Baujat, Geneviève; Gherbi, Souad; Couloigner, Vincent; Marlin, Sandrine

2017-09-01

To highlight Noonan syndrome as a clinically recognizable cause of severe to profound sensorineural hearing impairment. New clinical cases and review. Patients evaluated for etiological diagnosis by a medical geneticist in a reference center for hearing impairment. Five patients presenting with confirmed Noonan syndrome and profound sensorineural hearing impairment. Diagnostic and review of the literature. Five patients presented with profound sensorineural hearing impairment and molecularly confirmed Noonan syndrome. Sensorineural hearing impairment has been progressive for three patients. Cardiac echography identified pulmonary stenosis in two patients and was normal for the three other patients. Short stature was found in two patients. Mild intellectual disability was found in one patient. Inconspicuous clinical features as facial dysmorphism, cryptorchidism, or easy bruising were of peculiar interest to reach the diagnosis of Noonan syndrome. Profound sensorineural hearing impairment can be the main feature of Noonan syndrome. Associated features are highly variable; thus, detailed medical history and careful physical examination are mandatory to consider the diagnosis in case of a sensorineural hearing impairment.

An atypical case of Noonan syndrome with mutation diagnosed by targeted exome sequencing

Directory of Open Access Journals (Sweden)

Jinsup Kim

2017-09-01

Full Text Available Noonan syndrome (NS is a genetic disorder caused by autosomal dominant inheritance and is characterized by a distinctive facial appearance, short stature, chest deformity, and congenital heart disease. In individuals with NS, germline mutations have been identified in several genes involved in the RAS/mitogen-activated protein kinase signal transduction pathway. Because of its clinical and genetic heterogeneity, the conventional diagnostic protocol with Sanger sequencing requires a multistep approach. Therefore, molecular genetic diagnosis using targeted exome sequencing (TES is considered a less expensive and faster method, particularly for patients who do not fulfill the clinical diagnostic criteria of NS. In this case, the patient showed short stature, dysmorphic facial features suggestive of NS, feeding intolerance, cryptorchidism, and intellectual disability in early childhood. At the age of 16, the patient still showed extreme short stature with delayed puberty and characteristic facial features suggestive of NS. Although the patient had no cardiac problems or chest wall deformities, which are commonly present in NS and are major concerns for patients and clinicians, the patient showed several other characteristic clinical features of NS. Considering the possibility of a genetic disorder, including NS, a molecular genetic study with TES was performed. With TES analysis, we detected a pathogenic variant of c.458A > T in KRAS in this patient with atypical NS phenotype and provided appropriate clinical management and genetic counseling. The application of TES enables accurate molecular diagnosis of patients with nonspecific or atypical features in genetic diseases with several responsible genes, such as NS.

Mutation Spectrum and Phenotypic Features in Noonan Syndrome with PTPN11 Mutations: Definition of Two Novel Mutations.

Science.gov (United States)

Atik, Tahir; Aykut, Ayca; Hazan, Filiz; Onay, Huseyin; Goksen, Damla; Darcan, Sukran; Tukun, Ajlan; Ozkinay, Ferda

2016-06-01

To evaluate the spectrum of PTPN11 gene mutations in Noonan syndrome patients and to study the genotype-phenotype associations. In this study, twenty Noonan syndrome patients with PTPN11 mutations were included. The patients underwent a detailed clinical and physical evaluation. To identify inherited cases, parents of all mutation positive patients were analyzed. Thirteen different PTPN11 mutations, two of them being novel, were detected in the study group. These mutations included eleven missense mutations: p.G60A, p.D61N, p.Y62D, p.Y63C, p.E69Q, p.Q79R, p.Y279C,p.N308D, p.N308S, p.M504V, p.Q510R and two novel missense mutations: p.I56V and p.I282M. The frequency of cardiac abnormalities and short stature were found to be 80 % and 80 %, respectively. Mental retardation was not observed in patients having exon 8 mutations. No significant correlations were detected between other phenotypic features and genotypes. By identifying genotype-phenotype correlations, this study provides information on phenotypes observed in NS patients with different PTPN11 mutations.

The Effects of Explicit Instruction on the Writing Ability of a Student with Noonan Syndrome

Science.gov (United States)

Asaro-Saddler, Kristie; Saddler, Bruce; Ellis-Robinson, Tammy

2014-01-01

In this study, we sought to determine the effectiveness of a sentence creation intervention on the sentence writing ability of a young writer with Noonan Syndrome. Noonan syndrome is an autosomal dominant condition characterized by shortness in stature, with neck and ear anomalies, hypertelorism, ptosis of the eyelids, low set ears, and instances…

The impact of growth hormone therapy on adult height in noonan syndrome: a systematic review.

Science.gov (United States)

Giacomozzi, Claudio; Deodati, Annalisa; Shaikh, Mohamad Guftar; Ahmed, Syed Faisal; Cianfarani, Stefano

2015-01-01

Recombinant human growth hormone (rhGH) is being used to promote linear growth in short children with Noonan syndrome. However, its efficacy is still controversial. To systematically determine the impact of rhGH therapy on adult height in children with Noonan syndrome. We searched the Cochrane Central Register of Controlled Trials, ISI Web of Science, MEDLINE, and the bibliographic references from all retrieved articles published until April 2014. Studies reporting adult/near-adult height in children with Noonan syndrome treated with rhGH or reporting at least a 3-year follow-up were analysed. Quality and strength of recommendation were assessed according to the Endocrine Society criteria. No controlled trials reporting adult height were available. Five studies were identified reporting adult height or near adult height. Data comparison showed inter-individual variability in the response to rhGH, mean height gain standard deviation score ranging between 0.6 and 1.4 according to national standards, and between 0.6 and 2 according to Noonan standards. Significant biases affected all the studies. High-quality controlled trials on the impact of rhGH therapy on adult height are lacking, and the robustness of available data is not sufficient to recommend such therapy in children with Noonan syndrome. © 2015 S. Karger AG, Basel.

Expanding the cardiac spectrum of Noonan syndrome with RIT1 variant: Left main coronary artery atresia causing sudden death.

Science.gov (United States)

Ramond, Francis; Duband, Sébastien; Croisille, Pierre; Cavé, Hélène; Teyssier, Georges; Adouard, Véronique; Touraine, Renaud

2017-06-01

Noonan syndrome is a well-known genetic condition associating congenital heart defects, short stature, and distinctive facial features. Pulmonary valve stenosis and hypertrophic cardiomyopathy are the most frequent cardiac abnormalities, the latter being associated with a higher mortality. Here we report for the first time, a case of congenital left main coronary artery atresia in a Noonan syndrome associated with RIT1 variant, leading to unrescued sudden death. This case-report supports the already-suspected severity of the RIT1-related Noonan syndrome compared to average Noonan syndrome, and should encourage clinicians to be very cautious with these patients. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

A Novel Mutation on RAF1 in Association with Fetal Findings Suggestive of Noonan Syndrome.

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Kneitel, Anna W; Norby, Audrey; Vettraino, Ivana; Treadwell, Marjorie C

2015-01-01

Noonan syndrome is a multisystem genetic disorder caused by genes encoding proteins involved in the RAS-MAPK pathway. Affected fetuses have variable presentations ranging from the absence of prenatal findings to increased nuchal fold, cystic hygromas, pleural effusions, cardiac malformations, or skin edema. We describe a male fetus who had features consistent with Noonan syndrome at the time of fetal anatomic survey, including hydrops and a possible cardiac defect. Subsequent scan revealed persistent bilateral pleural effusions (with predominance of lymphocytes). After bilateral thoracoamniotic shunt placement, the fetus did well and delivered at term. Prenatal testing revealed an S650F missense mutation in the RAF1 gene, which had not previously been associated with Noonan syndrome.

1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency

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Natália Duarte Linhares

Full Text Available Abstract Deletion-induced hemizygosity may unmask deleterious autosomal recessive variants and be a cause of the phenotypic variability observed in microdeletion syndromes. We performed complete exome sequencing (WES analysis to examine this possibility in a patient with 1p13.2 microdeletion. Since the patient displayed clinical features suggestive of Noonan Syndrome (NS, we also used WES to rule out the presence of pathogenic variants in any of the genes associated with the different types of NS. We concluded that the clinical findings could be attributed solely to the 1p13.2 haploinsufficiency. Retrospective analysis of other nine reported patients with 1p13.2 microdeletions showed that six of them also presented some characteristics of NS. In all these cases, the deleted segment included the NRAS gene. Gain-of-function mutations of NRAS gene are causally related to NS type 6. Thus, it is conceivable that NRAS haploinsufficiency and gain-of-function mutations may have similar clinical consequences. The same phenomenon has been described for two other genes belonging to the Ras/MAPK pathway: MAP2K2 and SHOC2. In conclusion, we here report genotype-phenotype correlations in patients with chromosome 1p13.2 microdeletions and we propose that NRAS may be a critical gene for the NS characteristics in the patients.

A restricted spectrum of NRAS mutations causes Noonan syndrome

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Cirstea, Ion C.; Kutsche, Kerstin; Dvorsky, Radovan; Gremer, Lothar; Carta, Claudio; Horn, Denise; Roberts, Amy E.; Lepri, Francesca; Merbitz-Zahradnik, Torsten; Koenig, Rainer; Kratz, Christian P.; Pantaleoni, Francesca; Dentici, Maria L.; Joshi, Victoria A.; Kucherlapati, Raju S.; Mazzanti, Laura; Mundlos, Stefan; Patton, Michael A.; Silengo, Margherita Cirillo; Rossi, Cesare; Zampino, Giuseppe; Digilio, Cristina; Stuppia, Liborio; Seemanova, Eva; Pennacchio, Len A.; Gelb, Bruce D.; Dallapiccola, Bruno; Wittinghofer, Alfred; Ahmadian, Mohammad R.; Tartaglia, Marco; Zenker, Martin

Noonan syndrome, a developmental disorder characterized by congenital heart defects, reduced growth, facial dysmorphism and variable cognitive deficits, is caused by constitutional dysregulation of the RAS-MAPK signaling pathway. Here we report that germline NRAS mutations conferring enhanced

Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature.

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Milosavljević, Doris; Overwater, Eline; Tamminga, Saskia; de Boer, Karin; Elting, Mariet W; van Hoorn, Marion E; Rinne, Tuula; Houweling, Arjan C

2016-07-01

Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively. Including our patients, a total of 52 patients have been reported with Noonan syndrome caused by a RIT1 mutation. Our report contributes to the delineation of the phenotype associated with RIT1 mutations and underlines that lymphatic involvement is part of this spectrum. In addition, we provide an overview of the currently described Noonan syndrome patients with RIT1 mutations in literature. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Ocular manifestations of Noonan syndrome in twin siblings: A case report of keratoconus with acute corneal hydrops

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Anna Lee

2014-01-01

Full Text Available Ocular manifestations of Noonan syndrome (NS in a set of healthy 20-year-old African-American fraternal twins are reported with emphasis on a rare finding of keratoconus with acute corneal hydrops in one twin. Both the twins had learning disabilities and attended a special needs school. Evaluation included visual acuity assessment, tonometry and external eye, slit lamp and dilated fundus examinations, topography with Pentacam and external photographs. The first case was more remarkable as keratoconus with acute corneal hydrops was observed. The patient presented with severe cloudy vision that had worsened over a span of 1 month. It improved significantly on follow-up. The second case included a unique constellation of ocular pathology that highlights the diversity of NS manifestations even amongst twins. Conservative treatment of keratoconus with acute corneal hydrops in a NS patient helped largely resolve the patient′s condition. We report the diverse spectrum of ocular manifestations associated with this rare congenital disorder.

Hypertrophic neuropathy in Noonan syndrome with multiple lentigines.

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Maridet, Claire; Sole, Guilhem; Morice-Picard, Fanny; Taieb, Alain

2016-06-01

RASopathies comprise several genetic syndromes with mainly cardio-facial-cutaneous manifestations. We report a patient with Noonan syndrome with multiple lentigines (NSML) due to a PTPN11 (p.Thr468Met) mutation associated with hypertrophic neuropathy of lumbar plexus in an adult woman, initially referred for neuropathic pain. Differential diagnosis of neurofibromatosis type 1 (NF1) and other RASopathies is difficult without molecular testing. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Perceived motor problems in daily life: Focus group interviews with people with Noonan syndrome and their relatives

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Croonen, E.A.; Harmsen, M.; Burgt, I. van der; Draaisma, J.M.T.; Noordam, C.; Essink, M.; Nijhuis-Van der Sanden, M.W.G.

2016-01-01

Studies from a patient perspective on motor performance problems in Noonan syndrome in daily life are lacking. The aims of this study were to provide insight into the motor performance problems that people with Noonan syndrome and/or their relatives experienced, the major consequences they suffered,

Development of bilateral coronary artery aneurysms in a child with Noonan syndrome

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Mauro, David M.; Flors, Lucia; Norton, Patrick T.; Hagspiel, Klaus D.; Hoyer, Andrew W.

2016-01-01

Noonan syndrome is a constellation of congenital malformations including heart defects, facial anomalies and short stature. The cardiovascular defects are variable and extensive, with the most common being pulmonary stenosis and hypertrophic cardiomyopathy. Coronary artery anomalies have only been reported in a few cases. We report a child with Noonan syndrome status post pulmonary stenosis and atrial septal defect repair, who developed bilateral coronary artery aneurysms. The aneurysms were diagnosed with both cardiac magnetic resonance imaging and coronary computed tomography angiography. There had been no evidence of them on a cardiac MR exam 5 years previously. (orig.)

Development of bilateral coronary artery aneurysms in a child with Noonan syndrome

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Mauro, David M.; Flors, Lucia; Norton, Patrick T.; Hagspiel, Klaus D. [University of Virginia Health System, Department of Radiology and Medical Imaging, Charlottesville, VA (United States); Hoyer, Andrew W. [University of Virginia Health System, Department of Pediatrics, Division of Pediatric Cardiology, Charlottesville, VA (United States); Pediatric Cardiology Center of Oregon, Portland, OR (United States)

2016-03-15

Noonan syndrome is a constellation of congenital malformations including heart defects, facial anomalies and short stature. The cardiovascular defects are variable and extensive, with the most common being pulmonary stenosis and hypertrophic cardiomyopathy. Coronary artery anomalies have only been reported in a few cases. We report a child with Noonan syndrome status post pulmonary stenosis and atrial septal defect repair, who developed bilateral coronary artery aneurysms. The aneurysms were diagnosed with both cardiac magnetic resonance imaging and coronary computed tomography angiography. There had been no evidence of them on a cardiac MR exam 5 years previously. (orig.)

The Face of Noonan Syndrome: Does Phenotype Predict Genotype

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Allanson, Judith E.; Bohring, Axel; Dorr, Helmuth-Guenther; Dufke, Andreas; Gillessen-Kaesbach, Gabrielle; Horn, Denise; König, Rainer; Kratz, Christian P.; Kutsche, Kerstin; Pauli, Silke; Raskin, Salmo; Rauch, Anita; Turner, Anne; Wieczorek, Dagmar; Zenker, Martin

2011-01-01

The facial photographs of 81 individuals with Noonan syndrome, from infancy to adulthood, have been evaluated by two dysmorphologists (JA and MZ), each of whom has considerable experience with disorders of the Ras/MAPK pathway. Thirty-two of this cohort have PTPN11 mutations, 21 SOS1 mutations, 11 RAF1 mutations, and 17 KRAS mutations. The facial appearance of each person was judged to be typical of Noonan syndrome or atypical. In each gene category both typical and unusual faces were found. We determined that some individuals with mutations in the most commonly affected gene, PTPN11, which is correlated with the cardinal physical features, may have a quite atypical face. Conversely, some individuals with KRAS mutations, which may be associated with a less characteristic intellectual phenotype and a resemblance to Costello and cardio-facio-cutaneous syndromes, can have a very typical face. Thus, the facial phenotype, alone, is insufficient to predict the genotype, but certain facial features may facilitate an educated guess in some cases. PMID:20602484

Functional evaluation of circulating hematopoietic progenitors in Noonan syndrome

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TIMEUS, FABIO; CRESCENZIO, NICOLETTA; BALDASSARRE, GIUSEPPINA; DORIA, ALESSANDRA; VALLERO, STEFANO; FOGLIA, LUISELDA; PAGLIANO, SARA; ROSSI, CESARE; SILENGO, MARGHERITA CIRILLO; RAMENGHI, UGO; FAGIOLI, FRANCA; DI MONTEZEMOLO, LUCA CORDERO; FERRERO, GIOVANNI BATTISTA

2013-01-01

Noonan syndrome (NS) is an autosomal dominant disorder, characterized by short stature, multiple dysmorphisms and congenital heart defects. A myeloproliferative disorder (NS/MPD), resembling juvenile myelomonocytic leukemia (JMML), is occasionally diagnosed in infants with NS. In the present study, we performed a functional evaluation of the circulating hematopoietic progenitors in a series of NS, NS/MPD and JMML patients. The different functional patterns were compared with the aim to identify a possible NS subgroup worthy of stringent hematological follow-up for an increased risk of MPD development. We studied 27 NS and 5 JMML patients fulfilling EWOG-MDS criteria. The more frequent molecular defects observed in NS were mutations in the PTPN11 and SOS genes. The absolute count of monocytes, circulating CD34+ hematopoietic progenitors, their apoptotic rate and the number of circulating CFU-GMs cultured in the presence of decreasing concentrations or in the absence of granulocyte-macrophage colony-stimulating factor (GM-CSF) were evaluated. All JMML patients showed monocytosis >1,000/μl. Ten out of the 27 NS patients showed monocytosis >1,000/μl, which included the 3 NS/MPD patients. In JMML patients, circulating CD34+ cells were significantly increased (median, 109.8/μl; range, 44–232) with a low rate of apoptosis (median, 2.1%; range, 0.4–12.1%), and circulating CFU-GMs were hyper-responsive to GM-CSF. NS/MPD patients showed the same flow cytometric pattern as the JMML patients (median, CD34+ cells/μl, 205.7; range, 58–1374; median apoptotic rate, 1.4%; range, 0.2–2.4%) and their circulating CFU-GMs were hyper-responsive to GM-CSF. These functional alterations appeared 10 months before the typical clinical manifestations in 1 NS/MPD patient. In NS, the CD34+ absolute cell count and circulating CFU-GMs showed a normal pattern (median CD34+ cells/μl, 4.9; range, 1.3–17.5), whereas the CD34+ cell apoptotic rate was significantly decreased in

Bilateral branch pulmonary artery stenosis and Mitral valve prolapse in a patient with Noonan syndrome: A case report

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Meenakshi Kadiyala

2014-01-01

Full Text Available Rasopathy syndromes are a class of phenotypically similar, but genetically distinct multiple anomaly syndromes caused by germ line mutations in genes that encode protein components of the Ras/mitogen activated protein kinase (MAPK pathway. Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome are part of this group of developmental syndromes and have similar cardiac abnormalities. A 19-year-old male presented with complaints of exertional breathlessness class I for 6 months. Clinical examination revealed characteristic facial features, skeletal abnormalities, growth and neurocognitive problems reported in patients with Noonan syndrome. There was evidence of severe pulmonary hypertension. Trans-thoracic echocardiography revealed right atrial and right ventricular enlargement, severe pulmonary hypertension, no intra cardiac shunt, prolapse of anterior mitral leaflet with mild mitral regurgitation. CT pulmonary angiogram revealed bilateral branch pulmonary artery stenosis. A final diagnosis of Noonan syndrome was made.

Targeted ultrasound examination and DNA testing for Noonan syndrome, in fetuses with increased nuchal translucency and normal karyotype

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Bakker, M.; Pajkrt, E.; Mathijssen, I. B.; Bilardo, C. M.

2011-01-01

OBJECTIVE: To define sonographic criteria that may improve the prenatal diagnosis of Noonan syndrome by targeted DNA testing. METHODS: We searched our Fetal Medicine Unit records for all cases with a final diagnosis of Noonan syndrome. A literature review was undertaken to identify the sonographic

Targeted ultrasound examination and DNA testing for Noonan syndrome, in fetuses with increased nuchal translucency and normal karyotype

NARCIS (Netherlands)

Bakker, Merel; Pajkrt, E.; Mathijssen, I. B.; Bilardo, C. M.

Objective To define sonographic criteria that may improve the prenatal diagnosis of Noonan syndrome by targeted DNA testing. Methods We searched our Fetal Medicine Unit records for all cases with a final diagnosis of Noonan syndrome. A literature review was undertaken to identify the sonographic

A novel Noonan syndrome RAF1 mutation: lethal course in a preterm infant

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Ana Ratola

2015-06-01

Full Text Available Noonan syndrome is a relatively common and heterogeneous genetic disorder, associated with congenital heart defect in about 50% of the cases. If the defect is not severe, life expectancy is normal. We report a case of Noonan syndrome in a preterm infant with hypertrophic cardiomyopathy and lethal outcome associated to acute respiratory distress syndrome caused by Adenovirus pneumonia. A novel mutation in the RAF1 gene was identified: c.782C>G (p.Pro261Arg in heterozygosity, not described previously in the literature. Consequently, the common clinical course in this mutation and its respective contribution to the early fatal outcome is unknown. No conclusion can be established regarding genotype/phenotype correlation.

Candida albicans meningitis in an infant with noonan syndrome

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Faezeh Ahmadi

Full Text Available Noonan syndrome is a rare disorder, characterized by several malformations such as dysplasia and stenosis of the pulmonary valve, atrial septal defect and a typical pattern of hypertrophic cardiomyopathy. We describe here a 1-month old girl, who was referred to our center with seizure and apnea. She had wide anterior fontanel, head circumference and sunset eye. Intaventricular hemorrhage by sonography and atrial septal defect and hypertrophy cardiomyopathy by echocardiography were detected. Clinical and laboratory findings of the patient were compatible with a diagnosis of Noonan syndrome, which was also confirmed by molecular analysis. Candida albicans was grown in the blood and cerebrospinal fluid cultures. Treatment with Amphotrycine B was started for the patient and she responded well to this therapy. Early diagnosis and appropriate diagnosis of a rare condition in the patient with such rare disease are the main keys to avoid further complications and even death of patient.

GH Therapy and first final height data in Noonan-like syndrome with loose anagen hair (Mazzanti syndrome).

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Mazzanti, Laura; Tamburrino, Federica; Scarano, Emanuela; Perri, Annamaria; Vestrucci, Benedetta; Guidetti, Monica; Rossi, Cesare; Tartaglia, Marco

2013-11-01

Noonan-like syndrome with loose anagen hair (NS/LAH or Mazzanti Syndrome) is caused by a single missense mutation in SHOC2 promoting tN-myristoylation of the encoded protein. Cardinal features include facial features resembling NS, short stature often associated with proven growth hormone deficiency (GHD), typical ectodermal anomalies, and distinctive behavior. Overall, the clinical features are more severe than those generally observed in NS, even though the phenotype improves with age. We report on growth and pubertal trend in seven patients heterozygous for a mutated SHOC2 allele, treated with long-term GH-therapy, and final height (FH) in three of them. They were approximately -3 SDS below the Italian general population standards, they had very low IGF1 levels at baseline and GHD at pharmacological tests. All patients were treated with GH (0.035 mg/kg/day) for a mean period of 8.49 ± 5.72 years. After the 1st year of GH-therapy, IGF1 level and height velocity had increased. Three of 7 patients reached the FH (-2.34 ± 0.12 SDS) at 18.25 ± 0.73 years, after GH administration for 12.39 ± 2.12 years. Pubertal development was variable, showing a prolonged and delayed puberty or rapid pubertal progression that could impair the FH. Overall, our data in this small cohort suggest that NS/LAH patients benefit from long-term GH-therapy, although they do not show the characteristic catch-up growth of isolated GHD. While the observed growth and pubertal behavior is consistent with a dysfunction of the hypothalamic-pituitary-gonadal axis, the functional link between SHOC2 and the GH/IGF signaling pathways remains to be clarified. © 2013 Wiley Periodicals, Inc.

Increased BRAF Heterodimerization Is the Common Pathogenic Mechanism for Noonan Syndrome-Associated RAF1 Mutants

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Wu, Xue; Yin, Jiani; Simpson, Jeremy; Kim, Kyoung-Han; Gu, Shengqing; Hong, Jenny H.; Bayliss, Peter; Backx, Peter H.

2012-01-01

Noonan syndrome (NS) is a relatively common autosomal dominant disorder characterized by congenital heart defects, short stature, and facial dysmorphia. NS is caused by germ line mutations in several components of the RAS–RAF–MEK–extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway, including both kinase-activating and kinase-impaired alleles of RAF1 (∼3 to 5%), which encodes a serine-threonine kinase for MEK1/2. To investigate how kinase-impaired RAF1 mutants cause NS, we generated knock-in mice expressing Raf1D486N. Raf1D486N/+ (here D486N/+) female mice exhibited a mild growth defect. Male and female D486N/D486N mice developed concentric cardiac hypertrophy and incompletely penetrant, but severe, growth defects. Remarkably, Mek/Erk activation was enhanced in Raf1D486N-expressing cells compared with controls. RAF1D486N, as well as other kinase-impaired RAF1 mutants, showed increased heterodimerization with BRAF, which was necessary and sufficient to promote increased MEK/ERK activation. Furthermore, kinase-activating RAF1 mutants also required heterodimerization to enhance MEK/ERK activation. Our results suggest that an increased heterodimerization ability is the common pathogenic mechanism for NS-associated RAF1 mutations. PMID:22826437

Surgical Orthodontic Treatment for Open Bite in Noonan Syndrome Patient: A Case Report.

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Kawakami, Masayoshi; Yamamoto, Kazuhiko; Shimomura, Tadahiro; Kirita, Tadaaki

2016-03-01

Noonan syndrome, characterized by short stature, facial anomalies, and congenital heart defects, may also be associated with hematopoietic disorders. Craniofacial anomalies in affected patients include hypertelorism and severe open bite associated with masticatory dysfunction. We treated a Noonan syndrome patient with a skeletal open bite. Surgical orthodontic treatment including two-jaw surgery established a good occlusal relationship after correction of severe anemia. Both upper and lower incisors were moved to upright positions, while clockwise rotation of the palatal plane and decreased mandibular plane angle were accomplished. Lower masticatory activity may affect posttreatment occlusion in such cases.

Co-occurrence of hypertrophic cardiomyopathy and myeloproliferative disorder in a neonate with Noonan syndrome carrying Thr73Ile mutation in PTPN11.

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Yagasaki, Hideaki; Nakane, Takaya; Hasebe, Youhei; Watanabe, Atsushi; Kise, Hiroaki; Toda, Takako; Koizumi, Keiichi; Hoshiai, Minako; Sugita, Kanji

2015-12-01

Most cases of Noonan syndrome (NS) result from mutations in one of the RAS-MAPK signaling genes, including PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 (MAP2K1), and CBL. Cardiovascular diseases of varying severity, such as pulmonary stenosis and hypertrophic cardiomyopathy (HCM), are common in NS patients. RAF1 mutations are most frequent in NS with HCM, while PTPN11 mutations are also well known. Thr73Ile is a gain-of-function mutation of PTPN11, which has been highly associated with juvenile myelomonocytic leukemia and NS/myeloproliferative disease (MPD), but has not previously been reported in HCM. Here, we report a Japanese female infant with NS carrying the PTPN11 T73I mutation with NS/MPD, complete atrio-ventricular septal defect, and rapidly progressive HCM. No other HCM-related mutations were detected in PTPN11, RAF1, KRAS, BRAF, and SHOC2. This patient provides additional information regarding the genotype-phenotype correlation for PTPN11 T73I mutation in NS. © 2015 Wiley Periodicals, Inc.

Anesthetic considerations and difficult airway management in a case of Noonan syndrome

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Sukhminder Jit Singh Bajwa

2011-01-01

Full Text Available Noonan syndrome is a genetically transmitted autosomal dominant disorder characterized by various anatomic anomalies and pathophysiologic derangements. Anesthetic management in such cases poses a multitude of challenges, especially related to the airway management and maintenance of cardiovascular stability. We report a case of a 9-year-old male child weighing 24 kg, who was diagnosed as a case of Noonan syndrome and had undergone ligation of patent ductus arteriosus during early childhood. The child was operated on for release of bilateral neck bands under general anesthesia. The case report pertains to the successful airway and anesthetic management in the background of difficult airway and existence of various cardiac lesions.

Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature

NARCIS (Netherlands)

Milosavljević, Doris; Overwater, Eline; Tamminga, Saskia; de Boer, Karin; Elting, Mariet W.; van Hoorn, Marion E.; Rinne, Tuula; Houweling, Arjan C.

2016-01-01

Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal

IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene.

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Bertelloni, Silvano; Baroncelli, Giampiero I; Dati, Eleonora; Ghione, Silvia; Baldinotti, Fulvia; Toschi, Benedetta; Simi, Paolo

2013-01-01

Short stature represents one of the main features of children with Noonan syndrome. The reason for impaired growth remains largely unknown. To assess GH and IGF1 secretion in children with Noonan syndrome. 12 prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene [7 males, 6 females; median age, years: 8.6 (range 5.1-13.4)] were studied; 12 prepubertal children with short stature (SS) [7 males, 5 females; median age, years: 8.1 (range 4.8-13.1)] served as the control group. GH secretion after arginine stimulation test; IGF1 generation test by measurement of IGF1 levels before and after recombinant GH (rGH) administration (0.05 mg/kg/day for 4 days). Baseline and stimulated peak values of GH were not significantly different between the two groups. At +120 minutes, GH levels remained significantly higher (p = 0.0121) in comparison with baseline values in children with Noonan syndrome. Baseline IGFI levels in patients and in SS controls were not significantly different, in contrast to values after the rGH generation test [205 ng/mL (interquartiles 138.2-252.5 ng/mL) and 284.5 ng/mL (interquartiles 172-476 ng/mL), respectively; p = 0.0248]. IGF1 values were significantly related to height (baseline: r = 773, p = 0.0320; peak: r = 0.591, p = 0.0428) in children with Noonan syndrome. Blunted increase of IGF1 after the rGH generation test was present in children with Noonan syndrome due to mutations in the PTPN11 gene in comparison with SS children. This finding may be due to partial GH resistance in the former likely related to altered Ras-MAPK signaling pathway.

Neonatal pulmonary arterial hypertension and Noonan syndrome: two fatal cases with a specific RAF1 mutation.

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Hopper, Rachel K; Feinstein, Jeffrey A; Manning, Melanie A; Benitz, William; Hudgins, Louanne

2015-04-01

Mutations in RAF1 are associated with Noonan syndrome and hypertrophic cardiomyopathy. We present two infants with Noonan syndrome and an identical RAF1 mutation, p.Ser257Leu (c.770C>T), who developed severe pulmonary arterial hypertension (PAH) that proved to be fatal. The RAF1 gene encodes Raf-1 kinase, part of the Ras/mitogen-activated kinase (MAPK) signaling pathway, which has been linked to the development of PAH. This specific mutation has been associated with dephosphorylation of a critical serine residue and constitutive activation of the Raf-1 kinase. These two cases suggest that abnormal activation of the Ras/MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation. © 2015 Wiley Periodicals, Inc.

Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth.

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Tajan, Mylène; Pernin-Grandjean, Julie; Beton, Nicolas; Gennero, Isabelle; Capilla, Florence; Neel, Benjamin G; Araki, Toshiyuki; Valet, Philippe; Tauber, Maithé; Salles, Jean-Pierre; Yart, Armelle; Edouard, Thomas

2018-04-12

Growth retardation is a constant feature of Noonan syndrome (NS) but its physiopathology remains poorly understood. We previously reported that hyperactive NS-causing SHP2 mutants impair the systemic production of insulin-like growth factor 1 (IGF1) through hyperactivation of the RAS/extracellular signal-regulated kinases (ERK) signalling pathway. Besides endocrine defects, a direct effect of these mutants on growth plate has not been explored, although recent studies have revealed an important physiological role for SHP2 in endochondral bone growth. We demonstrated that growth plate length was reduced in NS mice, mostly due to a shortening of the hypertrophic zone and to a lesser extent of the proliferating zone. These histological features were correlated with decreased expression of early chondrocyte differentiation markers, and with reduced alkaline phosphatase staining and activity, in NS murine primary chondrocytes. Although IGF1 treatment improved growth of NS mice, it did not fully reverse growth plate abnormalities, notably the decreased hypertrophic zone. In contrast, we documented a role of RAS/ERK hyperactivation at the growth plate level since 1) NS-causing SHP2 mutants enhance RAS/ERK activation in chondrocytes in vivo (NS mice) and in vitro (ATDC5 cells) and 2) inhibition of RAS/ERK hyperactivation by U0126 treatment alleviated growth plate abnormalities and enhanced chondrocyte differentiation. Similar effects were obtained by chronic treatment of NS mice with statins.In conclusion, we demonstrated that hyperactive NS-causing SHP2 mutants impair chondrocyte differentiation during endochondral bone growth through a local hyperactivation of the RAS/ERK signalling pathway, and that statin treatment may be a possible therapeutic approach in NS.

Development of disease-specific growth charts in Turner syndrome and Noonan syndrome

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Tsuyoshi Isojima

2017-12-01

Full Text Available Many congenital diseases are associated with growth failure, and patients with these diseases have specific growth patterns. As the growth patterns of affected individuals differ from those of normal populations, it is challenging to detect additional conditions that can influence growth using standard growth charts. Disease-specific growth charts are thus very useful tools and can be helpful for understanding the growth pattern and pathogenesis of congenital diseases. In addition, disease-specific growth charts allow doctors to detect deviations from the usual growth patterns for early diagnosis of an additional condition and can be used to evaluate the effects of growth-promoting treatment for patients. When developing these charts, factors that can affect the reliability of the charts should be considered. These factors include the definition of the disease with growth failure, selection bias in the measurements used to develop the charts, secular trends of the subjects, the numbers of subjects of varying ages and ethnicities, and the statistical method used to develop the charts. In this review, we summarize the development of disease-specific growth charts for Japanese individuals with Turner syndrome and Noonan syndrome and evaluate the efforts to collect unbiased measurements of subjects with these diseases. These charts were the only available disease-specific growth charts of Turner syndrome and Noonan syndrome for Asian populations and were developed using a Japanese population. Therefore, when these charts are adopted for Asian populations other than Japanese, different growth patterns should be considered.

Development of disease-specific growth charts in Turner syndrome and Noonan syndrome.

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Isojima, Tsuyoshi; Yokoya, Susumu

2017-12-01

Many congenital diseases are associated with growth failure, and patients with these diseases have specific growth patterns. As the growth patterns of affected individuals differ from those of normal populations, it is challenging to detect additional conditions that can influence growth using standard growth charts. Disease-specific growth charts are thus very useful tools and can be helpful for understanding the growth pattern and pathogenesis of congenital diseases. In addition, disease-specific growth charts allow doctors to detect deviations from the usual growth patterns for early diagnosis of an additional condition and can be used to evaluate the effects of growth-promoting treatment for patients. When developing these charts, factors that can affect the reliability of the charts should be considered. These factors include the definition of the disease with growth failure, selection bias in the measurements used to develop the charts, secular trends of the subjects, the numbers of subjects of varying ages and ethnicities, and the statistical method used to develop the charts. In this review, we summarize the development of disease-specific growth charts for Japanese individuals with Turner syndrome and Noonan syndrome and evaluate the efforts to collect unbiased measurements of subjects with these diseases. These charts were the only available disease-specific growth charts of Turner syndrome and Noonan syndrome for Asian populations and were developed using a Japanese population. Therefore, when these charts are adopted for Asian populations other than Japanese, different growth patterns should be considered.

Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia.

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Cavé, Hélène; Caye, Aurélie; Ghedira, Nehla; Capri, Yline; Pouvreau, Nathalie; Fillot, Natacha; Trimouille, Aurélien; Vignal, Cédric; Fenneteau, Odile; Alembik, Yves; Alessandri, Jean-Luc; Blanchet, Patricia; Boute, Odile; Bouvagnet, Patrice; David, Albert; Dieux Coeslier, Anne; Doray, Bérénice; Dulac, Olivier; Drouin-Garraud, Valérie; Gérard, Marion; Héron, Delphine; Isidor, Bertrand; Lacombe, Didier; Lyonnet, Stanislas; Perrin, Laurence; Rio, Marlène; Roume, Joëlle; Sauvion, Sylvie; Toutain, Annick; Vincent-Delorme, Catherine; Willems, Marjorie; Baumann, Clarisse; Verloes, Alain

2016-08-01

Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.

Giant cell lesion of the jaw as a presenting feature of Noonan syndrome.

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Sinnott, Bridget P; Patel, Maya

2018-05-30

This is a case of a 20-year-old woman who presented with a left jaw mass which was resected and found to be a giant cell granuloma of the mandible. Her history and physical examination were suggestive for Noonan syndrome which was confirmed with genetic testing and the finding of a PTPN11 gene mutation which has rarely been associated with giant cell lesions of the jaw. Given her particular genetic mutation and the presence of a giant cell lesion, we present a case of Noonan-like/multiple giant cell lesion syndrome. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Novel mutations and their genotype-phenotype correlations in patients with Noonan syndrome, using next-generation sequencing.

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Tafazoli, Alireza; Eshraghi, Peyman; Pantaleoni, Francesca; Vakili, Rahim; Moghaddassian, Morteza; Ghahraman, Martha; Muto, Valentina; Paolacci, Stefano; Golyan, Fatemeh Fardi; Abbaszadegan, Mohammad Reza

2018-03-01

Noonan Syndrome (NS) is an autosomal dominant disorder with many variable and heterogeneous conditions. The genetic basis for 20-30% of cases is still unknown. This study evaluates Iranian Noonan patients both clinically and genetically for the first time. Mutational analysis of PTPN11 gene was performed in 15 Iranian patients, using PCR and Sanger sequencing at phase one. Then, as phase two, Next Generation Sequencing (NGS) in the form of targeted resequencing was utilized for analysis of exons from other related genes. Homology modelling for the novel founded mutations was performed as well. The genotype, phenotype correlation was done according to the molecular findings and clinical features. Previously reported mutation (p.N308D) in some patients and a novel mutation (p.D155N) in one of the patients were identified in phase one. After applying NGS methods, known and new variants were found in four patients in other genes, including: CBL (p. V904I), KRAS (p. L53W), SOS1 (p. I1302V), and SOS1 (p. R552G). Structural studies of two deduced novel mutations in related genes revealed deficiencies in the mutated proteins. Following genotype, phenotype correlation, a new pattern of the presence of intellectual disability in two patients was registered. NS shows strong variable expressivity along the high genetic heterogeneity especially in distinct populations and ethnic groups. Also possibly unknown other causative genes may be exist. Obviously, more comprehensive and new technologies like NGS methods are the best choice for detection of molecular defects in patients for genotype, phenotype correlation and disease management. Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.

Germline mutation of CBL is associated with moyamoya disease in a child with juvenile myelomonocytic leukemia and Noonan syndrome-like disorder.

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Hyakuna, Nobuyuki; Muramatsu, Hideki; Higa, Takeshi; Chinen, Yasutsugu; Wang, Xinan; Kojima, Seiji

2015-03-01

Germline mutations in CBL have been identified in patients with Noonan syndrome-like phenotypes, while juvenile myelomonocytic leukemia (JMML) harbors duplication of a germline CBL, resulting in acquired isodisomy. The association between moyamoya disease and Noonan syndrome carrying a PTPN11 mutation has recently been reported. We present a patient with JMML who developed moyamoya disease and neovascular glaucoma. Our patient exhibited a Noonan syndrome-like phenotype. Genetic analysis revealed acquired isodisomy and a germline heterozygous mutation in CBL. This is a rare case of CBL mutation associated with moyamoya disease. Prolonged RAS pathway signaling may cause disruption of cerebrovascular development. © 2014 Wiley Periodicals, Inc.

Noonan syndrome, PTPN11 mutations, and brain tumors. A clinical report and review of the literature.

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Siegfried, Aurore; Cances, Claude; Denuelle, Marie; Loukh, Najat; Tauber, Maïté; Cavé, Hélène; Delisle, Marie-Bernadette

2017-04-01

Noonan syndrome (NS), an autosomal dominant disorder, is characterized by short stature, congenital heart defects, developmental delay, and facial dysmorphism. PTPN11 mutations are the most common cause of NS. PTPN11 encodes a non-receptor protein tyrosine phosphatase, SHP2. Hematopoietic malignancies and solid tumors are associated with NS. Among solid tumors, brain tumors have been described in children and young adults but remain rather rare. We report a 16-year-old boy with PTPN11-related NS who, at the age of 12, was incidentally found to have a left temporal lobe brain tumor and a cystic lesion in the right thalamus. He developed epilepsy 2 years later. The temporal tumor was surgically resected because of increasing crises and worsening radiological signs. Microscopy showed nodules with specific glioneuronal elements or glial nodules, leading to the diagnosis of dysembryoplastic neuroepithelial tumor (DNT). Immunohistochemistry revealed positive nuclear staining with Olig2 and pERK in small cells. SHP2 plays a key role in RAS/MAPK pathway signaling which controls several developmental cell processes and oncogenesis. An amino-acid substitution in the N-terminal SHP2 domain disrupts the self-locking conformation and leads to ERK activation. Glioneuronal tumors including DNTs and pilocytic astrocytomas have been described in NS. This report provides further support for the relation of DNTs with RASopathies and for the implication of RAS/MAPK pathways in sporadic low-grade glial tumors including DNTs. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Compositions and methods for detecting Noonan syndrome

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Gelb, Bruce D [New York, NY; Tartaglia, Marco [Rome, IT; Pennacchio, Len [Walnut Creek, CA

2012-07-17

Diagnostic and therapeutic applications for Noonan Syndrome are described. The diagnostic and therapeutic applications are based on certain mutations in a RAS-specific guanine nucleotide exchange factor gene SOS1 or its expression product. The diagnostic and therapeutic applications are also based on certain mutations in a serine/threonine protein kinase gene RAF1 or its expression product thereof. Also described are nucleotide sequences, amino acid sequences, probes, and primers related to RAF1 or SOS1, and variants thereof, as well as host cells expressing such variants.

Expanding the clinical spectrum of ocular anomalies in Noonan syndrome: Axenfeld-anomaly in a child with PTPN11 mutation.

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Guerin, Andrea; So, Joyce; Mireskandari, Kamiar; Jougeh-Doust, Soghra; Chisholm, Caitlin; Klatt, Regan; Richer, Julie

2015-02-01

Ocular anomalies have been frequently reported in Noonan syndrome. Anterior segment anomalies have been described in 57% of PTPN11 positive patients, with the most common findings being corneal changes and in particular, prominent corneal nerves and cataracts. We report on a neonate with a confirmed PTPN11 mutation and ocular findings consistent with Axenfeld anomaly. The patient initially presented with non-immune hydrops and subsequently developed hypertrophic cardiomyopathy and dysmorphic features typical of Noonan syndrome. While a pathogenic mutation in PTPN11 was confirmed, prior testing for the two common genes associated with Axenfeld-Rieger syndrome, PITX2, and FOXC1 was negative. This finding expands the spectrum of anterior chamber anomalies seen in Noonan syndrome and perhaps suggests a common neural crest related mechanism that plays a critical role in the development of the eye and other organs. © 2014 Wiley Periodicals, Inc.

Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells.

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Nakamura, Yuki; Umeki, Nobuhisa; Abe, Mitsuhiro; Sako, Yasushi

2017-10-26

Noonan syndrome (NS) is a congenital hereditary disorder associated with developmental and cardiac defects. Some patients with NS carry mutations in SOS, a guanine nucleotide exchange factor (GEF) for the small GTPase RAS. NS mutations have been identified not only in the GEF domain, but also in various domains of SOS, suggesting that multiple mechanisms disrupt SOS function. In this study, we examined three NS mutations in different domains of SOS to clarify the abnormality in its translocation to the plasma membrane, where SOS activates RAS. The association and dissociation kinetics between SOS tagged with a fluorescent protein and the living cell surface were observed in single molecules. All three mutants showed increased affinity for the plasma membrane, inducing excessive RAS signalling. However, the mechanisms by which their affinity was increased were specific to each mutant. Conformational disorder in the resting state, increased probability of a conformational change on the plasma membrane, and an increased association rate constant with the membrane receptor are the suggested mechanisms. These different properties cause the specific phenotypes of the mutants, which should be rescuable with different therapeutic strategies. Therefore, single-molecule kinetic analyses of living cells are useful for the pathological analysis of genetic diseases.

Management of Cardiovascular Disorders in Patients with Noonan Syndrome: A Case Report.

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Khorgami, Mohammad Rafie; Moradian, Maryam; Omidi, Negar; Aarabi Moghadam, Mohammad Yousef

2017-10-01

The Noonan syndrome is a rare disorder, one of whose major complications is cardiovascular involvement. A wide spectrum of congenital heart diseases has been observed in this syndrome. The most common cardiac disorder is pulmonary valve stenosis, which has a progressive nature. Hypertrophic cardiomyopathy is less common, but its morbidity and mortality rates are high. We herein introduce a 12-year-old boy with the typical findings of the Noonan syndrome. His symptoms began from infancy, and there was a gradual exacerbation in his respiratory and cardiac manifestations with age. The cardiac involvement included right ventricular outflow tract and pulmonary valve stenosis, hypertrophic cardiomyopathy, and subaortic valve stenosis. Due to the progressive course of the disease, surgical repair was done. Although the patient had a difficult postoperative period, his general condition improved and he was discharged. At 3 months' follow-up, his symptoms showed improvement. Additionally, there was a reduction in the echocardiographic parameters of the outflow tract stenosis gradient as well as a significant improvement in the cardiac hemodynamic indices.

Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome.

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Pannone, Luca; Bocchinfuso, Gianfranco; Flex, Elisabetta; Rossi, Cesare; Baldassarre, Giuseppina; Lissewski, Christina; Pantaleoni, Francesca; Consoli, Federica; Lepri, Francesca; Magliozzi, Monia; Anselmi, Massimiliano; Delle Vigne, Silvia; Sorge, Giovanni; Karaer, Kadri; Cuturilo, Goran; Sartorio, Alessandro; Tinschert, Sigrid; Accadia, Maria; Digilio, Maria C; Zampino, Giuseppe; De Luca, Alessandro; Cavé, Hélène; Zenker, Martin; Gelb, Bruce D; Dallapiccola, Bruno; Stella, Lorenzo; Ferrero, Giovanni B; Martinelli, Simone; Tartaglia, Marco

2017-04-01

Germline mutations in PTPN11, the gene encoding the Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu 261 , Leu 262 , and Arg 265 in 16 unrelated individuals with clinical diagnosis of NS or with features suggestive for this disorder, specifying a novel disease-causing mutation cluster. Expression of the mutant proteins in HEK293T cells documented their activating role on MAPK signaling. Structural data predicted a gain-of-function role of substitutions at residues Leu 262 and Arg 265 exerted by disruption of the N-SH2/PTP autoinhibitory interaction. Molecular dynamics simulations suggested a more complex behavior for changes affecting Leu 261 , with possible impact on SHP2's catalytic activity/selectivity and proper interaction of the PTP domain with the regulatory SH2 domains. Consistent with that, biochemical data indicated that substitutions at codons 262 and 265 increased the catalytic activity of the phosphatase, while those affecting codon 261 were only moderately activating but impacted substrate specificity. Remarkably, these mutations underlie a relatively mild form of NS characterized by low prevalence of cardiac defects, short stature, and cognitive and behavioral issues, as well as less evident typical facial features. © 2017 WILEY PERIODICALS, INC.

Objective studies of the face of Noonan, Cardio-facio-cutaneous, and Costello syndromes: A comparison of three disorders of the Ras/MAPK signaling pathway.

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Allanson, Judith E

2016-10-01

Noonan, Cardio-facio-cutaneous, and Costello syndromes are disorders of the Ras/MAPK pathway that share many clinical features. This observational and anthropometric study was conducted to describe the key facial features of each syndrome in order to improve discrimination between the three conditions, particularly in young children where diagnosis is most challenging. Direct measurement of the head and face was used to enhance diagnostic accuracy, and identify the most unusual or specific dimensions. The Noonan syndrome cohort included 123 individuals, aged 6 months to 41 years. There were 20 children and adolescents with Cardio-facio-cutaneous syndrome, and 28 individuals with Costello syndrome, aged 1-32 years. The facial phenotypes of these syndromes, particularly Noonan syndrome, are well-described but objective data have not been published in peer-reviewed literature. In this study, subjective observations, in the main, were validated by anthropometry with one exception. In individuals with Costello syndrome, mouth width was normal, thus the impression of wide mouth is likely due to full lips or the mouth being viewed in relation to a narrow lower face. When the three conditions were compared objectively, syndrome-specific pattern profiles showed high concordance in early life. At older ages, Cardio-facio-cutaneous syndrome was distinguished by increased width of the mid/lower face, and reduced growth of maxillary and mandibular dimensions was noted in both Noonan and Costello syndromes. Despite substantial similarities in face shape in older individuals with these two conditions, bulbous nasal tip, full lips, and an apparently wide mouth in those with Costello Syndrome facilitate discrimination from Noonan syndrome. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The Noonan Syndrome--A Review of the Clinical and Genetic Features of 27 Cases

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Collins, Edith; Turner, Gillian

1973-01-01

Reviewed were clinical and genetic features of 27 cases of the Noonan Syndrome, a condition with characteristics such as webbing of the neck, short stature, frequent congential heart lesions, and chromosomal irregularities. (DB)

Computed tomography after lymphangiography in the diagnosis of intestinal lymphangiectasia with protein-losing enteropathy in Noonan's syndrome

International Nuclear Information System (INIS)

Keberle, M.; Jenett, M.; Hahn, D.; Moerk, H.; Scheurlen, M.

2000-01-01

Noonan's syndrome is a rare congenital disorder that may be associated with abnormalities in the lymphatic drainage. In this case of a 21-year-old man CT after bipedal lymphangiography confirmed the diagnosis of intestinal lymphangiectasy causing protein-losing enteropathy in Noonan's syndrome by showing contrast-enhanced abnormal lymphatic vessels in the mesentery and the intestinal wall. Because of the benefit of diet in case of intestinal involvement, we recommend a thorough documentation of the lymphatic drainage with lymphangiography followed by CT, if clinical signs of lymphatic dysplasia, such as pleural effusions, lymphedema, or hypoproteinemia are present. (orig.)

K-Ras(V14I) -induced Noonan syndrome predisposes to tumour development in mice.

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Hernández-Porras, Isabel; Schuhmacher, Alberto J; Garcia-Medina, Raquel; Jiménez, Beatriz; Cañamero, Marta; de Martino, Alba; Guerra, Carmen

2016-06-01

The Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. A significant proportion of NS patients may also develop myeloproliferative disorders (MPDs), including juvenile myelomonocytic leukaemia (JMML). Surprisingly, scarce information is available in relation to other tumour types in these patients. We have previously developed and characterized a knock-in mouse model that carries one of the most frequent KRAS-NS-related mutations, the K-Ras(V14I) substitution, which recapitulates most of the alterations described in NS patients, including MPDs. The K-Ras(V14I) mutation is a mild activating K-Ras protein; thus, we have used this model to study tumour susceptibility in comparison with mice expressing the classical K-Ras(G12V) oncogene. Interestingly, our studies have shown that these mice display a generalized tumour predisposition and not just MPDs. In fact, we have observed that the K-Ras(V14I) mutation is capable of cooperating with the p16Ink4a/p19Arf and Trp53 tumour suppressors, as well as with other risk factors such as pancreatitis, thereby leading to a higher cancer incidence. In conclusion, our results illustrate that the K-Ras(V14I) activating protein is able to induce cancer, although at a much lower level than the classical K-Ras(G12V) oncogene, and that it can be significantly modulated by both genetic and non-genetic events. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The recurrent PPP1CB mutation p.Pro49Arg in an additional Noonan-like syndrome individual: Broadening the clinical phenotype.

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Bertola, Débora; Yamamoto, Guilherme; Buscarilli, Michelle; Jorge, Alexander; Passos-Bueno, Maria Rita; Kim, Chong

2017-03-01

We report on a 12-year-old Brazilian boy with the p.Pro49Arg mutation in PPP1CB, a novel gene associated with RASopathies. This is the fifth individual described, and the fourth presenting the same variant, suggesting a mutational hotspot. Phenotypically, he also showed the same hair pattern-sparse, thin, and with slow growing-, similar to the typical ectodermal finding observed in Noonan syndrome-like disorder with loose anagen hair. Additionally, he presented craniosynostosis, a rare clinical finding in RASopathies. This report gives further support that this novel RASopathy-PPP1CB-related Noonan syndrome with loose anagen hair-shares great similarity to Noonan syndrome-like disorder with loose anagen hair, and expands the phenotypic spectrum by adding the cranial vault abnormality. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Doença celíaca associada à tireoidite de Hashimoto e síndrome de Noonan Celiac disease associated with Hashimoto's thyroiditis and Noonan syndrome

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Mariana Ortega Perez

2010-12-01

Full Text Available OBJETIVO: Relatar o caso clínico de uma criança portadora de doença celíaca, tireoidite de Hashimoto e síndrome de Noonan. DESCRIÇÃO DE CASO: Menina de dez anos e seis meses, branca, apresentando história de diarreia líquida há cinco meses e "aumento da barriga". Ao exame, mostrava peso de 20.580g (pOBJECTIVE: To describe the clinical case of a child with celiac disease, Hashimoto's thyroiditis and Noonan syndrome. CASE DESCRIPTION: A Caucasian girl aged ten years and six months had liquid diarrhea for five months, and a "distended belly". At the physical exam: weight of 20,580g (p<3, length of 114cm (p<3, hydrated, anemic 2+/4+ and conscious. The patient presented triangular facies, apparent ocular hypertelorism, antimongoloid position of the palpebral fissures, ears with low implantation, micrognathia, short neck and pectus excavatum. The abdomen was globular, flaccid and painless; the liver was 2cm below the right costal margin. Lymphedema in right upper limb and lower limb edema was also noted. Laboratory exams showed microcytic and hypochromic anemia, deficit of total proteins, Hashimoto's thyroiditis and a 5-year delay in bone age. Abdominal ultrasonography showed the bowel slightly dilated. Due to lymphedema and chronic diarrhea, the initial hypothesis was intestinal lymphangiectasis, which was confirmed by a jejunal biopsy, which also showed celiac disease. The genetic evaluation revealed a 46XX karyotype and a clinical diagnosis of Noonan syndrome. COMMENTS: Different autoimmune diseases can be associated. In this case, the celiac disease and the Hashimoto's thyroiditis are possibly related to the presence of HLA system antigens. However, the association of the celiac disease with the Noonan syndrome is very rare, and this is the third report in the literature.

Prenatal and Postnatal Sonographic Confirmation of Congenital Absence of the Ductus Venosus in a Child with Noonan Syndrome

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Christopher L. Newman

2017-01-01

Full Text Available The ductus venosus serves as an important vascular pathway for intrauterine circulation. This case presents a description of an absent ductus venosus in a female patient with Noonan syndrome, including both prenatal and postnatal imaging of the anomaly. In the setting of the anomalous vascular connection, the umbilical vein courses inferiorly to the iliac vein in parallel configuration with the umbilical artery. This finding was suspected based on prenatal imaging and the case was brought to attention when placement of an umbilical catheter was thought to be malpositioned given its appearance on radiography. Ultrasound imaging confirmed the anomalous course. This is in keeping with prior descriptions in the literature of an association between Noonan syndrome and aberrant umbilical venous drainage. This case illustrates the need for awareness of this condition by the radiologist, allowing for identification on radiographs and the recommendation for further confirmatory imaging. Further, the case illustrates the value of paying particular attention to the fetal course of the umbilical vessels in patients with suspected Noonan syndrome, as this population is particularly at risk for anomalous vasculature.

From clinical suspect to molecular confirmation of noonan syndrome; contribution of “best practice” genetic counseling and new technical possibilities

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Bukvic Nenad

2015-01-01

Full Text Available Noonan syndrome (NS is an autosomal dominant disorder, characterized by variable expressivity of clinical features such as: postnatal growth reduction, congenital heart disease, characteristic facial dysmorphisms and development delay. In ~75% of all NS cases, germline mutations involving RAS-MAPK signaling pathway genes (PTPN11, SOS1, RAF1, KRAS, NRAS, BRAF, SHOC2, MEK1, CBL are causative. We reported a case of 13-year-old girl [born at 36w by CS (BW 3250 g (~95°, BL 48 cm (~75°] referred for genetic counseling due to growth retardation, facial dysmorphisms, development delay and learning disability. After birth she presented frequent vomiting, with failure to thrive and at 5 months of age underwent surgery for intestinal malrotation. Because of short stature, Growth Hormone (GH therapy have been introduced at age of 3yrs up to 11yrs. Negative molecular testing for PTPN11 and SOS1 genes, normal female karyotype and aCGH analysis were observed. Objective examination: H 138 cm, (A; p.Val14Ile has been identified. Even though KRAS mutations are usually associated with NS severe phenotype with cardiac involvement (hypertrophic cardiomyopathy, this finding is not present in our patient.

RSK3 is required for concentric myocyte hypertrophy in an activated Raf1 model for Noonan syndrome.

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Passariello, Catherine L; Martinez, Eliana C; Thakur, Hrishikesh; Cesareo, Maria; Li, Jinliang; Kapiloff, Michael S

2016-04-01

Noonan syndrome (NS) is a congenital disorder resulting from mutations of the Ras-Raf signaling pathway. Hypertrophic cardiomyopathy associated with RAF1 "RASopathy" mutations is a major risk factor for heart failure and death in NS and has been attributed to activation of MEK1/2-ERK1/2 mitogen-activated protein kinases. We recently discovered that type 3 p90 ribosomal S6 kinase (RSK3) is an ERK effector that is required, like ERK1/2, for concentric myocyte hypertrophy in response to pathological stress such as pressure overload. In order to test whether RSK3 also contributes to NS-associated hypertrophic cardiomyopathy, RSK3 knock-out mice were crossed with mice bearing the Raf1(L613V) human NS mutation. We confirmed that Raf1(L613V) knock-in confers a NS-like phenotype, including cardiac hypertrophy. Active RSK3 was increased in Raf1(L613V) mice. Constitutive RSK3 gene deletion prevented the Raf1(L613V)-dependent concentric growth in width of the cardiac myocyte and attenuated cardiac hypertrophy in female mice. These results are consistent with RSK3 being an important mediator of ERK1/2-dependent growth in RASopathy. In conjunction with previously published data showing that RSK3 is important for pathological remodeling of the heart, these data suggest that targeting of this downstream MAP-kinase pathway effector should be considered in the treatment of RASopathy-associated hypertrophic cardiomyopathy. Copyright © 2016 Elsevier Ltd. All rights reserved.

A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair.

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Gripp, Karen W; Aldinger, Kimberly A; Bennett, James T; Baker, Laura; Tusi, Jessica; Powell-Hamilton, Nina; Stabley, Deborah; Sol-Church, Katia; Timms, Andrew E; Dobyns, William B

2016-09-01

Noonan syndrome is a rasopathy caused by mutations in multiple genes encoding components of the RAS/MAPK pathway. Despite its variable phenotype, limited genotype-phenotype correlations exist. Noonan syndrome with loose anagen hair (NS-LAH) is characterized by its distinctive hair anomalies, developmental differences, and structural brain abnormalities and is caused by a single recurrent missense SHOC2 mutation. SHOC2 forms a complex with protein phosphatase 1 (PP1C). Protein phosphatases counterbalance kinases and control activation of signaling proteins, such as the mitogen-activated protein kinases of the RAS/MAPK pathway. Here we report four patients with de novo missense mutations in protein phosphatase one catalytic subunit beta (PPP1CB), sharing a recognizable phenotype. Three individuals had the recurrent PPP1CB c.146G>C, p.Pro49Arg mutation, the fourth had a c.166G>C, p.Ala56Pro change. All had relative or absolute macrocephaly, low-set and posteriorly angulated ears, and developmental delay. Slow growing and/or sparse hair and/or an unruly hair texture was present in all. Three individuals had feeding difficulties requiring feeding tubes. One of two males had cryptorchidism, another had pectus excavatum. Short stature was present in three. A female with the recurrent mutation had a Dandy-Walker malformation and optic nerve hypoplasia. Mild ventriculomegaly occurred in all, cerebellar tonsillar ectopia was seen in two and progressed to Chiari 1 malformation in one individual. Based on the combination of phenotypic findings and PPP1CB's effect on RAF dephosphorylation within the RAS/MAPK pathway, this novel condition can be considered a rasopathy, most similar to NS-LAH. Collectively, these mutations meet the standardized criteria for pathogenicity. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The other side of Turner′s: Noonan′s syndrome

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Pankaj Agarwal

2013-01-01

Full Text Available Noonan Syndrome (NS is an autosomal dominant disorder characterized by short stature, typical face dysmorphology, and congenital heart defects. NS is a clinical diagnosis. Establishing the diagnosis can be very difficult, especially in adulthood. There is a great variability in expression, and the phenotype becomes less pronounced with increasing age.

Noonan syndrome-like disorder with loose anagen hair: a second case with neuroblastoma.

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Garavelli, Livia; Cordeddu, Viviana; Errico, Stefania; Bertolini, Patrizia; Street, Maria Elisabeth; Rosato, Simonetta; Pollazzon, Marzia; Wischmeijer, Anita; Ivanovski, Ivan; Daniele, Paola; Bacchini, Ermanno; Lombardi, Alfonsa Anna; Izzi, Giancarlo; Biasucci, Giacomo; Del Rossi, Carmine; Corradi, Domenico; Cazzaniga, Giovanni; Dominici, Carlo; Rossi, Cesare; De Luca, Alessandro; Bernasconi, Sergio; Riccardi, Riccardo; Legius, Eric; Tartaglia, Marco

2015-08-01

Noonan-like syndrome with loose anagen hair (NSLH), also known as Mazzanti syndrome, is a RASopathy characterized by craniofacial features resembling Noonan syndrome, cardiac defects, cognitive deficits and behavioral issues, reduced growth generally associated with GH deficit, darkly pigmented skin, and an unique combination of ectodermal anomalies. Virtually all cases of NSLH are caused by an invariant and functionally unique mutation in SHOC2 (c.4A>G, p.Ser2Gly). Here, we report on a child with molecularly confirmed NSLH who developed a neuroblastoma, first suspected at the age 3 months by abdominal ultrasound examination. Based on this finding, scanning of the SHOC2 coding sequence encompassing the c.4A>G change was performed on selected pediatric cohorts of malignancies documented to occur in RASopathies (i.e., neuroblastoma, brain tumors, rhabdomyosarcoma, acute lymphoblastic, and myeloid leukemia), but failed to identify a functionally relevant cancer-associated variant. While these results do not support a major role of somatic SHOC2 mutations in these pediatric cancers, this second instance of neuroblastoma in NSLAH suggests a possible predisposition to this malignancy in subjects heterozygous for the c.4A>G SHOC2 mutation. © 2015 Wiley Periodicals, Inc.

Pulmonary Vasculitis and a Horseshoe Kidney in Noonan Syndrome

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Surasak Puvabanditsin

2018-01-01

Full Text Available We report a term male neonate with congenital myeloproliferative disorder, thrombocytopenia, a horseshoe kidney, feeding difficulty secondary to dysphagia/foregut dysmotility, and respiratory failure. Prenatal molecular genetic analysis revealed a fetus carrying c.184T>G (p.Tyr62Asp pathogenic variant in PTPN11. The infant eventually succumbed to respiratory failure. Bacterial and viral cultures/studies were all no growth/negative. Pulmonary capillaritis and vasculitis were noted at autopsy. This report presents a new case of Noonan syndrome with unusual associated disorders and a review of the literature.

Pulmonary Vasculitis and a Horseshoe Kidney in Noonan Syndrome.

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Puvabanditsin, Surasak; Abellar, Rosanna; Madubuko, Adaora; Mehta, Rajeev; Walzer, Lauren

2018-01-01

We report a term male neonate with congenital myeloproliferative disorder, thrombocytopenia, a horseshoe kidney, feeding difficulty secondary to dysphagia/foregut dysmotility, and respiratory failure. Prenatal molecular genetic analysis revealed a fetus carrying c.184T>G (p.Tyr62Asp) pathogenic variant in PTPN11 . The infant eventually succumbed to respiratory failure. Bacterial and viral cultures/studies were all no growth/negative. Pulmonary capillaritis and vasculitis were noted at autopsy. This report presents a new case of Noonan syndrome with unusual associated disorders and a review of the literature.

Anterior uveitis and congenital fibrosis of the extraocular muscles in a patient with Noonan syndrome

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Elgohary Mostafa

2005-01-01

Full Text Available We describe a patient with Noonan syndrome who presented with Human Leukocyte Antigen B27-associated recurrent acute anterior uveitis and manifestations of congenital fibrosis of the extraocular muscles, which has not been reported before.

Computed tomography after lymphangiography in the diagnosis of intestinal lymphangiectasia with protein-losing enteropathy in Noonan's syndrome

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Keberle, M.; Jenett, M.; Hahn, D. [Univ. of Wuerzburg (Germany). Dept. of Radiology; Moerk, H.; Scheurlen, M. [Wuerzburg Univ. (Germany). Medizinische Poliklinik

2000-10-01

Noonan's syndrome is a rare congenital disorder that may be associated with abnormalities in the lymphatic drainage. In this case of a 21-year-old man CT after bipedal lymphangiography confirmed the diagnosis of intestinal lymphangiectasy causing protein-losing enteropathy in Noonan's syndrome by showing contrast-enhanced abnormal lymphatic vessels in the mesentery and the intestinal wall. Because of the benefit of diet in case of intestinal involvement, we recommend a thorough documentation of the lymphatic drainage with lymphangiography followed by CT, if clinical signs of lymphatic dysplasia, such as pleural effusions, lymphedema, or hypoproteinemia are present. (orig.)

Multiple giant cell lesions in a patient with Noonan syndrome with multiple lentigines

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van den Berg, Henk; Schreuder, Willem Hans; Jongmans, Marjolijn; van Bommel-Slee, Danielle; Witsenburg, Bart; de Lange, Jan

2016-01-01

A patient with Noonan syndrome with multiple lentigines (NSML) and multiple giant cell lesions (MGCL) in mandibles and maxillae is described. A mutation p.Thr468Met in the PTPN11-gene was found. This is the second reported NSML patient with MGCL. Our case adds to the assumption that, despite a

Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype

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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

MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1L613V mutation

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Wu, Xue; Simpson, Jeremy; Hong, Jenny H.; Kim, Kyoung-Han; Thavarajah, Nirusha K.; Backx, Peter H.; Neel, Benjamin G.; Araki, Toshiyuki

2011-01-01

Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden death in children and young adults. Abnormalities in several signaling pathways are implicated in the pathogenesis of HCM, but the role of the RAS-RAF-MEK-ERK MAPK pathway has been controversial. Noonan syndrome (NS) is one of several autosomal-dominant conditions known as RASopathies, which are caused by mutations in different components of this pathway. Germline mutations in RAF1 (which encodes the serine-threonine kinase RAF1) account for approximately 3%–5% of cases of NS. Unlike other NS alleles, RAF1 mutations that confer increased kinase activity are highly associated with HCM. To explore the pathogenesis of such mutations, we generated knockin mice expressing the NS-associated Raf1L613V mutation. Like NS patients, mice heterozygous for this mutation (referred to herein as L613V/+ mice) had short stature, craniofacial dysmorphia, and hematologic abnormalities. Valvuloseptal development was normal, but L613V/+ mice exhibited eccentric cardiac hypertrophy and aberrant cardiac fetal gene expression, and decompensated following pressure overload. Agonist-evoked MEK-ERK activation was enhanced in multiple cell types, and postnatal MEK inhibition normalized the growth, facial, and cardiac defects in L613V/+ mice. These data show that different NS genes have intrinsically distinct pathological effects, demonstrate that enhanced MEK-ERK activity is critical for causing HCM and other RAF1-mutant NS phenotypes, and suggest a mutation-specific approach to the treatment of RASopathies. PMID:21339642

Transient juvenile myelomonocytic leukemia in the setting of PTPN11 mutation and Noonan syndrome with secondary development of monosomy 7.

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O'Halloran, Katrina; Ritchey, A Kim; Djokic, Miroslav; Friehling, Erika

2017-07-01

Juvenile myelomonocytic leukemia (JMML) is a rare childhood neoplasm with poor prognosis except in the setting of Noonan syndrome, where prognosis is generally favorable. We present the case of a child with JMML in the setting of germline PTPN11 mutation and Noonan syndrome with suspected secondary development of monosomy 7 in the bone marrow. Diagnosed shortly after birth, she has been managed with active surveillance alone. Myeloblast percentages initially fluctuated; however, bone marrow biopsy at 4 years of age showed spontaneous remission despite persistence of the monosomy 7 clone, supporting a cautious approach in similar cases. © 2017 Wiley Periodicals, Inc.

The efficacy and safety of growth hormone therapy in children with noonan syndrome: a review of the evidence.

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Noonan, Jacqueline A; Kappelgaard, Anne-Marie

2015-01-01

Noonan syndrome is a genetic disorder associated with short stature. We reviewed 15 studies in which growth hormone (GH) therapy was used in children with Noonan syndrome. Data show consistent increases in mean height standard deviation score (SDS), with first-year changes of up to 1.26 SDS. Among studies reporting adult or near-adult height, GH therapy over 5-7 years resulted in adult height SDS from -0.6 to -2.1, with up to 60% of subjects in some studies achieving adult height within 1 SDS of mid-parental height. GH treatment results in an acceleration of bone age, likely reflecting normalization from the retarded bone age common in Noonan syndrome patients at the start of therapy. BMI is not affected by GH treatment, but favorable changes in fat mass and body composition are achievable. Longer-term studies and observational studies suggest a waning of the effect of GH therapy over time, as is seen in other GH-treated conditions, and early initiation of therapy and prepubertal status are important predictors of response. GH treatment does not appear to be associated with adverse cardiac or metabolic effects, and data on malignancy during GH treatment give no cause for concern, although they are limited. © 2014 S. Karger AG, Basel.

Transcatheter closure of atrial septal defect in a patient with Noonan syndrome after corrective surgery

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Mangovski Ljupčo

2015-01-01

Full Text Available Introduction. Transcatheter atrial septal defect (ASD closure is considered to be a gold standard for patients with the suitable anatomy as compared to cardiac surgery. Reocurrence of ASD after surgical closure is a very rare late complication which can be successfully managed with transcatheter procedure. Case report. We reported a female patient with Noonan syndrome who presented with hemodinamically significant ASD 37 years after the corrective cardiac surgery. Due to numerous comorbidities which included severe kyphoscoliosis, pectus excavatum and multiple surgeries we decided to perform transcatheter closure of ASD. The procedure itself was very challenging due to the patient’s short stature and heart’s orientation in the chest, but was performed successfully. The subsequent follow-up was uneventful and the patient reported improvement in the symptoms. Conclusion. Transcatheter closure of ASD in a patient with Noonan syndrome with the history of surgically corrected ASD can be performed successfully, despite challenging chest anatomy.

Shp2 knockdown and Noonan/LEOPARD mutant Shp2-induced gastrulation defects.

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Chris Jopling

2007-12-01

Full Text Available Shp2 is a cytoplasmic protein-tyrosine phosphatase that is essential for normal development. Activating and inactivating mutations have been identified in humans to cause the related Noonan and LEOPARD syndromes, respectively. The cell biological cause of these syndromes remains to be determined. We have used the zebrafish to assess the role of Shp2 in early development. Here, we report that morpholino-mediated knockdown of Shp2 in zebrafish resulted in defects during gastrulation. Cell tracing experiments demonstrated that Shp2 knockdown induced defects in convergence and extension cell movements. In situ hybridization using a panel of markers indicated that cell fate was not affected by Shp2 knock down. The Shp2 knockdown-induced defects were rescued by active Fyn and Yes and by active RhoA. We generated mutants of Shp2 with mutations that were identified in human patients with Noonan or LEOPARD Syndrome and established that Noonan Shp2 was activated and LEOPARD Shp2 lacked catalytic protein-tyrosine phosphatase activity. Expression of Noonan or LEOPARD mutant Shp2 in zebrafish embryos induced convergence and extension cell movement defects without affecting cell fate. Moreover, these embryos displayed craniofacial and cardiac defects, reminiscent of human symptoms. Noonan and LEOPARD mutant Shp2s were not additive nor synergistic, consistent with the mutant Shp2s having activating and inactivating roles in the same signaling pathway. Our results demonstrate that Shp2 is required for normal convergence and extension cell movements during gastrulation and that Src family kinases and RhoA were downstream of Shp2. Expression of Noonan or LEOPARD Shp2 phenocopied the craniofacial and cardiac defects of human patients. The finding that defective Shp2 signaling induced cell movement defects as early as gastrulation may have implications for the monitoring and diagnosis of Noonan and LEOPARD syndrome.

Síndrome de Noonan: Presentación de dos casos Noonan's syndrome: Presentation of two cases

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Lucy Pons Castro

2009-06-01

Full Text Available Se presentan las características oftalmológicas y clínicas de dos pacientes hermanos (hembra y varón con diagnóstico del síndrome de Noonan. Este es un trastorno genético que produce desarrollo anormal de múltiples partes del cuerpo. Se caracteriza por una serie de signos y particularidades físicas que pueden variar ampliamente en rango y severidad según los casos. Generalmente se transmite como un rasgo genético autosómico dominante. Los casos que presentamos se caracterizan por: estenosis valvular pulmonar, hipertelorismo, retardo mental moderado, aspecto típico de la cara con filtrum (surco vertical en el centro del labio superior, párpados gruesos, epicanto, exoftalmos y ptosis palpebral.The ophthalmological and clinical characteristics of two sibling patients (male and female diagnosed with Noonan´s syndrome were presented in this paper. This is a genetic disorder that causes abnormal development of many parts of the body. It is characterized by a series of signs and physical peculiarities that may widely vary in range and severity from one case to another. Generally, it is transmitted as a dominant autosomal genetic trait. The two cases had the following features: pulmonary valve stenosis, hypertelorism, moderate mental retardation, typical aspect of the individual's face with filtrum (vertical sulcus located in the center of the upper lip, thick eyelids, epicanthus, exophthalmos and palpebral ptosis

An Evaluation of the Possible Association of Malignant Hyperpyrexia with the Noonan Syndrome Using Serum Creatine Phosphokinase Levels

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Hunter, Alasdair; Pinsky, Leonard

1975-01-01

Examined for malignant hyperpyrexia (extremely high fever) were serum creatine phosphokinase (enzyme) levels of 27 children from 1-to 17-years-old with Noonan syndrome which is characterized by webbed neck, short stature and low set ears. (CL)

Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation

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Chen, Peng-Chieh; Wakimoto, Hiroko; Conner, David; Araki, Toshiyuki; Yuan, Tao; Roberts, Amy; Seidman, Christine E.; Bronson, Roderick; Neel, Benjamin G.; Seidman, Jonathan G.; Kucherlapati, Raju

2010-01-01

Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, unique facial features, and congenital heart disease. About 10%–15% of individuals with NS have mutations in son of sevenless 1 (SOS1), which encodes a RAS and RAC guanine nucleotide exchange factor (GEF). To understand the role of SOS1 in the pathogenesis of NS, we generated mice with the NS-associated Sos1E846K gain-of-function mutation. Both heterozygous and homozygous mutant mice showed many NS-associated phenotypes, including growth delay, distinctive facial dysmorphia, hematologic abnormalities, and cardiac defects. We found that the Ras/MAPK pathway as well as Rac and Stat3 were activated in the mutant hearts. These data provide in vivo molecular and cellular evidence that Sos1 is a GEF for Rac under physiological conditions and suggest that Rac and Stat3 activation might contribute to NS phenotypes. Furthermore, prenatal administration of a MEK inhibitor ameliorated the embryonic lethality, cardiac defects, and NS features of the homozygous mutant mice, demonstrating that this signaling pathway might represent a promising therapeutic target for NS. PMID:21041952

Long-term efficacy of recombinant human growth hormone therapy in short-statured patients with Noonan syndrome

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Insook Jeong

2016-03-01

Full Text Available PurposeNoonan syndrome (NS is characterized by short stature, heart anomalies, developmental delays, dysmorphic features, cryptorchidism, and coagulation defects. Several studies reported the short-term effects of recombinant human growth hormone (rhGH treatment on the improvement of height. This study was performed to evaluate the long-term efficacy of rhGH in children with NS in Korea.MethodsThis study included 15 prepubertal NS children who received rhGH subcutaneously at a dose of 50–75 µg/kg/day for 6 days a week for at least >3 years. Preand posttreatment data, such as height, weight, bone age, insulin-like growth factor 1 (IGF-1, and IGF binding protein 3 (IGFBP-3 levels, were collected every 6 months.ResultsChronologic age and bone age at the start of treatment were 7.97±1.81 and 5.09±2.12 years, respectively. Height standard deviation score (SDS was increased from –2.64±0.64 to –1.54±1.24 years after 3 years (P<0.001. Serum IGF-1 SDS levels were elevated from –1.28±1.03 to –0.10±0.94 (P<0.001. Height SDS was more increased in subjects without PTPN11 mutations compared to those with mutations after 3 years (P=0.012. However, the other parameters, including bone age, IGF-1 SDS, and IGFBP-3 SDS, were not significantly different between patients with and without PTPN11 mutations.ConclusionAlthough this study included a relatively small number of patients, long-term rhGH therapy in NS patients was safe and effective at improving height, growth velocity, and serum IGF-1 levels, in accordance with previous studies. However, the meticulous monitoring of potential adverse events is still needed because of high dose of rhGH and preexisting hyperactivity of RAS-MAPK pathway. Patients with PTPN11 mutations demonstrated a decreased response to rhGH therapy compared to those without mutations.

Noonan's syndrome: case report

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Dias, Vanderson Glerian; Gigante, Edmilson; Valério, Fátima Jesus Passador; Gonçalves, Flávia Fauaz; Bezzon, Ana Karina Teixeira; Aguni, Joran Seiko

2004-01-01

Os autores apresentam um caso de síndrome de Noonan em criança de 14 anos de idade, diagnosticada por meio de exame genético-clínico, demonstrando alterações oftalmológicas como hipertelorismo, alterações da fenda palpebral, hipotropia direita com pequena anisotropia em V, nistagmo, ptose palpebral bilateral e ambliopia do olho direito. Discute-se a importância do oftalmologista para esta síndrome e a necessidade do acompanhamento por equipe médica multidisciplinar.The authors present the cas...

LEOPARD syndrome

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Multiple lentigines syndrome; Noonan syndrome with multiple lentigines ... Genetics Home Reference -- ghr.nlm.nih.gov/condition/noonan-syndrome-with-multiple-lentigines National Organization for Rare Disorders -- ...

Efficacy and safety of two doses of Norditropin® (somatropin) in short stature due to Noonan syndrome: a 2-year randomized, double-blind, multicenter trial in Japanese patients.

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Ozono, Keiichi; Ogata, Tsutomu; Horikawa, Reiko; Matsubara, Yoichi; Ogawa, Yoshihisa; Nishijima, Keiji; Yokoya, Susumu

2018-02-26

This randomized double-blind multicenter trial (NCT01927861) evaluated the growth-promoting effect and safety of Norditropin ® (NN220; somatropin) in Japanese children with short stature due to Noonan syndrome. Prepubertal children aged 3-Noonan syndrome were randomized to receive GH 0.033 mg/kg/day (n = 25, mean age 6.57 years, 11 females) or 0.066 mg/kg/day (n = 26, mean age 6.06 years, eight females) for 104 weeks. Change in height standard deviation score (HSDS) from baseline was analyzed based on an ANCOVA model. Baseline HSDS was -3.24. Estimated change in HSDS [95% CI] after 104 weeks' treatment was 0.84 [0.66, 1.02] and 1.47 [1.29, 1.64] for the lower and higher doses, respectively; estimated mean difference 0.63 [0.38, 0.88], p Noonan syndrome, with a favorable safety profile. The effect was greater with 0.066 mg/kg/day compared with 0.033 mg/kg/day.

Nutritional aspects of Noonan syndrome and Noonan-related disorders.

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da Silva, Fernanda Marchetto; Jorge, Alexander Augusto; Malaquias, Alexandra; da Costa Pereira, Alexandre; Yamamoto, Guilherme Lopes; Kim, Chong Ae; Bertola, Debora

2016-06-01

Rasopathies are a group of rare disorders characterized by neurocardiofaciocutaneous involvement, and caused by mutations in several genes of the RAS/MAPK pathway. In the present study, we characterized growth parameters, body composition, and nutritional aspects of children and adults (n = 62) affected by these disorders, mainly Noonan syndrome, using an indirect method-anthropometry-and a 24-hr recall questionnaire. The growth parameters in our cohort showed short stature, especially in individuals with RAF1 and SHOC2 mutations, lower obesity rates compared to the control population, and BMI scores highest in individuals with BRAF mutations and lowest in individuals with SHOC2. Body composition showed a compromise in the upper arm muscle circumference, with a statistically significant difference in the z-score of triceps skinfold (P = 0.0204) and upper arm fat area (P = 0.0388) between BRAF and SHOC2 groups and in the z-score of triceps skinfold between RAF1 and SHOC2 (P = 0.0218). The pattern of macronutrient consumption was similar to the control population. Our study is the first to address body composition in RASopathy individuals and the data indicate a compromise not only in adipose tissue, but also in muscle mass. Studies using different techniques, such as dual-energy X-ray absorptiometry or imaging studies, which give a more precise delineation of fat and non-fat mass, are required to confirm our results, ultimately causing an impact on management strategies. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Nodding syndrome (NS) and Onchocerca Volvulus (OV) in Northern Uganda.

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Lagoro, David Kitara; Arony, Denis Anywar

2017-01-01

Nodding Syndrome (NS) is a childhood neurological disorder characterized by atonic seizures, cognitive decline, school dropout, muscle weakness, thermal dysfunction, wasting and stunted growth. There are recent published information suggesting associations between Nodding Syndrome (NS) with cerebrospinal fluid (CSF) VGKC antibodies and serum leiomidin-1 antibody cross reacting with Onchocerca Volvulus ( OV ). These findings suggest a neuro-inflammatory cause of NS and they are important findings in the search for the cause of Nodding Syndrome. These observations perhaps provide further, the unique explanation for the association between Nodding Syndrome and Onchocerca Volvulus . Many clinical and epidemiological studies had shown a significant correlation between NS and infestation with a nematode, Onchocerca volvulus which causes a disease, Onchocerciasis , some of which when left untreated can develop visual defect ("River Blindness"). While these studies conducted in Northern Uganda and Southern Sudan indicate a statistically significant association with ( OV infection (using positive skin snips), we observe that ( OV is generally endemic in many parts of Sub Saharan Africa and Latin America and that to date, no NS cases have been recorded in those regions. This letter to the Editor is to provide additional information on the current view about the relationship between Nodding Syndrome and Onchocerca Volvulus as seen in Northern Uganda.

Moyamoya disease in two patients with Noonan-like syndrome with loose anagen hair.

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Lo, Fu-Sung; Wang, Chao-Jan; Wong, Mun-Ching; Lee, Ni-Chung

2015-06-01

Moyamoya disease is a unique chronic cerebrovascular condition caused by progressive stenosis of the arteries around the circle of Willis with prominent arterial collateral circulation. Noonan-like syndrome with loose anagen hair (NSLH) is characterized by short stature, characteristic facial phenotype, darkly pigmented and hairless skin, mild psychomotor delay with attention deficit disorder, and easily pluckable, sparse, thin, slow growing hair. Mutations in SHOC2 have been reported to underlie NSLH. In this paper, we describe two individuals with NSLH who also have moyamoya disease and in whom heterozygous germline mutation in SHOC2 was found. © 2015 Wiley Periodicals, Inc.

Multiple spinal nerve enlargement and SOS1 mutation: Further evidence of overlap between neurofibromatosis type 1 and Noonan phenotype.

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Santoro, C; Giugliano, T; Melone, M A B; Cirillo, M; Schettino, C; Bernardo, P; Cirillo, G; Perrotta, S; Piluso, G

2018-01-01

Neurofibromatosis type 1 (NF1) has long been considered a well-defined, recognizable monogenic disorder, with neurofibromas constituting a pathognomonic sign. This dogma has been challenged by recent descriptions of patients with enlarged nerves or paraspinal tumors, suggesting that neurogenic tumors and hypertrophic neuropathy may be a complication of Noonan syndrome with multiple lentigines (NSML) or RASopathy phenotype. We describe a 15-year-old boy, whose mother previously received clinical diagnosis of NF1 due to presence of bilateral cervical and lumbar spinal lesions resembling plexiform neurofibromas and features suggestive of NS. NF1 molecular analysis was negative in the mother. The boy presented with Noonan features, multiple lentigines and pectus excavatum. Next-generation sequencing analysis of all RASopathy genes identified p.Ser548Arg missense mutation in SOS1 in the boy, confirmed in his mother. Brain and spinal magnetic resonance imaging scans were negative in the boy. No heart involvement or deafness was observed in proband or mother. This is the first report of a SOS1 mutation associated with hypertrophic neuropathy resembling plexiform neurofibromas, a rare complication in Noonan phenotypes with mutations in RASopathy genes. Our results highlight the overlap between RASopathies, suggesting that NF1 diagnostic criteria need rethinking. Genetic analysis of RASopathy genes should be considered when diagnosis is uncertain. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Life-Threatening Obstructive Sleep Apnea Caused by Adenoid Hypertrophy in an Infant with Noonan Syndrome

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Sonia Khirani

2012-01-01

Full Text Available Adenoidectomy is a commonly performed surgery in children, even though its effectiveness is still under investigation. However, in children with risk factors such as age under 3 years old, associated comorbidities, or severe obstructive sleep apneas, a high postoperative respiratory morbidity is possible. We report the case of a 15-month-old boy with Noonan syndrome and a complex clinical history, who presented with a life-threatening obstructive sleep apnea due to hypertrophy of the adenoids which resolved completely after adenoidectomy.

Genetics Home Reference: Costello syndrome

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... other genetic conditions, cardiofaciocutaneous syndrome (CFC syndrome) and Noonan syndrome . In affected infants, it can be difficult to ... These individuals may actually have CFC syndrome or Noonan syndrome , which are caused by mutations in related genes. ...

Impaired binding of 14-3-3 to C-RAF in noonan syndrome suggests new approaches in diseases with increased ras signaling

NARCIS (Netherlands)

Molzan, M.; Schumacher, B.; Ottmann, C.; Baljuls, A.; Polzien, L.; Weyand, M.; Thiel, P.; Rose, R.; Rose, M.; Kuhenne, P.; Kaiser, M.; Rapp, U.R.; Kuhlmann, J.; Ottmann, C.

2010-01-01

The Ras-RAF-mitogen-activated protein kinase (Ras-RAF-MAPK) pathway is overactive in many cancers and in some developmental disorders. In one of those disorders, namely, Noonan syndrome, nine activating C-RAF mutations cluster around Ser(259), a regulatory site for inhibition by 14-3-3 proteins. We

Protein tyrosine phosphatase SHP2/PTPN11 mistargeting as a consequence of SH2-domain point mutations associated with Noonan Syndrome and leukemia

DEFF Research Database (Denmark)

Müller, Pia J; Rigbolt, Kristoffer T G; Paterok, Dirk

2013-01-01

SHP2/PTPN11 is a key regulator of cytokine, growth factor and integrin signaling. SHP2 influences cell survival, proliferation and differentiation by regulating major signaling pathways. Mutations in PTPN11 cause severe diseases like Noonan, LEOPARD syndrome or leukemia. Whereas several...

Genetic Defects Underlie the Non-syndromic Autosomal Recessive Intellectual Disability (NS-ARID

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Saleha Shamim

2017-05-01

Full Text Available Intellectual disability (ID is a neurodevelopmental disorder which appears frequently as the result of genetic mutations and may be syndromic (S-ID or non-syndromic (NS-ID. ID causes an important economic burden, for patient's family, health systems, and society. Identifying genes that cause S-ID can easily be evaluated due to the clinical symptoms or physical anomalies. However, in the case of NS-ID due to the absence of co-morbid features, the latest molecular genetic techniques can be used to understand the genetic defects that underlie it. Recent studies have shown that non-syndromic autosomal recessive (NS-ARID is extremely heterogeneous and contributes much more than X-linked ID. However, very little is known about the genes and loci involved in NS-ARID relative to X-linked ID, and whose complete genetic etiology remains obscure. In this review article, the known genetic etiology of NS-ARID and possible relationships between genes and the associated molecular pathways of their encoded proteins has been reviewed which will enhance our understanding about the underlying genes and mechanisms in NS-ARID.

Noonan 症候群に原発性肺高血圧症を合併した1症例

OpenAIRE

Okahatau, Hiroyasu; Nishi, Yoshikazu; Yoshimitsu, Hajime; Tanimoto, Takeshi; Usui, Tomofusa

1982-01-01

A case of Noonan's syndrome with primary pulmonary hypertension is reported. The patient has multiple anomalies (small mandible, high arched palate, low set ears, hypertelorism, and webbed neck). He has normal karyotype. Cardiac examinations show pulmonary hypertension, right ventricular hypertrophy, high RPEP/RVET and no other shunt diseases. We consider that this is the first reported case of Noonan's syndrome with primary pulmonary hypertension.

Evolutionary analyses of entire genomes do not support the association of mtDNA mutations with Ras/MAPK pathway syndromes.

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Alberto Gómez-Carballa

Full Text Available BACKGROUND: There are several known autosomal genes responsible for Ras/MAPK pathway syndromes, including Noonan syndrome (NS and related disorders (such as LEOPARD, neurofibromatosis type 1, although mutations of these genes do not explain all cases. Due to the important role played by the mitochondrion in the energetic metabolism of cardiac muscle, it was recently proposed that variation in the mitochondrial DNA (mtDNA genome could be a risk factor in the Noonan phenotype and in hypertrophic cardiomyopathy (HCM, which is a common clinical feature in Ras/MAPK pathway syndromes. In order to test these hypotheses, we sequenced entire mtDNA genomes in the largest series of patients suffering from Ras/MAPK pathway syndromes analyzed to date (n = 45, most of them classified as NS patients (n = 42. METHODS/PRINCIPAL FINDINGS: The results indicate that the observed mtDNA lineages were mostly of European ancestry, reproducing in a nutshell the expected haplogroup (hg patterns of a typical Iberian dataset (including hgs H, T, J, and U. Three new branches of the mtDNA phylogeny (H1j1, U5b1e, and L2a5 are described for the first time, but none of these are likely to be related to NS or Ras/MAPK pathway syndromes when observed under an evolutionary perspective. Patterns of variation in tRNA and protein genes, as well as redundant, private and heteroplasmic variants, in the mtDNA genomes of patients were as expected when compared with the patterns inferred from a worldwide mtDNA phylogeny based on more than 8700 entire genomes. Moreover, most of the mtDNA variants found in patients had already been reported in healthy individuals and constitute common polymorphisms in human population groups. CONCLUSIONS/SIGNIFICANCE: As a whole, the observed mtDNA genome variation in the NS patients was difficult to reconcile with previous findings that indicated a pathogenic role of mtDNA variants in NS.

Evolutionary Analyses of Entire Genomes Do Not Support the Association of mtDNA Mutations with Ras/MAPK Pathway Syndromes

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Cerezo, María; Balboa, Emilia; Heredia, Claudia; Castro-Feijóo, Lidia; Rica, Itxaso; Barreiro, Jesús; Eirís, Jesús; Cabanas, Paloma; Martínez-Soto, Isabel; Fernández-Toral, Joaquín; Castro-Gago, Manuel; Pombo, Manuel; Carracedo, Ángel; Barros, Francisco

2011-01-01

Background There are several known autosomal genes responsible for Ras/MAPK pathway syndromes, including Noonan syndrome (NS) and related disorders (such as LEOPARD, neurofibromatosis type 1), although mutations of these genes do not explain all cases. Due to the important role played by the mitochondrion in the energetic metabolism of cardiac muscle, it was recently proposed that variation in the mitochondrial DNA (mtDNA) genome could be a risk factor in the Noonan phenotype and in hypertrophic cardiomyopathy (HCM), which is a common clinical feature in Ras/MAPK pathway syndromes. In order to test these hypotheses, we sequenced entire mtDNA genomes in the largest series of patients suffering from Ras/MAPK pathway syndromes analyzed to date (n = 45), most of them classified as NS patients (n = 42). Methods/Principal Findings The results indicate that the observed mtDNA lineages were mostly of European ancestry, reproducing in a nutshell the expected haplogroup (hg) patterns of a typical Iberian dataset (including hgs H, T, J, and U). Three new branches of the mtDNA phylogeny (H1j1, U5b1e, and L2a5) are described for the first time, but none of these are likely to be related to NS or Ras/MAPK pathway syndromes when observed under an evolutionary perspective. Patterns of variation in tRNA and protein genes, as well as redundant, private and heteroplasmic variants, in the mtDNA genomes of patients were as expected when compared with the patterns inferred from a worldwide mtDNA phylogeny based on more than 8700 entire genomes. Moreover, most of the mtDNA variants found in patients had already been reported in healthy individuals and constitute common polymorphisms in human population groups. Conclusions/Significance As a whole, the observed mtDNA genome variation in the NS patients was difficult to reconcile with previous findings that indicated a pathogenic role of mtDNA variants in NS. PMID:21526175

Effect of 4 years of growth hormone therapy in children with Noonan syndrome in the American Norditropin Studies: Web-Enabled Research (ANSWER Program® registry

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Lee Peter A

2012-06-01

Full Text Available Abstract Background Noonan syndrome (NS is a genetic disorder characterized by phenotypic features, including facial dysmorphology, cardiovascular anomalies, and short stature. Growth hormone (GH has been approved by the United States Food and Drug Administration for short stature in children with NS. The objective of this analysis was to assess the height standard deviation score (HSDS and change in HSDS (ΔHSDS for up to 4 years (Y4 of GH therapy in children with NS. Methods The American Norditropin Studies: Web-Enabled Research (ANSWER Program®, a US-based registry, collects long-term efficacy and safety information on patients treated with Norditropin® (somatropin rDNA origin, Novo Nordisk A/S at the discretion of participating physicians. A total of 120 children (90 boys, 30 girls with NS, naïve to previous GH treatment, were included in this analysis. Results The mean (SD baseline age of subjects (n = 120 was 9.2 (3.8 years. Mean (SD HSDS increased from –2.65 (0.73 at baseline to –1.32 (1.11 at Y4 (n = 17. Subjects showed continued increase in HSDS from baseline to Y4 without significant differences between genders at Y1 or Y2. The mean (SD GH dose was 47 (11 mcg/kg/day at baseline and 59 (16 mcg/kg/day at Y4. There was a negative correlation between baseline age and ΔHSDS at Y1 (R = –0.3156; P = 0.0055 and Y2 (R = –0.3394; P = 0.017. ΔHSDS at Y1 was significantly correlated with ΔHSDS at Y2 (n = 37; R = 0.8527, P  Conclusions GH treatment-naïve patients with NS showed continued increases in HSDS during 4 years of treatment with GH with no significant differences between genders up to 2 years. Baseline age was negatively correlated with ΔHSDS at Y1 and Y2. Whether long-term therapy in NS results in continued increase in HSDS to adult height remains to be investigated. Trial registration ClinicalTrials.gov NCT01009905

Celiac disease associated with Hashimoto's thyroiditis and Noonan syndrome

OpenAIRE

Perez, Mariana Ortega; Ciambelli, Giuliano Serafino; Nigri, Alcinda Aranha; Vieira, Marta Wey; Costa, Clóvis Duarte

2010-01-01

OBJETIVO: Relatar o caso clínico de uma criança portadora de doença celíaca, tireoidite de Hashimoto e síndrome de Noonan. DESCRIÇÃO DE CASO: Menina de dez anos e seis meses, branca, apresentando história de diarreia líquida há cinco meses e "aumento da barriga". Ao exame, mostrava peso de 20.580g (p

Noonan′s Syndrome

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Yesudian P Devakar

1995-01-01

Full Text Available Noonan’s syndrome is characterized by hypertelorism, webbed neck, curly or wooly hair, congenital heart defects, micrognathia and low set ears. A 15 year old male presented with features of Noonan’s syndrome with hypertelorism, cryptorchidism, low hairline, large and low set ears, curly hair, pulmonary stenosis and lentigenes. This case is presented to alert the physicians towards the occurrence of lentigenes, characteristic facies and pulmonary stenosis in the syndrome. A few hitherto unreported associations like macrothelia and high arched palate were also seen.

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.

Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome

NARCIS (Netherlands)

Narumi, Yoko; Aoki, Yoko; Niihori, Tetsuya; Neri, Giovanni; Cave, Helene; Verloes, Alain; Nava, Caroline; Kavamura, Maria Ines; Okamoto, Nobuhiko; Kurosawa, Kenji; Hennekam, Raoul C. M.; Wilson, Louise C.; Gillessen-Kaesbach, Gabriele; Wieczorek, Dagmar; Lapunzina, Pablo; Ohashi, Hirofumi; Makita, Yoshio; Kondo, Ikuko; Tsuchiya, Shigeru; Ito, Etsuro; Sameshima, Kiyoko; Kato, Kumi; Kure, Shigeo; Matsubara, Yokhi

2007-01-01

Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by heart defects, a distinctive facial appearance, ectodermal abnormalities and mental retardation. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are

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 ...

Cardiac imaging in RASopathies/mitogen activated protein kinase syndromes

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Rita Gravino

2014-07-01

Full Text Available RASopathies include a spectrum of disorders due to dysregulation of RAS/mitogen activated protein kinase pathway that plays an essential role in the control of the cell cycle and differentiation. As a consequence, its dysregulation has profound developmental consequences, in particular cardiac malformations. RASopathies with cardiac features are: Noonan syndrome, multiple lentigines syndrome, cardio-faciocutaneous syndrome, Costello syndrome, neurofibromatosis- 1, Legius syndrome, neurofibromatosis- Noonan syndrome. The former syndromes are associated with a high rate of cardiac involvement (60-85% and 12 genes: PTPN11, SOS1, RAF1, KRAS, HRAS, BRAF, MEK1/MAP2K1, MEK2/MAP2K2, NRAS, SHOC2, CBL and SPRED1. Although the majority of these diseases are readily distinguishable in clinical terms, an integrated imaging study of the cardiac condition associated to RASopathies helps to better define risk assessment, surveillance, and management of these patients.

Patient with confirmed LEOPARD syndrome developing multiple melanoma

OpenAIRE

Colmant, Caroline; Franck, Deborah; Marot, Liliane; Matthijs, Gert; Sznajer, Yves; Blomme, Sandrine; Tromme, Isabelle

2018-01-01

LEOPARD syndrome, also known as Gorlin syndrome II, cardiocutaneous syndrome, lentiginosis profusa syndrome, Moynahan syndrome, was more recently coined as Noonan syndrome with multiple lentigines (NSML), inside the RASopathies. Historically, the acronym LEOPARD refers to the presence of distinctive clinical features such as: lentigines (L), electrocardiographic/conduction abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), genital abnormalities (A), retardation of growth (R)...

Separate origins of the left internal and external carotid arteries from the aortic arch and cervical internal carotid artery aneurysm in a patient with Noonan syndrome.

Science.gov (United States)

Tahir, Rizwan Ahmad; Asmaro, Karam; Pabaney, Aqueel; Kole, Max; Nypaver, Timothy; Marin, Horia

2017-04-01

Distinct origins of the external carotid artery and the internal carotid artery (ICA) from the aortic arch have been rarely described, and represent an aberrant development of the aortic arches during fetal life. This anatomical variation is usually discovered incidentally; infrequently, an aneurysm of the cervical ICA might accompany this rare configuration. We describe one such case in a patient with Noonan syndrome who presented with pulsatile neck mass. The diagnostic features and management of the aneurysm and a review of the literature are presented. 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/.

Mutations in RIT1 cause Noonan syndrome - additional functional evidence and expanding the clinical phenotype.

Science.gov (United States)

Koenighofer, M; Hung, C Y; McCauley, J L; Dallman, J; Back, E J; Mihalek, I; Gripp, K W; Sol-Church, K; Rusconi, P; Zhang, Z; Shi, G-X; Andres, D A; Bodamer, O A

2016-03-01

RASopathies are a clinically heterogeneous group of conditions caused by mutations in 1 of 16 proteins in the RAS-mitogen activated protein kinase (RAS-MAPK) pathway. Recently, mutations in RIT1 were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of RIT1 mutations and expand the associated phenotypic spectrum. We identified two de novo missense variants p.Met90Ile and p.Ala57Gly. Both variants resulted in increased MEK-ERK signaling compared to wild-type, underscoring gain-of-function as the primary functional mechanism. Introduction of p.Met90Ile and p.Ala57Gly into zebrafish embryos reproduced not only aspects of the human phenotype but also revealed abnormalities of eye development, emphasizing the importance of RIT1 for spatial and temporal organization of the growing organism. In addition, we observed severe lymphedema of the lower extremity and genitalia in one patient. We provide additional evidence for a causal relationship between pathogenic mutations in RIT1, increased RAS-MAPK/MEK-ERK signaling and the clinical phenotype. The mutant RIT1 protein may possess reduced GTPase activity or a diminished ability to interact with cellular GTPase activating proteins; however the precise mechanism remains unknown. The phenotypic spectrum is likely to expand and includes lymphedema of the lower extremities in addition to nuchal hygroma. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome

NARCIS (Netherlands)

Niihori, Tetsuya; Aoki, Yoko; Narumi, Yoko; Neri, Giovanni; Cavé, Hélène; Verloes, Alain; Okamoto, Nobuhiko; Hennekam, Raoul C. M.; Gillessen-Kaesbach, Gabriele; Wieczorek, Dagmar; Kavamura, Maria Ines; Kurosawa, Kenji; Ohashi, Hirofumi; Wilson, Louise; Heron, Delphine; Bonneau, Dominique; Corona, Giuseppina; Kaname, Tadashi; Naritomi, Kenji; Baumann, Clarisse; Matsumoto, Naomichi; Kato, Kumi; Kure, Shigeo; Matsubara, Yoichi

2006-01-01

Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively. In 43 individuals with CFC, we identified two

Baraitser–Winter syndrome: An additional Egyptian patient with ...

African Journals Online (AJOL)

Rabah M. Shawky

2015-05-08

May 8, 2015 ... Abstract We report a 3.5 year old male child, second in order of birth of non consanguineous ... in this syndrome, bilateral congenital ptosis, hypertelorism, moderate mental .... ged from 2 month to 14 years and it may be intractable in some ... retardation: Baraitser–Winter syndrome or Noonan syndrome? J.

HYPERTROPHIC CARDIOMYOPATHY AS A PART OF INHERITED MALFORMATION SYNDROMES IN INFANTS

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M.V. Tural'chuk

2011-01-01

Full Text Available The data of clinical and instrumental examination of two infantile patients with obstructive hypertrophic cardiomyopathy in association with marked multisystem involvement as a picture of inherited malformation syndromes are given.Key words: infants, hypertrophic cardiomyopathy, LEOPARD syndrome, Noonan syndrome.(Voprosy sovremennoi pediatrii — Current Pediatrics. 2011; 10 (3: 166–169

Mutational analysis of the PTPN11 gene in Egyptian patients with Noonan syndrome

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Mona L. Essawi

2013-11-01

Conclusion: Knowing that NS is phenotypically heterogeneous, molecular characterization of the PTPN11 gene should serve to establish NS diagnosis in patients with atypical features, although lack of a mutation does not exclude the possibility of NS.

Gastrointestinal and renal abnormalities in cardio-facio-cutaneous syndrome

Energy Technology Data Exchange (ETDEWEB)

Herman, Thomas E.; McAlister, William H. [Washington University School of Medicine, St. Louis Children' s Hospital, Mallinckrodt Institute of Radiology, St. Louis, MO (United States)

2005-02-01

Cardio-facio-cutaneous syndrome (CFC) is an uncommon autosomal recessive condition recently distinguished from Noonan syndrome but with more marked growth failure and ectodermal dysplasia. Abdominal symptoms are frequently described but anatomic lesions in CFC have rarely been described. We have found significant anatomic abnormalities in CFC patients including antral foveolar hyperplasia, severe constipation with fecal impaction, nephrocalcinosis and renal cysts. (orig.)

Gastrointestinal and renal abnormalities in cardio-facio-cutaneous syndrome

International Nuclear Information System (INIS)

Herman, Thomas E.; McAlister, William H.

2005-01-01

Cardio-facio-cutaneous syndrome (CFC) is an uncommon autosomal recessive condition recently distinguished from Noonan syndrome but with more marked growth failure and ectodermal dysplasia. Abdominal symptoms are frequently described but anatomic lesions in CFC have rarely been described. We have found significant anatomic abnormalities in CFC patients including antral foveolar hyperplasia, severe constipation with fecal impaction, nephrocalcinosis and renal cysts. (orig.)

FOXI2: a possible gene contributing to ectodermal dysplasia.

Science.gov (United States)

Kurban, Mazen; Zeineddine, Savo Bou; Hamie, Lamiaa; Safi, Remi; Abbas, Ossama; Kibbi, Abdul Ghani; Bitar, Fadi; Nemer, Georges

2017-12-01

Cardio-facio-cutaneous syndrome (CFC), Noonan syndrome (NS), and Costello syndrome are a group of diseases that belong to the RASopathies. The syndromes share clinical features making diagnosis a challenge. To investigate the phenotype and genotype of a 10-year-old Iraqi girl with overlapping features of CFC, NS, and Costello syndromes, with additional features of ectodermal dysplasia. DNA was examined by exome sequencing and protein expression by immunohistochemistry. Exome sequencing identified a mutation in the SOS1 gene and a de novo deletion in the FOXI2 gene which was neither present in the international databases, nor in 400 chromosomes from the same population. Based on immunohistochemical staining, FOXI2 was identified in the basal cell layer of the skin and overlapped with the expression of P63, a major player in ectodermal dysplasia. We therefore suggest screening for FOXI2 mutation in the setting of ectodermal features that are not associated with genes known to contribute to ectodermal dysplasia.

Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia

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Sonia Mulero-Navarro

2015-10-01

Full Text Available Somatic PTPN11 mutations cause juvenile myelomonocytic leukemia (JMML. Germline PTPN11 defects cause Noonan syndrome (NS, and specific inherited mutations cause NS/JMML. Here, we report that hematopoietic cells differentiated from human induced pluripotent stem cells (hiPSCs harboring NS/JMML-causing PTPN11 mutations recapitulated JMML features. hiPSC-derived NS/JMML myeloid cells exhibited increased signaling through STAT5 and upregulation of miR-223 and miR-15a. Similarly, miR-223 and miR-15a were upregulated in 11/19 JMML bone marrow mononuclear cells harboring PTPN11 mutations, but not those without PTPN11 defects. Reducing miR-223’s function in NS/JMML hiPSCs normalized myelogenesis. MicroRNA target gene expression levels were reduced in hiPSC-derived myeloid cells as well as in JMML cells with PTPN11 mutations. Thus, studying an inherited human cancer syndrome with hiPSCs illuminated early oncogenesis prior to the accumulation of secondary genomic alterations, enabling us to discover microRNA dysregulation, establishing a genotype-phenotype association for JMML and providing therapeutic targets.

In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy.

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Jianxun Wang

Full Text Available Noonan Syndrome with Multiple Lentigines (NSML, formerly LEOPARD syndrome is an autosomal dominant "RASopathy" disorder manifesting in congenital heart disease. Most cases of NSML are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP, non-receptor type 11 (PTPN11, encoding the SH2 domain-containing PTP-2 (SHP2 protein. We previously generated knock-in mice harboring the PTPN11 mutation Y279C, one of the most common NSML alleles; these now-termed SHP2Y279C/+ mice recapitulate the human disorder and develop hypertrophic cardiomyopathy (HCM by 12 weeks of age. Functionally, heart and/or cardiomyocyte lysates from SHP2Y279C/+ mice exhibit increased basal and agonist-induced AKT and mTOR activities. Here, we sought to determine whether we could reverse the hypertrophy in SHP2Y279C/+ mice using ARQ 092, an oral and selective allosteric AKT inhibitor currently in clinical trials for patients with PI3K/AKT-driven tumors or Proteus syndrome. We obtained echocardiographs of SHP2Y279C/+ and wildtype (SHP2+/+ littermates, either in the presence or absence of ARQ 092 at 12, 14, and 16 weeks of age. While SHP2Y279C/+ mice developed significant left ventricular hypertrophy by 12 weeks, as indicated by decreased chamber dimension and increased posterior wall thickness, treatment of SHP2Y279C/+ mice with ARQ 092 normalized the hypertrophy in as early as 2 weeks following treatment, with hearts comparable in size to those in wildtype (SHP2+/+ mice. In addition, we observed an increase in fractional shortening (FS% in SHP2Y279C/+ mice, an effect of increased compensatory hypertrophy, which was not apparent in SHP2Y279C/+ mice treated with ARQ 092, suggesting functional improvement of HCM upon treatment with the AKT inhibitor. Finally, we found that ARQ 092 specifically inhibited AKT activity, as well as its downstream effectors, PRAS and S6RP in NSML mice. Taken together, these data suggest ARQ 092 may be a promising novel

Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus

Energy Technology Data Exchange (ETDEWEB)

Lee, Hyun; Ren, Jinhong; Nocadello, Salvatore; Rice, Amy J.; Ojeda, Isabel; Light, Samuel; Minasov, George; Vargas, Jason; Nagarathnam, Dhanapalan; Anderson, Wayne F.; Johnson, Michael E. (UIC); (NWU); (Novalex); (DNSK)

2016-12-26

Zika flavivirus infection during pregnancy appears to produce higher risk of microcephaly, and also causes multiple neurological problems such as Guillain–Barré syndrome. The Zika virus is now widespread in Central and South America, and is anticipated to become an increasing risk in the southern United States. With continuing global travel and the spread of the mosquito vector, the exposure is expected to accelerate, but there are no currently approved treatments against the Zika virus. The Zika NS2B/NS3 protease is an attractive drug target due to its essential role in viral replication. Our studies have identified several compounds with inhibitory activity (IC50) and binding affinity (KD) of ~5–10 μM against the Zika NS2B-NS3 protease from testing 71 HCV NS3/NS4A inhibitors that were initially discovered by high-throughput screening of 40,967 compounds. Competition surface plasmon resonance studies and mechanism of inhibition analyses by enzyme kinetics subsequently determined the best compound to be a competitive inhibitor with a Ki value of 9.5 μM. We also determined the X-ray structure of the Zika NS2B-NS3 protease in a “pre-open conformation”, a conformation never observed before for any flavivirus proteases. This provides the foundation for new structure-based inhibitor design.

SHP2 sails from physiology to pathology.

Science.gov (United States)

Tajan, Mylène; de Rocca Serra, Audrey; Valet, Philippe; Edouard, Thomas; Yart, Armelle

2015-10-01

Over the two past decades, mutations of the PTPN11 gene, encoding the ubiquitous protein tyrosine phosphatase SHP2 (SH2 domain-containing tyrosine phosphatase 2), have been identified as the causal factor of several developmental diseases (Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML), and metachondromatosis), and malignancies (juvenile myelomonocytic leukemia). SHP2 plays essential physiological functions in organism development and homeostasis maintenance by regulating fundamental intracellular signaling pathways in response to a wide range of growth factors and hormones, notably the pleiotropic Ras/Mitogen-Activated Protein Kinase (MAPK) and the Phosphoinositide-3 Kinase (PI3K)/AKT cascades. Analysis of the biochemical impacts of PTPN11 mutations first identified both loss-of-function and gain-of-function mutations, as well as more subtle defects, highlighting the major pathophysiological consequences of SHP2 dysregulation. Then, functional genetic studies provided insights into the molecular dysregulations that link SHP2 mutants to the development of specific traits of the diseases, paving the way for the design of specific therapies for affected patients. In this review, we first provide an overview of SHP2's structure and regulation, then describe its molecular roles, notably its functions in modulating the Ras/MAPK and PI3K/AKT signaling pathways, and its physiological roles in organism development and homeostasis. In the second part, we describe the different PTPN11 mutation-associated pathologies and their clinical manifestations, with particular focus on the biochemical and signaling outcomes of NS and NS-ML-associated mutations, and on the recent advances regarding the pathophysiology of these diseases. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling

International Nuclear Information System (INIS)

Noda, Saori; Takahashi, Atsushi; Hayashi, Takeru; Tanuma, Sei-ichi; Hatakeyama, Masanori

2016-01-01

SHP2, encoded by the PTPN11 gene, is a protein tyrosine phosphatase that plays a key role in the proliferation of cells via RAS-ERK activation. SHP2 also promotes Wnt signaling by dephosphorylating parafibromin. Germline missense mutations of PTPN11 are found in more than half of patients with Noonan syndrome (NS) and LEOPARD syndrome (LS), both of which are congenital developmental disorders with multiple common symptoms. However, whereas NS-associated PTPN11 mutations give rise to gain-of-function SHP2 mutants, LS-associated SHP2 mutants are reportedly loss-of-function mutants. To determine the phosphatase activity of LS-associated SHP2 more appropriately, we performed an in vitro phosphatase assay using tyrosine-phosphorylated parafibromin, a biologically relevant substrate of SHP2 and the positive regulator of Wnt signaling that is activated through SHP2-mediated dephosphorylation. We found that LS-associated SHP2 mutants (Y279C, T468M, Q506P, and Q510E) exhibited a substantially reduced phosphatase activity toward parafibromin when compared with wild-type SHP2. Furthermore, each of the LS-associated mutants displayed a differential degree of decrease in phosphatase activity. Deviation of the SHP2 catalytic activity from a certain range, either too strong or too weak, may therefore lead to similar clinical outcomes in NS and LS, possibly through an imbalanced Wnt signal caused by inadequate dephosphorylation of parafibromin. - Highlights: • LS-associated SHP2 mutants dephosphorylate parafibromin on Y290, Y293, and Y315. • LS-associated SHP2 mutants display a reduced tyrosine phosphatase activity. • LS-specific SHP2-Y279C is catalytically less active than LS-specific SHP2-T468M. • NS/LS-associated SHP2-Q506P has both hyper- and hypomorphic enzymatic properties.

Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling

Energy Technology Data Exchange (ETDEWEB)

Noda, Saori [Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba (Japan); Takahashi, Atsushi; Hayashi, Takeru [Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Tanuma, Sei-ichi [Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba (Japan); Hatakeyama, Masanori, E-mail: mhata@m.u-tokyo.ac.jp [Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan)

2016-01-22

SHP2, encoded by the PTPN11 gene, is a protein tyrosine phosphatase that plays a key role in the proliferation of cells via RAS-ERK activation. SHP2 also promotes Wnt signaling by dephosphorylating parafibromin. Germline missense mutations of PTPN11 are found in more than half of patients with Noonan syndrome (NS) and LEOPARD syndrome (LS), both of which are congenital developmental disorders with multiple common symptoms. However, whereas NS-associated PTPN11 mutations give rise to gain-of-function SHP2 mutants, LS-associated SHP2 mutants are reportedly loss-of-function mutants. To determine the phosphatase activity of LS-associated SHP2 more appropriately, we performed an in vitro phosphatase assay using tyrosine-phosphorylated parafibromin, a biologically relevant substrate of SHP2 and the positive regulator of Wnt signaling that is activated through SHP2-mediated dephosphorylation. We found that LS-associated SHP2 mutants (Y279C, T468M, Q506P, and Q510E) exhibited a substantially reduced phosphatase activity toward parafibromin when compared with wild-type SHP2. Furthermore, each of the LS-associated mutants displayed a differential degree of decrease in phosphatase activity. Deviation of the SHP2 catalytic activity from a certain range, either too strong or too weak, may therefore lead to similar clinical outcomes in NS and LS, possibly through an imbalanced Wnt signal caused by inadequate dephosphorylation of parafibromin. - Highlights: • LS-associated SHP2 mutants dephosphorylate parafibromin on Y290, Y293, and Y315. • LS-associated SHP2 mutants display a reduced tyrosine phosphatase activity. • LS-specific SHP2-Y279C is catalytically less active than LS-specific SHP2-T468M. • NS/LS-associated SHP2-Q506P has both hyper- and hypomorphic enzymatic properties.

RAS signalling in energy metabolism and rare human diseases.

Science.gov (United States)

Dard, L; Bellance, N; Lacombe, D; Rossignol, R

2018-05-08

The RAS pathway is a highly conserved cascade of protein-protein interactions and phosphorylation that is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Recent findings indicate that the RAS pathway plays a role in the regulation of energy metabolism via the control of mitochondrial form and function but little is known on the participation of this effect in RAS-related rare human genetic diseases. Germline mutations that hyperactivate the RAS pathway have been discovered and linked to human developmental disorders that are known as RASopathies. Individuals with RASopathies, which are estimated to affect approximately 1/1000 human birth, share many overlapping characteristics, including cardiac malformations, short stature, neurocognitive impairment, craniofacial dysmorphy, cutaneous, musculoskeletal, and ocular abnormalities, hypotonia and a predisposition to developing cancer. Since the identification of the first RASopathy, type 1 neurofibromatosis (NF1), which is caused by the inactivation of neurofibromin 1, several other syndromes have been associated with mutations in the core components of the RAS-MAPK pathway. These syndromes include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), which was formerly called LEOPARD syndrome, Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome (LS) and capillary malformation-arteriovenous malformation syndrome (CM-AVM). Here, we review current knowledge about the bioenergetics of the RASopathies and discuss the molecular control of energy homeostasis and mitochondrial physiology by the RAS pathway. Copyright © 2018 Elsevier B.V. All rights reserved.

LEOPARD-syndrom

DEFF Research Database (Denmark)

Hansen, Lars Kjaersgård; Risby, Kirsten; Bygum, Anette

2009-01-01

We describe a 12-year-old boy with a typical phenotype of the LEOPARD syndrome (LS). The diagnosis was confirmed in the boy and his mother, who both had a mutation in the PTPN11 gene at Thr468Met (c.1403C > T). Several other members of the maternal family are suspected also to have the LEOPARD sy...... syndrome. We discuss the clinical characteristics of LS, the need for follow-up and genetic counselling, and the molecular-genetic background as well as the relationship to the allelic disease Noonan syndrome. Udgivelsesdato: 2009-Jan-26......We describe a 12-year-old boy with a typical phenotype of the LEOPARD syndrome (LS). The diagnosis was confirmed in the boy and his mother, who both had a mutation in the PTPN11 gene at Thr468Met (c.1403C > T). Several other members of the maternal family are suspected also to have the LEOPARD...

Gain-of-function SOS1 mutations cause a distinctive form of noonansyndrome

Energy Technology Data Exchange (ETDEWEB)

Tartaglia, Marco; Pennacchio, Len A.; Zhao, Chen; Yadav, KamleshK.; Fodale, Valentina; Sarkozy, Anna; Pandit, Bhaswati; Oishi, Kimihiko; Martinelli, Simone; Schackwitz, Wendy; Ustaszewska, Anna; Martin, Joes; Bristow, James; Carta, Claudio; Lepri, Francesca; Neri, Cinzia; Vasta,Isabella; Gibson, Kate; Curry, Cynthia J.; Lopez Siguero, Juan Pedro; Digilio, Maria Cristina; Zampino, Giuseppe; Dallapiccola, Bruno; Bar-Sagi, Dafna; Gelb, Brude D.

2006-09-01

Noonan syndrome (NS) is a developmental disordercharacterized by short stature, facial dysmorphia, congenital heartdefects and skeletal anomalies1. Increased RAS-mitogenactivated proteinkinase (MAPK) signaling due to PTPN11 and KRAS mutations cause 50 percentof NS2-6. Here, we report that 22 of 129 NS patients without PTPN11 orKRAS mutation (17 percent) have missense mutations in SOS1, which encodesa RAS-specific guanine nucleotide exchange factor (GEF). SOS1 mutationscluster at residues implicated in the maintenance of SOS1 in itsautoinhibited form and ectopic expression of two NS-associated mutantsinduced enhanced RAS activation. The phenotype associated with SOS1defects is distinctive, although within NS spectrum, with a highprevalence of ectodermal abnormalities but generally normal developmentand linear growth. Our findings implicate for the first timegain-of-function mutations in a RAS GEF in inherited disease and define anew mechanism by which upregulation of the RAS pathway can profoundlychange human development.

The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway

NARCIS (Netherlands)

D.A. Stevenson (David A.); L. Schill (Lisa); L. Schoyer (Lisa); B.S. Andresen (B.); A. Bakker (Annette); P. Bayrak-Toydemir (Pinar); E.M.M. Burkitt Wright (Emma M.); K. Chatfield (Kathryn); F. Elefteriou (Florent); Y. Elgersma (Ype); M.J. Fisher (Michael J.); D. Franz (David); B.D. Gelb (Bruce); A. Goriely (Anne); K.W. Gripp (Karen); A.Y. Hardan (Antonio Y.); K.M. Keppler-Noreuil (Kim M.); B. Kerr (Bronwyn); B. Korf (Bruce); C. Leoni (Chiara); F. Mccormick (Frank); S.R. Plotkin (Scott R.); K.A. Rauen (Katherine); K. Reilly (Karlyne); A.E. Roberts; A. Sandler (Abby); D. Siegel (Dawn); K.S. Walsh (Karin S.); B.C. Widemann (Brigitte C.)

2016-01-01

textabstractThe RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome,

PECAM-1 and Angiogenesis

Science.gov (United States)

2009-12-01

activity have been identified in the Noonan syndrome , a human developmental disorder (43, 48), and in various childhood leukemias (29, 44). Activating...Velculescu VE, Vogelstein B, Meyerson M, Sellers WR, Neel BG. Activating mutations of the noonan syndrome -associated SHP2/PTPN11 gene in human solid...Kalidas K, Patton MA, Kucherlapati RS, Gelb BD. Mutations in PTPN11, encod- ing the protein tyrosine phosphatase SHP-2, cause Noonan syndrome . Nat

Causes of Pediatric Cardiomyopathy

Science.gov (United States)

... inherited metabolic or congenital muscle disorder such as Noonan syndrome, Pompe disease, fatty acid oxidation defect or Barth ... where a specific chromosome is deleted or duplicated. Noonan syndrome is the most common form associated with pediatric ...

Genetics Home Reference: neurofibromatosis type 1

Science.gov (United States)

... in the NF1 gene are associated with Neurofibromatosis-Noonan syndrome (NFNS). Am J Med Genet A. 2003 May ... mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. Am J Hum Genet. 2005 Dec;77(6): ...

Nelson Syndrome: Update on Therapeutic Approaches.

Science.gov (United States)

Azad, Tej D; Veeravagu, Anand; Kumar, Sunny; Katznelson, Laurence

2015-06-01

To review the pathophysiology and therapeutic modalities availble for Nelson syndrome. We reviewed the current literature including managment for Nelson syndrome. For patients with NS, surgical intervention is often the first-line therapy. With refractory NS or tumors with extrasellar involvement, radiosurgery offers an important alternative or adjuvant option. Pharmacologic interventions have demonstrated limited usefulness, although recent evidence supports the feasibility of a novel somatostatin analog for patients with NS. Modern neuroimaging, improved surgical techniques, and the advent of stereotactic radiotherapy have transformed the management of NS. An up-to-date understanding of the pathophysiology underlying Nelson Syndrome and evidence-based management is imperative. Early detection may allow for more successful therapy in patients with Nelson Syndrome. Improved radiotherapeutic interventions and rapidly evolving pharmacologic therapies offer an opportunity to create targeted, multifocal treatment regiments for patients with Nelson Syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.

Nicolau syndrome following intramuscular benzathine penicillin

Directory of Open Access Journals (Sweden)

De Sousa R

2008-01-01

Full Text Available Nicolau syndrome (NS is a rare complication of an intramuscular injection characterized by severe pain, skin discoloration, and varying levels of tissue necrosis. The case outcomes vary from atrophic ulcers and severe pain to sepsis and limb amputation. We describe a case of a seven-year-old boy with diagnosis of NS after intramuscular benzathine penicillin injection to the ventrolateral aspect of the left thigh. Characteristic violaceous discoloration of skin and immediate injection site pain identified it as a case of NS. The case was complicated by rapid progression of compartment syndrome of the lower limb, proceeding to acute renal failure and death. Associated compartment syndrome can be postulated as a poor prognostic factor for NS.

Chiari I malformation associated with turner syndrome

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Kamble Jayaprakash Harsha

2017-01-01

Full Text Available Turner syndrome (TS is a rare genetic disease due to the absence of one X chromosome. Patients with TS have more subtle neurological/neuropsychiatric problems, while headache is an uncommon clinical presentation which needs attention. We report a 12-year-old child presenting with typical cough headache. Her magnetic resonance imaging revealed Chiari I malformation associated with TS. To the best of our knowledge, Chiari I malformation associated with TS is not described in literature. We report the first case of TS associated with Chiari I malformation. Interestingly, Chiari I malformation is also associated with Noonan's syndrome, which is a close morphological mimicker of TS, raising the possibility of sharing similar pathogenesis in both conditions.

Hipoacusia neurosensorial en un síndrome de Noonan y secuencia Poland Neurosensory hypoacusis in a Noonan's syndrome and Poland's sequence

Directory of Open Access Journals (Sweden)

Julianis Loraine Quintero Noa

2010-09-01

Full Text Available Se calcula que el 50 % de los casos de sordera profunda en la infancia puede ser de origen genético. Se presenta el caso de un niño de 9 años, atendido en los Servicios de Otorrinolaringología y Genética del Hospital Pediátrico Docente «William Soler», por presentar hipoacusia neurosensorial grave unilateral y displasia congénita de Mondini en el oído izquierdo, del lado contrario a la hipoplasia del músculo pectoral mayor, lo cual coincide con un síndrome de Noonan y secuencia de Poland, que resulta de especial interés. Se constató la hipoacusia con audiometría tonal y potencial evocado auditivo de tallo cerebral. En la tomografía del oído se observó una hipoplasia coclear con agenesia de la espira apical. Se destacan las manifestaciones clínicas y la importancia del estudio otológico e imaginólogico en el diagnóstico de la pérdida auditiva.It is estimated that the 50% of cases of deep deafness during childhood may be or genetic origin. This is the case of a child aged 9 seen in Otorhinolaryngology and Genetics Services of the "Wiliam Soler" Teaching Children Hospital due to a unilateral severe neurosensory hypoacusis and Mondini's congenital dysplasia in left ear contralateral to the major pectoral muscle hypoplasia, an interesting situation. Hypoacusis was confirmed using tone audiometry and auditory evoked potential of brain stem. Ear tomography demonstrated a cochlear hypoplasia with agenesis of apical spiral. The clinical manifestations and the significance of the ontological and imaging study in diagnosis of auditory loss are emphasized.

Interference of transcription across H-NS binding sites and repression by H-NS.

Science.gov (United States)

Rangarajan, Aathmaja Anandhi; Schnetz, Karin

2018-05-01

Nucleoid-associated protein H-NS represses transcription by forming extended DNA-H-NS complexes. Repression by H-NS operates mostly at the level of transcription initiation. Less is known about how DNA-H-NS complexes interfere with transcription elongation. In vitro H-NS has been shown to enhance RNA polymerase pausing and to promote Rho-dependent termination, while in vivo inhibition of Rho resulted in a decrease of the genome occupancy by H-NS. Here we show that transcription directed across H-NS binding regions relieves H-NS (and H-NS/StpA) mediated repression of promoters in these regions. Further, we observed a correlation of transcription across the H-NS-bound region and de-repression. The data suggest that the transcribing RNA polymerase is able to remodel the H-NS complex and/or dislodge H-NS from the DNA and thus relieve repression. Such an interference of transcription and H-NS mediated repression may imply that poorly transcribed AT-rich loci are prone to be repressed by H-NS, while efficiently transcribed loci escape repression. © 2018 John Wiley & Sons Ltd.

Peripheral blood cells from children with RASopathies show enhanced spontaneous colonies growth in vitro and hyperactive RAS signaling

International Nuclear Information System (INIS)

Gaipa, G; Bugarin, C; Cianci, P; Sarno, J; Bonaccorso, P; Biondi, A; Selicorni, A

2015-01-01

Germline mutations in genes coding for molecules involved in the RAS/RAF/MEK/ERK pathway are the hallmarks of a newly classified family of autosomal dominant syndromes termed RASopathies. Myeloproliferative disorders (MPDs), in particular, juvenile myelomonocytic leukemia, can lead to potentially severe complications in children with Noonan syndrome (NS). We studied 27 children with NS or other RASopathies and 35 age-matched children as control subjects. Peripheral blood (PB) cells from these patients were studied for in vitro colony-forming units (CFUs) activity, as well as for intracellular phosphosignaling. Higher spontaneous growth of both burst-forming units-erythroid (BFU-E) and CFU-granulocyte/macrophage (CFU-GM) colonies from RAS-mutated patients were observed as compared with control subjects. We also observed a significantly higher amount of GM-colony-stimulating factor-induced p-ERK in children with RASopathies. Our findings demonstrate for the first time that PB cells isolated from children suffering from NS or other RASopathies without MPD display enhanced BFU-E and CFU-GM colony formation in vitro. The biological significance of these findings clearly awaits further studies. Collectively, our data provide a basis for further investigating of only partially characterized hematological alterations present in children suffering from RASopathies, and may provide new markers for progression toward malignant MPD in these patients

Congenital Chylothorax in a Newborn with Down Syndrome

Directory of Open Access Journals (Sweden)

Nazan Neslihan Doğan

2017-03-01

Full Text Available In the neonatal period, the most common cause of pleural effusion is idiopathic congenital chylothorax. Congenital chylothorax is rarely associated with chromosomal abnormalities, such as Down, Turner and Noonan syndromes. The diagnosis can be made after analysis of the pleural fluid drained by thoracentesis or chest tube placement. During the neonatal period, chylothorax treatment is composed of conservative and surgical therapies. Nowadays, for cases among which conservative therapies fail, treatment with octreotide has been reported to be beneficial with promising results. In this report, a case of congenital chylothorax, in a newborn with Down syndrome, treated by octreotide after failure of chest tube drainage and medical treatment (total parenteral nutrition and medium chain fatty acid formula is presented.

Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm

Directory of Open Access Journals (Sweden)

Eleanor G. Seaby

2017-05-01

Full Text Available CBL is a tumor suppressor gene on chromosome 11 encoding a multivalent adaptor protein with E3 ubiquitin ligase activity. Germline CBL mutations are dominant. Pathogenic de novo mutations result in a phenotype that overlaps Noonan syndrome (1. Some patients with CBL mutations go on to develop juvenile myelomonocytic leukemia (JMML, an aggressive malignancy that usually necessitates bone marrow transplantation. Using whole exome sequencing methods, we identified a known mutation in CBL in a 4-year-old Caucasian boy with atypical hemolytic uremic syndrome, moyamoya phenomenon, and dysmorphology consistent with a mild Noonan-like phenotype. Exome data revealed loss of heterozygosity across chromosome 11q consistent with JMML but in the absence of clinical leukemia. Our finding challenges conventional clinical diagnostics since we have identified a pathogenic variant in the CBL gene previously only ascertained in children presenting with leukemia. The increasing affordability of expansive sequencing is likely to increase the scope of clinical profiles observed for previously identified pathogenic variants and calls into question the interpretability and indications for clinical management.

Patient with confirmed LEOPARD syndrome developing multiple melanoma.

Science.gov (United States)

Colmant, Caroline; Franck, Deborah; Marot, Liliane; Matthijs, Gert; Sznajer, Yves; Blomme, Sandrine; Tromme, Isabelle

2018-01-01

LEOPARD syndrome, also known as Gorlin syndrome II, cardiocutaneous syndrome, lentiginosis profusa syndrome, Moynahan syndrome, was more recently coined as Noonan syndrome with multiple lentigines (NSML), inside the RASopathies. Historically, the acronym LEOPARD refers to the presence of distinctive clinical features such as: lentigines (L), electrocardiographic/conduction abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), genital abnormalities (A), retardation of growth (R), and sensorineural deafness (D). This condition is identified in 85% of patients with phenotype hallmarks caused by presence a germline point mutation in PTPN11 gene. Association of melanoma to NSML seems to be rare: to our knowledge, two patients so far were reported in the literature. We herein present a patient diagnosed with LEOPARD syndrome, in whom molecular investigation confirmed the presence of the c.1403C>T mutation in exon 12 of the PTPN11 gene, who developed four superficial spreading melanomas and three atypical lentiginous hyperplasias. Three of the melanomas were achromic or hypochromic, three were in situ, and one had a Breslow index under 0.5 mm. Dermoscopic examination showed some characteristic white structures in most of the lesions, which were a signature pattern and a key for the diagnosis.

Genetic Aspects of Nephrotic Syndrome

DEFF Research Database (Denmark)

Joshi, Shivani

Nephrotic syndrome (NS) is characterized by severe proteinuria, hypoalbuminemia, and edema. Depending on response to steroid treatment, patients either have steroid sensitive NS (SSNS) or steroid resistant NS (SRNS). Patients with SRNS often have a poor renal prognosis, focal segmental glomerulos......Nephrotic syndrome (NS) is characterized by severe proteinuria, hypoalbuminemia, and edema. Depending on response to steroid treatment, patients either have steroid sensitive NS (SSNS) or steroid resistant NS (SRNS). Patients with SRNS often have a poor renal prognosis, focal segmental...... steroid dependence or become frequent relapsers. Repeated courses of corticosteroid treatment often cause significant associated morbidity. Familial occurrence of SSNS is rare and suggests a potential genetic origin. However, very little data on molecular genetics of familial SSNS is available...... SSNS. Study I is the first study to describe the genetic findings in 39 patients with sporadic FSGS and/or SRNS, in a highly selected Danish population. We developed a screening tool (high resolution melting analysis) to search for variants in NPHS1, NPHS2, and INF2 genes. This method was shown...

Next Generation Sequencing Approach in a Prenatal Case of Cardio-Facio-Cutaneus Syndrome.

Science.gov (United States)

Mucciolo, Mafalda; Dello Russo, Claudio; D'Emidio, Laura; Mesoraca, Alvaro; Giorlandino, Claudio

2016-06-16

Cardiofaciocutaneous syndrome (CFCS) belongs to a group of developmental disorders due to defects in the Ras/Mitogen-Activated Protein Kinase (RAS/MAPK) signaling pathway named RASophaties. While postnatal presentation of these disorders is well known, the prenatal and neonatal characteristics are less recognized. Noonan syndrome, Costello syndrome, and CFCS diagnosis should be considered in pregnancies with a normal karyotype and in the case of ultrasound findings such as increased nuchal translucency, polyhydramnios, macrosomia and cardiac defect. Because all the RASopathies share similar clinical features, their molecular characterization is complex, time consuming and expensive. Here we report a case of CFCS prenatally diagnosed through Next Generation Prenatal Diagnosis (NGPD), a new targeted approach that allows us to concurrently investigate all the genes involved in the RASophaties.

NS19504

DEFF Research Database (Denmark)

Nausch, Bernhard; Rode, Frederik; Jørgensen, Susanne

2014-01-01

channel activators and identified a small-molecule positive modulator, NS19504 (5-[(4-bromophenyl)methyl]-1,3-thiazol-2-amine), which activated the BK channel with an EC50 value of 11.0 ± 1.4 µM. Hit validation was performed using high-throughput electrophysiology (QPatch), and further characterization......19504 activated BK channels in native smooth muscle cells from guinea pig urinary bladder. In guinea pig urinary bladder strips, NS19504 (1 µM) reduced spontaneous phasic contractions, an effect that was significantly inhibited by the specific BK channel blocker iberiotoxin. In contrast, NS19504 (1 µ......M) only modestly inhibited nerve-evoked contractions and had no effect on contractions induced by a high K(+) concentration consistent with a K(+) channel-mediated action. Collectively, these results show that NS19504 is a positive modulator of BK channels and provide support for the role of BK channels...

Syndrome identification based on 2D analysis software.

Science.gov (United States)

Boehringer, Stefan; Vollmar, Tobias; Tasse, Christiane; Wurtz, Rolf P; Gillessen-Kaesbach, Gabriele; Horsthemke, Bernhard; Wieczorek, Dagmar

2006-10-01

Clinical evaluation of children with developmental delay continues to present a challenge to the clinicians. In many cases, the face provides important information to diagnose a condition. However, database support with respect to facial traits is limited at present. Computer-based analyses of 2D and 3D representations of faces have been developed, but it is unclear how well a larger number of conditions can be handled by such systems. We have therefore analysed 2D pictures of patients each being affected with one of 10 syndromes (fragile X syndrome; Cornelia de Lange syndrome; Williams-Beuren syndrome; Prader-Willi syndrome; Mucopolysaccharidosis type III; Cri-du-chat syndrome; Smith-Lemli-Opitz syndrome; Sotos syndrome; Microdeletion 22q11.2; Noonan syndrome). We can show that a classification accuracy of >75% can be achieved for a computer-based diagnosis among the 10 syndromes, which is about the same accuracy achieved for five syndromes in a previous study. Pairwise discrimination of syndromes ranges from 80 to 99%. Furthermore, we can demonstrate that the criteria used by the computer decisions match clinical observations in many cases. These findings indicate that computer-based picture analysis might be a helpful addition to existing database systems, which are meant to assist in syndrome diagnosis, especially as data acquisition is straightforward and involves off-the-shelf digital camera equipment.

Williams-Beuren's Syndrome: A Case Report.

Science.gov (United States)

Zamani, Hassan; Babazadeh, Kazem; Fattahi, Saeid; Mokhtari-Esbuie, Farzad

2012-01-01

Williams-Beuren syndrome is a rare familial multisystem disorder occurring in 1 per 20,000 live births. It is characterized by congenital heart defects (CHD), skeletal and renal anomalies, cognitive disorder, social personality disorder and dysmorphic facies. We present a case of Williams syndrome that presented to us with heart murmur and cognitive problem. A 5-year-old girl referred to pediatric cardiologist because of heart murmurs. She had a systolic murmur (2-3/6) in right upper sternal border with radiation to right cervical region. She also had a bulge forehead. Angiography showed mild supra valvular aortic stenosis and mild multiple peripheral pulmonary stenosis. Fluorescent in situ hybridization (FISH) was performed and the result was: 46.XX, ish del (7q11.2) (ELN X1) (7q22 X2) ELN deletion compatible with Williams syndrome. Peripheral pulmonary artery stenosis is associated with Noonan syndrome, Alagille syndrome, Cutis laxa, Ehler-Danlos syndrome, and Silver-Russel syndrome. The patient had peripheral pulmonary artery stenosis, but no other signs of these syndromes were present, and also she had a supravalvular aortic stenosis which was not seen in other syndromes except Williams syndrome. Conclusion. According to primary symptoms, paraclinical and clinical finding such as dysmorphic facies, cognitive disorder and congenital heart defect, Williams syndrome was the first diagnosis. We suggest a more attention for evaluating heart murmur in childhood period, especially when the patient has abnormal facial features or mental problem.

Williams-Beuren's Syndrome: A Case Report

Directory of Open Access Journals (Sweden)

Hassan Zamani

2012-01-01

Full Text Available Williams-Beuren syndrome is a rare familial multisystem disorder occurring in 1 per 20,000 live births. It is characterized by congenital heart defects (CHD, skeletal and renal anomalies, cognitive disorder, social personality disorder and dysmorphic facies. We present a case of Williams syndrome that presented to us with heart murmur and cognitive problem. A 5-year-old girl referred to pediatric cardiologist because of heart murmurs. She had a systolic murmur (2-3/6 in right upper sternal border with radiation to right cervical region. She also had a bulge forehead. Angiography showed mild supra valvular aortic stenosis and mild multiple peripheral pulmonary stenosis. Fluorescent in situ hybridization (FISH was performed and the result was: 46.XX, ish del (7q11.2 (ELN X1 (7q22 X2 ELN deletion compatible with Williams syndrome. Peripheral pulmonary artery stenosis is associated with Noonan syndrome, Alagille syndrome, Cutis laxa, Ehler-Danlos syndrome, and Silver-Russel syndrome. The patient had peripheral pulmonary artery stenosis, but no other signs of these syndromes were present, and also she had a supravalvular aortic stenosis which was not seen in other syndromes except Williams syndrome. Conclusion. According to primary symptoms, paraclinical and clinical finding such as dysmorphic facies, cognitive disorder and congenital heart defect, Williams syndrome was the first diagnosis. We suggest a more attention for evaluating heart murmur in childhood period, especially when the patient has abnormal facial features or mental problem.

50 ns Backup Solution

CERN Document Server

Kain, V; Bartosik, H; Goddard, B; Höfle, W; Iadarola, G; Meddahi, M; Pieloni, T; Rumolo, G; Salvant, B; Wenninger, J

2014-01-01

The baseline bunch spacing for LHC high luminosity proton-proton operation after LS3 is 25 ns to maximize the integrated luminosity while keeping the pile-up low. The success of this mode of operation is not guaranteed. Electron cloud, UFOs, long-range beambeam, heating and other effects might make 25 ns operation in the LHC and/or the injectors difficult. This talk will review possible showstoppers in the LHC and injectors for 25 ns operation and discuss possible remedies. An alternative would be re-considering 50 ns operation. An estimate of the 50 ns performance will be given. The question of whether a different upgrade path would have to be chosen in case of 50 ns operation will also be addressed.

50 ns Backup Solution

International Nuclear Information System (INIS)

Kain, V; Arduini, G; Bartosik, H; Goddard, B; Höfle, W; Iadarola, G; Meddahi, M; Pieloni, T; Rumolo, G; Salvant, B; Wenninger, J

2014-01-01

The baseline bunch spacing for LHC high luminosity proton-proton operation after LS3 is 25 ns to maximize the integrated luminosity while keeping the pile-up low. The success of this mode of operation is not guaranteed. Electron cloud, UFOs, long-range beambeam, heating and other effects might make 25 ns operation in the LHC and/or the injectors difficult. This talk will review possible showstoppers in the LHC and injectors for 25 ns operation and discuss possible remedies. An alternative would be re-considering 50 ns operation. An estimate of the 50 ns performance will be given. The question of whether a different upgrade path would have to be chosen in case of 50 ns operation will also be addressed

Nicolau syndrome caused by the "self-injection" of diclofenac

Directory of Open Access Journals (Sweden)

Selcuk Yaylaci

2016-01-01

Full Text Available Nicolau syndrome (NS is a rare injection-related local complication. Some drugs have been implicated to cause this syndrome. Several cases were previously reported in the literature. In this paper, an interesting case of NS in a 30-year-old male patient after intramuscular self-injection of diclofenac was presented.

Next Generation Sequencing Approach in a Prenatal Case of Cardio-Facio-Cutaneus Syndrome

Directory of Open Access Journals (Sweden)

Mafalda Mucciolo

2016-06-01

Full Text Available Cardiofaciocutaneous syndrome (CFCS belongs to a group of developmental disorders due to defects in the Ras/Mitogen-Activated Protein Kinase (RAS/MAPK signaling pathway named RASophaties. While postnatal presentation of these disorders is well known, the prenatal and neonatal characteristics are less recognized. Noonan syndrome, Costello syndrome, and CFCS diagnosis should be considered in pregnancies with a normal karyotype and in the case of ultrasound findings such as increased nuchal translucency, polyhydramnios, macrosomia and cardiac defect. Because all the RASopathies share similar clinical features, their molecular characterization is complex, time consuming and expensive. Here we report a case of CFCS prenatally diagnosed through Next Generation Prenatal Diagnosis (NGPD, a new targeted approach that allows us to concurrently investigate all the genes involved in the RASophaties.

Giant magnons under NS-NS and Melvin fields

International Nuclear Information System (INIS)

Huang, W.-H.

2006-01-01

The giant magnon is a rotating spiky string configuration which has the same dispersion relation between the energy and angular momentum as that of a spin magnon. In this paper we investigate the effects of the NS-NS and Melvin fields on the giant magnon. We first analyze the energy and angular momenta of the two-spin spiky D-string moving on the AdS 3 x S 1 with the NS-NS field. Due to the infinite boundary of the AdS spacetime the D-string solution will extend to infinity and it appears the divergences. After adding the counter terms we obtain the dispersion relation of the corresponding giant magnon. The result shows that there will appear a prefactor before the angular momentum, in addition to some corrections in the sine function. We also see that the spiky profile of a rotating D-string plays an important role in mapping it to a spin magnon. We next investigate the energy and angular momentum of the one-spin spiky fundamental string moving on the R x S 2 with the electric or magnetic Melvin field. The dispersion relation of the corresponding deformed giant magnon is also obtained. We discuss some properties of the correction terms and their relations to the spin chain with deformations

Host cell killing by the West Nile Virus NS2B-NS3 proteolytic complex: NS3 alone is sufficient to recruit caspase-8-based apoptotic pathway

International Nuclear Information System (INIS)

Ramanathan, Mathura P.; Chambers, Jerome A.; Pankhong, Panyupa; Chattergoon, Michael; Attatippaholkun, Watcharee; Dang, Kesen; Shah, Neelima; Weiner, David B.

2006-01-01

The West Nile Virus (WNV) non-structural proteins 2B and 3 (NS2B-NS3) constitute the proteolytic complex that mediates the cleavage and processing of the viral polyprotein. NS3 recruits NS2B and NS5 proteins to direct protease and replication activities. In an effort to investigate the biology of the viral protease, we cloned cDNA encoding the NS2B-NS3 proteolytic complex from brain tissue of a WNV-infected dead crow, collected from the Lower Merion area (Merion strain). Expression of the NS2B-NS3 gene cassette induced apoptosis within 48 h of transfection. Electron microscopic analysis of NS2B-NS3-transfected cells revealed ultra-structural changes that are typical of apoptotic cells including membrane blebbing, nuclear disintegration and cytoplasmic vacuolations. The role of NS3 or NS2B in contributing to host cell apoptosis was examined. NS3 alone triggers the apoptotic pathways involving caspases-8 and -3. Experimental results from the use of caspase-specific inhibitors and caspase-8 siRNA demonstrated that the activation of caspase-8 was essential to initiate apoptotic signaling in NS3-expressing cells. Downstream of caspase-3 activation, we observed nuclear membrane ruptures and cleavage of the DNA-repair enzyme, PARP in NS3-expressing cells. Nuclear herniations due to NS3 expression were absent in the cells treated with a caspase-3 inhibitor. Expression of protease and helicase domains themselves was sufficient to trigger apoptosis generating insight into the apoptotic pathways triggered by NS3 from WNV

Multiple Unerupted Permanent Teeth Associated with Noonan ...

African Journals Online (AJOL)

[2] Oral findings in patients with NS include a high arched palate ... the atypical dental anomalies such as multiple unerupted permanent ... clinical features in a child with NS. .... Disabilities, Centers for Disease Control and Prevention (CDC).

RENIN ANGIOTENSIN SYSTEM GENE POLYMORPHISMS IN CHILDREN WITH NEPHROTIC SYNDROM

Directory of Open Access Journals (Sweden)

Zh.P. Sharnova

2006-01-01

Full Text Available To investigate the role of the reninangiotensin system genes polymorphisms in develop and progression of nephrotic syndrom (NS in children we determined the genotypes of angiotensin converting enzyme (ACE, angiotensinogen (AGT and angiotensin ii receptor (ATII-R of 1 type in 80 russian children with ns including and 15 children with chronic renal failure (CRF. Genotype frequencies did not differ between patients with ns and controls (n = 165. The distribution of ace, AGT and ATII-R 1 type genotypes was similar among ns sub groups, such as focal segmental glomerulosclerosis (FSGS (n = 18, steroid-sensitive nephrotic syndrome (n = 32, nephrotic syndrome with hypertension and hemoturia (n = 22 and with control group. When ns subjects with CRF (n = 15 were compared with control, the prevalence of ace DD genotype was significantly higher (47% VS 21%; χ2 = 4,44; p < 0,05. Our results indicate that the DD genotype ace may be a factor of risk for the dеvеlopment of progressive renal impairment in the children with nephrotic syndrome. The analysis of treatment's effect with inhibitor of ace in groups patients with steroid resistant NS (SRNS demonstrated decreasing of renoprotective effect of this drugs in patients with id and dd genotypes com? Pared with ii genotype: the degree of blood pressure, proteinuria and the rate of glomerular filtration decrease was significantly lower (55,46 ± 9,25 VS 92,74 ± 25; р < 0,05 in these patients.Key words: nephrotic syndrom, chronic renal failure, polymorphism of genes, renin-angiotensin system.

Disease: H00886 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available CD-10: Q87.8 MeSH: C536390 OMIM: 222448 PMID:20301732 (description, gene) ... AUTHORS ... Kant...993) ... PMID:18553518 (description, gene) ... AUTHORS ... Kantarci S, Ragge NK, Thomas NS, Robinson DO, Noonan KM,

Congenital heart disease and genetic syndromes: new insights into molecular mechanisms.

Science.gov (United States)

Calcagni, Giulio; Unolt, Marta; Digilio, Maria Cristina; Baban, Anwar; Versacci, Paolo; Tartaglia, Marco; Baldini, Antonio; Marino, Bruno

2017-09-01

Advances in genetics allowed a better definition of the role of specific genetic background in the etiology of syndromic congenital heart defects (CHDs). The identification of a number of disease genes responsible for different syndromes have led to the identification of several transcriptional regulators and signaling transducers and modulators that are critical for heart morphogenesis. Understanding the genetic background of syndromic CHDs allowed a better characterization of the genetic basis of non-syndromic CHDs. In this sense, the well-known association of typical CHDs in Down syndrome, 22q11.2 microdeletion and Noonan syndrome represent paradigms as chromosomal aneuploidy, chromosomal microdeletion and intragenic mutation, respectively. Area covered: For each syndrome the anatomical features, distinctive cardiac phenotype and molecular mechanisms are discussed. Moreover, the authors include recent genetic findings that may shed light on some aspects of still unclear molecular mechanisms of these syndromes. Expert commentary: Further investigations are needed to enhance the translational approach in the field of genetics of CHDs. When there is a well-established definition of genotype-phenotype (reverse medicine) and genotype-prognosis (predictive and personalized medicine) correlations, hopefully preventive medicine will make its way in this field. Subsequently a reduction will be achieved in the morbidity and mortality of children with CHDs.

Renal Doppler Indices in Children with Nephrotic Syndrome ...

African Journals Online (AJOL)

olayemitoyin

in proteinuric conditions like Paediatric Nephrotic syndrome (NS) which is a glomerular disease. ... the mean RI and PI of the NS cases and controls, except in the left middle .... predominantly either overweight or obese, when ... Weight (Kg).

Introduction to Network Simulator NS2

CERN Document Server

Issariyakul, Teerawat

2012-01-01

"Introduction to Network Simulator NS2" is a primer providing materials for NS2 beginners, whether students, professors, or researchers for understanding the architecture of Network Simulator 2 (NS2) and for incorporating simulation modules into NS2. The authors discuss the simulation architecture and the key components of NS2 including simulation-related objects, network objects, packet-related objects, and helper objects. The NS2 modules included within are nodes, links, SimpleLink objects, packets, agents, and applications. Further, the book covers three helper modules: timers, ra

Molecular dynamic simulation of complex NS2B-NS3 DENV2 ...

African Journals Online (AJOL)

Several vaccines have been developed against the disease, but they only ... a two component NS2B-NS3 protease that cleaves viral precursor proteins, and ... The results provide conformational changes of enzyme-inhibitor complex that is ...

Notes on the Wess-Zumino-Witten-like structure: L{sub ∞} triplet and NS-NS superstring field theory

Energy Technology Data Exchange (ETDEWEB)

Matsunaga, Hiroaki [Institute of Physics, the Czech Academy of Sciences,Na Slovance 2, Prague 8 (Czech Republic); Yukawa Institute for Theoretical Physics, Kyoto University,Kyoto 606-8502 (Japan)

2017-05-17

In the NS-NS sector of superstring field theory, there potentially exist three nilpotent generators of gauge transformations and two constraint equations: it makes the gauge algebra of type II theory somewhat complicated. In this paper, we show that every NS-NS actions have their WZW-like forms, and that a triplet of mutually commutative L{sub ∞} products completely determines the gauge structure of NS-NS superstring field theory via its WZW-like structure. We give detailed analysis about it and present its characteristic properties by focusing on two NS-NS actions proposed by https://www.doi.org/10.1007/JHEP01(2017)022 and https://www.doi.org/10.1007/JHEP08(2014)158.

NMR analysis of the dynamic exchange of the NS2B cofactor between open and closed conformations of the West Nile virus NS2B-NS3 protease.

Directory of Open Access Journals (Sweden)

Xun-Cheng Su

Full Text Available BACKGROUND: The two-component NS2B-NS3 proteases of West Nile and dengue viruses are essential for viral replication and established targets for drug development. In all crystal structures of the proteases to date, the NS2B cofactor is located far from the substrate binding site (open conformation in the absence of inhibitor and lining the substrate binding site (closed conformation in the presence of an inhibitor. METHODS: In this work, nuclear magnetic resonance (NMR spectroscopy of isotope and spin-labeled samples of the West Nile virus protease was used to investigate the occurrence of equilibria between open and closed conformations in solution. FINDINGS: In solution, the closed form of the West Nile virus protease is the predominant conformation irrespective of the presence or absence of inhibitors. Nonetheless, dissociation of the C-terminal part of the NS2B cofactor from the NS3 protease (open conformation occurs in both the presence and the absence of inhibitors. Low-molecular-weight inhibitors can shift the conformational exchange equilibria so that over 90% of the West Nile virus protease molecules assume the closed conformation. The West Nile virus protease differs from the dengue virus protease, where the open conformation is the predominant form in the absence of inhibitors. CONCLUSION: Partial dissociation of NS2B from NS3 has implications for the way in which the NS3 protease can be positioned with respect to the host cell membrane when NS2B is membrane associated via N- and C-terminal segments present in the polyprotein. In the case of the West Nile virus protease, discovery of low-molecular-weight inhibitors that act by breaking the association of the NS2B cofactor with the NS3 protease is impeded by the natural affinity of the cofactor to the NS3 protease. The same strategy can be more successful in the case of the dengue virus NS2B-NS3 protease.

Perinatally lethal short rib-polydactyly syndromes. Pt. 1

International Nuclear Information System (INIS)

Sillence, D.; Kozlowski, K.; Bar-ziv, J.; Fuhrmann-Rieger, A.; Fuhrmann, W.; Pascu, F.

1987-01-01

Thirteen newborns with lethal short rib-polydactyly (SRP) have been reviewed, 11 with SRP type 3 (Verma-Naumoff) and 2 with SRP tye 2 (Majewski). In the former group there were three sets of siblings. The excess of males with SRP type III (Verma-Naumoff) is confirmed in this present study. A high frequency of phenotypic females including sex-reversed constitutional males with SRP type 1 (Saldino-Noonan) is in marked contrast to these findings in SRP type 3. Possible hypotheses include variable expressivity in non-Majewski short rib-polydactyly syndromes with sex-reversed and constitutional female cases tending to show more severe phenotypic expression both in terms of major anomalies and skeletal dysplastic effects. (orig.)

Flavivirus NS3 and NS5 proteins interaction network: a high-throughput yeast two-hybrid screen

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Canard Bruno

2011-10-01

Full Text Available Abstract Background The genus Flavivirus encompasses more than 50 distinct species of arthropod-borne viruses, including several major human pathogens, such as West Nile virus, yellow fever virus, Japanese encephalitis virus and the four serotypes of dengue viruses (DENV type 1-4. Each year, flaviviruses cause more than 100 million infections worldwide, some of which lead to life-threatening conditions such as encephalitis or haemorrhagic fever. Among the viral proteins, NS3 and NS5 proteins constitute the major enzymatic components of the viral replication complex and are essential to the flavivirus life cycle. Results We report here the results of a high-throughput yeast two-hybrid screen to identify the interactions between human host proteins and the flavivirus NS3 and NS5 proteins. Using our screen results and literature curation, we performed a global analysis of the NS3 and NS5 cellular targets based on functional annotation with the Gene Ontology features. We finally created the first flavivirus NS3 and NS5 proteins interaction network and analysed the topological features of this network. Our proteome mapping screen identified 108 human proteins interacting with NS3 or NS5 proteins or both. The global analysis of the cellular targets revealed the enrichment of host proteins involved in RNA binding, transcription regulation, vesicular transport or innate immune response regulation. Conclusions We proposed that the selective disruption of these newly identified host/virus interactions could represent a novel and attractive therapeutic strategy in treating flavivirus infections. Our virus-host interaction map provides a basis to unravel fundamental processes about flavivirus subversion of the host replication machinery and/or immune defence strategy.

Analysis of hepatitis C virus core/NS5A protein co-localization using novel cell culture systems expressing core-NS2 and NS5A of genotypes 1-7

DEFF Research Database (Denmark)

Galli, Andrea; Scheel, Troels K H; Prentoe, Jannick C

2013-01-01

Hepatitis C virus (HCV) is an important human pathogen infecting hepatocytes. With the advent of infectious cell culture systems, the HCV particle assembly and release processes are finally being uncovered. The HCV core and NS5A proteins co-localize on cytoplasmic lipid droplets (c......LDs) or on the endoplasmic reticulum (ER) at different stages of particle assembly. Current knowledge on assembly and release is primarily based on studies in genotype 2a cell culture systems; however, given the high genetic heterogeneity of HCV, variations might exist among genotypes. Here, we developed novel HCV strain...... JFH1-based recombinants expressing core-NS2 and NS5A from genotypes 1-7, and analysed core and NS5A co-localization in infected cells. Huh7.5 cells were transfected with RNA of core-NS2/NS5A recombinants and putative adaptive mutations were analysed by reverse genetics. Adapted core-NS2/NS5A...

Computer Aided Screening of Phytochemicals from Garcinia against the Dengue NS2B/NS3 Protease.

Science.gov (United States)

Qamar, Tahir Ul; Mumtaz, Arooj; Ashfaq, Usman Ali; Azhar, Samia; Fatima, Tabeer; Hassan, Muhammad; Hussain, Syed Sajid; Akram, Waheed; Idrees, Sobia

2014-01-01

Dengue virus NS2/NS3 protease because of its ability to cleave viral proteins is considered as an attractive target to screen antiviral agents. Medicinal plants contain a variety of phytochemicals that can be used as drug against different diseases and infections. Therefore, this study was designed to uncover possible phytochemical of different classes (Aromatic, Carbohydrates, Lignin, Saponins, Steroids, Tannins, Terpenoids, Xanthones) that could be used as inhibitors against the NS2B/NS3 protease of DENV. With the help of molecular docking, Garcinia phytochemicals found to be bound deeply inside the active site of DENV NS2B/NS3 protease among all tested phytochemicals and had interactions with catalytic triad (His51, Asp75, Ser135). Thus, it can be concluded from the study that these Gracinia phytochemicals could serve as important inhibitors to inhibit the viral replication inside the host cell. Further in-vitro investigations require confirming their efficacy.

NS simulator for beginners

CERN Document Server

Altman, Eitan

2012-01-01

NS-2 is an open-source discrete event network simulator which is widely used by both the research community as well as by the people involved in the standardization protocols of IETF. The goal of this book is twofold: on one hand to learn how to use the NS-2 simulator, and on the other hand, to become acquainted with and to understand the operation of some of the simulated objects using NS-2 simulations. The book is intended to help students, engineers or researchers who need not have much background in programming or who want to learn through simple examples how to analyse some simulated obje

Mutagenesis of Dengue Virus Protein NS2A Revealed a Novel Domain Responsible for Virus-Induced Cytopathic Effect and Interactions between NS2A and NS2B Transmembrane Segments.

Science.gov (United States)

Wu, Ren-Huang; Tsai, Ming-Han; Tsai, Kuen-Nan; Tian, Jia Ni; Wu, Jian-Sung; Wu, Su-Ying; Chern, Jyh-Haur; Chen, Chun-Hong; Yueh, Andrew

2017-06-15

The NS2A protein of dengue virus (DENV) has eight predicted transmembrane segments (pTMS1 to -8) and participates in RNA replication, virion assembly, and host antiviral response. However, the roles of specific amino acid residues within the pTMS regions of NS2A during the viral life cycle are not clear. Here, we explore the function of DENV NS2A by introducing a series of alanine substitutions into the N-terminal half (pTMS1 to -4) of the protein in the context of a DENV infectious clone or subgenomic replicon. Six NS2A mutants (NM5, -7, -9, and -17 to -19) around pTMS1 and -2 displayed a novel phenotype showing a >1,000-fold reduction in virus yield, an absence of plaque formation despite wild-type-like replicon activity, and infectious-virus-like particle yields. HEK-293 cells infected with the six NS2A mutant viruses failed to cause a virus-induced cytopathic effect (CPE) by MitoCapture staining, cell proliferation, and lactate dehydrogenase release assays. Sequencing analyses of pseudorevertant viruses derived from lethal-mutant viruses revealed two consensus reversion mutations, leucine to phenylalanine at codon 181 (L181F) within pTMS7 of NS2A and isoleucine to threonine at codon 114 (I114T) within NS2B. The introduction of an NS2A-L181F mutation into the lethal (NM15, -16, -25, and -33) and CPE-defective (NM7, -9, and -19) mutants substantially rescued virus infectivity and virus-induced CPE, respectively, whereas the NS2B-L114T mutation rescued the NM16, -25, and -33 mutants. In conclusion, the results revealed the essential roles of the N-terminal half of NS2A in RNA replication and virus-induced CPE. Intramolecular interactions between pTMSs of NS2A and intermolecular interactions between the NS2A and NS2B proteins were also implicated. IMPORTANCE The characterization of the N-terminal (current study) and C-terminal halves of DENV NS2A is the most comprehensive mutagenesis study to date to investigate the function of NS2A during the flaviviral life cycle

Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E.

Directory of Open Access Journals (Sweden)

Panisadee Avirutnan

2007-11-01

Full Text Available Dengue virus (DENV nonstructural protein-1 (NS1 is a secreted glycoprotein that is absent from viral particles but accumulates in the supernatant and on the plasma membrane of cells during infection. Immune recognition of cell surface NS1 on endothelial cells has been hypothesized as a mechanism for the vascular leakage that occurs during severe DENV infection. However, it has remained unclear how NS1 becomes associated with the plasma membrane, as it contains no membrane-spanning sequence motif. Using flow cytometric and ELISA-based binding assays and mutant cell lines lacking selective glycosaminoglycans, we show that soluble NS1 binds back to the surface of uninfected cells primarily via interactions with heparan sulfate and chondroitin sulfate E. DENV NS1 binds directly to the surface of many types of epithelial and mesenchymal cells yet attaches poorly to most peripheral blood cells. Moreover, DENV NS1 preferentially binds to cultured human microvascular compared to aortic or umbilical cord vein endothelial cells. This binding specificity was confirmed in situ as DENV NS1 bound to lung and liver but not intestine or brain endothelium of mouse tissues. Differential binding of soluble NS1 by tissue endothelium and subsequent recognition by anti-NS1 antibodies could contribute to the selective vascular leakage syndrome that occurs during severe secondary DENV infection.

Doença celíaca associada à tireoidite de Hashimoto e síndrome de Noonan

OpenAIRE

Perez,Mariana Ortega; Ciambelli,Giuliano Serafino; Nigri,Alcinda Aranha; Vieira,Marta Wey; Costa,Clóvis Duarte

2010-01-01

OBJETIVO: Relatar o caso clínico de uma criança portadora de doença celíaca, tireoidite de Hashimoto e síndrome de Noonan. DESCRIÇÃO DE CASO: Menina de dez anos e seis meses, branca, apresentando história de diarreia líquida há cinco meses e "aumento da barriga". Ao exame, mostrava peso de 20.580g (p

Observational Prospective Study on Patients Treated With Norditropin®

Science.gov (United States)

2017-10-11

Growth Hormone Disorder; Growth Hormone Deficiency in Children; Adult Growth Hormone Deficiency; Genetic Disorder; Turner Syndrome; Foetal Growth Problem; Small for Gestational Age; Chronic Kidney Disease; Chronic Renal Insufficiency; Noonan Syndrome

In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4

Directory of Open Access Journals (Sweden)

Thi Thanh Hanh Nguyen

2013-12-01

Full Text Available The discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3pro of dengue fever virus carries out all enzymatic activities needed for polyprotein processing and is considered to be amenable to antiviral inhibition by analogy. Virtual screening of 300,000 compounds using Autodock 3 on the GVSS platform was conducted to identify novel inhibitors against the NS2B-NS3pro. Thirty-six compounds were selected for in vitro assay against NS2B-NS3pro expressed in Pichia pastoris. Seven novel compounds were identified as inhibitors with IC50 values of 3.9 ± 0.6–86.7 ± 3.6 μM. Three strong NS2B-NS3pro inhibitors were further confirmed as competitive inhibitors with Ki values of 4.0 ± 0.4, 4.9 ± 0.3, and 3.4 ± 0.1 μM, respectively. Hydrophobic and hydrogen bond interactions between amino acid residues in the NS3pro active site with inhibition compounds were also identified.

NS1-binding protein abrogates the elevation of cell viability by the influenza A virus NS1 protein in association with CRKL

Energy Technology Data Exchange (ETDEWEB)

Miyazaki, Masaya [Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan); Nishihara, Hiroshi, E-mail: hnishihara@med.hokudai.ac.jp [Department of Translational Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan); Hasegawa, Hideki [Department of Pathology, National Institute of Infectious Diseases, Sinjuku-ku, Tokyo (Japan); Tashiro, Masato [Influenza Virus Research Center, National Institute of Infectious Diseases, Sinjuku-ku, Tokyo (Japan); Wang, Lei [Department of Translational Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan); Kimura, Taichi; Tanino, Mishie; Tsuda, Masumi [Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan); Tanaka, Shinya [Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan); Department of Translational Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan)

2013-11-29

Highlights: •NS1 induced excessive phosphorylation of ERK and elevated cell viability. •NS1-BP expression and CRKL knockdown abolished survival effect of NS1. •NS1-BP and NS1 formed the complex through the interaction with CRKL-SH3(N). -- Abstract: The influenza A virus non-structural protein 1 (NS1) is a multifunctional virulence factor consisting of an RNA binding domain and several Src-homology (SH) 2 and SH3 binding motifs, which promotes virus replication in the host cell and helps to evade antiviral immunity. NS1 modulates general host cell physiology in association with various cellular molecules including NS1-binding protein (NS1-BP) and signaling adapter protein CRK-like (CRKL), while the physiological role of NS1-BP during influenza A virus infection especially in association with NS1 remains unclear. In this study, we analyzed the intracellular association of NS1-BP, NS1 and CRKL to elucidate the physiological roles of these molecules in the host cell. In HEK293T cells, enforced expression of NS1 of A/Beijing (H1N1) and A/Indonesia (H5N1) significantly induced excessive phosphorylation of ERK and elevated cell viability, while the over-expression of NS1-BP and the abrogation of CRKL using siRNA abolished such survival effect of NS1. The pull-down assay using GST-fusion CRKL revealed the formation of intracellular complexes of NS1-BP, NS1 and CRKL. In addition, we identified that the N-terminus SH3 domain of CRKL was essential for binding to NS1-BP using GST-fusion CRKL-truncate mutants. This is the first report to elucidate the novel function of NS1-BP collaborating with viral protein NS1 in modulation of host cell physiology. In addition, an alternative role of adaptor protein CRKL in association with NS1 and NS1-BP during influenza A virus infection is demonstrated.

hnRNP A2/B1 interacts with influenza A viral protein NS1 and inhibits virus replication potentially through suppressing NS1 RNA/protein levels and NS1 mRNA nuclear export

Energy Technology Data Exchange (ETDEWEB)

Wang, Yimeng; Zhou, Jianhong; Du, Yuchun, E-mail: ydu@uark.edu

2014-01-20

The NS1 protein of influenza viruses is a major virulence factor and exerts its function through interacting with viral/cellular RNAs and proteins. In this study, we identified heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) as an interacting partner of NS1 proteins by a proteomic method. Knockdown of hnRNP A2/B1 by small interfering RNA (siRNA) resulted in higher levels of NS vRNA, NS1 mRNA, and NS1 protein in the virus-infected cells. In addition, we demonstrated that hnRNP A2/B1 proteins are associated with NS1 and NS2 mRNAs and that knockdown of hnRNP A2/B1 promotes transport of NS1 mRNA from the nucleus to the cytoplasm in the infected cells. Lastly, we showed that knockdown of hnRNP A2/B1 leads to enhanced virus replication. Our results suggest that hnRNP A2/B1 plays an inhibitory role in the replication of influenza A virus in host cells potentially through suppressing NS1 RNA/protein levels and NS1 mRNA nucleocytoplasmic translocation. - Highlights: • Cellular protein hnRNP A2/B1 interacts with influenza viral protein NS1. • hnRNP A2/B1 suppresses the levels of NS1 protein, vRNA and mRNA in infected cells. • hnRNP A2/B1 protein is associated with NS1 and NS2 mRNAs. • hnRNP A2/B1 inhibits the nuclear export of NS1 mRNAs. • hnRNP A2/B1 inhibits influenza virus replication.

Massive Cervico-Lingual Cystic Hygroma

African Journals Online (AJOL)

alcohol consumption. Karyotype abnormalities are found in 25 -70% of children with CH. The Genetic syndromes reported with CH include; Turner's syndrome, Down's syndrome, Noonan syndrome and chromosomal abnormalities such as trisomy. 13, 18, and 21. Isolated CH can also be inherited as an autosomal recessive ...

Assessment of Drug Binding Potential of Pockets in the NS2B/NS3 Dengue Virus Protein

Science.gov (United States)

Amelia, F.; Iryani; Sari, P. Y.; Parikesit, A. A.; Bakri, R.; Toepak, E. P.; Tambunan, U. S. F.

2018-04-01

Every year an endemic dengue fever estimated to affect over 390 million cases in over 128 countries occurs. However, the antigen types which stimulate the human immune response are variable, as a result, neither effective vaccines nor antiviral treatments have been successfully developed for this disease. The NS2B/NS3 protease of the dengue virus (DENV) responsible for viral replication is a potential drug target. The ligand-enzyme binding site determination is a key role in the success of virtual screening of new inhibitors. The NS2B/NS3 protease of DENV (PDB ID: 2FOM) has two pockets consisting of 37 (Pocket 1) and 27 (Pocket 2) amino acid residues in each pocket. In this research, we characterized the amino acid residues for binding sites in NS3/NS2B based on the hydrophobicity, the percentage of charged residues, volume, depth, ΔGbinding, hydrogen bonding and bond length. The hydrophobic percentages of both pockets are high, 59 % (Pocket 1) and 41% (Pocket 2) and the percentage of charged residues in Pocket 1 and 2 are 22% and 48%, and the pocket volume is less than 700 Å3. An interaction analysis using molecular docking showed that interaction between the ligand complex and protein in Pocket 1 is more negative than Pocket 2. As a result, Pocket 1 is the better potential target for a ligand to inhibit the action of NS2B/NS3 DENV.

Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner.

Science.gov (United States)

Zheng, Hong; Yu, Wen-Mei; Waclaw, Ronald R; Kontaridis, Maria I; Neel, Benjamin G; Qu, Cheng-Kui

2018-03-20

Catalytically activating mutations in Ptpn11 , which encodes the protein tyrosine phosphatase SHP2, cause 50% of Noonan syndrome (NS) cases, whereas inactivating mutations in Ptpn11 are responsible for nearly all cases of the similar, but distinct, developmental disorder Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome). However, both types of disease mutations are gain-of-function mutations because they cause SHP2 to constitutively adopt an open conformation. We found that the catalytic activity of SHP2 was required for the pathogenic effects of gain-of-function, disease-associated mutations on the development of hydrocephalus in the mouse. Targeted pan-neuronal knockin of a Ptpn11 allele encoding the active SHP2 E76K mutant resulted in hydrocephalus due to aberrant development of ependymal cells and their cilia. These pathogenic effects of the E76K mutation were suppressed by the additional mutation C459S, which abolished the catalytic activity of SHP2. Moreover, ependymal cells in NSML mice bearing the inactive SHP2 mutant Y279C were also unaffected. Mechanistically, the SHP2 E76K mutant induced developmental defects in ependymal cells by enhancing dephosphorylation and inhibition of the transcription activator STAT3. Whereas STAT3 activity was reduced in Ptpn11 E76K/+ cells, the activities of the kinases ERK and AKT were enhanced, and neural cell-specific Stat3 knockout mice also manifested developmental defects in ependymal cells and cilia. These genetic and biochemical data demonstrate a catalytic-dependent role of SHP2 gain-of-function disease mutants in the pathogenesis of hydrocephalus. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Plasma homocysteine and B vitamins levels in Nigerian children with nephrotic syndrome.

Science.gov (United States)

Orimadegun, Bose Etaniamhe; Orimadegun, Adebola Emmanuel; Ademola, Adebowale Dele; Agbedana, Emmanuel Oluyemi

2014-01-01

Available data on plasma homocysteine level in patients with nephrotic syndrome (NS) are controversial with increased, decreased and unchanged values reported. Therefore, plasma homocysteine and serum B vitamins in Nigerian children with NS were assessed in this study. Fasting blood samples were analysed for plasma homocysteine, serum folate and B vitamins in 42 children with NS and 42 age and sex-matched healthy controls in this case control study. Data were compared between NS and control using t test and Chi square. Relationships were tested with regression analysis with p set at 0.05. Prevalence of hyperhomocysteinaemia, low folate and cyanocobalamin in NS was 57.1%, 14.3% and 9.5% respectively. The mean homocysteine level was significantly higher in NS than control (11.3±2.6 µmol/L versus 5.5±2.3 µmol/L). Also, NS had lower folate and cyanocobalamin than control: 9.1±3.9 ng/mL versus 11.2±3.1 ng/dL and 268.5±95.7 pg/mL versus 316±117.2 pg/mL respectively. Weak but significant correlation between homocysteine and serum albumin (r = 0.347), folate (r = -0.607) and vitamin B12 (r = -0.185) were found in the NS group. Significant relationship was also found between homocysteine and vitamin B12 (ß = -0.64, 95% CI = -1.20, -0.08) after controlling for folate and vitamin B6 levels. Clinically important hyperhomocysteinaemia and low B vitamins occur in Nigerian children with nephrotic syndrome. This data suggest that potential usefulness of folate and vitamin B supplementation for reducing high homocysteine levels in nephrotic syndrome need to be further investigated.

Boron tolerance in NS wheat lines

Directory of Open Access Journals (Sweden)

Brdar Milka

2006-01-01

Full Text Available Boron is an essential micronutrient for higher plants. Present in excessive amounts boron becomes toxic and can limit plant growth and yield. Suppression of root growth is one of the symptoms of boron toxicity in wheat. This study was undertaken to investigate the response of 10 perspective NS lines of wheat to high concentrations of boron. Analysis of root growth was done on young plants, germinated and grown in the presence of different concentrations of boric acid (0, 50,100 and 150 mg/1. Significant differences occurred between analyzed genotypes and treatments regarding root length. Average suppression of root growth was between 11,6 and 34,2%, for line NS 252/02 are even noted 61,4% longer roots at treatments in relation to the control. Lines with mean suppression of root growth less than 20% (NS 101/02, NS 138/01, NS 53/03 and NS 73/02 may be considered as boron tolerant. Spearmans coefficients showed high level of agreement regarding rang of root length for genotypes treated with 100 and 150 mg H3BO3/l.

Docking, synthesis and bioassay studies of imine derivatives as potential inhibitors for dengue NS2B/ NS3 serine protease

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Neni Frimayanti

2017-11-01

Full Text Available Objective: To search imine derivatives as new active agents against dengue type 2 NS2B/NS3 using molecular docking, since there is no effective vaccine against flaviviral infections. Methods: In this research, molecular docking was performed for a series of imine derivatives and the information obtained from the docking studies was used to explore the binding modes of these imine derivatives with dengue type 2 NS2B/NS3 serine protease. A set of imine were synthesized and bioassay study of the inhibitory activities of these compounds was then performed. Results: The results indicated that MY8 and MY4 have the ability to inhibit DEN2 NS2B/NS3 proteolytic activity. Conclusions: These two compounds were chosen as the reference for the next stage in drug design as new inhibitor agents against NS2B/NS3.

Genetic Syndromes Associated with Congenital Cardiac Defects and Ophthalmologic Changes - Systematization for Diagnosis in the Clinical Practice.

Science.gov (United States)

Oliveira, Priscila H A; Souza, Beatriz S; Pacheco, Eimi N; Menegazzo, Michele S; Corrêa, Ivan S; Zen, Paulo R G; Rosa, Rafael F M; Cesa, Claudia C; Pellanda, Lucia C; Vilela, Manuel A P

2018-01-01

Numerous genetic syndromes associated with heart disease and ocular manifestations have been described. However, a compilation and a summarization of these syndromes for better consultation and comparison have not been performed yet. The objective of this work is to systematize available evidence in the literature on different syndromes that may cause congenital heart diseases associated with ocular changes, focusing on the types of anatomical and functional changes. A systematic search was performed on Medline electronic databases (PubMed, Embase, Cochrane, Lilacs) of articles published until January 2016. Eligibility criteria were case reports or review articles that evaluated the association of ophthalmic and cardiac abnormalities in genetic syndrome patients younger than 18 years. The most frequent genetic syndromes were: Down Syndrome, Velo-cardio-facial / DiGeorge Syndrome, Charge Syndrome and Noonan Syndrome. The most associated cardiac malformations with ocular findings were interatrial communication (77.4%), interventricular communication (51.6%), patent ductus arteriosus (35.4%), pulmonary artery stenosis (25.8%) and tetralogy of Fallot (22.5%). Due to their clinical variability, congenital cardiac malformations may progress asymptomatically to heart defects associated with high morbidity and mortality. For this reason, the identification of extra-cardiac characteristics that may somehow contribute to the diagnosis of the disease or reveal its severity is of great relevance.

Resistance Analyses of HCV NS3/4A Protease and NS5B Polymerase from Clinical Studies of Deleobuvir and Faldaprevir.

Directory of Open Access Journals (Sweden)

Kristi L Berger

Full Text Available The resistance profile of anti-hepatitis C virus (HCV agents used in combination is important to guide optimal treatment regimens. We evaluated baseline and treatment-emergent NS3/4A and NS5B amino-acid variants among HCV genotype (GT-1a and -1b-infected patients treated with faldaprevir (HCV protease inhibitor, deleobuvir (HCV polymerase non-nucleoside inhibitor, and ribavirin in multiple clinical studies.HCV NS3/4A and NS5B population sequencing (Sanger method was performed on all baseline plasma samples (n = 1425 NS3; n = 1556 NS5B and on post-baseline plasma samples from patients with virologic failure (n = 113 GT-1a; n = 221 GT-1b. Persistence and time to loss of resistance-associated variants (RAVs was estimated using Kaplan-Meier analysis.Faldaprevir RAVs (NS3 R155 and D168 and deleobuvir RAVs (NS5B 495 and 496 were rare (90%. Virologic relapse was associated with RAVs in both NS3 and NS5B (53% GT-1b; 52% GT-1b; some virologic relapses had NS3 RAVs only (47% GT-1a; 17% GT-1b. Median time to loss of GT-1b NS5B P495 RAVs post-treatment (5 months was less than that of GT-1b NS3 D168 (8.5 months and GT-1a R155 RAVs (11.5 months.Faldaprevir and deleobuvir RAVs are more prevalent among virologic failures than at baseline. Treatment response was not compromised by common NS3 polymorphisms; however, alanine at NS5B amino acid 499 at baseline (wild-type in GT-1a, polymorphism in GT-1b may reduce response to this deleobuvir-based regimen.

Purification and crystallization of dengue and West Nile virus NS2B–NS3 complexes

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D’Arcy, Allan, E-mail: allan.darcy@novartis.com; Chaillet, Maxime; Schiering, Nikolaus; Villard, Frederic [Novartis Institutes of Biomedical Research, Protease Platform, Klybeckstrasse 144, CH 4002 Basel (Switzerland); Lim, Siew Pheng [Novartis Institutes of Tropical Diseases (Singapore); Lefeuvre, Peggy [Novartis Institutes of Biomedical Research, Protease Platform, Klybeckstrasse 144, CH 4002 Basel (Switzerland); Erbel, Paul [Novartis Institutes of Biomedical Research, Protease Platform, Klybeckstrasse 144, CH 4002 Basel (Switzerland); Novartis Institutes of Tropical Diseases (Singapore)

2006-02-01

Crystals of dengue serotype 2 and West Nile virus NS2B–NS3 protease complexes have been obtained and the crystals of both diffract to useful resolution. Sample homogeneity was essential for obtaining X-ray-quality crystals of the dengue protease. Controlled proteolysis produced a crystallizable fragment of the apo West Nile virus NS2B–NS3 and crystals were also obtained in the presence of a peptidic inhibitor. Both dengue and West Nile virus infections are an increasing risk to humans, not only in tropical and subtropical areas, but also in North America and parts of Europe. These viral infections are generally transmitted by mosquitoes, but may also be tick-borne. Infection usually results in mild flu-like symptoms, but can also cause encephalitis and fatalities. Approximately 2799 severe West Nile virus cases were reported this year in the United States, resulting in 102 fatalities. With this alarming increase in the number of West Nile virus infections in western countries and the fact that dengue virus already affects millions of people per year in tropical and subtropical climates, there is a real need for effective medicines. A possible therapeutic target to combat these viruses is the protease, which is essential for virus replication. In order to provide structural information to help to guide a lead identification and optimization program, crystallizations of the NS2B–NS3 protease complexes from both dengue and West Nile viruses have been initiated. Crystals that diffract to high resolution, suitable for three-dimensional structure determinations, have been obtained.

Purification and crystallization of dengue and West Nile virus NS2B–NS3 complexes

International Nuclear Information System (INIS)

D’Arcy, Allan; Chaillet, Maxime; Schiering, Nikolaus; Villard, Frederic; Lim, Siew Pheng; Lefeuvre, Peggy; Erbel, Paul

2006-01-01

Crystals of dengue serotype 2 and West Nile virus NS2B–NS3 protease complexes have been obtained and the crystals of both diffract to useful resolution. Sample homogeneity was essential for obtaining X-ray-quality crystals of the dengue protease. Controlled proteolysis produced a crystallizable fragment of the apo West Nile virus NS2B–NS3 and crystals were also obtained in the presence of a peptidic inhibitor. Both dengue and West Nile virus infections are an increasing risk to humans, not only in tropical and subtropical areas, but also in North America and parts of Europe. These viral infections are generally transmitted by mosquitoes, but may also be tick-borne. Infection usually results in mild flu-like symptoms, but can also cause encephalitis and fatalities. Approximately 2799 severe West Nile virus cases were reported this year in the United States, resulting in 102 fatalities. With this alarming increase in the number of West Nile virus infections in western countries and the fact that dengue virus already affects millions of people per year in tropical and subtropical climates, there is a real need for effective medicines. A possible therapeutic target to combat these viruses is the protease, which is essential for virus replication. In order to provide structural information to help to guide a lead identification and optimization program, crystallizations of the NS2B–NS3 protease complexes from both dengue and West Nile viruses have been initiated. Crystals that diffract to high resolution, suitable for three-dimensional structure determinations, have been obtained

Performance of commercial dengue NS1 ELISA and molecular analysis of NS1 gene of dengue viruses obtained during surveillance in Indonesia.

Science.gov (United States)

Aryati, Aryati; Trimarsanto, Hidayat; Yohan, Benediktus; Wardhani, Puspa; Fahri, Sukmal; Sasmono, R Tedjo

2013-12-29

Early diagnosis of dengue infection is crucial for better management of the disease. Diagnostic tests based on the detection of dengue virus (DENV) Non Structural Protein 1 (NS1) antigen are commercially available with different sensitivities and specificities observed in various settings. Dengue is endemic in Indonesia and clinicians are increasingly using the NS1 detection for dengue confirmation. This study described the performance of Panbio Dengue Early NS1 and IgM Capture ELISA assays for dengue detection during our surveillance in eight cities in Indonesia as well as the genetic diversity of DENV NS1 genes and its relationship with the NS1 detection. The NS1 and IgM/IgG ELISA assays were used for screening and confirmation of dengue infection during surveillance in 2010-2012. Collected serum samples (n = 440) were subjected to RT-PCR and virus isolation, in which 188 samples were confirmed for dengue infection. The positivity of the ELISA assays were correlated with the RT-PCR results to obtain the sensitivity of the assays. The NS1 genes of 48 Indonesian virus isolates were sequenced and their genetic characteristics were studied. Using molecular data as gold standard, the sensitivity of NS1 ELISA assay for samples from Indonesia was 56.4% while IgM ELISA was 73.7%. When both NS1 and IgM results were combined, the sensitivity increased to 89.4%. The NS1 sensitivity varied when correlated with city/geographical origins and DENV serotype, in which the lowest sensitivity was observed for DENV-4 (19.0%). NS1 sensitivity was higher in primary (67.6%) compared to secondary infection (48.2%). The specificity of NS1 assay for non-dengue samples were 100%. The NS1 gene sequence analysis of 48 isolates revealed the presence of polymorphisms of the NS1 genes which apparently did not influence the NS1 sensitivity. We observed a relatively low sensitivity of NS1 ELISA for dengue detection on RT-PCR-positive dengue samples. The detection rate increased significantly

Therapeutic Effects of Monoclonal Antibody against Dengue Virus NS1 in a STAT1 Knockout Mouse Model of Dengue Infection.

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Wan, Shu-Wen; Chen, Pei-Wei; Chen, Chin-Yu; Lai, Yen-Chung; Chu, Ya-Ting; Hung, Chia-Yi; Lee, Han; Wu, Hsuan Franziska; Chuang, Yung-Chun; Lin, Jessica; Chang, Chih-Peng; Wang, Shuying; Liu, Ching-Chuan; Ho, Tzong-Shiann; Lin, Chiou-Feng; Lee, Chien-Kuo; Wu-Hsieh, Betty A; Anderson, Robert; Yeh, Trai-Ming; Lin, Yee-Shin

2017-10-15

Dengue virus (DENV) is the causative agent of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome and is endemic to tropical and subtropical regions of the world. Our previous studies showed the existence of epitopes in the C-terminal region of DENV nonstructural protein 1 (NS1) which are cross-reactive with host Ags and trigger anti-DENV NS1 Ab-mediated endothelial cell damage and platelet dysfunction. To circumvent these potentially harmful events, we replaced the C-terminal region of DENV NS1 with the corresponding region from Japanese encephalitis virus NS1 to create chimeric DJ NS1 protein. Passive immunization of DENV-infected mice with polyclonal anti-DJ NS1 Abs reduced viral Ag expression at skin inoculation sites and shortened DENV-induced prolonged bleeding time. We also investigated the therapeutic effects of anti-NS1 mAb. One mAb designated 2E8 does not recognize the C-terminal region of DENV NS1 in which host-cross-reactive epitopes reside. Moreover, mAb 2E8 recognizes NS1 of all four DENV serotypes. We also found that mAb 2E8 caused complement-mediated lysis in DENV-infected cells. In mouse model studies, treatment with mAb 2E8 shortened DENV-induced prolonged bleeding time and reduced viral Ag expression in the skin. Importantly, mAb 2E8 provided therapeutic effects against all four serotypes of DENV. We further found that mAb administration to mice as late as 1 d prior to severe bleeding still reduced prolonged bleeding time and hemorrhage. Therefore, administration with a single dose of mAb 2E8 can protect mice against DENV infection and pathological effects, suggesting that NS1-specific mAb may be a therapeutic option against dengue disease. Copyright © 2017 by The American Association of Immunologists, Inc.

Rationalizing meat consumption. The 4Ns.

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Piazza, Jared; Ruby, Matthew B; Loughnan, Steve; Luong, Mischel; Kulik, Juliana; Watkins, Hanne M; Seigerman, Mirra

2015-08-01

Recent theorizing suggests that the 4Ns - that is, the belief that eating meat is natural, normal, necessary, and nice - are common rationalizations people use to defend their choice of eating meat. However, such theorizing has yet to be subjected to empirical testing. Six studies were conducted on the 4Ns. Studies 1a and 1b demonstrated that the 4N classification captures the vast majority (83%-91%) of justifications people naturally offer in defense of eating meat. In Study 2, individuals who endorsed the 4Ns tended also to objectify (dementalize) animals and included fewer animals in their circle of moral concern, and this was true independent of social dominance orientation. Subsequent studies (Studies 3-5) showed that individuals who endorsed the 4Ns tend not to be motivated by ethical concerns when making food choices, are less involved in animal-welfare advocacy, less driven to restrict animal products from their diet, less proud of their animal-product decisions, tend to endorse Speciesist attitudes, tend to consume meat and animal products more frequently, and are highly committed to eating meat. Furthermore, omnivores who strongly endorsed the 4Ns tended to experience less guilt about their animal-product decisions, highlighting the guilt-alleviating function of the 4Ns. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Study of Hypoalbuminemia and Pleural Effusionin Pediatric Nephrotic Syndrome

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Tovan Perinandika

2017-06-01

Full Text Available Background: Nephrotic syndrome (NS is a kidney disease that is most often found in children. Hypoalbuminemia in NS can cause a decrease in oncotic pressure causing extravasation of fluid into the interstitial space. In conditions of severe hypoalbuminemia, fluid extravasation may cause occurrence of pleural effusion. The objectives of this study was to analyze the correlation between hypoalbuminemia and pleural effusion in children with NS. Methods: An analytical study was conducted on 69 medical records of pediatric nephrotic syndrome from 1 January 2008–31 December 2013 in dr. Hasan Sadikin General Hospital. Inclusion criteria were pediatric patients between 1-14 years old with NS. Exclusion criteria were patients who already had albumin transfusion, malnutrition, patients with chronic disease, and incomplete medical record information. Contingency coefficient test was carried out to discover the correlation between variables. Results: Out of 89 samples, 69 samples were included. Characteristics of the included patients are male (n=48, female (n=21, age 1–5 (n=24, 6–10 (n=22, 11–14 (n=23, mild hypoalbuminemia (n=3, moderate hypoalbuminemia (n=27, severe hypoalbuminemia (n=39, patients with pleural effusion (n=23, and non-pleural effusion (n=46. There was a significant correlation between  hypoalbuminemia and pleural effusion with p=0.000 (p<0.05 and moderate correlation (r=0.437. Conclusions: Hypoalbuminemia has correlation with pleural effusion in pediatric nephrotic syndrome. Keywords: Hypoalbuminemia, pediatric nephrotic syndrome, pleural effusion DOI: 10.15850/amj.v4n2.1075

Endothelial ERK signaling controls lymphatic fate specification

Science.gov (United States)

Deng, Yong; Atri, Deepak; Eichmann, Anne; Simons, Michael

2013-01-01

Lymphatic vessels are thought to arise from PROX1-positive endothelial cells (ECs) in the cardinal vein in response to induction of SOX18 expression; however, the molecular event responsible for increased SOX18 expression has not been established. We generated mice with endothelial-specific, inducible expression of an RAF1 gene with a gain-of-function mutation (RAF1S259A) that is associated with Noonan syndrome. Expression of mutant RAF1S259A in ECs activated ERK and induced SOX18 and PROX1 expression, leading to increased commitment of venous ECs to the lymphatic fate. Excessive production of lymphatic ECs resulted in lymphangiectasia that was highly reminiscent of abnormal lymphatics seen in Noonan syndrome and similar “RASopathies.” Inhibition of ERK signaling during development abrogated the lymphatic differentiation program and rescued the lymphatic phenotypes induced by expression of RAF1S259A. These data suggest that ERK activation plays a key role in lymphatic EC fate specification and that excessive ERK activation is the basis of lymphatic abnormalities seen in Noonan syndrome and related diseases. PMID:23391722

Antenatal imaging of cutis verticis gyrata

International Nuclear Information System (INIS)

Kennedy, Ana; Perry, David; Battin, Malcolm

2008-01-01

Cutis verticis gyrata (CVG) is a skin condition characterized by thick folds and deep furrows, resembling a cortical gyral pattern. There is a recognized but rare association with Noonan syndrome. We report the antenatal imaging, including three-dimensional surface-rendered sonography and MRI, of a fetus with CVG who was subsequently diagnosed with Noonan syndrome. The case illustrates the antenatal appearances of congenital CVG and the potential yield of antenatal imaging in excluding a major central nervous system anomaly. This is important because without prior knowledge of this condition and its imaging characteristics, it is possible to get a false impression of an underlying skull defect on mid-trimester imaging. (orig.)

Antenatal imaging of cutis verticis gyrata

Energy Technology Data Exchange (ETDEWEB)

Kennedy, Ana [Starship Hospital, Department of Paediatric Cardiology, Auckland (New Zealand); Perry, David [Starship Children' s Hospital, Radiology Department, Auckland (New Zealand); Battin, Malcolm [Auckland City Hospital, Newborn Services, National Women' s Health, Auckland (New Zealand); University of Auckland, Department of Paediatrics, Auckland (New Zealand)

2008-05-15

Cutis verticis gyrata (CVG) is a skin condition characterized by thick folds and deep furrows, resembling a cortical gyral pattern. There is a recognized but rare association with Noonan syndrome. We report the antenatal imaging, including three-dimensional surface-rendered sonography and MRI, of a fetus with CVG who was subsequently diagnosed with Noonan syndrome. The case illustrates the antenatal appearances of congenital CVG and the potential yield of antenatal imaging in excluding a major central nervous system anomaly. This is important because without prior knowledge of this condition and its imaging characteristics, it is possible to get a false impression of an underlying skull defect on mid-trimester imaging. (orig.)

Genetic Syndromes Associated with Congenital Cardiac Defects and Ophthalmologic Changes - Systematization for Diagnosis in the Clinical Practice

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Priscila H. A. Oliveira

Full Text Available Abstract Background: Numerous genetic syndromes associated with heart disease and ocular manifestations have been described. However, a compilation and a summarization of these syndromes for better consultation and comparison have not been performed yet. Objective: The objective of this work is to systematize available evidence in the literature on different syndromes that may cause congenital heart diseases associated with ocular changes, focusing on the types of anatomical and functional changes. Method: A systematic search was performed on Medline electronic databases (PubMed, Embase, Cochrane, Lilacs of articles published until January 2016. Eligibility criteria were case reports or review articles that evaluated the association of ophthalmic and cardiac abnormalities in genetic syndrome patients younger than 18 years. Results: The most frequent genetic syndromes were: Down Syndrome, Velo-cardio-facial / DiGeorge Syndrome, Charge Syndrome and Noonan Syndrome. The most associated cardiac malformations with ocular findings were interatrial communication (77.4%, interventricular communication (51.6%, patent ductus arteriosus (35.4%, pulmonary artery stenosis (25.8% and tetralogy of Fallot (22.5%. Conclusion: Due to their clinical variability, congenital cardiac malformations may progress asymptomatically to heart defects associated with high morbidity and mortality. For this reason, the identification of extra-cardiac characteristics that may somehow contribute to the diagnosis of the disease or reveal its severity is of great relevance.

Identification of drug resistance and immune-driven variations in hepatitis C virus (HCV) NS3/4A, NS5A and NS5B regions reveals a new approach toward personalized medicine.

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Ikram, Aqsa; Obaid, Ayesha; Awan, Faryal Mehwish; Hanif, Rumeza; Naz, Anam; Paracha, Rehan Zafar; Ali, Amjad; Janjua, Hussnain Ahmed

2017-01-01

Cellular immune responses (T cell responses) during hepatitis C virus (HCV) infection are significant factors for determining the outcome of infection. HCV adapts to host immune responses by inducing mutations in its genome at specific sites that are important for HLA processing/presentation. Moreover, HCV also adapts to resist potential drugs that are used to restrict its replication, such as direct-acting antivirals (DAAs). Although DAAs have significantly reduced disease burden, resistance to these drugs is still a challenge for the treatment of HCV infection. Recently, drug resistance mutations (DRMs) observed in HCV proteins (NS3/4A, NS5A and NS5B) have heightened concern that the emergence of drug resistance may compromise the effectiveness of DAAs. Therefore, the NS3/4A, NS5A and NS5B drug resistance variations were investigated in this study, and their prevalence was examined in a large number of protein sequences from all HCV genotypes. Furthermore, potential CD4 + and CD8 + T cell epitopes were predicted and their overlap with genetic variations was explored. The findings revealed that many reported DRMs within NS3/4A, NS5A and NS5B are not drug-induced; rather, they are already present in HCV strains, as they were also detected in HCV-naïve patients. This study highlights several hot spots in which HLA and drug selective pressure overlap. Interestingly, these overlapping mutations were frequently observed among many HCV genotypes. This study implicates that knowledge of the host HLA type and HCV subtype/genotype can provide important information in defining personalized therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

The Evidence-Based Approach to Adult-Onset Idiopathic Nephrotic Syndrome.

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Canetta, Pietro A A; Radhakrishnan, Jai

2015-01-01

Adult-onset nephrotic syndrome (NS) differs from its pediatric counterpart in several important ways. Most importantly, NS in adults is more etiologically heterogeneous compared to children, and thus treatment approaches rely heavily on the histological diagnosis provided by renal biopsy. The evidence-based approach to treatment of adult NS has been critically examined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in glomerulonephritis, published in 2012. Here, we examine the strengths and limits of those guidelines and review recent work that expands the evidence-based approach.

Atrioventricular canal defect and associated genetic disorders: new insights into polydactyly syndromes

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M. Cristina Digilio

2011-07-01

Full Text Available Atrioventricular canal defect (AVCD is a common congenital heart defect (CHD, representing 7.4% of all cardiac malformations, considered secondary to an extracellular matrix anomaly. The AVCD is associated with extracardiac defects in about 75% of the cases. In this review we analyzed different syndromic AVCDs, in particular those associated with polydactyly disorders, which show remarkable genotype-phenotype correlations. Chromo - some imbalances more frequently associated with AVCD include Down syndrome, deletion 8p23 and deletion 3p25, while mendelian disorders include Noonan syndrome and related RASopathies, several polydactyly syndromes, CHARGE and 3C (cranio-cerebello-cardiac syndrome. The complete form of AVCD is prevalent in patients with chromosomal imbalances. Additional cardiac defects are found in patients affected by chromosomal imbalances different from Down syndrome. Left-sided obstructive lesions are prevalently found in patients with RASopathies. Patients with deletion 8p23 often display AVCD with tetralogy of Fallot or with pulmonary valve stenosis. Tetralogy of Fallot is the only additional cardiac defect found in patients with Down syndrome and AVCD. On the other hand, the association of AVCD and tetralogy of Fallot is also quite characteristic of CHARGE and 3C syndromes. Heterotaxia defects, including common atrium and anomalous pulmonary venous return, occur in patients with AVCD associated with polydactyly syndromes (Ellis-van Creveld, short rib polydactyly, oral-facial-digital, Bardet-Biedl, and Smith-Lemli-Opitz syndromes. The initial clinical evidence of anatomic similarities between AVCD and heterotaxia in polydactyly syndromes was corroborated and explained by experimental studies in transgenic mice. These investigations have suggested the involvement of the Sonic Hedgehog pathway in syndromes with postaxial polydactyly and heterotaxia, and ciliary dysfunction was detected as pathomechanism for these disorders

Localisation system in wireless sensor networks using ns-2

CSIR Research Space (South Africa)

Abu-Mahfouz, Adnan M

2012-04-01

Full Text Available -1 /************************************************************************** ********** * * File: readme.asn * * Author: Adnan Abu-Mahfouz * * Date: March 2012 * * Description: Localisation system in wireless sensor networks using ns-2... *************************************************************************** *********/ /************************************************************************** *************************************************************************** *****/ 1. Introduction: ns-2 contains several flexible features that encourage researchers to use ns-2 to investigate the characteristics of wireless sensor networks (WSNs). However, to implement and evaluate localisation algorithms, the current ns- 2...

Functional investigation of grass carp reovirus nonstructural protein NS80

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Shao Ling

2011-04-01

Full Text Available Abstract Background Grass Carp Reovirus (GCRV, a highly virulent agent of aquatic animals, has an eleven segmented dsRNA genome encased in a multilayered capsid shell, which encodes twelve proteins including seven structural proteins (VP1-VP7, and five nonstructural proteins (NS80, NS38, NS31, NS26, and NS16. It has been suggested that the protein NS80 plays an important role in the viral replication cycle that is similar to that of its homologous protein μNS in the genus of Orthoreovirus. Results As a step to understanding the basis of the part played by NS80 in GCRV replication and particle assembly, we used the yeast two-hybrid (Y2H system to identify NS80 interactions with proteins NS38, VP4, and VP6 as well as NS80 and NS38 self-interactions, while no interactions appeared in the four protein pairs NS38-VP4, NS38-VP6, VP4-VP4, and VP4-VP6. Bioinformatic analyses of NS80 with its corresponding proteins were performed with all currently available homologous protein sequences in ARVs (avian reoviruses and MRVs (mammalian reoviruses to predict further potential functional domains of NS80 that are related to VFLS (viral factory-like structures formation and other roles in viral replication. Two conserved regions spanning from aa (amino acid residues of 388 to 433, and 562 to 580 were discovered in this study. The second conserved region with corresponding conserved residues Tyr565, His569, Cys571, Asn573, and Glu576 located between the two coiled-coils regions (aa ~513-550 and aa ~615-690 in carboxyl-proximal terminus were supposed to be essential to form VFLS, so that aa residues ranging from 513 to 742 of NS80 was inferred to be the smallest region that is necessary for forming VFLS. The function of the first conserved region including Ala395, Gly419, Asp421, Pro422, Leu438, and Leu443 residues is unclear, but one-third of the amino-terminal region might be species specific, dominating interactions with other viral components. Conclusions Our

Síndrome de Noonan. Reavaliação clínica e estudo molecular de 16 casos

OpenAIRE

B. Sousa, Sérgio; Venâncio, Margarida; Gabriel, Helena; Ramos, Lina; Santos, Isabel; Beck, Sebastian; Jorge, Marta; Simão, Luisa; Tavares, Purificação; M. Saraiva, Jorge

2014-01-01

ResumoO Síndrome de Noonan (SN, MIM#163950) é uma patologia do desenvolvimento caracterizada por dismorfia facial típica, baixa estatura e cardiopatia congénita. Tem uma frequência estimada de 1:1000-2500 nascimentos e transmissão autossómica dominante, com neomutações frequentes. Em 30-60% dos casos é possível identificar uma mutação no gene PTPN11.Foram reavaliados clínica, laboratorial e cognitivamente 16 indivíduos com a hipótese diagnóstica de SN, incluindo o estudo molecular do gene PTP...

Lyso-myristoyl phosphatidylcholine micelles sustain the activity of Dengue non-structural (NS) protein 3 protease domain fused with the full-length NS2B.

Science.gov (United States)

Huang, Qiwei; Li, Qingxin; Joy, Joma; Chen, Angela Shuyi; Ruiz-Carrillo, David; Hill, Jeffrey; Lescar, Julien; Kang, Congbao

2013-12-01

Dengue virus (DENV), a member of the flavivirus genus, affects 50-100 million people in tropical and sub-tropical regions. The DENV protease domain is located at the N-terminus of the NS3 protease and requires for its enzymatic activity a hydrophilic segment of the NS2B that acts as a cofactor. The protease is an important antiviral drug target because it plays a crucial role in virus replication by cleaving the genome-coded polypeptide into mature functional proteins. Currently, there are no drugs to inhibit DENV protease activity. Most structural and functional studies have been conducted using protein constructs containing the NS3 protease domain connected to a soluble segment of the NS2B membrane protein via a nine-residue linker. For in vitro structural and functional studies, it would be useful to produce a natural form of the DENV protease containing the NS3 protease domain and the full-length NS2B protein. Herein, we describe the expression and purification of a natural form of DENV protease (NS2BFL-NS3pro) containing the full-length NS2B protein and the protease domain of NS3 (NS3pro). The protease was expressed and purified in detergent micelles necessary for its folding. Our results show that this purified protein was active in detergent micelles such as lyso-myristoyl phosphatidylcholine (LMPC). These findings should facilitate further structural and functional studies of the protease and will facilitate drug discovery targeting DENV. Copyright © 2013 Elsevier Inc. All rights reserved.

Identification and subcellular localization of porcine deltacoronavirus accessory protein NS6

International Nuclear Information System (INIS)

Fang, Puxian; Fang, Liurong; Liu, Xiaorong; Hong, Yingying; Wang, Yongle; Dong, Nan; Ma, Panpan; Bi, Jing; Wang, Dang; Xiao, Shaobo

2016-01-01

Porcine deltacoronavirus (PDCoV) is an emerging swine enteric coronavirus. Accessory proteins are genus-specific for coronavirus, and two putative accessory proteins, NS6 and NS7, are predicted to be encoded by PDCoV; however, this remains to be confirmed experimentally. Here, we identified the leader-body junction sites of NS6 subgenomic RNA (sgRNA) and found that the actual transcription regulatory sequence (TRS) utilized by NS6 is non-canonical and is located upstream of the predicted TRS. Using the purified NS6 from an Escherichia coli expression system, we obtained two anti-NS6 monoclonal antibodies that could detect the predicted NS6 in cells infected with PDCoV or transfected with NS6-expressing plasmids. Further studies revealed that NS6 is always localized in the cytoplasm of PDCoV-infected cells, mainly co-localizing with the endoplasmic reticulum (ER) and ER-Golgi intermediate compartments, as well as partially with the Golgi apparatus. Together, our results identify the NS6 sgRNA and demonstrate its expression in PDCoV-infected cells. -- Highlights: •The leader-body fusion site of NS6 sgRNA is identified. •NS6 sgRNA uses a non-canonical transcription regulatory sequence (TRS). •NS6 can be expressed in PDCoV-infected cell. •NS6 predominantly localize to the ER complex and ER-Golgi intermediate compartment.

Identification and subcellular localization of porcine deltacoronavirus accessory protein NS6

Energy Technology Data Exchange (ETDEWEB)

Fang, Puxian; Fang, Liurong; Liu, Xiaorong; Hong, Yingying; Wang, Yongle; Dong, Nan; Ma, Panpan [State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China); The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070 (China); Bi, Jing [State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China); Department of Immunology and Aetology, College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan 430065 (China); Wang, Dang [State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China); The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070 (China); Xiao, Shaobo, E-mail: vet@mail.hzau.edu.cn [State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China); The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070 (China)

2016-12-15

Porcine deltacoronavirus (PDCoV) is an emerging swine enteric coronavirus. Accessory proteins are genus-specific for coronavirus, and two putative accessory proteins, NS6 and NS7, are predicted to be encoded by PDCoV; however, this remains to be confirmed experimentally. Here, we identified the leader-body junction sites of NS6 subgenomic RNA (sgRNA) and found that the actual transcription regulatory sequence (TRS) utilized by NS6 is non-canonical and is located upstream of the predicted TRS. Using the purified NS6 from an Escherichia coli expression system, we obtained two anti-NS6 monoclonal antibodies that could detect the predicted NS6 in cells infected with PDCoV or transfected with NS6-expressing plasmids. Further studies revealed that NS6 is always localized in the cytoplasm of PDCoV-infected cells, mainly co-localizing with the endoplasmic reticulum (ER) and ER-Golgi intermediate compartments, as well as partially with the Golgi apparatus. Together, our results identify the NS6 sgRNA and demonstrate its expression in PDCoV-infected cells. -- Highlights: •The leader-body fusion site of NS6 sgRNA is identified. •NS6 sgRNA uses a non-canonical transcription regulatory sequence (TRS). •NS6 can be expressed in PDCoV-infected cell. •NS6 predominantly localize to the ER complex and ER-Golgi intermediate compartment.

A Prospective Observational Survey on the Long-Term Effect of LDL Apheresis on Drug-Resistant Nephrotic Syndrome

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Eri Muso

2015-08-01

Full Text Available Background/Aims: LDL apheresis (LDL-A is used for drug-resistant nephrotic syndrome (NS as an alternative therapy to induce remission by improvement of hyperlipidemia. Several clinical studies have suggested the efficacy of LDL-A for refractory NS, but the level of evidence remains insufficient. A multicenter prospective study, POLARIS (Prospective Observational Survey on the Long-Term Effects of LDL Apheresis on Drug-Resistant Nephrotic Syndrome, was conducted to evaluate its clinical efficacy with high-level evidence. Methods: Patients with NS who showed resistance to primary medication for at least 4 weeks were prospectively recruited to the study and treated with LDL-A. The long-term outcome was evaluated based on the rate of remission of NS 2 years after treatment. Factors affecting the outcome were also examined. Results: A total of 58 refractory NS patients from 40 facilities were recruited and enrolled as subjects of the POLARIS study. Of the 44 subjects followed for 2 years, 21 (47.7% showed remission of NS based on a urinary protein (UP level Conclusions: Almost half of the cases of drug-resistant NS showed remission 2 years after LDL-A. Improvement of nephrotic parameters at termination of the LDL-A treatment was a predictor of a favorable outcome.

Novel nucleotide and amino acid covariation between the 5'UTR and the NS2/NS3 proteins of hepatitis C virus: bioinformatic and functional analyses.

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Hung-Yu Sun

Full Text Available Molecular covariation of highly polymorphic viruses is thought to have crucial effects on viral replication and fitness. This study employs association rule data mining of hepatitis C virus (HCV sequences to search for specific evolutionary covariation and then tests functional relevance on HCV replication. Data mining is performed between nucleotides in the untranslated regions 5' and 3'UTR, and the amino acid residues in the non-structural proteins NS2, NS3 and NS5B. Results indicate covariance of the 243(rd nucleotide of the 5'UTR with the 14(th, 41(st, 76(th, 110(th, 211(th and 212(th residues of NS2 and with the 71(st, 175(th and 621(st residues of NS3. Real-time experiments using an HCV subgenomic system to quantify viral replication confirm replication regulation for each covariant pair between 5'UTR₂₄₃ and NS2-41, -76, -110, -211, and NS3-71, -175. The HCV subgenomic system with/without the NS2 region shows that regulatory effects vanish without NS2, so replicative modulation mediated by HCV 5'UTR₂₄₃ depends on NS2. Strong binding of the NS2 variants to HCV RNA correlates with reduced HCV replication whereas weak binding correlates with restoration of HCV replication efficiency, as determined by RNA-protein immunoprecipitation assay band intensity. The dominant haplotype 5'UTR₂₄₃-NS2-41-76-110-211-NS3-71-175 differs according to the HCV genotype: G-Ile-Ile-Ile-Gly-Ile-Met for genotype 1b and A-Leu-Val-Leu-Ser-Val-Leu for genotypes 1a, 2a and 2b. In conclusion, 5'UTR₂₄₃ co-varies with specific NS2/3 protein amino acid residues, which may have significant structural and functional consequences for HCV replication. This unreported mechanism involving HCV replication possibly can be exploited in the development of advanced anti-HCV medication.

Profound nephrotic syndrome in a patient with ovarian teratoma

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Abdallah Jeroudi

2013-01-01

Full Text Available The nephrotic syndrome (NS has been associated with a variety of malignancies in a number of reports in the literature, but has been reported in only nine cases associated with ovarian neoplasms. Membranous nephropathy is the most common glomerular pathology causing the NS in patients with solid tumors. There has been only one report of an ovarian neoplasm associated with minimal change disease (MCD. We describe the case of a 36-year-old woman who presented with the NS secondary to biopsy-proven MCD, likely secondary to mature ovarian teratoma. Treatment by tumor removal and prednisone led to remission of the NS. To the best of our knowledge, this is the first report of an ovarian teratoma and the second report of an ovarian neoplasm associated with MCD.

Rab5 Enhances Classical Swine Fever Virus Proliferation and Interacts with Viral NS4B Protein to Facilitate Formation of NS4B Related Complex

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Jihui Lin

2017-08-01

Full Text Available Classical swine fever virus (CSFV is a fatal pig pestivirus and causes serious financial losses to the pig industry. CSFV NS4B protein is one of the most important viral replicase proteins. Rab5, a member of the small Rab GTPase family, is involved in infection and replication of numerous viruses including hepatitis C virus and dengue virus. Until now, the effects of Rab5 on the proliferation of CSFV are poorly defined. In the present study, we showed that Rab5 could enhance CSFV proliferation by utilizing lentivirus-mediated constitutive overexpression and eukaryotic plasmid transient overexpression approaches. On the other hand, lentivirus-mediated short hairpin RNA knockdown of Rab5 dramatically inhibited virus production. Co-immunoprecipitation, glutathione S-transferase pulldown and laser confocal microscopy assays further confirmed the interaction between Rab5 and CSFV NS4B protein. In addition, intracellular distribution of NS4B-Red presented many granular fluorescent signals (GFS in CSFV infected PK-15 cells. Inhibition of basal Rab5 function with Rab5 dominant negative mutant Rab5S34N resulted in disruption of the GFS. These results indicate that Rab5 plays a critical role in facilitating the formation of the NS4B related complexes. Furthermore, it was observed that NS4B co-localized with viral NS3 and NS5A proteins in the cytoplasm, suggesting that NS3 and NS5A might be components of the NS4B related complex. Taken together, these results demonstrate that Rab5 positively modulates CSFV propagation and interacts with NS4B protein to facilitate the NS4B related complexes formation.

NS Pudarka: A new winter wheat cultivar

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Hristov Nikola

2014-01-01

Full Text Available The high-yielding, medium late winter wheat cultivar NS Pudarka was developed by crossing genetic divergent parents: line NMNH-07 and cv. NS 40S and Simonida. In cultivar NS Pudarka genes responsible for high yield potential, very good technological quality, resistance to lodging, low temperature and diseases, were successfully combined. It was registered by Ministry of agriculture, forestry and water management of Serbia Republic in 2013. This cultivar has wide adaptability and stability of yield that enable growing in different environments with optimal agricultural practice. On the base of technological quality this cultivar belongs to the second quality class, A2 farinograph subgroup and second technological group.

The interactomes of influenza virus NS1 and NS2 proteins identify new host factors and provide insights for ADAR1 playing a supportive role in virus replication.

Science.gov (United States)

de Chassey, Benoît; Aublin-Gex, Anne; Ruggieri, Alessia; Meyniel-Schicklin, Laurène; Pradezynski, Fabrine; Davoust, Nathalie; Chantier, Thibault; Tafforeau, Lionel; Mangeot, Philippe-Emmanuel; Ciancia, Claire; Perrin-Cocon, Laure; Bartenschlager, Ralf; André, Patrice; Lotteau, Vincent

2013-01-01

Influenza A NS1 and NS2 proteins are encoded by the RNA segment 8 of the viral genome. NS1 is a multifunctional protein and a virulence factor while NS2 is involved in nuclear export of viral ribonucleoprotein complexes. A yeast two-hybrid screening strategy was used to identify host factors supporting NS1 and NS2 functions. More than 560 interactions between 79 cellular proteins and NS1 and NS2 proteins from 9 different influenza virus strains have been identified. These interacting proteins are potentially involved in each step of the infectious process and their contribution to viral replication was tested by RNA interference. Validation of the relevance of these host cell proteins for the viral replication cycle revealed that 7 of the 79 NS1 and/or NS2-interacting proteins positively or negatively controlled virus replication. One of the main factors targeted by NS1 of all virus strains was double-stranded RNA binding domain protein family. In particular, adenosine deaminase acting on RNA 1 (ADAR1) appeared as a pro-viral host factor whose expression is necessary for optimal viral protein synthesis and replication. Surprisingly, ADAR1 also appeared as a pro-viral host factor for dengue virus replication and directly interacted with the viral NS3 protein. ADAR1 editing activity was enhanced by both viruses through dengue virus NS3 and influenza virus NS1 proteins, suggesting a similar virus-host co-evolution.

The interactomes of influenza virus NS1 and NS2 proteins identify new host factors and provide insights for ADAR1 playing a supportive role in virus replication.

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Benoît de Chassey

Full Text Available Influenza A NS1 and NS2 proteins are encoded by the RNA segment 8 of the viral genome. NS1 is a multifunctional protein and a virulence factor while NS2 is involved in nuclear export of viral ribonucleoprotein complexes. A yeast two-hybrid screening strategy was used to identify host factors supporting NS1 and NS2 functions. More than 560 interactions between 79 cellular proteins and NS1 and NS2 proteins from 9 different influenza virus strains have been identified. These interacting proteins are potentially involved in each step of the infectious process and their contribution to viral replication was tested by RNA interference. Validation of the relevance of these host cell proteins for the viral replication cycle revealed that 7 of the 79 NS1 and/or NS2-interacting proteins positively or negatively controlled virus replication. One of the main factors targeted by NS1 of all virus strains was double-stranded RNA binding domain protein family. In particular, adenosine deaminase acting on RNA 1 (ADAR1 appeared as a pro-viral host factor whose expression is necessary for optimal viral protein synthesis and replication. Surprisingly, ADAR1 also appeared as a pro-viral host factor for dengue virus replication and directly interacted with the viral NS3 protein. ADAR1 editing activity was enhanced by both viruses through dengue virus NS3 and influenza virus NS1 proteins, suggesting a similar virus-host co-evolution.

Silencing by H-NS potentiated the evolution of Salmonella.

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Sabrina S Ali

2014-11-01

Full Text Available The bacterial H-NS protein silences expression from sequences with higher AT-content than the host genome and is believed to buffer the fitness consequences associated with foreign gene acquisition. Loss of H-NS results in severe growth defects in Salmonella, but the underlying reasons were unclear. An experimental evolution approach was employed to determine which secondary mutations could compensate for the loss of H-NS in Salmonella. Six independently derived S. Typhimurium hns mutant strains were serially passaged for 300 generations prior to whole genome sequencing. Growth rates of all lineages dramatically improved during the course of the experiment. Each of the hns mutant lineages acquired missense mutations in the gene encoding the H-NS paralog StpA encoding a poorly understood H-NS paralog, while 5 of the mutant lineages acquired deletions in the genes encoding the Salmonella Pathogenicity Island-1 (SPI-1 Type 3 secretion system critical to invoke inflammation. We further demonstrate that SPI-1 misregulation is a primary contributor to the decreased fitness in Salmonella hns mutants. Three of the lineages acquired additional loss of function mutations in the PhoPQ virulence regulatory system. Similarly passaged wild type Salmonella lineages did not acquire these mutations. The stpA missense mutations arose in the oligomerization domain and generated proteins that could compensate for the loss of H-NS to varying degrees. StpA variants most able to functionally substitute for H-NS displayed altered DNA binding and oligomerization properties that resembled those of H-NS. These findings indicate that H-NS was central to the evolution of the Salmonellae by buffering the negative fitness consequences caused by the secretion system that is the defining characteristic of the species.

Jacobsen syndrome

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Grossfeld Paul

2009-03-01

Full Text Available Abstract Jacobsen syndrome is a MCA/MR contiguous gene syndrome caused by partial deletion of the long arm of chromosome 11. To date, over 200 cases have been reported. The prevalence has been estimated at 1/100,000 births, with a female/male ratio 2:1. The most common clinical features include pre- and postnatal physical growth retardation, psychomotor retardation, and characteristic facial dysmorphism (skull deformities, hypertelorism, ptosis, coloboma, downslanting palpebral fissures, epicanthal folds, broad nasal bridge, short nose, v-shaped mouth, small ears, low set posteriorly rotated ears. Abnormal platelet function, thrombocytopenia or pancytopenia are usually present at birth. Patients commonly have malformations of the heart, kidney, gastrointestinal tract, genitalia, central nervous system and skeleton. Ocular, hearing, immunological and hormonal problems may be also present. The deletion size ranges from ~7 to 20 Mb, with the proximal breakpoint within or telomeric to subband 11q23.3 and the deletion extending usually to the telomere. The deletion is de novo in 85% of reported cases, and in 15% of cases it results from an unbalanced segregation of a familial balanced translocation or from other chromosome rearrangements. In a minority of cases the breakpoint is at the FRA11B fragile site. Diagnosis is based on clinical findings (intellectual deficit, facial dysmorphic features and thrombocytopenia and confirmed by cytogenetics analysis. Differential diagnoses include Turner and Noonan syndromes, and acquired thrombocytopenia due to sepsis. Prenatal diagnosis of 11q deletion is possible by amniocentesis or chorionic villus sampling and cytogenetic analysis. Management is multi-disciplinary and requires evaluation by general pediatrician, pediatric cardiologist, neurologist, ophthalmologist. Auditory tests, blood tests, endocrine and immunological assessment and follow-up should be offered to all patients. Cardiac malformations can be

Calcium and Vitamin D Metabolism in Pediatric Nephrotic Syndrome; An Update on the Existing Literature

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Mohammad Esmaeeili

2015-03-01

Full Text Available  Minimal Change Disease (MCD is the leading cause of childhood Nephrotic Syndrome (NS. Therefore in pediatrics nephrotic syndrome, most children beyond the first year of life will be treated with corticosteroids without an initial biopsy. Children with NS often display a number of calcium homeostasis disturbances causing abnormal bone histology, including hypocalcemia, reduced serum vitamin D metabolites, impaired intestinal absorption of calcium, and elevated levels of immunoreactive parathyroid hormone (iPTH. These are mainly attributed to the loss of a variety of plasma proteins and minerals in the urine as well as steroid therapy. Early diagnosis and management of these abnormalities, could prevent the growth retardation and renal osteodystrophy that affects children with nephrotic syndrome. Here we reviewed the literature for changes of calcium and vitamin D metabolism in nephrotic syndrome and its consequences on bones, also the effect of corticosteroid and possible preventive strategies that could be done to avoid long term outcomes in children. Although the exact biochemical basis for Changes in levels of calcium and vitamin D metabolites in patients with NS remains speculative; Because of the potential adverse effects of these changes among growing children, widespread screening for vitamin D deficiency or routine vitamin D supplementation should be considered.

Case Report: Multiple Unerupted Permanent Teeth Associated with ...

African Journals Online (AJOL)

The present report describes a case of Noonan's syndrome from a dental viewpoint. ... and malocclusions are some of the frequently observed clinical features. ... fixed orthodontic therapy for forced eruption of unerupted permanent teeth.

A descriptive retrospective study on children with newly diagnosed nephrotic syndrome presented to Tripoli Children Hospital during the period between Jan. to Dec. 2014

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Naziha Ramadan Rhuma

2016-10-01

Full Text Available Introduction: Nephrotic syndrome is a clinical picture characterized by severe proteinuria, hypoalbuminemia, edema and hypercholesterolemia. A retrospective study was carried out in order to describe disease pattern in newly diagnosed nephrotic syndrome of children admitted to Tripoli children hospital during the year 2014. Methods: The medical data of 56 patients aged between 1 year and 11 years diagnosed with idiopathic nephrotic syndrome were analysed using SPSS software. The data included gender differences, sensitivity to steroid therapy, relapses during six months of follow up and the effect of variable factors such as family history, hypertension, hematuria, serum urea on the degree of relapse. Results: Out of 56 patients with newly diagnosed nephrotic syndrome (NS, 60.7% were boys and 39.3% were girls, with a mean age 4.2±2.2 years. Age  was related significantly to the response to steroid therapy, where 79.5% of patients aged between 2-8 years (group 1 had steroid sensitive nephrotic syndrome (SSNS compared with only 41.7% of patients aged less than 2 years or more than 8 years (group 2  (P<0.001.  Although girls relapsed more than boys (70.5% versus 57.1% during six months of therapy, this difference was not statistically significant. Similarly, no other factors measured such as family history of NS, hypertension, hematuria, serum complement and urea had any effect on the percentage of relapse in patients with newly diagnosed NS.  Conclusion: NS is one of the commonest reasons for admission to nephrology ward. It is more common in boys than girls. The age at presentation related significantly to the response to steroidal therapy. Regarding relapses, girls seems to relapse more frequent than boys and relapses was seen more in age group 1 than group 2, however, these differences were not significant. Other factors studied seems to have no effect on the relapse rate of children with newly diagnosed NS. Key-words:  Idiopathic

Cleavage preference distinguishes the two-component NS2B-NS3 serine proteinases of Dengue and West Nile viruses.

Science.gov (United States)

Shiryaev, Sergey A; Kozlov, Igor A; Ratnikov, Boris I; Smith, Jeffrey W; Lebl, Michal; Strongin, Alex Y

2007-02-01

Regulated proteolysis of the polyprotein precursor by the NS2B-NS3 protease is required for the propagation of infectious virions. Unless the structural and functional parameters of NS2B-NS3 are precisely determined, an understanding of its functional role and the design of flaviviral inhibitors will be exceedingly difficult. Our objectives were to define the substrate recognition pattern of the NS2B-NS3 protease of West Nile and Dengue virises (WNV and DV respectively). To accomplish our goals, we used an efficient, 96-well plate format, method for the synthesis of 9-mer peptide substrates with the general P4-P3-P2-P1-P1'-P2'-P3'-P4'-Gly structure. The N-terminus and the constant C-terminal Gly of the peptides were tagged with a fluorescent tag and with a biotin tag respectively. The synthesis was followed by the proteolytic cleavage of the synthesized, tagged peptides. Because of the strict requirement for the presence of basic amino acid residues at the P1 and the P2 substrate positions, the analysis of approx. 300 peptide sequences was sufficient for an adequate representation of the cleavage preferences of the WNV and DV proteinases. Our results disclosed the strict substrate specificity of the WNV protease for which the (K/R)(K/R)R/GG amino acid motifs was optimal. The DV protease was less selective and it tolerated well the presence of a number of amino acid residue types at either the P1' or the P2' site, as long as the other position was occupied by a glycine residue. We believe that our data represent a valuable biochemical resource and a solid foundation to support the design of selective substrates and synthetic inhibitors of flaviviral proteinases.

NS&T Management Observations

Energy Technology Data Exchange (ETDEWEB)

Gianotto, David [Idaho National Laboratory (INL), Idaho Falls, ID (United States)

2014-09-01

The INL Management Observation Program (MOP) is designed to improve managers and supervisors understanding of work being performed by employees and the barriers impacting their success. The MOP also increases workers understanding of managements’ expectations as they relate to safety, security, quality, and work performance. Management observations (observations) are designed to improve the relationship and trust between employees and managers through increased engagement and interactions between managers and researchers in the field. As part of continuous improvement, NS&T management took initiative to focus on the participation and quality of observations in FY 14. This quarterly report is intended to (a) summarize the participation and quality of management’s observations, (b) assess observations for commonalities or trends related to facility or process barriers impacting research, and (c) provide feedback and make recommendations for improvements NS&T’s MOP.

Recombinant HCV variants with NS5A from genotypes 1-7 have different sensitivities to an NS5A inhibitor but not interferon-a

DEFF Research Database (Denmark)

Scheel, Troels K H; Gottwein, Judith M; Mikkelsen, Lotte S

2011-01-01

Heterogeneity in the hepatitis C virus (HCV) protein NS5A influences its sensitivity to interferon-based therapy. Furthermore, NS5A is an important target for development of HCV-specific inhibitors. We aimed to develop recombinant infectious cell culture systems that express NS5A from isolates...

Nephrotic syndrome and Obstetric anesthesia

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Vijay Kumar Nagpal

2017-01-01

Full Text Available Renal disorders in pregnancy can be both difficult to diagnose and manage. They are associated with poor maternal and/or fetal outcomes. In pregnancy, proteinuria is common and can range from mild urinary protein elevations to nephrotic levels. The diagnosis of nephrotic syndrome (NS can be challenging, especially in pregnancy as it can be confused with preeclampsia. NS has an incidence of 0.012%–0.025% in pregnant women. It is diagnosed by the presence of more than 3 g/day of proteins in urine, serum albumin <30 g/dL, generalized edema, hypercholesterolemia, and lipiduria. Proteinuria with hypertension is characterized by the presence of hematuria, red cell casts, raised serum creatinine, and features suggestive of systemic disease. Other causes of proteinuria include preeclampsia, diabetes mellitus (Type 1 and Type 2, Immunoglobulin A nephropathy (Ig A glomerulonephritis, focal and segmental glomerulosclerosis, and lupus nephritis. The maternal risks of NS include acute kidney insult, chronic renal failure, gestational hypertension, preeclampsia, and complications due to hypoalbuminemia. Fetal considerations in NS include fetal growth retardation, prematurity, stillbirth, fetal anasarca, and polyhydramnios. Preconception counseling and immunosuppressive drug therapy can improve overall fetomaternal outcome. We hereby present a unique case of successful anesthetic management of NS in a parturient along with concurrent hypothyroidism and hypertension, for elective cesarean section.

Candida spp. and gingivitis in children with nephrotic syndrome or type 1 diabetes.

Science.gov (United States)

Olczak-Kowalczyk, Dorota; Pyrżak, Beata; Dąbkowska, Maria; Pańczyk-Tomaszewska, Małgorzata; Miszkurka, Grażyna; Rogozińska, Izabela; Swoboda-Kopeć, Ewa; Gozdowski, Dariusz; Kalińska, Angelika; Piróg, Anna; Mizerska-Wasiak, Małgorzata; Roszkowska-Blaim, Maria

2015-05-08

Diabetes and Nephrotic syndrome (NS) promote plaque-related gingivitis and yeast-like fungal infections. The study assesses the impact of Candida spp. and general disease- or treatment-related factors on plaque-related gingivitis severity in children and adolescents with Nephrotic syndrome /diabetes. Body mass index (BMI), BMI standard deviation score, and oral cavity (Plaque Index--PLI, Gingival Index--GI, mucosa status, presence and Candida enzymatic activity) were assessed in 96 patients (32 with NS: 30- immunosuppressive treatment, 35--type 1 diabetes, and 29 generally healthy), aged; 3-18 years. Laboratory included cholesterol and triglyceride measurements; in diabetic subjects- glycated haemoglobin, in NS: total protein, albumin, creatinine, haemoglobin, haematocrit, white cell count, urinary protein excretion. Medical records supplied information on disease duration and treatment. A statistical analysis was performed; Kendall Tau coefficient, chi-square test, t-test, and multiple regression analysis ( P Gingivitis occurred more frequently in patients with NS/diabetes. Gingivitis severity was correlated with PLI, age, and yeast enzyme activity in NS--to with immunosuppressive treatment with >1 drug, drug doses, treatment duration, lipid disorders, and BMI; in diabetes, with blood glucose and glycated haemoglobin >8%. Poor hygiene control is the main cause of gingivitis. Gingivitis severity is most likely related to age, lipid disorders and increase in body mass. Candida spp., in uncompensated diabetes and in those using immunosuppressive treatment, might intensify plaque-related gingivitis.

The impact of pediatric nephrotic syndrome on families.

Science.gov (United States)

Mitra, Sulagna; Banerjee, Sushmita

2011-08-01

The objective of our study was to assess the psychologic and economic effects of pediatric nephrotic syndrome (NS) on caregivers. Caregivers of 50 children with NS were compared with a control group of 50 families of children with minor illnesses attending the same outpatient facility. Beck's Depression Inventory (BDI) IA was used to assess the mental status of the primary caregiver. The socioeconomic status of the family was assessed using the modified Kuppuswamy scale. Expenditure for the illness was calculated during parent interviews. The difference between groups was analyzed using analysis of variance (ANOVA) and Duncan's multiple range test. BDI scores signified moderate to severe depression in 48% of NS caregivers compared with 12% controls. The mean BDI score was significantly higher in NS caregivers, correlating positively with disease severity and negatively with socioeconomic status. Expenditure for disease also was significantly higher in families with NS patients, varying between 30% and 60% of monthly income depending on disease severity compared with 6.9% in controls. In 10% of NS families, it was more than total income, forcing families to break into savings or go into debt. Although pediatric NS most commonly has an excellent long-term outcome, it causes significant mental and economic stress on families. Severe forms should be categorized as a chronic illness and be eligible for disability benefits and subsidized travel and medical care. Establishing support groups and supportive care at local levels would help reduce the burden on families of patients wtih NS.

Role of nonstructural protein NS2A in flavivirus assembly

NARCIS (Netherlands)

Leung, J.Y.; Pijlman, G.P.; Kondratieva, N.; Hyde, J.; Mackenzie, J.M.; Khromykh, A.A.

2008-01-01

Flavivirus nonstructural (NS) proteins are involved in RNA replication and modulation of the host antiviral response; however, evidence is mounting that some NS proteins also have essential roles in virus assembly. Kunjin virus (KUN) NS2A is a small, hydrophobic, transmembrane protein that is part

Aberrant neuronal activity-induced signaling and gene expression in a mouse model of RASopathy.

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Franziska Altmüller

2017-03-01

Full Text Available Noonan syndrome (NS is characterized by reduced growth, craniofacial abnormalities, congenital heart defects, and variable cognitive deficits. NS belongs to the RASopathies, genetic conditions linked to mutations in components and regulators of the Ras signaling pathway. Approximately 50% of NS cases are caused by mutations in PTPN11. However, the molecular mechanisms underlying cognitive impairments in NS patients are still poorly understood. Here, we report the generation and characterization of a new conditional mouse strain that expresses the overactive Ptpn11D61Y allele only in the forebrain. Unlike mice with a global expression of this mutation, this strain is viable and without severe systemic phenotype, but shows lower exploratory activity and reduced memory specificity, which is in line with a causal role of disturbed neuronal Ptpn11 signaling in the development of NS-linked cognitive deficits. To explore the underlying mechanisms we investigated the neuronal activity-regulated Ras signaling in brains and neuronal cultures derived from this model. We observed an altered surface expression and trafficking of synaptic glutamate receptors, which are crucial for hippocampal neuronal plasticity. Furthermore, we show that the neuronal activity-induced ERK signaling, as well as the consecutive regulation of gene expression are strongly perturbed. Microarray-based hippocampal gene expression profiling revealed profound differences in the basal state and upon stimulation of neuronal activity. The neuronal activity-dependent gene regulation was strongly attenuated in Ptpn11D61Y neurons. In silico analysis of functional networks revealed changes in the cellular signaling beyond the dysregulation of Ras/MAPK signaling that is nearly exclusively discussed in the context of NS at present. Importantly, changes in PI3K/AKT/mTOR and JAK/STAT signaling were experimentally confirmed. In summary, this study uncovers aberrant neuronal activity

Dengue Virus NS2B/NS3 Protease Inhibitors Exploiting the Prime Side.

Science.gov (United States)

Lin, Kuan-Hung; Ali, Akbar; Rusere, Linah; Soumana, Djade I; Kurt Yilmaz, Nese; Schiffer, Celia A

2017-05-15

The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and subtropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including processing of 8 of the 13 substrate cleavage sites by dengue virus NS2B/NS3 protease. With no available direct-acting antiviral targeting DENV, NS2/NS3 protease is a promising target for inhibitor design. Current design efforts focus on the nonprime side of the DENV protease active site, resulting in highly hydrophilic and nonspecific scaffolds. However, the prime side also significantly modulates DENV protease binding affinity, as revealed by engineering the binding loop of aprotinin, a small protein with high affinity for DENV protease. In this study, we designed a series of cyclic peptides interacting with both sides of the active site as inhibitors of dengue virus protease. The design was based on two aprotinin loops and aimed to leverage both key specific interactions of substrate sequences and the entropic advantage driving aprotinin's high affinity. By optimizing the cyclization linker, length, and amino acid sequence, the tightest cyclic peptide achieved a K i value of 2.9 μM against DENV3 wild-type (WT) protease. These inhibitors provide proof of concept that both sides of DENV protease active site can be exploited to potentially achieve specificity and lower hydrophilicity in the design of inhibitors targeting DENV. IMPORTANCE Viruses of the flaviviral family, including DENV and Zika virus transmitted by Aedes aegypti , continue to be a threat to global health by causing major outbreaks in tropical and subtropical regions, with no available direct-acting antivirals for treatment. A better understanding of the molecular requirements for the design of potent and specific inhibitors against flaviviral proteins will contribute to the development of targeted therapies for infections by these viruses. The cyclic peptides reported here as DENV protease inhibitors

Serum lipoprotein (a) concentration in patients with nephrotic syndrome and its clinical implication.

Science.gov (United States)

Yang, X; Wang, H; Zhu, Z; Deng, A

1998-01-01

Serum lipoprotein(a) [Lp(a)] concentration was determined in 42 patients with primary nephrotic syndrome (NS) and the relationships between Lp (a) and plasma lipids, apolipoproteins, serum creatinine (Scr), albumin, urinary proteins (Upro) were also analyzed. The results showed that: (1) serum Lp(a) concentrations in the patients with NS were higher than those in healthy controls; (2) the levels of serum Lp(a) were correlated positively with total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), apolipoprotein B (Apo-B), Upros (Upro). It is concluded that the NS patients had the potential risk of suffering from coronary artery disease, glomerular sclerosis and thrombosis. The remission of NS may partially decrease the serum Lp(a) levels. Further studies are needed to explore the prevention and treatment of dislipedemia in patients with NS.

A conformational switch high-throughput screening assay and allosteric inhibition of the flavivirus NS2B-NS3 protease.

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Matthew Brecher

2017-05-01

Full Text Available The flavivirus genome encodes a single polyprotein precursor requiring multiple cleavages by host and viral proteases in order to produce the individual proteins that constitute an infectious virion. Previous studies have revealed that the NS2B cofactor of the viral NS2B-NS3 heterocomplex protease displays a conformational dynamic between active and inactive states. Here, we developed a conformational switch assay based on split luciferase complementation (SLC to monitor the conformational change of NS2B and to characterize candidate allosteric inhibitors. Binding of an active-site inhibitor to the protease resulted in a conformational change of NS2B and led to significant SLC enhancement. Mutagenesis of key residues at an allosteric site abolished this induced conformational change and SLC enhancement. We also performed a virtual screen of NCI library compounds to identify allosteric inhibitors, followed by in vitro biochemical screening of the resultant candidates. Only three of these compounds, NSC135618, 260594, and 146771, significantly inhibited the protease of Dengue virus 2 (DENV2 in vitro, with IC50 values of 1.8 μM, 11.4 μM, and 4.8 μM, respectively. Among the three compounds, only NSC135618 significantly suppressed the SLC enhancement triggered by binding of active-site inhibitor in a dose-dependent manner, indicating that it inhibits the conformational change of NS2B. Results from virus titer reduction assays revealed that NSC135618 is a broad spectrum flavivirus protease inhibitor, and can significantly reduce titers of DENV2, Zika virus (ZIKV, West Nile virus (WNV, and Yellow fever virus (YFV on A549 cells in vivo, with EC50 values in low micromolar range. In contrast, the cytotoxicity of NSC135618 is only moderate with CC50 of 48.8 μM on A549 cells. Moreover, NSC135618 inhibited ZIKV in human placental and neural progenitor cells relevant to ZIKV pathogenesis. Results from binding, kinetics, Western blot, mass spectrometry and

Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2

NARCIS (Netherlands)

Zazo Seco, C.; Castro, L.S. de; Nierop, J.W. van; Morin, M.; Jhangiani, S.; Verver, E.J.; Schraders, M.; Maiwald, N.; Wesdorp, F.M.; Venselaar, H.; Spruijt, L.; Oostrik, J.; Schoots, J.; Reeuwijk, J. van; Lelieveld, S.H.; Huygen, P.L.M.; Insenser, M.; Admiraal, R.J.C.; Pennings, R.J.E.; Hoefsloot, L.H.; Arias Vasquez, A.; Ligt, J. de; Yntema, H.G.; Jansen, J.H.; Muzny, D.M.; Huls, G.A.; Rossum, M.M. van; Lupski, J.R.; Moreno-Pelayo, M.A.; Kunst, H.P.M.; Kremer, H.

2015-01-01

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a

Noonan Syndrome: Symptoms and Causes

Science.gov (United States)

... be delayed. But because this disorder causes bone maturity to be delayed, growth sometimes continues into the ... mild intellectual disability A wide range of mental, emotional and behavioral issues that are usually mild Hearing ...

Modifying Cement Hydration with NS@PCE Core-Shell Nanoparticles

Directory of Open Access Journals (Sweden)

Yue Gu

2017-01-01

Full Text Available It is generally accepted that fine particles could accelerate cement hydration process, or, more specifically, this accelerating effect can be attributed to additional surface area introduced by fine particles. In addition to this view, the surface state of fine particles is also an important factor, especially for nanoparticles. In the previous study, a series of nano-SiO2-polycarboxylate superplasticizer core-shell nanoparticles (NS@PCE were synthesized, which have a similar particle size distribution but different surface properties. In this study, the impact of NS@PCE on cement hydration was investigated by heat flow calorimetry, mechanical property measurement, XRD, and SEM. Results show that, among a series of NS@PCE, NS@PCE-2 with a moderate shell-core ratio appeared to be more effective in accelerating cement hydration. As dosage increases, the efficiency of NS@PCE-2 would reach a plateau which is quantified by various characteristic values. Compressive strength results indicate that strength has a linear correlation with cumulative heat release. A hypothesis was proposed to explain the modification effect of NS@PCE, which highlights a balance between initial dispersion and pozzolanic reactivity. This paper provides a new understanding for the surface modification of supplementary cementitious materials and their application and also sheds a new light on nano-SiO2 for optimizing cement-based materials.

Enzymatic Activity of Candida spp. from Oral Cavity and Urine in Children with Nephrotic Syndrome.

Science.gov (United States)

Olczak-Kowalczyk, Dorota; Roszkowska-Blaim, Maria; Dąbkowska, Maria; Swoboda-Kopeć, Ewa; Gozdowski, Dariusz; Mizerska-Wasiak, Małgorzata; Demkow, Urszula; Pańczyk-Tomaszewska, Małgorzata

2017-01-01

Oral colonization with Candida spp. is not synonymous with a systemic active infection. The aim of the study was to evaluate enzymatic activity of Candida strains isolated from the oral cavity in patients with nephrotic syndrome (NS) and to compare it with the activity determined in urine. We studied 32 children with NS and 26 control healthy children. Children with NS were treated with glucocorticosteroids, cyclosporin A, mycophenolate mofetil or azathioprine. In all children, API-ZYM enzymatic tests were performed to evaluate hydrolytic enzymes of Candida isolated from the oral cavity and in urine. Candida spp. were isolated from the oral cavity in 11 patients with NS (34.4%), all receiving immunosuppressive treatment. All strains produced valine arylamidase, 9 alpha-glucosidase (E16), and 9 N-acetyl-beta-glucosaminidase (E18). A positive correlation between the presence of Candida in the oral cavity and E16 and E18 enzymatic activity in both oral cavity and urine was found. A dose of cyclosporin A had an effect on the enzymatic activity (p Candida invasion. The results of this study suggest that oral candida infection should be monitored in children with nephrotic syndrome, particularly those treated with immunosuppressive agents.

Degree of Left Renal Vein Compression Predicts Nutcracker Syndrome

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Patrick T. Hangge

2018-05-01

Full Text Available Nutcracker syndrome (NS refers to symptomatic compression of the left renal vein (LRV between the abdominal aorta and superior mesenteric artery with potential symptoms including hematuria, proteinuria, left flank pain, and renal venous hypertension. No consensus diagnostic criteria exist to guide endovascular treatment. We aimed to evaluate the specificity of LRV compression to NS symptoms through a retrospective study including 33 NS and 103 control patients. The size of the patent lumen at point of compression and normal portions of the LRV were measured for all patients. Multiple logistic regression analyses (MLR assessing impact of compression, body mass index (BMI, age, and gender on the likelihood of each symptom with NS were obtained. NS patients presented most commonly with abdominal pain (72.7%, followed by hematuria (57.6%, proteinuria (39.4%, and left flank pain (30.3%. These symptoms were more commonly seen than in the control group at 10.6, 11.7, 6.8, and 1.9%, respectively. The degree of LRV compression for NS was 74.5% and 25.2% for controls (p < 0.0001. Higher compression led to more hematuria (p < 0.0013, abdominal pain (p < 0.006, and more proteinuria (p < 0.002. Furthermore, the average BMI of NS patients was 21.4 and 27.2 for controls (p < 0.001 and a low BMI led to more abdominal pain (p < 0.005. These results demonstrate a strong correlation between the degree of LRV compression on imaging in diagnosing NS.

Renal Doppler Indices in Children with Nephrotic Syndrome ...

African Journals Online (AJOL)

Summary: The resistive and pulsatility indices are known tools for assessing renal function in kidney diseases, especially in proteinuric conditions like Paediatric Nephrotic syndrome (NS) which is a glomerular disease. However, there is a limited knowledge in the use of Doppler Resistive and pulsatility indices in the ...

Significance of glucocorticoids and their receptors in patients with nephritic syndrome

International Nuclear Information System (INIS)

Yang Liusong; Li Dapei; Liu Deyi; Wang Weiyue; Wang Haodan

1996-01-01

The glucocorticoid receptor (GCR) in 34 patients with nephritic syndrome (NS) and 40 normal controls is investigated by radioligand binding assay. The results show that the GCR levels of NS patients are correlated well with the treatment results by glucocorticoids (GC). These patients who are sensitive to GC treatment have much higher levels of GCR than those who are not responsive to GC treatment (P<0.01) and the normal controls. The plasma ACTH and cortisol in the same subjects are also measured and the results show that NS patients have much lower levels of these two hormones than the normal controls', but no significant correlation is noted between the levels and the GC treatment effects

Infection of Common Marmosets with GB Virus B Chimeric Virus Encoding the Major Nonstructural Proteins NS2 to NS4A of Hepatitis C Virus.

Science.gov (United States)

Zhu, Shaomei; Li, Tingting; Liu, Bochao; Xu, Yuxia; Sun, Yachun; Wang, Yilin; Wang, Yuanzhan; Shuai, Lifang; Chen, Zixuan; Allain, Jean-Pierre; Li, Chengyao

2016-09-15

A lack of immunocompetent-small-primate models has been an obstacle for developing hepatitis C virus (HCV) vaccines and affordable antiviral drugs. In this study, HCV/GB virus B (GBV-B) chimeric virus carrying the major nonstructural proteins NS2 to NS4A (HCV NS2 to -4A chimera) was produced and used to infect common marmosets, since HCV NS2 to NS4A proteins are critical proteases and major antigens. Seven marmosets were inoculated intrahepatically with HCV NS2 to -4A chimera RNA for primary infection or intravenously injected with chimera-containing serum for passage infection. Three animals used as controls were injected with phosphate-buffered saline (PBS) or GBV-B, respectively. Six of seven HCV NS2 to -4A chimera-infected marmosets exhibited consistent viremia and one showed transient viremia during the course of follow-up detection. All six infected animals with persistent circulating viremia presented characteristics typical of viral hepatitis, including viral RNA and proteins in hepatocytes and histopathological changes in liver tissue. Viremia was consistently detected for 5 to 54 weeks of follow-up. FK506 immunosuppression facilitated the establishment of persistent chimera infection in marmosets. An animal with chimera infection spontaneously cleared the virus in blood 7 weeks following the first inoculation, but viral-RNA persistence, low-level viral protein, and mild necroinflammation remained in liver tissue. The specific antibody and T-cell response to HCV NS3 in this viremia-resolved marmoset was boosted by rechallenging, but no viremia was detected during 57 weeks of follow-up. The chimera-infected marmosets described can be used as a suitable small-primate animal model for studying novel antiviral drugs and T-cell-based vaccines against HCV infection. HCV infection causes approximately 70% of chronic hepatitis and is frequently associated with primary liver cancer globally. Chimpanzees have been used as a reliable primate model for HCV infection

Gene-specific paradoxical QT responses during rapid eye movement sleep in women with congenital long QT syndrome

Czech Academy of Sciences Publication Activity Database

Lanfranchi, P. A.; Ackerman, M. J.; Kára, T.; Shamsuzzaman, A. S.; Wolk, R.; Jurák, Pavel; Amin, R.; Somers, V. K.

2010-01-01

Roč. 7, č. 8 (2010), s. 1067-1074 ISSN 1547-5271 R&D Projects: GA MZd NS10098; GA MZd NS10099 Institutional research plan: CEZ:AV0Z20650511 Keywords : autonomic nervous system * heart rate * long QT syndrome * QT interval * sex * sleep Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 4.246, year: 2010

Dengue NS1 Antigen - for Early Detection of Dengue Virus Infection

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Amol Hartalkar

2015-08-01

Full Text Available Objectives: To evaluate the efficacy of NS1 antigen assay for early diagnosis of dengue virus infection in a tertiary care hospital. Methods: This cross sectional study was carried out in department of Medicine from August to December 2013. Total 100 patients with dengue fever were included. Complete blood count, alanine aminotransferase (ALT, aspartate aminotransferase (AST, Dengue NS1 antigen and IgM and IgG antibodies of dengue virus were done in all cases. Results: Of the 100 sera tested, 75% were positive for dengue virus infection based on dengue NS1 antigen, IgM antibody and IgG antibody. Dengue NS1 antigen and IgM, IgG antibody were able to detect dengue virus infection between day 1 to day 8 in 92% of samples, 86.7% of samples and 82.6% of samples respectively. Sixty nine percent (69% were found positive for dengue NS1 antigen, 65% were IgM positive and 62% were IgG positive. Based on the dengue NS1 antigen and IgM antibody combination, 74% were positive for dengue virus infections. Sensitivity of Dengue NS1 antigen was 92.3% and specificity of 74.28% in comparison to IgM antibody. Detection rate increased to 75%, based on the antigen and IgG antibody combination. Sensitivity of dengue NS1 antigen was 90.3% and specificity of 65.8% in comparison to IgG antibody. Conclusion: Dengue NS1 antigen is a useful, sensitive and specific test for early diagnosis of dengue virus infection and it improves diagnostic efficiency in combination with antibody test. Key words: Dengue fever, NS1 antigen. Introduction: Dengue fever (DF is the most common arboviral illness in humans. Each year, an estimated 50-100 million cases of dengue fever and 500,000 cases of dengue hemorrhagic fever occur worldwide, with 30000 deaths (mainly in children. Globally 2.5-3 billion people in approximately 112 tropical and subtropical countries are at risk of dengue.of samples respectively. Sixty nine percent (69% were found positive for dengue NS1 antigen, 65% were Ig

NS Otto Hahn

International Nuclear Information System (INIS)

Schafstall, H.G.

1983-01-01

For the bulk cargo ship had been chosen the advanced PWR, the secial characteristic of which is an integrated primary loop with automatic pressurisation. Altogether the Otto Hahn covered over half a million sea-miles. In-service inspections and examinations of the reactor plant were effected by control authorities every year. During the whole operating period the NS Otto Hahn showed a safe and reliable behaviour even from the view of radiation protection. (DG) [de

Efficient hepatitis c virus genotype 1b core-NS5A recombinants permit efficacy testing of protease and NS5A inhibitors

DEFF Research Database (Denmark)

Pham, Long V.; Ramirez Almeida, Santseharay; Carlsen, Thomas H R

2017-01-01

Hepatitis C virus (HCV) strains belong to seven genotypes with numerous subtypes that respond differently to antiviral therapies. Genotype 1, and primarily subtype 1b, is the most prevalent genotype worldwide. The development of recombinant HCV infectious cell culture systems for different variants......, permitted by the high replication capacity of strain JFH1 (genotype 2a), has advanced efficacy and resistance testing of antivirals. However, efficient infectious JFH1-based cell cultures of subtype 1b are limited and comprise only the 5= untranslated region (5=UTR)-NS2, NS4A, or NS5A regions. Importantly...

Effectiveness of Acupuncture in the Treatment of Gulf War Illness

Science.gov (United States)

2010-07-01

8217 heterogeneous presentation GWI neurological presentations ·A new disease for TCM ’Wei-zhang (Flaccidity Syndrome ) treatment of organophosphate...poisoning ·Bi Syndrome ’Autonomic Nervous System (ANS) dysregulation ’ Osher Research Center, Harvard Medical School F6 Study Methodology...Screener; Jessica Wolin, MD:Medical Monitor; Elaine Scarmoutzos, Project Coordinator; Christina Noonan , MAc., LicAc.: Research Assistant; Matthew Hitron

Pulmonary embolism as the primary presenting feature of nephrotic syndrome

Directory of Open Access Journals (Sweden)

Pallavi Periwal

2016-01-01

Full Text Available A 36-year-old previously healthy male presented with subacute onset of shortness of breath and chest pain. He was diagnosed with bilateral extensive pulmonary embolism (PE. In the absence of any predisposing factors, an extensive workup for unprovoked thrombophilia was done. During the course of his illness, the patient developed anasarca and was diagnosed to be suffering from nephrotic syndrome (NS, secondary to membranous glomerulopathy. Although, thrombotic complications are commonly associated with NS, it is unusual for PE to be the primary presenting feature in these patients.

Evolutionary dynamics of hepatitis C virus NS3 protease domain during and following treatment with narlaprevir, a potent NS3 protease inhibitor

NARCIS (Netherlands)

de Bruijne, J.; Thomas, X. V.; Rebers, S. P.; Weegink, C. J.; Treitel, M. A.; Hughes, E.; Bergmann, J. F.; de Knegt, R. J.; Janssen, H. L. A.; Reesink, H. W.; Molenkamp, R.; Schinkel, J.

2013-01-01

Narlaprevir, a hepatitis C virus (HCV) NS3/4A serine protease inhibitor, has demonstrated robust antiviral activity in a placebo-controlled phase 1 study. To study evolutionary dynamics of resistant variants, the NS3 protease sequence was clonally analysed in thirty-two HCV genotype 1-infected

Hepatitis C Virus NS3 Inhibitors: Current and Future Perspectives

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Kazi Abdus Salam

2013-01-01

Full Text Available Currently, hepatitis C virus (HCV infection is considered a serious health-care problem all over the world. A good number of direct-acting antivirals (DAAs against HCV infection are in clinical progress including NS3-4A protease inhibitors, RNA-dependent RNA polymerase inhibitors, and NS5A inhibitors as well as host targeted inhibitors. Two NS3-4A protease inhibitors (telaprevir and boceprevir have been recently approved for the treatment of hepatitis C in combination with standard of care (pegylated interferon plus ribavirin. The new therapy has significantly improved sustained virologic response (SVR; however, the adverse effects associated with this therapy are still the main concern. In addition to the emergence of viral resistance, other targets must be continually developed. One such underdeveloped target is the helicase portion of the HCV NS3 protein. This review article summarizes our current understanding of HCV treatment, particularly with those of NS3 inhibitors.

CIAE 600 kV ns pulse neutron generator

International Nuclear Information System (INIS)

Shen Guanren; Guan Xialing; Chen Hongtao

2001-01-01

The overall composition of CIAE 600 kV ns Pulse Neutron Generator (CPNG) are introduced, and its characteristic, main technological performance and application were also given. CPNG consists of high voltage power supply with highest output voltage 600 kV, direct current 15 mA, stability and ripple ≤0.1%, 2214 mm x 1604 mm x 1504 mm stainless steel high voltage electrode, built in head equipment uniform field accelerating tube, ns pulsed installation, turbomolecular vacuum pump system and drift pipes at 0 degree and 45 degree. Its characteristics are: (1) high current beam; (2) high current beam ns pulsed installation made use of low energy for chopper and high energy for buncher; (3) compactly laid out and simple in structure

[11C]NS8880, a promising PET radiotracer targeting the norepinephrine transporter

DEFF Research Database (Denmark)

Vase, Karina Højrup; Peters, Dan; Nielsen, Elsebeth Ø

2014-01-01

-azabicyclo[3.2.1]octane (NS8880), targeting NET. NS8880 has an in vitro binding profile comparable to desipramine and is structurally not related to reboxetine. METHODS: Labeling of NS8880 with [11C] was achieved by a non-conventional technique: substitution of pyridinyl fluorine with [11C]methanolate...... yields with high purity. The PET in vivo evaluation in pig and rat revealed a rapid brain uptake of [11C]NS8880 and fast obtaining of equilibrium. Highest binding was observed in thalamic and hypothalamic regions. Pretreatment with desipramine efficiently reduced binding of [11C]NS8880. CONCLUSION: Based...... on the pre-clinical results obtained so far [11C]NS8880 displays promising properties for PET imaging of NET....

Mosquito densonucleosis virus non-structural protein NS2 is necessary for a productive infection

International Nuclear Information System (INIS)

Azarkh, Eugene; Robinson, Erin; Hirunkanokpun, Supanee; Afanasiev, Boris; Kittayapong, Pattamaporn; Carlson, Jonathan; Corsini, Joe

2008-01-01

Mosquito densonucleosis viruses synthesize two non-structural proteins, NS1 and NS2. While NS1 has been studied relatively well, little is known about NS2. Antiserum was raised against a peptide near the N-terminus of NS2, and used to conduct Western blot analysis and immuno-fluorescence assays. Western blots revealed a prominent band near the expected size (41 kDa). Immuno-fluorescence studies of mosquito cells transfected with AeDNV indicate that NS2 has a wider distribution pattern than does NS1, and the distribution pattern appears to be a function of time post-infection. Nuclear localization of NS2 requires intact C-terminus but does not require additional viral proteins. Mutations ranging from complete NS2 knock-out to a single missense amino acid substitution in NS2 can significantly reduce viral replication and production of viable progeny

Neutrophil chemokines levels in different stages of nephrotic syndrome

Directory of Open Access Journals (Sweden)

Ashwag S Alsharidah

2017-01-01

Full Text Available Nephrotic syndrome (NS is a disease of glomerular filtration barrier failure presenting with variable degrees of proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Inflammation may contribute to the pathogenesis of NS. The aim of this study was to monitor the serum levels of three cytokines [i.e., granulocyte chemotactic protein-2 (GCP-2, growth-related oncogene-α (GRO-α, and interleukin-8 (IL-8] in different stages of NS and to find out whether changes in the levels of these cytokines could be related to the severity of NS. This study included 125 patients who were divided into 40 patients with nephrotic range proteinuria (NRP, 45 patients with NS, and 40 patients who were in remission. This study also included 80 healthy participants as a control group. Enzyme-linked immunosorbent assay was used for the determination of the plasma levels of GRO-α, GCP-2, and IL-8. GCP-2 plasma levels were significantly higher in the NS and NRP groups when compared to the control group, whereas the GRO-α and IL-8 levels were significantly higher in all patient groups in comparison with the control group. All these chemokine levels were significantly decreased in remission as compared with the participants in the NS group (P <0.0001. There was a significant correlation between the cytokine levels and proteinuria and serum albumin in the NS group (P <0.0001. However, in the follow-up group, GCP-2 levels were significantly lower during remission as compared to those with active NS (P <0.0001. Our findings suggest that the pro-inflammatory cytokines GCP-2, GRO-α, and IL-8 could play a role in the pathogenesis of NS, particularly glomerular permeability.

Chromosome 15q24 microdeletion syndrome

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Magoulas Pilar L

2012-01-01

involves a multi-disciplinary approach to care with the primary care physician and clinical geneticist playing a crucial role in providing appropriate screening, surveillance, and care for individuals with this syndrome. At the time of diagnosis, individuals should receive baseline echocardiograms, audiologic, ophthalmologic, and developmental assessments. Growth and feeding should be closely monitored. Other specialists that may be involved in the care of individuals with 15q24 deletion syndrome include immunology, endocrine, orthopedics, neurology, and urology. Chromosome 15q24 microdeletion syndrome should be differentiated from other genetic syndromes, particularly velo-cardio-facial syndrome (22q11.2 deletion syndrome, Prader-Willi syndrome, and Noonan syndrome. These conditions share some phenotypic similarity to 15q24 deletion syndrome yet have characteristic features specific to each of them that allows the clinician to distinguish between them. Molecular genetic testing and/or aCGH will be able to diagnose these conditions in the majority of individuals. Disease name and synonyms Chromosome 15q24 deletion syndrome 15q24 deletion syndrome 15q24 microdeletion syndrome

AGILE Observations of the Gravitational-wave Source GW170817: Constraining Gamma-Ray Emission from an NS-NS Coalescence

Science.gov (United States)

Verrecchia, F.; Tavani, M.; Donnarumma, I.; Bulgarelli, A.; Evangelista, Y.; Pacciani, L.; Ursi, A.; Piano, G.; Pilia, M.; Cardillo, M.; Parmiggiani, N.; Giuliani, A.; Pittori, C.; Longo, F.; Lucarelli, F.; Minervini, G.; Feroci, M.; Argan, A.; Fuschino, F.; Labanti, C.; Marisaldi, M.; Fioretti, V.; Trois, A.; Del Monte, E.; Antonelli, L. A.; Barbiellini, G.; Caraveo, P.; Cattaneo, P. W.; Colafrancesco, S.; Costa, E.; D'Amico, F.; Ferrari, A.; Giommi, P.; Morselli, A.; Paoletti, F.; Pellizzoni, A.; Picozza, P.; Rappoldi, A.; Soffitta, P.; Vercellone, S.; Baroncelli, L.; Zollino, G.

2017-12-01

The LIGO-Virgo Collaboration (LVC) detected, on 2017 August 17, an exceptional gravitational-wave (GW) event temporally consistent within ˜ 1.7 {{s}} with the GRB 1708117A observed by Fermi-GBM and INTEGRAL. The event turns out to be compatible with a neutron star-neutron star (NS-NS) coalescence that subsequently produced a radio/optical/X-ray transient detected at later times. We report the main results of the observations by the AGILE satellite of the GW170817 localization region (LR) and its electromagnetic (EM) counterpart. At the LVC detection time T 0, the GW170817 LR was occulted by the Earth. The AGILE instrument collected useful data before and after the GW/GRB event because in its spinning observation mode it can scan a given source many times per hour. The earliest exposure of the GW170817 LR by the gamma-ray imaging detector started about 935 s after T 0. No significant X-ray or gamma-ray emission was detected from the LR that was repeatedly exposed over timescales of minutes, hours, and days before and after GW170817, also considering Mini-calorimeter and Super-AGILE data. Our measurements are among the earliest ones obtained by space satellites on GW170817 and provide useful constraints on the precursor and delayed emission properties of the NS-NS coalescence event. We can exclude with high confidence the existence of an X-ray/gamma-ray emitting magnetar-like object with a large magnetic field of {10}15 {{G}}. Our data are particularly significant during the early stage of evolution of the EM remnant.

Unexpected Functional Divergence of Bat Influenza Virus NS1 Proteins.

Science.gov (United States)

Turkington, Hannah L; Juozapaitis, Mindaugas; Tsolakos, Nikos; Corrales-Aguilar, Eugenia; Schwemmle, Martin; Hale, Benjamin G

2018-03-01

Recently, two influenza A virus (FLUAV) genomes were identified in Central and South American bats. These sequences exhibit notable divergence from classical FLUAV counterparts, and functionally, bat FLUAV glycoproteins lack canonical receptor binding and destroying activity. Nevertheless, other features that distinguish these viruses from classical FLUAVs have yet to be explored. Here, we studied the viral nonstructural protein NS1, a virulence factor that modulates host signaling to promote efficient propagation. Like all FLUAV NS1 proteins, bat FLUAV NS1s bind double-stranded RNA and act as interferon antagonists. Unexpectedly, we found that bat FLUAV NS1s are unique in being unable to bind host p85β, a regulatory subunit of the cellular metabolism-regulating enzyme, phosphoinositide 3-kinase (PI3K). Furthermore, neither bat FLUAV NS1 alone nor infection with a chimeric bat FLUAV efficiently activates Akt, a PI3K effector. Structure-guided mutagenesis revealed that the bat FLUAV NS1-p85β interaction can be reengineered (in a strain-specific manner) by changing two to four NS1 residues (96L, 99M, 100I, and 145T), thereby creating a hydrophobic patch. Notably, ameliorated p85β-binding is insufficient for bat FLUAV NS1 to activate PI3K, and a chimeric bat FLUAV expressing NS1 with engineered hydrophobic patch mutations exhibits cell-type-dependent, but species-independent, propagation phenotypes. We hypothesize that bat FLUAV hijacking of PI3K in the natural bat host has been selected against, perhaps because genes in this metabolic pathway were differentially shaped by evolution to suit the unique energy use strategies of this flying mammal. These data expand our understanding of the enigmatic functional divergence between bat FLUAVs and classical mammalian and avian FLUAVs. IMPORTANCE The potential for novel influenza A viruses to establish infections in humans from animals is a source of continuous concern due to possible severe outbreaks or pandemics. The

Risk factors for low bone density in pediatric nephrotic syndrome

Directory of Open Access Journals (Sweden)

Corina Lisa

2011-04-01

Full Text Available Background Disturbances in bone mineral metabolism and side effects of corticosteroid treatment may cause decreased bone density in patients v.ith nephrotic syndrome (NS. Objectives To compare the prevalence oflow bone mineral density (BMD in children with and 'Without NS and to assess the effect of corticosteroid treatment on bone density in NS patients.  Methods We conducted a retrospective, cohort study in children aged 5-18 years diagnosed 'With NS for more than 2 months prior to data collection, and in children v.ithout NS as a control. BMD was assessed on calcaneal bone wlith ultrasound bone densitometry. Serum calcium, albumin, creatinine and phosphate levels were also assessed. Results The prevalence of low BMD was significantly higher in NS patients than nonNS subjects, 73.3% (22 in 30 vs. 33% (11 in 33, respectively. The prevalence ratio was 6.3 (95% CI 2.1 to 18.9. NS patients had lower serum calcium levels, With mean difference of -0.17 (95% CI -0.27 to -0.07 mMollL, P<0.009, and lower serum albumin, with mean difference of  -0.88 (95% CI -1.27 to -0.49 gIL; PNS subjects. After adjusting for other risk factors, we found NS to be an independent risk factor for low BMD. Steroid-resistant and steroid-dependent patients had lower BMD than steroid-sensitive subjects (P=0.02. There was also a significant correlation between the onset of corticosteroid treatment and BMD (r=O.3; P=0.02. Conclusions NS patients had higher risk for low BMD compared to normal subjects. Response to steroid treatment influences the severity of impaired bone density.

Nodding syndrome since 2012: recent progress, challenges and recommendations for future research.

Science.gov (United States)

Colebunders, R; Post, R; O'Neill, S; Haesaert, G; Opar, B; Lakwo, T; Laudisoit, A; Hendy, A

2015-02-01

We aim to review the current epidemiology of nodding syndrome (NS) and discuss relevant gaps in research. NS and convulsive epilepsy of unknown aetiology are clustered within the same villages and families in onchocerciasis-endemic areas. They are therefore potentially different clinical expressions of the same disease. It has been difficult to perform full autopsies on NS patients who die in remote villages. Adequate fixation of tissue immediately after death is critical for the examination of brain tissue. Therefore, post-mortem transsphenoidal brain biopsies, performed immediately after death by trained nurses, will provide the best option for obtaining tissue for analysis. We suspect that certain blackflies in onchocerciasis-endemic areas may transmit a novel pathogen that could cause NS and epilepsy. This is supported by a recent drop in the number of new NS cases coinciding with vector control activities aimed at reducing blackfly populations in northern Uganda. We propose that metagenomic studies of human samples, blackflies and microfilariae are conducted to screen for pathogens, and that a clinical trial is planned to evaluate the impact of larviciding against NS and epilepsy epidemics. © 2014 John Wiley & Sons Ltd.

[Clinical significance of NS1-BP expression in esophageal squamous cell carcinoma].

Science.gov (United States)

Ren, K; Qian, D; Wang, Y W; Pang, Q S; Zhang, W C; Yuan, Z Y; Wang, P

2018-01-23

Objective: To investigate the clinical significance of NS1-BP expression in patients with esophageal squamous cell carcinoma (ESCC), and to study the roles of NS1-BP in proliferation and apoptosis of ESCC cells. Methods: A total of 98 tumor tissues and 30 adjacent normal tissues from 98 ESCC patients were used as study group and control group, and these samples were collected in Sun Yat-Sen University Cancer Center between 2002 and 2008. In addition, 46 ESCC tissues which were collected in Cancer Institute and Hospital of Tianjin Medical University were used as validation group. Expression of mucosal NS1-BP was detected by immunohistochemistry. Kaplan-Meier curve and log-rank test were used to analyze the survival rate. Multivariate Cox proportional hazard model was used to analyze the prognostic factors. Furthermore, NS1-BP was over expressed or knocked down in ESCC cells by transient transfection. Protein levels of c-Myc were detected by western blot. Cell viability and apoptosis was analyzed by MTT assay and flow cytometry. Results: Among all of tested samples, NS1-BP were down-regulated in 9 out of 30 non-tumorous normal esophageal tissues (30.0%) and 85 out of 144 ESCC tissues (59.0%), respectively, showing a statistically significant difference ( P =0.012). In the study group, three-year disease-free survival rate of NS1-BP high expression group (53.2%) was significantly higher than that of NS1-BP low expression group (27.6%; P =0.009). In the validation group, the three-year disease-free survival rates were 57.8% and 25.5% in NS1-BP high and low levels groups, respectively, showing a similar results ( P =0.016). Importantly, multivariate analyses showed that low expression of NS1-BP was an independent predictor for chemoradiotherapy sensitivity and shorter disease-free survival time in ESCC patients( P <0.05 for all). Furthermore, overexpressed NS1-BP in TE-1 cells repressed c-Myc expression, inhibited cell proliferation and promoted apoptosis. In contrast

Structure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection in vitro and in vivo.

Science.gov (United States)

Yuan, Shuofeng; Chan, Jasper Fuk-Woo; den-Haan, Helena; Chik, Kenn Ka-Heng; Zhang, Anna Jinxia; Chan, Chris Chung-Sing; Poon, Vincent Kwok-Man; Yip, Cyril Chik-Yan; Mak, Winger Wing-Nga; Zhu, Zheng; Zou, Zijiao; Tee, Kah-Meng; Cai, Jian-Piao; Chan, Kwok-Hung; de la Peña, Jorge; Pérez-Sánchez, Horacio; Cerón-Carrasco, José Pedro; Yuen, Kwok-Yung

2017-09-01

Zika virus (ZIKV) infection may be associated with severe complications in fetuses and adults, but treatment options are limited. We performed an in silico structure-based screening of a large chemical library to identify potential ZIKV NS2B-NS3 protease inhibitors. Clinically approved drugs belonging to different drug classes were selected among the 100 primary hit compounds with the highest predicted binding affinities to ZIKV NS2B-NS3-protease for validation studies. ZIKV NS2B-NS3 protease inhibitory activity was validated in most of the selected drugs and in vitro anti-ZIKV activity was identified in two of them (novobiocin and lopinavir-ritonavir). Molecular docking and molecular dynamics simulations predicted that novobiocin bound to ZIKV NS2B-NS3-protease with high stability. Dexamethasone-immunosuppressed mice with disseminated ZIKV infection and novobiocin treatment had significantly (P < 0.05) higher survival rate (100% vs 0%), lower mean blood and tissue viral loads, and less severe histopathological changes than untreated controls. This structure-based drug discovery platform should facilitate the identification of additional enzyme inhibitors of ZIKV. Copyright © 2017 Elsevier B.V. All rights reserved.

Antiviral Activity and Resistance Analysis of NS3/4A Protease Inhibitor Grazoprevir and NS5A Inhibitor Elbasvir in Hepatitis C Virus GT4 Replicons.

Science.gov (United States)

Asante-Appiah, Ernest; Curry, Stephanie; McMonagle, Patricia; Ingravallo, Paul; Chase, Robert; Nickle, David; Qiu, Ping; Howe, Anita; Lahser, Frederick C

2017-07-01

Although genotype 4 (GT4)-infected patients represent a minor overall percentage of the global hepatitis C virus (HCV)-infected population, the high prevalence of the genotype in specific geographic regions coupled with substantial sequence diversity makes it an important genotype to study for antiviral drug discovery and development. We evaluated two direct-acting antiviral agents-grazoprevir, an HCV NS3/4A protease inhibitor, and elbasvir, an HCV NS5A inhibitor-in GT4 replicons prior to clinical studies in this genotype. Following a bioinformatics analysis of available GT4 sequences, a set of replicons bearing representative GT4 clinical isolates was generated. For grazoprevir, the 50% effective concentration (EC 50 ) against the replicon bearing the reference GT4a (ED43) NS3 protease and NS4A was 0.7 nM. The median EC 50 for grazoprevir against chimeric replicons encoding NS3/4A sequences from GT4 clinical isolates was 0.2 nM (range, 0.11 to 0.33 nM; n = 5). The difficulty in establishing replicons bearing NS3/4A resistance-associated substitutions was substantially overcome with the identification of a G162R adaptive substitution in NS3. Single NS3 substitutions D168A/V identified from de novo resistance selection studies reduced grazoprevir antiviral activity by 137- and 47-fold, respectively, in the background of the G162R replicon. For elbasvir, the EC 50 against the replicon bearing the reference full-length GT4a (ED43) NS5A gene was 0.0002 nM. The median EC 50 for elbasvir against chimeric replicons bearing clinical isolates from GT4 was 0.0007 nM (range, 0.0002 to 34 nM; n = 14). De novo resistance selection studies in GT4 demonstrated a high propensity to suppress the emergence of amino acid substitutions that confer high-potency reductions to elbasvir. Phenotypic characterization of the NS5A amino acid substitutions identified (L30F, L30S, M31V, and Y93H) indicated that they conferred 15-, 4-, 2.5-, and 7.5-fold potency losses, respectively, to elbasvir

Epitope Sequences in Dengue Virus NS1 Protein Identified by Monoclonal Antibodies

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Leticia Barboza Rocha

2017-10-01

Full Text Available Dengue nonstructural protein 1 (NS1 is a multi-functional glycoprotein with essential functions both in viral replication and modulation of host innate immune responses. NS1 has been established as a good surrogate marker for infection. In the present study, we generated four anti-NS1 monoclonal antibodies against recombinant NS1 protein from dengue virus serotype 2 (DENV2, which were used to map three NS1 epitopes. The sequence 193AVHADMGYWIESALNDT209 was recognized by monoclonal antibodies 2H5 and 4H1BC, which also cross-reacted with Zika virus (ZIKV protein. On the other hand, the sequence 25VHTWTEQYKFQPES38 was recognized by mAb 4F6 that did not cross react with ZIKV. Lastly, a previously unidentified DENV2 NS1-specific epitope, represented by the sequence 127ELHNQTFLIDGPETAEC143, is described in the present study after reaction with mAb 4H2, which also did not cross react with ZIKV. The selection and characterization of the epitope, specificity of anti-NS1 mAbs, may contribute to the development of diagnostic tools able to differentiate DENV and ZIKV infections.

The effect of glycosylation on cytotoxicity of Ibaraki virus nonstructural protein NS3

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URATA, Maho; WATANABE, Rie; IWATA, Hiroyuki

2015-01-01

The cytotoxicity of Ibaraki virus nonstructural protein NS3 was confirmed, and the contribution of glycosylation to this activity was examined by using glycosylation mutants of NS3 generated by site-directed mutagenesis. The expression of NS3 resulted in leakage of lactate dehydrogenase to the culture supernatant, suggesting the cytotoxicity of this protein. The lack of glycosylation impaired the transport of NS3 to the plasma membrane and resulted in reduced cytotoxicity. Combined with the previous observation that NS3 glycosylation was specifically observed in mammalian cells (Urata et al., Virus Research 2014), it was suggested that the alteration of NS3 cytotoxicity through modulating glycosylation is one of the strategies to achieve host specific pathogenisity of Ibaraki virus between mammals and vector arthropods. PMID:26178820

Role of the immune system in the pathogenesis of idiopathic nephrotic syndrome

NARCIS (Netherlands)

van den Berg, José G.; Weening, Jan J.

2004-01-01

Idiopathic NS (nephrotic syndrome) is characterized by massive proteinuria, due to a leak in the glomerular barrier to proteins. Genetic defects that affect the function and the composition of the glomerular capillary wall, in particular of the visceral epithelial cells, have recently been

The Future of HCV Therapy: NS4B as an Antiviral Target

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Hadas Dvory-Sobol

2010-11-01

Full Text Available Chronic hepatitis C virus (HCV infection is a major worldwide cause of liver disease, including cirrhosis and hepatocellular carcinoma. It is estimated that more than 170 million individuals are infected with HCV, with three to four million new cases each year. The current standard of care, combination treatment with interferon and ribavirin, eradicates the virus in only about 50% of chronically infected patients. Notably, neither of these drugs directly target HCV. Many new antiviral therapies that specifically target hepatitis C (e.g. NS3 protease or NS5B polymerase inhibitors are therefore in development, with a significant number having advanced into clinical trials. The nonstructural 4B (NS4B protein, is among the least characterized of the HCV structural and nonstructural proteins and has been subjected to few pharmacological studies. NS4B is an integral membrane protein with at least four predicted transmembrane (TM domains. A variety of functions have been postulated for NS4B, such as the ability to induce the membranous web replication platform, RNA binding and NTPase activity. This review summarizes potential targets within the nonstructural protein NS4B, with a focus on novel classes of NS4B inhibitors.

Uncoupling of Protease trans-Cleavage and Helicase Activities in Pestivirus NS3.

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Zheng, Fengwei; Lu, Guoliang; Li, Ling; Gong, Peng; Pan, Zishu

2017-11-01

The nonstructural protein NS3 from the Flaviviridae family is a multifunctional protein that contains an N-terminal protease and a C-terminal helicase, playing essential roles in viral polyprotein processing and genome replication. Here we report a full-length crystal structure of the classical swine fever virus (CSFV) NS3 in complex with its NS4A protease cofactor segment (PCS) at a 2.35-Å resolution. The structure reveals a previously unidentified ∼2,200-Å 2 intramolecular protease-helicase interface comprising three clusters of interactions, representing a "closed" global conformation related to the NS3-NS4A cis -cleavage event. Although this conformation is incompatible with protease trans -cleavage, it appears to be functionally important and beneficial to the helicase activity, as the mutations designed to perturb this conformation impaired both the helicase activities in vitro and virus production in vivo Our work reveals important features of protease-helicase coordination in pestivirus NS3 and provides a key basis for how different conformational states may explicitly contribute to certain functions of this natural protease-helicase fusion protein. IMPORTANCE Many RNA viruses encode helicases to aid their RNA genome replication and transcription by unwinding structured RNA. Being naturally fused to a protease participating in viral polyprotein processing, the NS3 helicases encoded by the Flaviviridae family viruses are unique. Therefore, how these two enzyme modules coordinate in a single polypeptide is of particular interest. Here we report a previously unidentified conformation of pestivirus NS3 in complex with its NS4A protease cofactor segment (PCS). This conformational state is related to the protease cis -cleavage event and is optimal for the function of helicase. This work provides an important basis to understand how different enzymatic activities of NS3 may be achieved by the coordination between the protease and helicase through different

The effects of non-synonymous single nucleotide polymorphisms (nsSNPs) on protein-protein interactions.

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Yates, Christopher M; Sternberg, Michael J E

2013-11-01

Non-synonymous single nucleotide polymorphisms (nsSNPs) are single base changes leading to a change to the amino acid sequence of the encoded protein. Many of these variants are associated with disease, so nsSNPs have been well studied, with studies looking at the effects of nsSNPs on individual proteins, for example, on stability and enzyme active sites. In recent years, the impact of nsSNPs upon protein-protein interactions has also been investigated, giving a greater insight into the mechanisms by which nsSNPs can lead to disease. In this review, we summarize these studies, looking at the various mechanisms by which nsSNPs can affect protein-protein interactions. We focus on structural changes that can impair interaction, changes to disorder, gain of interaction, and post-translational modifications before looking at some examples of nsSNPs at human-pathogen protein-protein interfaces and the analysis of nsSNPs from a network perspective. © 2013.

Production of recombinant dengue non-structural 1 (NS1) proteins from clinical virus isolates.

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Yohan, Benediktus; Wardhani, Puspa; Aryati; Trimarsanto, Hidayat; Sasmono, R Tedjo

2017-01-01

Dengue is a febrile disease caused by infection of dengue virus (DENV). Early diagnosis of dengue infection is important for better management of the disease. The DENV Non-Structural Protein 1 (NS1) antigen has been routinely used for the early dengue detection. In dengue epidemic countries such as Indonesia, clinicians are increasingly relying on the NS1 detection for confirmation of dengue infection. Various NS1 diagnostic tests are commercially available, however different sensitivities and specificities were observed in various settings. This study was aimed to generate dengue NS1 recombinant protein for the development of dengue diagnostic tests. Four Indonesian DENV isolates were used as the source of the NS1 gene cloning, expression, and purification in bacterial expression system. Recombinant NS1 proteins were successfully purified and their antigenicities were assessed. Immunization of mice with recombinant proteins observed the immunogenicity of the NS1 protein. The generated recombinant proteins can be potentially used in the development of NS1 diagnostic test. With minimal modifications, this method can be used for producing NS1 recombinant proteins from isolates obtained from other geographical regions. Copyright © 2016 Elsevier Inc. All rights reserved.

Gelatin nanoparticles enhance delivery of hepatitis C virus recombinant NS2 gene.

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Sabet, Salwa; George, Marina A; El-Shorbagy, Haidan M; Bassiony, Heba; Farroh, Khaled Y; Youssef, Tareq; Salaheldin, Taher A

2017-01-01

Development of an effective non-viral vaccine against hepatitis C virus infection is of a great importance. Gelatin nanoparticles (Gel.NPs) have an attention and promising approach as a viable carrier for delivery of vaccine, gene, drug and other biomolecules in the body. The present study aimed to develop stable Gel.NPs conjugated with nonstructural protein 2 (NS2) gene of Hepatitis C Virus genotype 4a (HCV4a) as a safe and an efficient vaccine delivery system. Gel.NPs were synthesized and characterized (size: 150±2 nm and zeta potential +17.6 mv). NS2 gene was successfully cloned and expressed into E. coli M15 using pQE-30 vector. Antigenicity of the recombinant NS2 protein was confirmed by Western blotting to verify the efficiency of NS2 as a possible vaccine. Then NS2 gene was conjugated to gelatin nanoparticles and a successful conjugation was confirmed by labeling and imaging using Confocal Laser Scanning Microscope (CLSM). Interestingly, the transformation of the conjugated NS2/Gel.NPs complex into E. coli DH5-α was 50% more efficient than transformation with the gene alone. In addition, conjugated NS2/Gel.NPs with ratio 1:100 (w/w) showed higher transformation efficiency into E. coli DH5-α than the other ratios (1:50 and 2:50). Gel.NPs effectively enhanced the gene delivery in bacterial cells without affecting the structure of NS2 gene and could be used as a safe, easy, rapid, cost-effective and non-viral vaccine delivery system for HCV.

Observational cohort study of ventricular arrhythmia in adults with Marfan syndrome caused by FBN1 mutations.

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Ali Aydin

Full Text Available Marfan syndrome is associated with ventricular arrhythmia but risk factors including FBN1 mutation characteristics require elucidation.We performed an observational cohort study of 80 consecutive adults (30 men, 50 women aged 42±15 years with Marfan syndrome caused by FBN1 mutations. We assessed ventricular arrhythmia on baseline ambulatory electrocardiography as >10 premature ventricular complexes per hour (>10 PVC/h, as ventricular couplets (Couplet, or as non-sustained ventricular tachycardia (nsVT, and during 31±18 months of follow-up as ventricular tachycardia (VT events (VTE such as sudden cardiac death (SCD, and sustained ventricular tachycardia (sVT. We identified >10 PVC/h in 28 (35%, Couplet/nsVT in 32 (40%, and VTE in 6 patients (8%, including 3 with SCD (4%. PVC>10/h, Couplet/nsVT, and VTE exhibited increased N-terminal pro-brain natriuretic peptide serum levels(P10/h and Couplet/nsVT also related to increased indexed end-systolic LV diameters (P = .024 and P = .020, to moderate mitral valve regurgitation (P = .018 and P = .003, and to prolonged QTc intervals (P = .001 and P = .006, respectively. Moreover, VTE related to mutations in exons 24-32 (P = .021. Kaplan-Meier analysis corroborated an association of VTE with increased NT-proBNP (P<.001 and with mutations in exons 24-32 (P<.001.Marfan syndrome with causative FBN1 mutations is associated with an increased risk for arrhythmia, and affected persons may require life-long monitoring. Ventricular arrhythmia on electrocardiography, signs of myocardial dysfunction and mutations in exons 24-32 may be risk factors of VTE.

D-Branes in the Background of NS Fivebranes

CERN Document Server

Elitzur, Shmuel; Rabinovici, Eliezer; Sarkisian, G; Kutasov, D; Elitzur, Shmuel; Giveon, Amit; Kutasov, David; Rabinovici, Eliezer; Sarkissian, Gor

2000-01-01

We study the dynamics of $D$-branes in the near-horizon geometry of $NS$ fivebranes. This leads to a holographically dual description of the physics of $D$-branes ending on and/or intersecting $NS5$-branes. We use it to verify some properties of such $D$-branes which were deduced indirectly in the past, and discuss some instabilities of non-supersymmetric brane configurations. Our construction also describes vacua of Little String Theory which are dual to open plus closed string theory in asymptotically linear dilaton spacetimes.

Predicting deleterious nsSNPs: an analysis of sequence and structural attributes

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Saqi Mansoor AS

2006-04-01

Full Text Available Abstract Background There has been an explosion in the number of single nucleotide polymorphisms (SNPs within public databases. In this study we focused on non-synonymous protein coding single nucleotide polymorphisms (nsSNPs, some associated with disease and others which are thought to be neutral. We describe the distribution of both types of nsSNPs using structural and sequence based features and assess the relative value of these attributes as predictors of function using machine learning methods. We also address the common problem of balance within machine learning methods and show the effect of imbalance on nsSNP function prediction. We show that nsSNP function prediction can be significantly improved by 100% undersampling of the majority class. The learnt rules were then applied to make predictions of function on all nsSNPs within Ensembl. Results The measure of prediction success is greatly affected by the level of imbalance in the training dataset. We found the balanced dataset that included all attributes produced the best prediction. The performance as measured by the Matthews correlation coefficient (MCC varied between 0.49 and 0.25 depending on the imbalance. As previously observed, the degree of sequence conservation at the nsSNP position is the single most useful attribute. In addition to conservation, structural predictions made using a balanced dataset can be of value. Conclusion The predictions for all nsSNPs within Ensembl, based on a balanced dataset using all attributes, are available as a DAS annotation. Instructions for adding the track to Ensembl are at http://www.brightstudy.ac.uk/das_help.html