WorldWideScience

Sample records for achondroplasia

  1. Achondroplasia

    Science.gov (United States)

    ... growth that causes the most common type of dwarfism. Causes Achondroplasia is one of a group of ... the condition. Symptoms The typical appearance of achondroplastic dwarfism can be seen at birth. Symptoms may include: ...

  2. Genetics Home Reference: achondroplasia

    Science.gov (United States)

    ... Description Achondroplasia is a form of short-limbed dwarfism. The word achondroplasia literally means "without cartilage formation." ... is the most common type of short-limbed dwarfism. The condition occurs in 1 in 15,000 ...

  3. Clinical management of achondroplasia.

    Science.gov (United States)

    Wright, M J; Irving, M D

    2012-02-01

    Achondroplasia, one of the skeletal dysplasias and the commonest form of disproportionate short stature, has a different developmental and growth profile compared to average stature children. In addition, a specific group of complications occur more frequently in children with achondroplasia. These include common but usually relatively minor complications such as recurrent otitis media, and rarer but more severe problems such as cervicomedullary compression. Knowledge of these complications, appropriate surveillance strategies and treatment options is essential for the paediatrician. The authors review the published literature in this area and provide a system based approach to the management of the healthcare needs of the child with achondroplasia.

  4. Orofacial manifestations of achondroplasia

    OpenAIRE

    Kaushik, Atul; Kumar, Munish; Rohilla, Smriti; Tanwar, Renu; V C Vinod

    2012-01-01

    Achondroplasia (Online Mendelian Inheritance in Man [OMIM] 100800), is considered as a form of skeletal dysplasia dwarfism that manifests with stunted stature and disproportionate limb shortening. Achondroplasia is of special interest in the field of dentistry because of its characteristic craniofacial features which include relative macrocephaly, depressed nasal bridge and maxillary hypoplasia. Presence of large head, implanted shunt, airway obstruction and difficulty in head control require...

  5. Growth Hormone Treatment in Achondroplasia

    National Research Council Canada - National Science Library

    Hiroyuki Tanaka

    2003-01-01

    Abstract Achondroplasia is the most common short-limb dwarfism. Since the approval of GH treatment for the short stature in achondroplasia in 1997, 444 patients have been registered in the database...

  6. Neurosurgical implications of achondroplasia.

    Science.gov (United States)

    King, James A J; Vachhrajani, Shobhan; Drake, James M; Rutka, James T

    2009-10-01

    Achondroplasia is the most common form of human short-limbed dwarfism. The pediatric neurosurgeon is frequently required to treat children with achondroplasia who have hydrocephalus, cervicomedullary compression (CMD), and spinal canal stenosis. Accordingly, the authors have reviewed the experience of neurosurgery in children with achondroplasia at The Hospital for Sick Children. The medical records and neurosurgery database at The Hospital for Sick Children were searched to identify all children with achondroplasia who underwent at least 1 neurosurgical procedure between 1956 and the present. Twenty-nine children with achondroplasia underwent 85 surgical procedures: 52 for CSF diversion in 12 patients, 20 for CMD in 18 patients, 8 for spinal disorders in 4 patients, and 5 for miscellaneous purposes in 4 patients. The CSF shunts were placed almost exclusively before 1990 and were associated with a significant number of complications. Patients undergoing CMD did very well, with only 1 patient failing to improve clinically. This review provides a historical perspective on the evolution of treatment of pediatric patients with achondroplasia. The use of CSF diversion procedures, formerly fraught with complications, is now rare following the realization of the natural history of CSF space enlargement in these patients. Cervicomedullary compression is more commonly recognized due to better imaging. Central apnea is now better detected by routine sleep studies. Spine surgery, although rare, requires evaluation of both spinal stenosis and instability. These patients are best evaluated by a multidisciplinary team.

  7. Achondroplasia: manifestations and treatment.

    Science.gov (United States)

    Shirley, Eric D; Ain, Michael C

    2009-04-01

    Achondroplasia, the most common skeletal dysplasia, is caused by a mutation of fibroblast growth factor receptor-3. This disorder is characterized by frontal bossing, midface hypoplasia, otolaryngeal system dysfunction, and rhizomelic short stature. Orthopaedic manifestations are exhibited in the spine and the extremities. In the infant with achondroplasia, foramen magnum stenosis may result in brainstem compression with apnea and sudden death. Thoracolumbar kyphosis is seen in most infants, but typically it resolves when the child begins to walk. Anatomic anomalies of the vertebral column place the patient at risk for spinal stenosis as early as the first decade and especially during adulthood. Radial head dislocation is one manifestation in the upper extremity. Lower extremity alignment often is characterized by genu varum, which may require correction osteotomy. Medical and surgical options are available to increase patient height, but indications are controversial, and treatment often consumes a large portion of the child's life.

  8. [Updated treatment of achondroplasia].

    Science.gov (United States)

    Seino, Yoshiki

    2009-03-01

    In achondroplasia, the mutation is an almost non-variable mutation in the transmembrane part of the receptor, G1138A/C, giving rise to a change in the amino acid sequence at position 380 in the protein (glycine to an arginine residue transition- Gly380Arg [G380R] . In hypochondroplasia, about 30-70% of individuals have been reported to be heterozygous for a mutation in the FGFR3 gene. The most common mutation found is the Asn540Lys (asparagine to lysine transition-N540K) in the intracellular tyrosine-kinase (TK1) region. GH Treatment significantly increased height, growth velocity and z-score of growth velocity GH therapy was more effective in hypochondroprasia than in achondroplasia. Increasing stature in individuals with skeletal dysplasias can also be accomplished by surgical leg lengthening.

  9. Achondroplasia and cervical laminoplasty.

    Science.gov (United States)

    Yoshii, June; Traynelis, Vincent C

    2009-10-01

    Achondroplasia is associated with short pedicles that predispose individuals with this trait to develop symptomatic spinal canal stenosis. Laminoplasty is an excellent means of treating cervical myelopathy due to stenosis in selected individuals. Laminoplasty preserves segmental motion and stability, both of which are of benefit to all individuals. The authors report the successful surgical treatment of an achondroplastic adult woman with laminoplasty. This procedure alleviated her symptoms, and she was doing well at 2-year follow-up.

  10. Growth Hormone Treatment in Achondroplasia

    OpenAIRE

    Hiroyuki, Tanaka; Department of Pediatrics, Okayama University Graduate School of Medicine and Dentistry

    2003-01-01

    Achondroplasia is the most common short-limb dwarfism. Since the approval of GH treatment for the short stature in achondroplasia in 1997, 444 patients have been registered in the database. The number of new registrations reached a steady state and it may settle between 20 and 40 patients per year. According to the data registered in the database, the effect of GH treatment in achondroplasia was analyzed. The first year of the treatment saw significantly increased annual height gain by 1.4 cm...

  11. Discoid Meniscus Associated With Achondroplasia.

    Science.gov (United States)

    Hoernschemeyer, Daniel G; Atanda, Alfred; Dean-Davis, Ellen; Gupta, Sumit K

    2016-05-01

    Achondroplasia is the most common skeletal dysplasia. This form of dwarfism is caused by a point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, leading to inhibition of endochondral ossification for these patients. This results in a normal trunk height but shortened limbs. The discoid meniscus may be an important associated finding to better understand the common complaints of leg pain for these patients. Although the incidence for a discoid meniscus is between 3% and 5% for the general population, it is unknown with achondroplasia. This case series includes 4 patients, with ages ranging from adolescence to early adulthood, with symptoms of knee pain that were not attributable to some of the more common findings seen in this patient population. Typically, patients with achondroplasia who experience knee pain are evaluated for more common and well-known etiologies such as genu varum, ligamentous instability, and neurogenic claudication. However, the authors propose that symptomatic discoid lateral meniscus should be added to the differential diagnosis for lower-extremity pain in the achondroplasia population. A thorough history and physical examination, in combination with magnetic resonance imaging, can aid in making the diagnosis. Treatment with arthroscopic debridement, saucerization of the meniscus, and repair for unstable injuries has yielded good outcomes for this patient population. [Orthopedics. 2016; 39(3):e498-e503.]. Copyright 2016, SLACK Incorporated.

  12. Achondroplasia: from genotype to phenotype.

    Science.gov (United States)

    Richette, Pascal; Bardin, Thomas; Stheneur, Chantal

    2008-03-01

    This review focuses on the rheumatological features of achondroplasia, which is the most common skeletal dysplasia and the most frequent cause of short-limbed dwarfism. It is inherited in an autosomal dominant manner but results in the majority of cases of de novo mutations. The disease is related to a mutation in the fibroblast growth factor receptor-3 (FGFR3) gene encoding one member of the FGFR subfamily of tyrosine kinase receptors, which results in constitutive activation of the receptor. Biochemical studies of FGFR3 combined with experiments in knock-out mice have demonstrated that FGFR3 is a negative regulator of chondrocytes proliferation and differentiation in growth plate. This mutation induces a disturbance of endochondral bone formation. The diagnosis of achondroplasia is based on typical clinical and radiological features including short stature, macrocephaly with frontal bossing, midface hypoplasia and rhizomelic shortening of the limbs. The most common rheumatological complications of achondroplasia are medullar and radicular compressions due to spinal stenosis and deformities of the lower limbs. Current treatment and future therapies are discussed.

  13. Achondroplasia and enchondromatosis: report of three boys

    Energy Technology Data Exchange (ETDEWEB)

    Numakura, Chikahiko [Yamagata University School of Medicine, Department of Pediatrics, Yamagata (Japan); Tokyo Metropolitan Kiyose Children' s Hospital, Endocrinology and Metabolism Unit, Tokyo (Japan); Kobayashi, Hironori [Shimane University School of Medicine, Department of Pediatrics, Shimane (Japan); Hasegawa, Yukihiro [Tokyo Metropolitan Kiyose Children' s Hospital, Endocrinology and Metabolism Unit, Tokyo (Japan); Adachi, Masanori [Kanagawa Children' s Medical Center, Department of Endocrinology and Metabolism, Clinical Research Institute, Kanagawa (Japan); Kim, Ok Hwa [Ajou University Hospital, Department of Radiology, Seoul (Korea); Nishimura, Gen [Tokyo Metropolitan Kiyose Children' s Hospital, Department of Radiology, Tokyo (Japan)

    2007-06-15

    We report on three boys suffering from achondroplasia concurrent with enchondromatosis-like metaphyseal changes. Two boys who were examined by molecular analysis harbored a mutation of FGFR3, which occurs in most achondroplastic individuals. Given the prevalence of achondroplasia and enchondromatosis, the metaphyseal changes in these patients are less likely to represent the coincidence of both disorders, but rather to result from a rare consequence of the FGFR3 mutation. Impaired FGFs/FGFR3 signaling pathway in achondroplasia inhibits chondrocytic proliferation, which accounts for most characteristics of achondroplasia. On the other hand, it causes conflicting biological consequences that can suppress or stimulate chondrocytic maturation. In a small subset of achondroplastic individuals, the suppression of chondrocytic maturation may outweigh the stimulation, which leads to cartilaginous overgrowth into the metaphysis, eventually causing the metaphyseal dysplasia found in the present patients. (orig.)

  14. Respiratory difficulties and breathing disorders in achondroplasia.

    Science.gov (United States)

    Afsharpaiman, S; Saburi, A; Waters, Karen A

    2013-12-01

    Respiratory difficulties and breathing disorders in achondroplasia are thought to underlie the increased risk for sudden infant death and neuropsychological deficits seen in this condition. This review evaluates literature regarding respiratory dysfunctions and their sequelae in patients with achondroplasia. The limited number of prospective studies of respiratory disease in achondroplasia means that observational studies and case series provide a large proportion of the data regarding the spectrum of respiratory diseases in achondroplasia and their treatments. Amongst clinical respiratory problems described, snoring is the commonest observed abnormality, but the reported incidence of obstructive sleep apnoea (OSA) shows wide variance (10% to 75%). Reported treatments of OSA include adenotonsillectomy, the use of CPAP, and surgical improvement of the airway, including mid-face advancement. Otolaryngologic manifestations are also common. Respiratory failure due to small thoracic volumes is reported, but uncommon. Mortality rate at all ages was 2.27 (CI: 1.7-3.0) with age-specific mortality increased at all ages. Sudden death was most common in infants and children. Cardiovascular events are the main cause of mortality in adults. Despite earlier recognition and treatment of respiratory complications of achondroplasia, increased mortality rates and other complications remain high. Future and ongoing evaluation of the prevalence and impact of respiratory disorders, particularly OSA, in achondroplasia is recommended. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  15. Analysis of sagittal spinopelvic parameters in achondroplasia.

    Science.gov (United States)

    Hong, Jae-Young; Suh, Seung-Woo; Modi, Hitesh N; Park, Jong-Woong; Park, Jung-Ho

    2011-08-15

    Prospective radiological analysis of patients with achondroplasia. To analyze sagittal spinal alignment and pelvic orientation in achondroplasia patients. Knowledge of sagittal spinopelvic parameters is important for the treatment of achondroplasia, because they differ from those of the normal population and can induce pain. The study and control groups were composed of 32 achondroplasia patients and 24 healthy volunteers, respectively. All underwent lateral radiography of the whole spine including hip joints. The radiographic parameters examined were sacral slope (SS), pelvic tilt, pelvic incidence (PI), S1 overhang, thoracic kyphosis, T10-L2 kyphosis, lumbar lordosis (LL1, LL2), and sagittal balance. Statistical analysis was performed to identify significant differences between the two groups. In addition, correlations between parameters and symptoms were sought. Sagittal spinopelvic parameters, namely, pelvic tilt, pelvic incidence, S1 overhang, thoracic kyphosis, T10-L2 kyphosis, lumbar lordosis 1 and sagittal balance were found to be significantly different in the patient and control groups (P achondroplasia patients and normal healthy controls. The present study shows that sagittal spinal and pelvic parameters can assist the treatment of spinal disorders in achondroplasia patients.

  16. Achondroplasia: pathogenesis and implications for future treatment.

    Science.gov (United States)

    Laederich, Melanie B; Horton, William A

    2010-08-01

    Although the genetic defect underlying achondroplasia has been known for over a decade, no effective therapies to stimulate bone growth have emerged. Here we review the recent literature and summarize the molecular mechanisms underlying disease pathology and examine their potential as therapeutic targets. Currently used preclinical models are discussed in the context of recent advances with a special focus on C-type natriuretic peptide. Research on the mutation in Fibroblast Growth Factor Receptor 3 (FGFR3) that causes achondroplasia suggests that disease results from increased signal transduction from the mutant receptor. Thus, current therapeutic strategies have focused on reducing signals emanating from FGFR3. First-generation therapies directly targeting FGFR3, such as kinase inhibitors and neutralizing antibodies, designed for targeting FGFR3 in cancer, are still in the preclinical phase and have yet to translate into the management of achondroplasia. Counteracting signal transduction pathways downstream of FGFR3 holds promise with the discovery that administration of C-type natriuretic peptide to achondroplastic mice ameliorates their clinical phenotype. However, more research into long-term effectiveness and safety of this strategy is needed. Direct targeting of therapeutic agents to growth plate cartilage may enhance efficacy and minimize side effects of these and future therapies. Current research into the pathogenesis of achondroplasia has expanded our understanding of the mechanisms of FGFR3-induced disease and has increased the number of approaches that we may use to potentially correct it. Further research is needed to validate these approaches in preclinical models of achondroplasia.

  17. Achondroplasia

    Science.gov (United States)

    ... ear infections. Without treatment, repeat ear infections can cause hearing loss . Obesity (being very overweight). Healthy eating and being active can help your child stay at a healthy weight as she grows. ...

  18. ACHONDROPLASIA AND ELLIS VAN CREVELD SYNDROME

    Directory of Open Access Journals (Sweden)

    Ramkumar

    2014-03-01

    Full Text Available Stunted growth of an individual occurs in many systemic conditions and the main cause is due to defective cartilage growth in the long bones particularly in the lower extremities. In achondroplasia and Ellis Van Creveld syndrome the endochondral ossification of long bones are affected but in Ellis Van Creveld syndrome, the stunted growth is associated with ectodermal dysplasia, polydactyly and cardiac diseases. The common feature for both achondroplasia and Ellis Van Creveld syndrome is the individual’s trunk is normal but the lower extremities are short. Though there is a cartilage dysfunction in these two cases, different clinical manifestation occurs in the body and these things are recorded from two case reports of Achondroplasia and Ellis Van Creveld syndrome and submitted the clinical differences with explanation and discussion.

  19. Achondroplasia in female twins: surgical indications.

    Science.gov (United States)

    Albisetti, Walter; Pedretti, Leopoldo; De Bartolomeo, Omar; Verdoni, Fabio; Memeo, Antonio

    2011-03-01

    Although in literature achondroplasia has been described profusely, reports on achondroplastic twins are limited. We present two cases of monozygotic female twins with achondroplasia, who underwent limb-lengthening surgical procedure with external fixation in the following five steps: tibia, femur, tibia; femur, homer. Both the cases presented a good limb length and an optimal correction of associated deformities after the treatment, fulfilling the indications. Surgical indications were mostly led by the axial deviations of the lower limbs, and the timing of the limb-lengthening procedures has been the same in both couples showing the importance of this aspect.

  20. Current Care and Investigational Therapies in Achondroplasia.

    Science.gov (United States)

    Unger, Sheila; Bonafé, Luisa; Gouze, Elvire

    2017-04-01

    The goal of this review is to evaluate the management options for achondroplasia, the most common non-lethal skeletal dysplasia. This disease is characterized by short stature and a variety of complications, some of which can be quite severe. Despite several attempts to standardize care, there is still no widely accepted consensus. This is in part due to absence of concrete data on the incidence of sudden unexplained death in infants with achondroplasia and the best investigation for ascertaining which individuals could benefit from foramen magnum decompression surgery. In this review, we identify the different options of care and management for the various orthopedic, neurologic, and respiratory complications. In parallel, several innovative or drug repositioning therapies are being investigated that would restore bone growth but may also prevent complications. Achondroplasia is the most common non-lethal skeletal dysplasia. It is characterized by short stature and a variety of complications, some of which can be quite severe. Despite several attempts to standardize care, there is still no widely accepted consensus. This is in part due to absence of concrete data on the incidence of sudden unexplained death in infants with achondroplasia and the best investigation for ascertaining which individuals could benefit from foramen magnum decompression surgery. In this review, we identify the different options of care and management for the various orthopedic, neurologic, and respiratory complications. In parallel, several innovative or drug repositioning therapies are being investigated that would restore bone growth but may also prevent complications.

  1. Arthroscopic knee anatomy in young achondroplasia patients.

    Science.gov (United States)

    Del Pilar Duque Orozco, M; Record, N C; Rogers, K J; Bober, M B; Mackenzie, W G; Atanda, A

    2017-06-01

    Achondroplasia is the most common form of skeletal dysplasia, affecting more than 250 000 individuals worldwide. In these patients, the developing knee undergoes multiple anatomical changes. The purpose of this study was to characterise the intra-articular knee anatomy in children with achondroplasia who underwent knee arthroscopy. Records of achondroplasia patients who underwent knee arthroscopy between 2009 and 2014 were reviewed. Demographic data, operative reports, follow-up notes, MRI and arthroscopy images were reviewed. Bony, cartilaginous and ligamentous changes were noted. The trochlea sulcus angle was measured from intra-operative arthroscopic images. A total of 12 knee arthroscopies in nine patients were performed. The mean age at surgery was 16.9 years (12 to 22). In all patients, the indication for surgery was knee pain and/or mechanical symptoms that were refractory to non-operative treatment. Three anatomical variations involving the distal femur were found in all knees: a deep femoral trochlea; a high A-shaped intercondylar notch; and a vertically oriented anterior cruciate ligament. The average trochlea sulcus angle measured 123°. Pathology included: synovial plica (one knee); chondral lesions (three knees); discoid lateral meniscus (11 knees); and meniscal tears (six knees). All patients were pain-free and returned to normal activity at final follow-up. Children with achondroplasia have characteristic distal femur anatomy noted during knee arthroscopy. These variations should be considered normal during knee arthroscopy in these patients. Arthroscopic findings confirmed previous MRI findings within this specific population with the addition of a deep trochlear groove which was not previously reported.

  2. Ventricular septal defect closure in a patient with achondroplasia.

    Science.gov (United States)

    Nakanishi, Keisuke; Kawasaki, Shiori; Amano, Atsushi

    2017-01-01

    Achondroplasia with co-morbid CHD is rare, as are reports of surgical treatment for such patients. We present the case of a 13-year-old girl with achondroplasia and ventricular septal defect. Her ventricular septal defect was surgically repaired focussing on the cardiopulmonary bypass flow, healing of the sternum, and her frail neck cartilage. The surgery and recovery were without complications.

  3. Achondroplasia: Craniofacial manifestations and considerations in dental management

    OpenAIRE

    Al-Saleem,Afnan; Al-Jobair, Asma

    2010-01-01

    Achondroplasia is the most common form of skeletal dysplasia dwarfism that manifests with stunted stature and disproportionate limb shortening. Achondroplasia is of dental interest because of its characteristic craniofacial features which include relative macrocephaly, depressed nasal bridge and maxillary hypoplasia. Presence of large head, implanted shunt, airway obstruction and difficulty in head control require special precautions during dental management. Craniofacial manifestations and c...

  4. Prenatal Diagnosis of Concurrent Achondroplasia and Klinefelter Syndrome

    Directory of Open Access Journals (Sweden)

    Esther Perez-Carbajo

    2015-01-01

    Full Text Available Achondroplasia is the most frequent nonlethal skeletal dysplasia, with a prevalence of 1 : 5000 to 1 : 40,000 live births, and it is caused by a fibroblast growth factor receptor alteration. The combination of achondroplasia and Klinefelter syndrome is extremely rare and just four reports have been published in the literature, which were all diagnosed postnatally. We report the fifth case described of this uncommon association and its prenatal diagnosis. In cases of prenatal diagnosis of achondroplasia with additional suspicious morphological abnormalities, an invasive test such as amniocentesis must be carried out to assess the karyotype normality.

  5. Sagging rope sign in achondroplasia is different from Perthes disease.

    Science.gov (United States)

    Oh, Chang-Wug; Shingade, Viraj Uttamrao; Song, Hae-Ryong; Suh, Seung-Woo; Hong, Jun-Seok; Lee, Seok-Hyun

    2005-01-01

    The "sagging rope" sign is a radiopaque line seen on radiographs of hips with Perthes disease. The main purpose of this study was to determine the incidence, cause, and importance of this sign in achondroplasia and to reveal how it differs from in Perthes disease. Serial radiograms, along with two- and three-dimensional CT images were studied in 42 patients with achondroplasia. The sign was observed bilaterally in all patients. Evaluation of CT images revealed spherical heads with the presence of circumferential overhang in all hips. This circumferential overhang seen on three-dimensional CT images corresponded to the sagging rope sign on plain radiographs. The presence of the sagging rope sign in bilateral hips is a characteristic feature of achondroplasia. It usually appears before epiphyseal closure. Its cause, incidence, and nature differ from in Perthes disease, and its presence does not carry a negative prognosis in achondroplasia.

  6. Achondroplasia: Current Options and Future Perspective.

    Science.gov (United States)

    Bouali, Houda; Latrech, Hanane

    2015-06-01

    Achondroplasia is a human bone genetic disorder of the growth plate and is the most common form of inherited disproportionate short stature. It is inherited as an autosomal dominant disease with essentially complete penetrance. Of these most have the same point mutation in the gene for fibroblast growth factor receptor 3 (FGFR3) which is a negative regulator of bone growth. The clinical and radiological features of achondroplasia can easily be identified; they include disproportionate short stature with rhizomelic shortening, macrocephaly with frontal bossing, midface hypoplasia, lumbar hyperlordosis, and a trident hand configuration. The majority of achondroplasts have a normal intelligence, but many social and medical complications may compromise a full and productive life. Some of them have serious health consequences related to hydrocephalus, craniocervical junction compression, or upper-airway obstruction. In this article, we discuss a number of treatments from the surgical limb lengthening approach and the Recombinant Growth Hormone (rhGH) treatment, to future treatments, which include the Natriuretic Peptide C-type (CNP). The discussion is a comparative study of the complications and drawbacks of various experiments using numerous strategies.

  7. Physeal growth arrest after tibial lengthening in achondroplasia

    OpenAIRE

    Song, Sang-Heon; Agashe, Mandar Vikas; Huh, Young-Jae; Hwang, Soon-Young; Song, Hae-Ryong

    2012-01-01

    Background and purpose Bilateral tibial lengthening has become one of the standard treatments for upper segment-lower segment disproportion and to improve quality of life in achondroplasia. We determined the effect of tibial lengthening on the tibial physis and compared tibial growth that occurred at the physis with that in non-operated patients with acondroplasia. Methods We performed a retrospective analysis of serial radiographs until skeletal maturity in 23 achondroplasia patients who und...

  8. Advances in research on and diagnosis and treatment of achondroplasia in China

    OpenAIRE

    Wang, Yao; Liu, Zeying; Liu, Zhenxing; Zhao, Heng; Zhou, Xiaoyan; Cui, Yazhou; Han, Jinxiang

    2013-01-01

    Achondroplasia is a rare autosomal dominant genetic disease. Research on achondroplasia in China, however, has received little emphasis. Around 80–90% of cases of neonatal achondroplasia result from mutations in fibroblast growth factor receptor 3 (FGFR3) according to polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). Recently, genetic research on achondroplasia in China made a major breakthrough by revealing two novel mutations located on the FGFR3 gene, thus helpi...

  9. Advances in research on and diagnosis and treatment of achondroplasia in China.

    Science.gov (United States)

    Wang, Yao; Liu, Zeying; Liu, Zhenxing; Zhao, Heng; Zhou, Xiaoyan; Cui, Yazhou; Han, Jinxiang

    2013-05-01

    Achondroplasia is a rare autosomal dominant genetic disease. Research on achondroplasia in China, however, has received little emphasis. Around 80-90% of cases of neonatal achondroplasia result from mutations in fibroblast growth factor receptor 3 (FGFR3) according to polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). Recently, genetic research on achondroplasia in China made a major breakthrough by revealing two novel mutations located on the FGFR3 gene, thus helping to complete the pathological molecular map of achondroplasia. There are still, however, unknown aspects of the diagnosis and treatment of achondroplasia. This review will summarize advances in research on and the clinical diagnosis and treatment of achondroplasia in China.

  10. Growth hormone treatment in 35 prepubertal children with achondroplasia

    DEFF Research Database (Denmark)

    Hertel, Niels Thomas; Eklöf, Ole; Ivarsson, Sten

    2005-01-01

    BACKGROUND: Achondroplasia is a skeletal dysplasia with extreme, disproportionate, short stature. AIM: In a 5-y growth hormone (GH) treatment study including 1 y without treatment, we investigated growth and body proportion response in 35 children with achondroplasia. METHODS: Patients were...... treatment of children with achondroplasia improves height during 4 y of therapy without adverse effect on trunk-leg disproportion. The short-term effect is comparable to that reported in Turner and Noonan syndrome and in idiopathic short stature....... randomized to either 0.1 IU/kg (n = 18) or 0.2 IU/kg (n = 17) per day. GH treatment was interrupted for 12 mo after 2 y of treatment in prepubertal patients to study catch-down growth. Mean height SDS (HSDS) at start was -5.6 and -5.2 for the low- and high-dose groups, respectively, and mean age 7.3 and 6...

  11. Sleep and upper airway obstruction in children with achondroplasia

    NARCIS (Netherlands)

    Zucconi, M; Weber, G; Castronovo, [No Value; FeriniStrambi, L; Russo, F; Chiumello, G; Smirne, S

    1996-01-01

    Objective: The features of achondroplasia, the most common form of dwarfism, includes short cranial base and midface hypoplasia; both abnormalities increased the risk of upper airway obstruction during sleep, The aim of our study was to evaluate sleep and respiratory function of children with achond

  12. Development in Children with Achondroplasia: A Prospective Clinical Cohort Study

    Science.gov (United States)

    Ireland, Penelope J.; Donaghey, Samantha; McGill, James; Zankl, Andreas; Ware, Robert S.; Pacey, Verity; Ault, Jenny; Savarirayan, Ravi; Sillence, David; Thompson, Elizabeth; Townshend, Sharron; Johnston, Leanne M.

    2012-01-01

    Aim: Achondroplasia is characterized by delays in the development of communication and motor skills. While previously reported developmental profiles exist across gross motor, fine motor, feeding, and communication skills, there has been no prospective study of development across multiple areas simultaneously. Method: This Australasian…

  13. Advances in treatment of achondroplasia and osteoarthritis.

    Science.gov (United States)

    Klag, Kendra A; Horton, William A

    2016-04-15

    Achondroplasia (ACH) is the prototype and most common of the human chondrodysplasias. It results from gain-of-function mutations that exaggerate the signal output of the fibroblast growth factor receptor 3 (FGFR3), a receptor tyrosine kinase that negatively regulates growth plate activity and linear bone growth. Several approaches to reduce FGFR3 signaling by blocking receptor activation or inhibiting downstream signals have been proposed. Five show promise in preclinical mouse studies. Two candidate therapies target the extracellular domain of FGFR3. The first is a decoy receptor that competes for activating ligands. The second is a synthetic blocking peptide that prevents ligands from binding and activating FGFR3. Two established drugs, statins and meclozine, improve growth of ACH mice. The strongest candidate therapy employs an analog of C-type natriuretic peptide (CNP), which antagonizes the mitogen-activated-protein (MAP) kinase pathway downstream of the FGFR3 receptor and may also act independently in the growth plate. Only the CNP analog has reached clinical trials. Preliminary results of Phase 2 studies show a substantial increase in growth rate of ACH children after six months of therapy with no serious adverse effects. A challenge for drug therapy in ACH is targeting agents to the avascular growth plate. The application of gene therapy in osteoarthritis offers insights because it faces similar technical obstacles. Major advances in gene therapy include the emergence of recombinant adeno-associated virus as the vector of choice, capsid engineering to target vectors to specific tissues, and development of methods to direct vectors to articular chondrocytes. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. Surgical treatment for cervicomedullary compression among infants with achondroplasia.

    Science.gov (United States)

    Shimony, Nir; Ben-Sira, Liat; Sivan, Yakov; Constantini, Shlomi; Roth, Jonathan

    2015-05-01

    Achondroplasia is the most common form of dwarfism. Respiratory failure is responsible for most deaths among these children and is often related to cervicomedullary compression (CMC). We present our experience with early cervicomedullary decompression in infants with achondroplasia. Data was retrospectively collected for infants with achondroplasia who underwent CMC decompression between 1998 and 2013. Data included presurgical and postsurgical neurological examinations, MRI scans, and sleep study results. Ten infants were included. Ages at surgery were 4 to 23 months (12.5 ± 6.88 months). All infants displayed neurological findings prior to surgery, although often subtle. All infants underwent a foramen magnum opening with a wide C1 laminectomy. Following surgery, seven patients (70 %) demonstrated improved neurological status, and one displayed neurological deterioration. Seven patients demonstrated improved sleep quality 1 year after surgery. These patients had a good or improved neurological status following surgery. Preoperative radiological findings included abnormal hyperintense T2 changes in all children (improved following surgery in six children), brainstem distortion in four children (improved in all), and diminished cerebrospinal fluid (CSF) spaces at the level of the foramen magnum in eight children (improved in seven). One child with extensive preoperative T2 changes accompanied by neurological and respiratory decline, deteriorated following surgery, and remains chronically ventilated. Infants with achondroplasia are prone to neurological and respiratory symptoms. We believe that early diagnosis and early surgery for decompression of the foramen magnum and C1 lamina can alleviate respiratory symptoms, improve neurological status, and perhaps prevent sudden infant death in this population.

  15. Spinal stenosis surgery in pediatric patients with achondroplasia.

    Science.gov (United States)

    Sciubba, Daniel M; Noggle, Joseph C; Marupudi, Neena I; Bagley, Carlos A; Bookland, Markus J; Carson, Benjamin S; Ain, Michael C; Jallo, George I

    2007-05-01

    Achondroplasia is a hereditary form of dwarfism caused by a defect in endochondral bone formation, resulting in skeletal abnormalities including short stature, shortened limb bones, macrocephaly, and small vertebral bodies. In the pediatric population, symptomatic spinal stenosis occurs at all spinal levels due to the abnormally narrow bone canal. In this study, clinical outcomes were assessed in children with achondroplasia after spinal canal decompression. A retrospective review was conducted involving pediatric patients with heterozygous achondroplasia and symptomatic stenosis after decompressive procedures at the authors' institution within a 9-year period. Measured outcomes included resolution of symptoms, need for repeated surgery, presence of fusion, development of deformity, and complications. Forty-four pediatric patients underwent a total of 60 decompressive procedures. The average patient age at surgery was 12.7 years (range 5-21 years). Forty-nine operations were performed for initial treatment of stenosis, and 11 were performed as revision surgeries on previously operated levels. A large proportion of patients (> 60%) required additional cervicomedullary decompressions, most often preceding the symptoms of spinal stenosis. Of the initial procedures, decompression locations included 32 thoracolumbar (65%), 10 lumbar (20%), four cervical (8%), two cervicothoracic (4%), and one thoracic (2%). Forty-three of the decompressive procedures (72%) included spinal fusion procedures. Of the 11 revisions, five were fusion procedures for progressive deformity at levels previously decompressed but not fused (all thoracolumbar), five were for decompressions of symptomatic junctional stenosis with extension of fusion, and one was for repeated decompression at the same level due to recurrence of symptomatic stenosis. Decompression of the spinal canal in pediatric patients with achondroplasia can be accomplished safely with significant clinical benefit. Patients with a

  16. Surgical decompression for lumbar stenosis in pediatric achondroplasia.

    Science.gov (United States)

    Baca, Kirsten E; Abdullah, Madeel A; Ting, Beverlie L; Schkrohowsky, Joshua G; Hoernschemeyer, Daniel G; Carson, Benjamin S; Ain, Michael C

    2010-01-01

    Spinal stenosis is a common complication of achondroplasia. To our knowledge, no study has evaluated a greater than 2-year outcome after surgical intervention for spinal stenosis in such children or compared decompression with and without instrumentation in relation to revision surgery. Our purpose was to assess the efficacy of lumbar decompression and instrumentation for symptomatic stenosis in children with achondroplasia. We retrospectively reviewed our institution's database to identify children (achondroplasia undergoing initial spinal decompression for lumbar stenosis from 1995 through 2003. We identified 18 such patients and reviewed their medical records for demographic data, presenting signs and symptoms, and treatment and outcome data. Mean follow-up was 72.0+/-27.6 months. We determined each patient's symptom score (SS) based on presence of leg weakness, numbness, or pain; abnormal reflexes; incontinence; and walking intolerance (unable to walk > or =5 blocks). Each finding was scored 1 point (6 points maximum). Nine patients requiring revision surgery were assigned a revision postoperative SS. All patients were contacted at the end of data collection and assigned a final follow-up SS. Baseline SS values were compared with postoperative, revision postoperative, and final follow-up scores using a paired t test (alpha=0.05). The mean preoperative and final SS values were significantly different: 4.0+/-0.9 (most common symptoms, leg weakness and incontinence) and 1.6+/-1.7 (most common symptom, leg weakness), respectively. Nine patients underwent decompression with instrumentation initially; 9 did not; 7 of the latter required instrumentation during revision; and 2 of the former also required revision. Those without initial instrumentation were 3.5 times more likely (odds ratio=12.3) to require revision. Surgical decompression with instrumentation significantly reduced the symptoms of lumbar stenosis and the likelihood of revision surgery in children with

  17. Physeal growth arrest after tibial lengthening in achondroplasia

    Science.gov (United States)

    2012-01-01

    Background and purpose Bilateral tibial lengthening has become one of the standard treatments for upper segment-lower segment disproportion and to improve quality of life in achondroplasia. We determined the effect of tibial lengthening on the tibial physis and compared tibial growth that occurred at the physis with that in non-operated patients with acondroplasia. Methods We performed a retrospective analysis of serial radiographs until skeletal maturity in 23 achondroplasia patients who underwent bilateral tibial lengthening before skeletal maturity (lengthening group L) and 12 achondroplasia patients of similar height and age who did not undergo tibial lengthening (control group C). The mean amount of lengthening of tibia in group L was 9.2 cm (lengthening percentage: 60%) and the mean age at the time of lengthening was 8.2 years. The mean duration of follow-up was 9.8 years. Results Skeletal maturity (fusion of physis) occurred at 15.2 years in group L and at 16.0 years in group C. The actual length of tibia (without distraction) at skeletal maturity was 238 mm in group L and 277 mm in group C (p = 0.03). The mean growth rates showed a decrease in group L relative to group C from about 2 years after surgery. Physeal closure was most pronounced on the anterolateral proximal tibial physis, with relative preservation of the distal physis. Interpretation Our findings indicate that physeal growth rate can be disturbed after tibial lengthening in achondroplasia, and a close watch should be kept for such an occurrence—especially when lengthening of more than 50% is attempted. PMID:22489887

  18. Fixator-Assisted Lengthening and Deformity Correction Over an Intramedullary Nail in a Patient with Achondroplasia

    Directory of Open Access Journals (Sweden)

    Erdal Uzun

    2014-12-01

    Full Text Available Achondroplasia is the most frequently encountered form of nonlethal skeletal dysplasia and a type of rhizomelic dwarfism. It results in considerable physical and psychologic handicaps owing to the disproportionate stature of the body and difficulty in performing routine activities of daily living. They also have major musculoskeletal problems including symptomatic malalignment of the lower limbs. Limb lengthening has been used in patients with achondroplasia by different techniques (Intramedullar nailing, monolateral or circular external fixator. We report our treatment of a patient 17 years of age with achondroplasia for bilateral lower limb length discrepancy and bilateral tibial varus deformity.

  19. Coronary artery surgery in a man with achondroplasia: a case report

    Directory of Open Access Journals (Sweden)

    Daskalopoulos Marios E

    2010-10-01

    Full Text Available Abstract Introduction Achondroplasia is a musculoskeletal disorder associated with short stature. Despite an estimated prevalence of 1:25,000 in the general population, there is little literature concerning the diagnostic and treatment challenges faced by doctors dealing with a heart operation on a patient with this condition. Case presentation We present the case of a 41-year-old Caucasian man of Greek ethnicity with achondroplasia, who underwent bypass heart surgery. Conclusions The surgery was successful and did not present particular difficulties, showing that heart surgery can be safely performed on people with achondroplasia.

  20. Correction of anterior open bite in a case of achondroplasia

    Directory of Open Access Journals (Sweden)

    Karpagam S

    2005-01-01

    Full Text Available Treatment planning for patients with skeletal deformities is often considered challenging. This article reports a female patient with achondroplasia who presented with severe maxillary retrognathism and vertical excess along with anterior open bite. The clinical and cephalometric findings of the patient are detailed here. The treatment plan consisted of modified anterior maxillary osteotomy for simultaneous vertical and sagittal augmentation along with orthodontic intervention. The course of surgical-orthodontic treatment and the results are presented. This treatment is to be followed by correction of vertical maxillary excess after completion of growth. This paper concludes that the dentoalveolar component of a skeletal deformity can be handled independent of the craniofacial management.

  1. A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia

    Energy Technology Data Exchange (ETDEWEB)

    Stoilov, I.; Kilpatrick, M.W.; Tsipouras, P. [Univ. of Connecticut Health Center, Farmington, CT (United States)

    1995-01-02

    Achondroplasia is the most common type of genetic dwarfism. It is characterized by disproportionate short stature and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. Recent studies mapped the achondroplasia gene on chromosome region 4p16.3 and identified a common mutation in the gene encoding the fibroblast growth factor receptor 3 (FGFR3). In an analysis of 19 achondroplasia families from a variety of ethnic backgrounds we confirmed the presence of the G380R mutation in 21 of 23 achondroplasia chromosomes studied. In contrast, the G380R mutation was not found in any of the 8 hypochondroplasia chromosomes studied. Futhermore, linkage studies in a 3-generation family with hypochondroplasia show discordant segregation with markers in the 4p16.3 region suggesting that at least some cases of hypochondroplasia are caused by mutations in a gene other than FGFR3. 27 refs., 2 figs.

  2. Endoscopic third ventriculostomy in hydrocephalus associated with achondroplasia.

    Science.gov (United States)

    Swift, Dale; Nagy, Laszlo; Robertson, Brian

    2012-01-01

    Hydrocephalus in patients with achondroplasia is thought to be due to increased dural sinus venous pressure resulting from narrowing of the jugular foramen. In this setting, where hydrocephalus is presumed to be "vascular" in origin and therefore communicating, endoscopic third ventriculostomy (ETV) would seem contraindicated. The authors describe 3 patients in whom ETV was successfully performed, resulting in MR imaging-documented decreases in ventricle size. The patients were 11 months, 33 months, and 13 years at the time of surgery. All patients had serial preoperative MR images demonstrating progressive hydrocephalus in a "triventricular" pattern with a small fourth ventricle but an open aqueduct. All patients had undergone suboccipital decompression for foramen magnum stenosis prior to the treatment of hydrocephalus. Preoperative retrograde venography revealed variable pressure gradients across the jugular foramen. It is postulated that the increase in intracranial venous pressure resulting from jugular foramen stenosis may lead to disproportionate venous engorgement of the cerebellum and some degree of obstructive hydrocephalus amenable to ETV. The authors discuss the role of suboccipital decompression in the progression of hydrocephalus in patients with achondroplasia.

  3. Fixator-Assisted Lengthening and Deformity Correction Over an Intramedullary Nail in a Patient with Achondroplasia

    OpenAIRE

    Erdal Uzun

    2016-01-01

    Achondroplasia is the most frequently encountered form of nonlethal skeletal dysplasia and a type of rhizomelic dwarfism. It results in considerable physical and psychologic handicaps owing to the disproportionate stature of the body and difficulty in performing routine activities of daily living. They also have major musculoskeletal problems including symptomatic malalignment of the lower limbs. Limb lengthening has been used in patients with achondroplasia by different techniques (Intramed...

  4. Neurological symptoms, evaluation and treatment in Danish patients with achondroplasia and hypochondroplasia

    OpenAIRE

    Doherty, Mia Aagaard; Hertel, Niels Thomas; Hove, Hanne Buciek; Haagerup, Annette

    2017-01-01

    AimTo investigate the prevalence of neurological symptoms and the types of complications in a cohort of Danish patients with mutation verified achondroplasia and hypochondroplasia and compare the results with previously reported findings.MethodsRetrospective descriptive study by chart review of patients followed in three outpatients clinics in the period 1997-2014. Forty-eight patients with achondroplasia and a median age of 9,5 years old and 20 patients with hypochondroplasia and a median ag...

  5. Coronary artery surgery in a man with achondroplasia: a case report

    OpenAIRE

    Daskalopoulos Marios E; Tsantsaridou Angeliki; Desimonas Nicholas; Baddour Andony J; Karangelis Dimos; Tagarakis Georgios I; Papadopoulos Dimitrios; Tsilimingas Nikolaos B

    2010-01-01

    Abstract Introduction Achondroplasia is a musculoskeletal disorder associated with short stature. Despite an estimated prevalence of 1:25,000 in the general population, there is little literature concerning the diagnostic and treatment challenges faced by doctors dealing with a heart operation on a patient with this condition. Case presentation We present the case of a 41-year-old Caucasian man of Greek ethnicity with achondroplasia, who underwent bypass heart surgery. Conclusions The surgery...

  6. Magnetic resonance evaluation of the knee in children and adolescents with achondroplasia

    Energy Technology Data Exchange (ETDEWEB)

    Akyol, Yakup; Averill, Lauren W. [Nemours/Alfred I. duPont Hospital for Children, Department of Medical Imaging, Wilmington, DE (United States); Atanda, Alfred; Mackenzie, William G. [Nemours/Alfred I. duPont Hospital for Children, Department of Orthopedics, Wilmington, DE (United States); Kecskemethy, Heidi H. [Nemours/Alfred I. duPont Hospital for Children, Department of Medical Imaging, Wilmington, DE (United States); Nemours/Alfred I. duPont Hospital for Children, Department of Biomedical Research, Wilmington, DE (United States); Bober, Michael B. [Nemours/Alfred I. duPont Hospital for Children, Division of Genetics, Department of Pediatrics, Wilmington, DE (United States)

    2015-06-15

    Achondroplasia is the most common form of skeletal dysplasia. Although the radiographic features are well described, MRI features of the knee in achondroplasia have not been reported. To describe common MRI characteristics of the knee joint in symptomatic children and adolescents with achondroplasia. We retrospectively evaluated 10 knee MRI examinations in 8 children and young adults (age range 11-20 years, mean 16.3 years) with achondroplasia. We measured modified Insall-Salvati index, knee flexion angle, anterior cruciate ligament (ACL)-Blumensaat line angle, ACL-tibial angle, posterior cruciate ligament (PCL) angle, intercondylar notch width index, and intercondylar notch depth index. We compared our findings with an age- and gender-matched control group of 20 children (age range 15-18 years; mean 16 years) with normal knee MRIs. All 10 knees in the achondroplasia group had discoid lateral meniscus; 8 meniscal tears were identified. Patella baja was present in half of the study cases. Greater knee flexion and increased ACL-Blumensaat line and PCL angles were seen in all achondroplasia knees. ACL-tibial angle was similar in the study and in the control group. Children with achondroplasia had deeper A-shape femoral notches that extended more anteriorly than those seen in the control group. MRI findings were confirmed in all seven knees with arthroscopic correlation. Discoid lateral meniscus, often with tear, is a consistent feature in knee MRIs of symptomatic children and adolescents with achondroplasia. Other findings include patella baja, knee flexion, deep A-shape intercondylar notch, increased ACL-Blumensaat line angle and taut PCL. (orig.)

  7. A case report of recurrent achondroplasia in fetuses of normal parents

    Directory of Open Access Journals (Sweden)

    Anbumani TL

    2015-06-01

    Full Text Available Achondroplasia, a skeletal dysplasia has an incidence of 1 in 15000 to 1 in 30000 live births. It is inherited in an autosomal dominant manner. The occurrence of recurrent achondroplasia in babies born to normal parents is rare. The present case report is one such type. A female fetus of 27 weeks gestational age was brought to the Department of Anatomy, Karpaga Vinayaga Institute of Medical Sciences, Maduranthagam. There was frontal bossing of forehead, rhizomelic type of limb shortening with limitation of elbow extension in the fetus. The mother of the fetus, who is 26 years old, gave history of recurrence of such condition. Her first pregnancy was a twin pregnancy, conceived by natural methods, where one of the twins was a male baby who also had achondroplasia and died 2 hours after delivery. The other twin is a girl and the child has delayed developmental milestones. Her second pregnancy was uneventful. The present fetus under study is from her third pregnancy. Her marriage is of second degree consanguineous type. The age of her husband is 36 years old. Germinal mosaicism has been attributed for the causation of recurrent achondroplasia in children, whose parents are normal. 80% of achondroplasia is due to a new mutation. Only 20% of achondroplasia is inherited. Increased paternal age is a risk factor for new mutations to occur. The other investigations of the case and the genetic analysis are described further in the article. [Int J Res Med Sci 2015; 3(6.000: 1533-1537

  8. Concomitant achondroplasia and developmental dysplasia of the hip

    Directory of Open Access Journals (Sweden)

    Tennison L. Malcolm, MD

    2015-12-01

    Full Text Available Achondroplasia (ACH is the most common form of hereditary dwarfism and presents with multiple musculoskeletal anomalies but is not normally associated with premature hip arthritis. Developmental dysplasia of the hip (DDH is a spectrum of disease resulting in shallow acetabular depth and a propensity for chronic femoral subluxation or dislocation; it is among the most common causes of premature arthritis. This case report describes the diagnosis of symptomatic DDH in a patient with ACH and highlights difficulties of primary total hip arthroplasty (THA as a treatment option. Intraoperative radiographic imaging is advised to ensure proper prosthesis placement. Femoral osteotomy may aid visualization, reduction, and avoidance of soft tissue injury. Concomitant ACH and DDH is a challenging problem that can be successfully treated with modified THA.

  9. Neurological symptoms, evaluation and treatment in Danish patients with achondroplasia and hypochondroplasia

    DEFF Research Database (Denmark)

    Doherty, Mia Aagaard; Hertel, Niels Thomas; Hove, Hanne Buciek

    2017-01-01

    Aim To investigate the prevalence of neurological symptoms and the types of complications in a cohort of Danish patients with mutation verified achondroplasia and hypochondroplasia and compare the results with previously reported findings. Methods Retrospective descriptive study by chart review...... of patients followed in three outpatients clinics in the period 1997-2014. Forty-eight patients with achondroplasia and a median age of 9,5 years old and 20 patients with hypochondroplasia and a median age of 12 years old were enrolled. Neurological manifestations, epidemiological variables and clinical data...... for referral to an MRI scan or neurosurgery. Conclusion Through investigation of phenotypes and genotypes in patients with achondroplasia and hypochondroplasia we report the frequencies of neurological symptoms, foramen magnum stenosis, spinal cord compression and neurosurgery in Danish patients. Variation...

  10. Arthroscopic Treatment of Discoid Lateral Meniscus Tears in Children With Achondroplasia.

    Science.gov (United States)

    Atanda, Alfred; Wallace, Maegen; Bober, Michael B; Mackenzie, William

    2016-01-01

    Achondroplasia is the most common form of skeletal dysplasia that presents to the pediatric orthopaedist. More than half of achondroplasia patients are affected with knee pain. It is thought that the majority of this pain may be due to spinal stenosis, hip pathology, or knee malalignment. Discoid menisci can be a source of lateral knee joint pain in skeletally immature patients in general. We present the first case series of patients with achondroplasia who had symptomatic discoid lateral menisci treated with arthroscopic knee surgery. The charts of 6 patients (8 knees) with achondroplasia who underwent arthroscopic knee surgery for symptomatic discoid lateral menisci were collected. History and physical examination data, magnetic resonance imaging findings, and operative reports were reviewed. Meniscal tear configuration and treatment type (meniscectomy vs. repair) were noted. Each patient was found to have a tear of the discoid meniscus. All menisci were treated with saucerization. In addition, meniscal repair was performed in 2 cases, partial meniscectomy in 3 cases, and subtotal meniscectomy in 3 cases. Two patients had bilateral discoid meniscal tears which were treated. Average follow-up was 2.4 years (range, 1 to 4.5 y) and the average pediatric International Knee Documentation Committee (pedi-IKDC) score was 85.3% (range, 75% to 95.4%). At final follow-up, all patients were pain free and able to return to full activities. Discoid meniscus tears may be a source of lateral joint line pain in patients with achondroplasia. These injuries can be successfully treated with arthroscopic surgery in this patient population. Future studies need to be done to determine the exact incidence of discoid menisci in achondroplasia patients and also to determine whether there is a genetic relationship between the 2 conditions. Level IV-case series.

  11. Is there a correlation between sleep disordered breathing and foramen magnum stenosis in children with achondroplasia?

    Science.gov (United States)

    White, Klane K; Parnell, Shawn E; Kifle, Yemiserach; Blackledge, Marcella; Bompadre, Viviana

    2016-01-01

    Children with achondroplasia have midface hypoplasia, frontal bossing, spinal stenosis, rhizomelia, and a small foramen magnum. Central sleep apnea, with potential resultant sudden death, is thought to be related to compression of the spinal cord at the cervicomedullary junction in these patients. Screening polysomnography and/or cervical spine MRI are often performed for infants with achondroplasia. Decompressive suboccipital craniectomy has been performed in selected cases. We aim to better delineate the relationship between polysomnography, cervical spine MRI, and indications for surgical decompression in achondroplasia.We retrospectively review electronic medical records of all children with achondroplasia in our IRB-approved skeletal dysplasia registry who had received screening polysomnography and cervical spine MRI examination was performed. We explored correlations of polysomnography, MRI parameters, and need for decompressive surgery. Seventeen patients with both polysomnography and MRI of the cervical spine met inclusion criteria. The average age at time of the sleep study was 2.4 ± 3.6 years. An abnormal apnea-hypopnea index was found in all patients, with central sleep apnea found in 6/17. Five patients (29%) required foramen magnum decompression. We found no statistically significant correlation between central sleep apnea and abnormal MRI findings suggestive of foramen magnum stenosis. Screening polysomnography is an important tool but does not appear to correlate with MRI findings of foramen magnum stenosis. Cord compression, with either associated T2 cord signal abnormality or clinical findings of clonus, was most predictive of subsequent surgical decompression. © 2015 Wiley Periodicals, Inc.

  12. C-Type Natriuretic Peptide Analog as Therapy for Achondroplasia.

    Science.gov (United States)

    Legeai-Mallet, Laurence

    2016-01-01

    Fibroblast growth factor receptor 3 (FGFR3) is an important regulator of bone formation. Gain-of-function mutations in the FGFR3 gene result in chondrodysplasias which include achondroplasia (ACH), the most common form of dwarfism, in which skull, appendicular and axial skeletons are affected. The skeletal phenotype of patients with ACH showed defective proliferation and differentiation of the chondrocytes in the growth plate cartilage. Both endochondral and membranous ossification processes are disrupted during development. At cellular level, Fgfr3 mutations induce increased phosphorylation of the tyrosine kinase receptor FGFR3, which correlate with an enhanced activation of its downstream signaling pathways. Potential therapeutic strategies have emerged for ACH. Several preclinical studies have been conducted such as the C-type natriuretic peptide (CNP) analog (BMN111), intermittent parathyroid hormone injections, soluble FGFR3 therapy, and meclozine and statin treatments. Among the putative targets to antagonize FGFR3 signaling, CNP (or BMN111) is one of the most promising strategies. BMN111 acts as a key regulator of longitudinal bone growth by downregulating the mitogen-activated protein kinase pathway, which is activated as a result of a FGFR3 gain-of-function mutation. Preclinical studies showed that BMN111 treatment led to a large improvement in skeletal parameters in Fgfr3Y367C/+ mice mimicking ACH. In 2014, a clinical trial (phase 2) of BMN111 in pediatric patients with ACH has started. This first clinical trial marks the first big step towards real treatment for these patients. © 2016 S. Karger AG, Basel.

  13. Physeal growth arrest after tibial lengthening in achondroplasia: 23 children followed to skeletal maturity.

    Science.gov (United States)

    Song, Sang-Heon; Agashe, Mandar Vikas; Huh, Young-Jae; Hwang, Soon-Young; Song, Hae-Ryong

    2012-06-01

    Bilateral tibial lengthening has become one of the standard treatments for upper segment-lower segment disproportion and to improve quality of life in achondroplasia. We determined the effect of tibial lengthening on the tibial physis and compared tibial growth that occurred at the physis with that in non-operated patients with achondroplasia. We performed a retrospective analysis of serial radiographs until skeletal maturity in 23 achondroplasia patients who underwent bilateral tibial lengthening before skeletal maturity (lengthening group L) and 12 achondroplasia patients of similar height and age who did not undergo tibial lengthening (control group C). The mean amount of lengthening of tibia in group L was 9.2 cm (lengthening percentage: 60%) and the mean age at the time of lengthening was 8.2 years. The mean duration of follow-up was 9.8 years. Skeletal maturity (fusion of physis) occurred at 15.2 years in group L and at 16.0 years in group C. The actual length of tibia (without distraction) at skeletal maturity was 238 mm in group L and 277 mm in group C (p = 0.03). The mean growth rates showed a decrease in group L relative to group C from about 2 years after surgery. Physeal closure was most pronounced on the anterolateral proximal tibial physis, with relative preservation of the distal physis. Our findings indicate that physeal growth rate can be disturbed after tibial lengthening in achondroplasia, and a close watch should be kept for such an occurrence-especially when lengthening of more than 50% is attempted.

  14. Low Prevalence of Anterior and Posterior Cruciate Ligament Injuries in Patients With Achondroplasia.

    Science.gov (United States)

    Brooks, Jaysson T; Ramji, Alim F; Lyapustina, Tatyana A; Yost, Mary T; Ain, Michael C

    2017-01-01

    Anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) injuries and their subsequent reconstructions are common in the general population, but there has been no research regarding ACL or PCL injuries in patients with achondroplasia, the most common skeletal dysplasia. Our goals were to (1) evaluate the prevalence of ACL and PCL injuries in adolescents and adults with achondroplasia, (2) compare this prevalence with that reported for the general population, (3) determine how many patients with ACL or PCL injuries underwent ligament reconstruction as treatment, and (4) determine patient activity levels as they relate to the rate of ACL/PCL injuries and reconstructions. We reviewed medical records of 430 patients with achondroplasia seen in the senior author's clinic from 2002 through 2014. Demographic data were reviewed, as well as any documentation of ACL or PCL injury or reconstruction. We called all 430 patients by telephone, and 148 agreed to participate in our survey, whereas 1 declined. We asked these patients about their history of ACL or PCL injury or reconstruction, as well as current and past physical activity levels. No ACL or PCL injuries were found on chart review. One patient reached by telephone reported an ACL injury that did not require reconstruction. This yielded a theoretical prevalence of 3/430 (0.7%). Of the 148 patients surveyed, 43 (29%) reported low physical activity, 75 (51%) reported moderate physical activity, and 26 (17%) reported high physical activity. There was no significant difference in the rate of ACL injury when stratified by physical activity level (P=0.102). ACL and PCL injuries and reconstructions are extremely rare in patients with achondroplasia, which cannot be completely ascribed to a low level of physical activity. One possible explanation is that patients with achondroplasia, on an average, have a more anterior tibial slope compared with those without achondroplasia, which decreases the force generated

  15. Treatment of Varus Deformities of the Lower Limbs in Patients with Achondroplasia and Hypochondroplasia

    Science.gov (United States)

    Kaissi, Ali Al; Farr, Sebastian; Ganger, Rudolf; Hofstaetter, Jochen G; Klaushofer, Klaus; Grill, Franz

    2013-01-01

    Angular deformities of the lower limbs are a common clinical problem encountered in pediatric orthopaedic practices particularly in patients with osteochondrodysplasias. The varus deformity is more common than the valgus deformity in achondroplasia and hypochondroplasia patients because of the unusual growth of the fibulae than that of the tibiae. We retrospectively reviewed six patients (four patients with achondroplasia and two patients with hypochondroplsia) with relevant limb deformities due to the above-mentioned entities. All patients manifested significant varus deformity of the lower limbs. Detailed phenotypic characterization, radiologic and genetic testing was carried out as baseline diagnostic tool. We described the re-alignment procedures, which have been applied accordingly. Therefore, bilateral multi-level procedures, multi-apical planning and limb lengthening have been successfully applied. While recognition of the underlying syndromic association in patients who are manifesting angular deformities is the baseline for proper orthopaedic management, this paper demonstrates how to evaluate and treat these complex patients. PMID:23459260

  16. Myxoedema in a patient with achondroplasia in rural area of Guatemala.

    Science.gov (United States)

    Juarez, Michel; Rohloff, Peter

    2017-03-09

    A 43-year-old indigenous Guatemalan woman with achondroplasia presented to our clinic with chronic fatigue and generalised oedema. She had limited contact with the formal healthcare system. However, 1 year prior, she had sought medical evaluation from a private physician. Her symptoms had been attributed to a combination of heart failure and physical disability due to the musculoskeletal complications of her achondroplasia. She was lost to follow-up due to inability to pay for further testing or treatment. On initial laboratory evaluation in our clinic, she was found to have a thyrotropin level greater than assay. With initiation of oral levothyroxine supplementation, her dyspnoea and oedema completely resolved. The case illustrates how indigenous patients in rural Guatemala experience many barriers to accessing high-quality medical care. As a result, presentations of common illnesses are often very advanced and definitive diagnoses and treatments are frequently delayed. 2017 BMJ Publishing Group Ltd.

  17. Intraoperative Computed Tomography for Cervicomedullary Decompression of Foramen Magnum Stenosis in Achondroplasia: Two Case Reports

    Science.gov (United States)

    Arishima, Hidetaka; Tsunetoshi, Kenzo; Kodera, Toshiaki; Kitai, Ryuhei; Takeuchi, Hiroaki; Kikuta, Ken-ichiro

    2013-01-01

    The authors report two cases of cervicomedullary decompression of foramen magnum (FM) stenosis in children with achondroplasia using intraoperative computed tomography (iCT). A 14-month-old girl with myelopathy and retarded motor development, and a 10-year-old girl who had already undergone incomplete FM decompression was presented with myelopathy. Both patients underwent decompressive sub-occipitalcraniectomy and C1 laminectomy without duraplasty using iCT. It clearly showed the extent of FM decompression during surgery, which finally enabled sufficient decompression. After the operation, their myelopathy improved. We think that iCT can provide useful information and guidance for sufficient decompression for FM stenosis in children with achondroplasia. PMID:24140778

  18. Lung function, diagnosis, and treatment of sleep-disordered breathing in children with achondroplasia.

    Science.gov (United States)

    Julliand, Sébastien; Boulé, Michèle; Baujat, Geneviève; Ramirez, Adriana; Couloigner, Vincent; Beydon, Nicole; Zerah, Michel; di Rocco, Federico; Lemerrer, Martine; Cormier-Daire, Valérie; Fauroux, Brigitte

    2012-08-01

    Children with achondroplasia are at risk of sleep-disordered breathing. The aim of the study was to evaluate lung function and sleep-disordered breathing in children with achondroplasia. An interview, clinical examination, lung function tests with blood gases, and a polygraphic sleep study were obtained as part of routine annual evaluation in consecutive children with achondroplasia. We included 30 children (median age 3.0 years, range: 0.4-17.1) over a period of 21 months. Habitual snoring and witnessed apneas were observed in 77% and 33% of the patients, respectively. Prior to the sleep study, 10/29 (34%) patients had undergone upper airway surgery and 5/29 (17%) craniocervical decompression operation. Arterial blood gases were abnormal in two (7%) patients. Sleep findings were abnormal in 28/30 (93%) patients. Eleven (37%) patients had an apnea index≥1 event/hr and 26 (87%) had an apnea-hypopnea index≥5 events/hr. The ≥3% desaturation index was >5/hr in 22 (73%) patients. Sixteen (53%) patients had a minimal pulse oximetry50 mmHg during sleep. As a consequence, the following therapeutic interventions were performed: upper airway surgery in four patients and noninvasive positive pressure ventilation (NPPV) in five other patients, resulting in an improvement in sleep studies in all nine patients. Systematic sleep studies are recommended in children with achondroplasia because of the high prevalence of sleep-disordered breathing. Upper airway surgery and NPPV are effective treatments of sleep-disordered breathing. Copyright © 2012 Wiley Periodicals, Inc.

  19. Physical Basis behind Achondroplasia, the Most Common Form of Human Dwarfism*

    Science.gov (United States)

    He, Lijuan; Horton, William; Hristova, Kalina

    2010-01-01

    Fibroblast growth factor receptor 3 (FGFR3) is a receptor tyrosine kinase that plays an important role in long bone development. The G380R mutation in FGFR3 transmembrane domain is known as the genetic cause for achondroplasia, the most common form of human dwarfism. Despite many studies, there is no consensus about the exact mechanism underlying the pathology. To gain further understanding into the physical basis behind the disorder, here we measure the activation of wild-type and mutant FGFR3 in mammalian cells using Western blots, and we analyze the activation within the frame of a physical-chemical model describing dimerization, ligand binding, and phosphorylation probabilities within the dimers. The data analysis presented here suggests that the mutation does not increase FGFR3 dimerization, as proposed previously. Instead, FGFR3 activity in achondroplasia is increased due to increased probability for phosphorylation of the unliganded mutant dimers. This finding has implications for the design of targeted molecular treatments for achondroplasia. PMID:20624921

  20. Long-term follow-up of a patient with achondroplasia treated with an orthodontic approach.

    Science.gov (United States)

    Mori, Hiroyo; Matsumoto, Kazuma; Kawai, Nobuhiko; Izawa, Takashi; Horiuchi, Shinya; Tanaka, Eiji

    2017-04-01

    We successfully treated a patient with achondroplasia with conventional orthodontic techniques. It was followed by long-term retention. The patient, a 12-year-old boy, had chief complaints of occlusal disturbance and mandibular protrusion. He had been diagnosed with achondroplasia and had growth hormone treatment in his early teenage years. His facial profile was concave with a bulging forehead and a retrognathic maxilla. It was characterized by a skeletal Class III jaw-base relationship with a retropositioned maxilla. At the age of 12 years 9 months, maxillary protraction was initiated with a reverse headgear; for 2 years 6 months, the maxillomandibular growth was controlled. After the growth spurt, at the age of 15 years 6 months, leveling and alignment of both dental arches were started with preadjusted edgewise appliances. After 83 months of multibracket treatment, an acceptable occlusion with a Class I molar relationship and an adequate interincisal relationship was achieved, despite the simultaneous marked vertical growth of the mandible. The resultant occlusion was stable during a 6-year retention period, although considerable forward-downward mandibular growth was observed. Conclusively, our results indicated the necessity of long-term observation in this patient with achondroplasia, especially because of the persistent mandibular growth. Copyright © 2017 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

  1. A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3

    Science.gov (United States)

    Wang, Yingcai; Spatz, Michal K.; Kannan, Karuppiah; Hayk, Hovhannisyan; Avivi, Aaron; Gorivodsky, Marat; Pines, Mark; Yayon, Avner; Lonai, Peter; Givol, David

    1999-01-01

    Achondroplasia, the most common form of dwarfism in man, is a dominant genetic disorder caused by a point mutation (G380R) in the transmembrane region of fibroblast growth factor receptor 3 (FGFR3). We used gene targeting to introduce the human achondroplasia mutation into the murine FGFR3 gene. Heterozygotes for this point mutation that carried the neo cassette were normal whereas neo+ homozygotes had a phenotype similar to FGFR3-deficient mice, exhibiting bone overgrowth. This was because of interference with mRNA processing in the presence of the neo cassette. Removal of the neo selection marker by Cre/loxP recombination yielded a dominant dwarf phenotype. These mice are distinguished by their small size, shortened craniofacial area, hypoplasia of the midface with protruding incisors, distorted brain case with anteriorly shifted foramen magnum, kyphosis, and narrowed and distorted growth plates in the long bones, vertebrae, and ribs. These experiments demonstrate that achondroplasia results from a gain-of-FGFR3-function leading to inhibition of chondrocyte proliferation. These achondroplastic dwarf mice represent a reliable and useful model for developing drugs for potential treatment of the human disease. PMID:10200283

  2. Physical basis behind achondroplasia, the most common form of human dwarfism.

    Science.gov (United States)

    He, Lijuan; Horton, William; Hristova, Kalina

    2010-09-24

    Fibroblast growth factor receptor 3 (FGFR3) is a receptor tyrosine kinase that plays an important role in long bone development. The G380R mutation in FGFR3 transmembrane domain is known as the genetic cause for achondroplasia, the most common form of human dwarfism. Despite many studies, there is no consensus about the exact mechanism underlying the pathology. To gain further understanding into the physical basis behind the disorder, here we measure the activation of wild-type and mutant FGFR3 in mammalian cells using Western blots, and we analyze the activation within the frame of a physical-chemical model describing dimerization, ligand binding, and phosphorylation probabilities within the dimers. The data analysis presented here suggests that the mutation does not increase FGFR3 dimerization, as proposed previously. Instead, FGFR3 activity in achondroplasia is increased due to increased probability for phosphorylation of the unliganded mutant dimers. This finding has implications for the design of targeted molecular treatments for achondroplasia.

  3. Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia during infancy.

    Science.gov (United States)

    White, Klane K; Bompadre, Viviana; Goldberg, Michael J; Bober, Michael B; Campbell, Jeffrey W; Cho, Tae-Joon; Hoover-Fong, Julie; Mackenzie, William; Parnell, Shawn E; Raggio, Cathleen; Rapoport, David M; Spencer, Samantha A; Savarirayan, Ravi

    2016-01-01

    Achondroplasia is the most common inherited disorder of bone growth (skeletal dysplasia). Despite this fact, consistent and evidence-based management approaches to recognized, life-threatening complications, such as foramen magnum stenosis, are lacking. This study aims to outline best practice, based on evidence and expert consensus, regarding the diagnosis, assessment, and management of foramen magnum stenosis in achondroplasia during infancy. A panel of 11 multidisciplinary international experts on skeletal dysplasia was invited to participate in a Delphi process. They were: 1) presented with a list of 26 indications and a thorough literature review, 2) given the opportunity to anonymously rate the indications and discuss in face to face discussion; 3) edit the list and rate it in a second round. Those indications with more than 80% agreement were considered as consensual. After two rounds of rating and a face-to-face meeting, consensus was reached to support 22 recommendations for the evaluation and treatment of foramen magnum stenosis in infants with achondroplasia. These recommendations include indications for surgical decompression, ventriculomegaly, and hydrocephalus, sleep-disordered breathing, physical exams and the use of polysomnography and imaging in this condition. We present a consensus-based best practice guidelines consisting of 22 recommendations. It is hoped that these guidelines will lead to more uniform and structured evaluation, standardizing care pathways, and improving mortality and morbidity outcomes for this cohort. © 2015 Wiley Periodicals, Inc.

  4. Achondroplasia and hypochondroplasia. Comments on frequency, mutation rate, and radiological features in skull and spine.

    Science.gov (United States)

    Oberklaid, F; Danks, D M; Jensen, F; Stace, L; Rosshandler, S

    1979-04-01

    An attempt was made to ascertain all the dwarfs in the State of Victoria. The incidence of achondroplasia proved to be approximately 1 in 26,000 live births in the period 1969 to 1975 when ascertainment was nearly complete. This indicates a mutation rate of 1.93 X 10(-5) per generation in this locus. Paternal age was shown to influence mutation. Ascertainment in earlier years of the study was low despite the very great effort made to find all cases. Patients with hypochondroplasia were particularly difficult to find. However, 25 cases were found for study. Overlap between hypochondroplasia and achondroplasia was found in all features except the facial appearance (which was the basis of definition). Achondroplasia was more severe in all regards, but some individuals with hypochondroplasia were very short and some had extreme degrees of spinal canal stenosis. The classical measurements used to describe the skull changes in acondroplasia failed to distinguish this condition from hypochondroplasia. More efficient indices were devised, but visual assessment of the size of the facial region compared to that of the cranial valult proved more reliable than any index. The clinical distinction based upon facial appearance remains the arbitrary basis of definition.

  5. Early impairment of somatosensory evoked potentials in very young children with achondroplasia with foramen magnum stenosis.

    Science.gov (United States)

    Fornarino, Stefania; Rossi, Daniela Paola; Severino, Mariasavina; Pistorio, Angela; Allegri, Anna Elsa Maria; Martelli, Simona; Doria Lamba, Laura; Lanteri, Paola

    2017-02-01

    To evaluate the contribution of somatosensory evoked potentials after median nerve (MN-SEPs) and posterior tibial nerve (PTN-SEPs) stimulation in functional assessment of cervical and lumbar spinal stenosis in children with achondroplasia. We reviewed MN-SEPs, PTN-SEPs, and spinal magnetic resonance imaging (MRI) examinations performed in 58 patients with achondroplasia (25 males, 33 females; age range 21d-16y 10mo; mean age 4y 3mo [SD 4y 1mo]). Patients were subdivided into four age categories: magnum or lumbar spinal stenosis were analysed in each age category. The ROC curve analysis showed that the most sensitive parameter in detecting the presence of foramen magnum stenosis was P37 latency in the first two age categories (magnum stenosis was IPLs N13-N20 (sensitivity 0.73, specificity 0.87), whereas in the last age category (≥8y), the most important parameter was N20 latency (sensitivity 0.75, specificity 0.77). In children with achondroplasia, the cortical component of PTN-SEPs is more sensitive than the cortical component and central conduction time of MN-SEPs in detection of cervical spinal cord compression at early ages. © 2016 Mac Keith Press.

  6. Deceleration in maturation of bone during adolescent age in achondroplasia - a retrospective study using RUS scoring system

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Suk-Ha [Konkuk University Hospital, Department of Orthopedics, Seoul (Korea); Modi, Hitesh N.; Suh, Seung Woo [Korea University Guro Hospital, Scoliosis Research Institute, Department of Orthopedics, Seoul (Korea); Song, Hae-Ryong; Hazra, Sunit; Modi, Chetna [Korea University Guro Hospital, Rare Disease Institute, Department of Orthopedics, Seoul (Korea)

    2009-02-15

    Knowledge of bone age in achondroplasia is required for the prediction of adult height, timings of limb lengthening, and epiphysiodesis procedures. The purpose of this investigation was to determine the differences in skeletal age in achondroplasia and a control population with the Tanner-Whitehouse 3 method using the RUS score and to determine the right age for the interventional procedure for limb lengthening procedure or deformity correction in these patients. Left hand radiographs of 34 patients (age range, 5-18 years) with achondroplasia were evaluated for skeletal age using the RUS scoring system, which were compared with the left hand radiographs of 41 patients (age range, 5-18 years) without achondroplasia measuring skeletal age. The difference in chronological age and RUS bone age were evaluated statistically according to gender and age group. In the achondroplasia group, chronological age were 10.5{+-}4.3 years for males and 10.1{+-}3.6 years for females and RUS bone age were 9.2{+-}4.0 years for males and 8.9{+-}3.4 years for females, which showed statistically significantly difference (males p=0.0003 and females p < 0.0001), while in the control group, chronological age were 11.1{+-}2.9 years for males and 10.7{+-}3.4 years for females and RUS bone age were 11.2{+-}3.4 years for males and 10.7{+-}3.3 years for females, which did not show statistically significantly difference (males p=0.54 and females p=0.76). Our finding suggested a delay of 1.4 years for males and 1.2 years for females in the maturation of bone in achondroplasia patients. Difference between chronological age and RUS bone age was 0.9{+-}1.1 for <10 years and 1.6{+-}0.9 for >10 years in the study group, while 0.1{+-}1.1 for <10 years and -0.2 {+-} 0.6 for >10 years in the control group, which also showed >statistically significant difference (<10 years p=0.04 and >10 years p<0.0001). These differences indicate that there was a delay in the maturation of bones by 1 year in the group <10

  7. Achondroplasia with 47, xxy karyotype: a case report of the neonatal diagnosis of an extremely unusual association

    Directory of Open Access Journals (Sweden)

    Ros-Pérez Purificación

    2012-06-01

    Full Text Available Abstract Background The association of achondroplasia and Klinefelter syndrome is extremely rare. To date, five cases have been previously reported, all of them diagnosed beyond the postnatal period, and only one was molecularly characterized. We describe the first case of this unusual association diagnosed in the neonatal period, the clinical findings and the molecular studies undertaken. Case presentation The boy was born at term with clinical and radiological features indicating the diagnosis of achondroplasia or hypochondroplasia combined with the prenatal karyotype of Klinefelter syndrome (47,XXY. Neonatal FGFR3 mutation screening showed that the newborn was heterozygous for the classic achondroplasia G340R mutation. Microsatellite marker analysis showed that the sex chromosome aneuploidy had arisen from a non-disjunction error in paternal meiosis I, with a recombination event in the pseudoautosomal region 1 (PAR1. Conclusion Specific mutation analysis is appropriate to confirm the clinical diagnosis of achondroplasia for appropriate diagnosis, prognosis, and genetic counseling, especially when the karyotype does not explain the abnormal prenatal sonographic findings. In the present case, a recombination event was observed in the PAR1 region, although recombinational events in paternally derived Klinefelter syndrome cases are much rarer than expected.

  8. Magnetic resonance imaging study determining cord level and occupancy at thoracolumbar junction in achondroplasia - A prospective study

    Directory of Open Access Journals (Sweden)

    Hitesh N Modi

    2011-01-01

    Conclusion: Our results indicated high level of spinal cord in achondroplasia patients compared to nonachondroplasia individuals. High prevalence of neurological symptoms at TL level in such patients can be associated with high cord level and developing progressive kyphosis at TL level along with degenerative process.

  9. Usefulness of phase contrast cine mode magnetic resonance imaging for surgical decision making in patients with hydrocephalus combined with achondroplasia. Case report.

    Science.gov (United States)

    Miyamoto, Junichi; Tatsuzawa, Kazunori; Sasajima, Hiroyasu; Mineura, Katsuyoshi

    2010-01-01

    A 1-year 9-month-old girl presented with achondroplasia. Serial magnetic resonance (MR) imaging demonstrated mild compression of the medulla oblongata by the occipital bone, macrocrania, and progressive hydrocephalus. Cerebrospinal fluid (CSF) flow study using MR imaging clearly demonstrated CSF flow disturbance at the cervicospinal junction. Foramen magnum decompression was performed for her hydrocephalus and compressed medulla. Postoperative CSF flow study demonstrated improvement of CSF flow at the craniocervical junction. The patient has remained in a stable condition for 7 months postoperatively. Achondroplasia represents hydrocephalus or medullary compression caused by narrowed foramen magnum, which can result in sudden death in some infants. Surgical indications and methods for hydrocephalus combined with achondroplasia remain controversial because the natural history of the hydrocephalus has remained unclear. CSF flow study using MR imaging can provide useful information regarding the surgical indication and methods for the treatment of hydrocephalus combined with achondroplasia.

  10. Reverse shoulder arthroplasty in young patient with achondroplasia - Ten year follow up: Case report.

    Science.gov (United States)

    van den Broek, M; Verborgt, O; Declercq, G

    2017-08-05

    Skeletal dysplasia in achondroplasia can affect all body joints - including the glenohumeral joint - and is prone to develop to degenerative osteoarthritis (OA). This may cause pain and mobility problems at young age. Surgical treatment is challenging due to the dysplastic anatomy of the shoulder joint - with a dysplastic deformed short humerus, a small, hypoplastic medialized glenoid and lateralized acromion - and the long life expectancy of these patients. The indications for reverse shoulder arthroplasty (RSA) evolved during years with rotator cuff tears and rotator cuff arthropathy in combination with or without glenohumeral OA as the main indicator, with good short to mid-term results. Long term results of RSA are rarely found in literature, especially in young patients. The use of a RSA in glenohumeral OA with an intact rotator cuff has rarely been reported. In this case report we present the ten-year clinical and radiographic results of a RSA for the treatment of degenerative OA with glenohumeral dysplasia in a young patient with achondroplasia. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. PTH has the potential to rescue disturbed bone growth in achondroplasia.

    Science.gov (United States)

    Ueda, Koso; Yamanaka, Yoshitaka; Harada, Daisuke; Yamagami, Emi; Tanaka, Hiroyuki; Seino, Yoshiki

    2007-07-01

    Achondroplasia (Ach), the most common form of short-limb short stature, and related disorders are caused by constitutively active point mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Recent studies have provided a large body of evidence for the role of the proliferation and differentiation of chondrocytes in these disorders. Furthermore, a G380R mutation in FGFR3 (FGFR3(Ach)), which results in achondroplasia, induces apoptosis in the chondrogenic cell line ATDC5. This is associated with a decrease in the expression of PTHrP, which shares the same receptor with PTH, and it is significant that PTHrP rescues these cells from apoptosis. Fetuses derived from transgenic mice expressing FGFR3(Ach) under the control of the type II collagen promoter (AchTG) or from wild-type mice were obtained on the 15th day of pregnancy. The femurs were collected from these specimens and cultured for 4 days with PTH. The effects of PTH treatment were then determined by morphometric and histological analyses, in situ hybridization of type X collagen mRNA, and the TUNEL assay. AchTG femurs showed suppressed growth compared with wild type (0.29+/-0.10 mm vs. 0.46+/-0.06 mm, respectively; ptreatments improved the growth velocity in the femurs of the AchTG (0.50+/-0.06 mm; pachondroplasia.

  12. [Posterior osteotomy and decompression for spinal deformity in patients with achondroplasia].

    Science.gov (United States)

    Sun, Wu; Zhang, Jian-Guo; Qiu, Gui-Xing; Li, Shu-Gang

    2010-11-23

    to evaluate the outcome of surgical treatment for spinal deformity in patients with achondroplasia. six consecutive cases of 3 males and 3 females were recruited. The average age at surgery was 18.5 years old with a range of 12 to 36 years old. All patients suffered thoracolumbar kyphosis and lumbar stenosis. Four patients had neurological deficits due to severe spinal deformity. Posterior osteotomy and decompression were performed in all cases. Long cassette supine radiographs were taken before and after surgery and at the final follow-up. Correction of kyphosis, neurological outcomes (JOA (Japanese Orthopedic Association) scores) and operative complications were recorded and analyzed. the average follow-up was 10.2 months with a range of 5 to 24 months. The average operative duration was 320 min with a mean 1300 ml of blood loss. The average number of fusion segments was 8 with a range of 5 to 10 segments. Kyphosis was corrected from 53.3° to 13.3° with a 75.0% correction rate. The average preoperative JOA score was 4.5 points and improved to 8.5 points at the final follow-up. posterior osteotomy and decompression is a preferred surgical regiment for thoracolumbar kyphosis and lumbar stenosis in patients with achondroplasia.

  13. Respiratory events and obstructive sleep apnea in children with achondroplasia: investigation and treatment outcomes.

    Science.gov (United States)

    Afsharpaiman, Shahla; Sillence, David O; Sheikhvatan, Mehrdad; Ault, Jenny E; Waters, Karen

    2011-12-01

    We report aspects of sleep-disordered breathing in a cohort of achondroplastic children who attended our hospital. A retrospective chart review was conducted for a 15-year period to further evaluate the diagnosis and treatment of sleep-disordered breathing in children with achondroplasia. A review of the medical records was undertaken for 46 children (63%, mean age 3.9 years) with achondroplasia that had overnight polysomnography. Among them, 25 (54.3%) had obstructive sleep apnea (OSA). For 19 out of 46 patients (follow-up rate, 41.3%) with a mean follow-up of 31.3 months (range, 3 month to 11 years), 13 had undergone adenotonsillectomy, while nine were treated with continuous positive airway pressure. Prospective evaluation of our clinic population confirms a high incidence of SDB in achondroplastic children. OSA has been linked to raise intracranial pressure as well as neurocognitive deficits in children and we hypothesize that associations between neurological and respiratory abnormalities in this disorder are a consequence of the early onset of associated respiratory, rather than the neurological complications.

  14. Achondroplasia among ancient populations of mesoamerica and South America: Iconographic and Archaeological Evidence.

    Science.gov (United States)

    Rodríguez, Carlos A; Isaza, Carolina; Pachajoa, Harry

    2012-07-01

    Achondroplasia is the most frequent form of short-limb dwarfism. Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and mid-face hypoplasia, genu varum, and trident hand. Although the etiology of this disease was reported in 1994, evidence of this disease in ancient populations has been found in populations of ancient Egypt (2500 BC) and it has been documented in ancient American populations. To analyze the presence of individuals with achondroplasia in the Mayan state society of Mexico and Guatemala, during the Classical (100- 950 AC ) and Post-Classical (950 - 1519 AC ) periods; likewise, in the hierarchical-chieftain society of Tumaco-la Tolita (300 BC - 600 AC ) from the Colombia-Ecuador Pacific coast, and the Moche state society (100 - 600 AC ) from the northern coast of Peru. Iconographic and clinical-morphological studies of some of the most important artistic representations of individuals of short stature in these three cultures. We present the hypothesis that the individuals with short stature were somehow associated with the political and religious power elite.

  15. Height Outcome of Recombinant Human Growth Hormone Treatment in Achondroplasia Children: A Meta-Analysis.

    Science.gov (United States)

    Miccoli, Mario; Bertelloni, Silvano; Massart, Francesco

    2016-01-01

    Although recombinant human growth hormone (rhGH) is not approved to treat short stature of achondroplasia (ACH), some studies suggested growth improvement during short-term rhGH treatment. A meta-analysis of rhGH therapy efficacy in ACH children was performed. From 12 English-language studies, 558 (54.0% males) rhGH-treated ACH children were enrolled. Administration of rhGH (median dosage 0.21 mg/kg/ week; range 0.16-0.42 mg/kg/week) improved height (Ht) from baseline [-5.069 standard deviation score (SDS; 95% CI -5.109 to -5.029); p treatment increased Ht from -5.0 to -4.0 SDS during 5 years, but insufficient data are available on both the adult Ht and the changes of body proportions. © 2016 S. Karger AG, Basel.

  16. Surgical decompression of thoracic spinal stenosis in achondroplasia: indication and outcome.

    Science.gov (United States)

    Vleggeert-Lankamp, Carmen; Peul, Wilco

    2012-08-01

    The achondroplastic spinal canal is narrow due to short pedicles and a small interpedicular distance. Compression of neural structures passing through this canal is therefore regularly encountered but rarely described. Symptomatology, radiological evaluation, and treatment of 20 patients with achondroplasia who underwent decompression of the thoracic spinal cord are described and outcome is correlated with the size of the spinal canal and the thoracolumbar kyphotic angle. Scores from the modified Japanese Orthopaedic Association scale, Nurick scale, European Myelopathy scale, Cooper myelopathy scale for lower extremities, and Odom criteria before and after surgery were compared. Magnetic resonance imaging was evaluated to determine the size of the spinal canal, spinal cord compression, and presence of myelomalacia. The thoracolumbar kyphotic angle was measured using fluoroscopy. Patient symptomatology included deterioration of walking pattern, pain, cramps, spasms, and incontinence. Magnetic resonance images of all patients demonstrated spinal cord compression due to degenerative changes. Surgery resulted in a slight improvement on all the ranking scales. Surgery at the wrong level occurred in 15% of cases, but no serious complications occurred. The mean thoracolumbar kyphotic angle was 20°, and no correlation was established between this angle and outcome after surgery. No postoperative increase in this angle was reported. There was also no correlation between size of the spinal canal and outcome. Decompressive surgery of the thoracic spinal cord in patients with achondroplasia can be performed safely if anatomical details are taken into consideration. Spondylodesis did not appear essential. Special attention should be given to the method of surgery, identification of the level of interest, and follow-up of the thoracolumbar kyphotic angle.

  17. Favorable Growth Hormone Treatment Response in a Young Boy with Achondroplasia.

    Science.gov (United States)

    Krstevska-Konstantinova, Marina; Stamatova, Ana; Gucev, Zoran

    2016-04-01

    Achondroplasia is a skeletal dysplasia, the most common cause of rhizomelic dwarfism. This is a ten year old boy who was first diagnosed prenatally. He had a mutation c1138G>A in the gene FGFR3 in a heterozygotic constellation. His IGF1 and IGFBP3 levels were normal. Two stimulation tests for growth hormone were performed with values within the reference range. His psychomotor development was adequate for his age except for speech difficulty. He started with recombinant hGH (r-hGH) at the age of 3.4 years in a dose of 0.06 mg/kg. His mean Height SDS (HtSDS) was -2.2. The growth increased to 10 cm/year in the first year of therapy (HtSDS -1.1). It decreased during the second year to 4 cm (HtSDS -1.7) and again increased during the third year to 8 cm/year (HtSDS-1.3). In the next years the growth was constant (6.5, 2.3, 3.5 cm / year). He is still growing in the 3(rd) percentile of the growth curve (HtSDS - 1.2) under GH treatment. The body disproportion remained the same. The growth response on GH treatment was satisfactory in the first 4 years of treatment, and the boy still continued to grow. The young age at the start of treatment was also of importance. Our other patients with achondroplasia who started treatment older had a poor response to growth hormone.

  18. Surgical treatment for sleep apnea: changes in craniofacial and pharyngeal airway morphology in a child with achondroplasia.

    Science.gov (United States)

    Sato, Kieko; Niikuni, Naoko; Nakajima, Ichiro; Shirakawa, Tetsuo; Sakata, Hideaki

    2007-06-01

    Here, we report the case of a male child with achondroplasia who was diagnosed with obstructive sleep apnea and underwent adenoidectomy and tonsillectomy. By analyzing lateral cephalograms, we evaluated the craniofacial and pharyngeal airway morphology immediately before surgery (age, 5 years 6 months) and 1 year 2 months after surgery (age, 6 years 8 months). Adenoidectomy and tonsillectomy dilated the pharynx and improved the craniofacial and pharyngeal morphologies, apparently thus improving the sleep apnea.

  19. Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism

    Energy Technology Data Exchange (ETDEWEB)

    Bonaventure, J.; Rousseau, F.; Legeai-Mallet, L.; LeMerrer, M.; Munnich, A.; Maroteaux, P. [INSERM, Paris (France)

    1996-05-03

    The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (G380R) in the fibroblast growth factor receptor 3 (FGFR-3) gene has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dwarfism (types I and II) and hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity as more than 98% of all patients hitherto reported exhibit mutations in the transmembrane receptor domain. Although most hypochondroplasia cases were accounted for by a recurrent missense substitution (N540K) in the first tyrosine kinase (TK 1) domain of the receptor, a significant proportion (40%) of our patients did not harbor the N540K mutation and three hypochondroplasia families were not linked to the FGFR-3 locus, thus supporting clinical heterogeneity of this condition. In thanatophoric dwarfism (TD), a recurrent FGFR-3 mutation located in the second tyrosine kinase (TK 2) domain of the receptor was originally detected in 100% of TD II cases; in our series, seven distinct mutations in three different protein domains were identified in 25 of 26 TD I patients, suggesting that TD, like achondroplasia, is a genetically homogenous skeletal disorder. 31 refs., 4 figs., 2 tabs.

  20. The role of endoscopic third ventriculostomy in the treatment of triventricular hydrocephalus seen in children with achondroplasia.

    Science.gov (United States)

    Etus, Volkan; Ceylan, Savas

    2005-09-01

    The authors of this paper describe two patients with achondroplasia in whom triventricular hydrocephalus has been successfully treated using endoscopic third ventriculostomy (ETV). The authors performed ETVs in two children with achondroplasia involving a moderate macrocranium and enlarged lateral and third ventricles with intermittent clinical evidence of increased intracranial pressure. The endoscopic procedure revealed a significant deformation of the floor of the third ventricle in both patients caused by longstanding hydrocephalus. Because of the anatomical variations such as empty sella and the persistence of the infundibular recess, the ETV procedure became technically demanding. The standard ventriculostomy on the tuber cinereum was not possible. Ventriculostomies were performed on the part of the third ventricular floor that was hanging ventral to the pons. Both patients became symptom free postoperatively, and phase-contrast cine magnetic resonance (MR) imaging studies confirmed the patency and effectivity of the ventriculostomy sites. The authors suggest that ETVs may constitute an alternative for ventriculoperitoneal shunt therapy as the treatment of choice for patients with achondroplasia who have triventricular hydrocephalus and clinical symptoms. Attention should be paid to the shape of the floor of the third ventricle, however, especially in cases of longstanding hydrocephalus. An association of the empty sella or the persistence of the infundibular recess must be carefully evaluated using MR imaging studies before attempting ETVs in such patients.

  1. Achondroplasia in children: correlation of ventriculomegaly, size of foramen magnum and jugular foramina, and emissary vein enlargement.

    Science.gov (United States)

    Bosemani, Thangamadhan; Orman, Gunes; Hergan, Benedikt; Carson, Kathryn A; Huisman, Thierry A G M; Poretti, Andrea

    2015-01-01

    Achondroplasia is a skeletal dysplasia with diminished growth of the skull base secondary to defective enchondral bone formation. This leads to narrowing of the foramen magnum and jugular foramina, which further leads to ventricular dilatation and prominence of the emissary veins. The primary goal of our study was to determine a correlation between the degree of ventricular dilatation, jugular foramina and foramen magnum narrowing, as well as emissary vein enlargement. Conventional T2-weighted MR images were evaluated for surface area of the foramen magnum and jugular foramina, ventricular dilatation, and emissary veins enlargement in 16 achondroplasia patients and 16 age-matched controls. Ratios were calculated for the individual parameters using median values from age-matched control groups to avoid age as a confounder. Compared to age-matched controls, in children with achondroplasia, the surface area of the foramen magnum (median 0.50 cm(2), range 0.23-1.37 cm(2) vs. 3.14 cm(2), 1.83-6.68 cm(2), p magnum compression and (2) stable ventricular size facilitated by interdependent factors likely obviates the need for ventricular shunt placement.

  2. An ICF-CY-based approach to assessing self- and observer-reported functioning in young persons with achondroplasia - development of the pilot version of the Achondroplasia Personal Life Experience Scale (APLES).

    Science.gov (United States)

    Sommer, Rachel; Blömeke, Janika; Dabs, Michaela; Witt, Stefanie; Bullinger, Monika; Quitmann, Julia

    2017-12-01

    Achondroplasia is the most common disproportionate short stature which impacts patients' well-being. Little is known about the burden of disease in terms of functioning of patients and few disease-specific patient-reported outcome (PRO) measures exist. To understand the consequences of achondroplasia, the objective of the study was to develop an achondroplasia-specific PRO tool. Focus group discussions including 34 German patients (age 8-18 years) and 21 parents were conducted and qualitatively analyzed. To identify relevant concepts, statements were coded according to the International Classification of Functioning, Disability and Health: Children & Youth version (ICF-CY). Upon condensation, relevant statements were reformulated as items. 1950 statements related to 125 ICF-CY categories were identified. After condensation and prioritization, 59 items were retained. These were generated based on the ICF-CY domains environmental factors (27 items), activities and participation (18 items), body functions (9 items), and body structures (5 items). A new instrument, the Achondroplasia Personal Life Experience Scale (APLES) to assess burden of disease and functioning from the patients perspective of children and adolescents with achondroplasia has been developed in its pilot version based on the classification of the ICF-CY. Psychometric performance of the APLES is currently being examined. Implications for Rehabilitation Using the ICF-CY within the development of a disease-specific instrument to assess burden of disease and functioning provides guidance for clinicians and researchers in the selection of appropriate instruments complying with ICF categories. Qualitative research based on focus group interviews is an effective method to elicit experiences, beliefs, points of view, understandings, perceptions, impressions, needs and concerns as well as attitudes from the perspective of the individuals on a specific topic such as functioning. Direct assessment of the

  3. ANÁLISIS MUTACIONAL DE LA ACONDROPLASIA EN 20 PACIENTES COLOMBIANOS Mutational analysis of achondroplasia in 20 Colombian patients

    Directory of Open Access Journals (Sweden)

    Ángela Castro

    2010-07-01

    Full Text Available Antecedentes. La acondroplasia es la más común de las displasias esqueléticas. Se trata de una enfermedad autosómica dominante con penetrancia completa. Esta enfermedad se debe a una mutación en el gen del receptor 3 del factor de crecimiento fibroblástico (FGFR3. El 90% o más de los casos se deben a mutaciones nuevas que se originan en las células germinales de padres sanos, asociada a una edad incrementada. Se ha calculado una frecuencia al nacimiento de 1:10.000 a 1:30.000. En la mayoría de los casos (97% la mutación presente es la transición G1138A, en el dominio transmembranal de gen. En el resto se presenta la transversión en el mismo nucleótido, G1138C. Objetivo. Detectar mutaciones del gen FGFR3 en un grupo de pacientes colombianos con acondroplasia. Material y métodos. Estudiamos un grupo de 20 pacientes con diagnóstico clínico de acondroplasia. Se utilizó el método, ARMS-PCR (Amplification Refractory Mutation System - Polymerase Chain Reaction que emplea dos pares primers diseñados específicamente para amplificar respectivamente los dos diferentes nucleótidos de una mutación puntual. Resultados. 19 pacientes (95%, presentaron la mutación G1138A y un paciente presentó la mutación G1138C (5%. Conclusión. No obstante la acondroplasia presentar un fenotipo considerado distinguible de otras displasias esqueléticas, algunas veces la hipocondroplasia, que se presenta por mutaciones en el mismo gen FGFR3, puede ser difícil de discriminar clínicamente, por lo que el análisis mutacional permite la correcta clasificación, así como de eventualmente otras displasias esqueléticas por mutaciones en otros genes.Background. Achondroplasia is the most common skeletal dysplasia, mainly affecting tubular bones, vertebrae and skull. This is an autosomal dominant syndrome with complete penetrance, due to a mutation in the fibroblast growth factor receptor 3 (FGFR3 gene. Approximately 90% of the achondroplasia cases, are due

  4. Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia

    Science.gov (United States)

    Lee, Yi-Ching; Song, I-Wen; Pai, Ya-Ju; Chen, Sheng-De; Chen, Yuan-Tsong

    2017-01-01

    Achondroplasia (ACH), the most common genetic dwarfism in human, is caused by a gain-of function mutation in fibroblast growth factor receptor 3 (FGFR3). Currently, there is no effective treatment for ACH. The development of an appropriate human-relevant model is important for testing potential therapeutic interventions before human clinical trials. Here, we have generated an ACH mouse model in which the endogenous mouse Fgfr3 gene was replaced with human FGFR3G380R (FGFR3ACH) cDNA, the most common mutation in human ACH. Heterozygous (FGFR3ACH/+) and homozygous (FGFR3ACH/ACH) mice expressing human FGFR3G380R recapitulate the phenotypes observed in ACH patients, including growth retardation, disproportionate shortening of the limbs, round head, mid-face hypoplasia at birth, and kyphosis progression during postnatal development. We also observed premature fusion of the cranial sutures and low bone density in newborn FGFR3G380R mice. The severity of the disease phenotypes corresponds to the copy number of activated FGFR3G380R, and the phenotypes become more pronounced during postnatal skeletal development. This mouse model offers a tool for assessing potential therapeutic approaches for skeletal dysplasias related to over-activation of human FGFR3, and for further studies of the underlying molecular mechanisms. PMID:28230213

  5. Meckel's and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible.

    Science.gov (United States)

    Biosse Duplan, Martin; Komla-Ebri, Davide; Heuzé, Yann; Estibals, Valentin; Gaudas, Emilie; Kaci, Nabil; Benoist-Lasselin, Catherine; Zerah, Michel; Kramer, Ina; Kneissel, Michaela; Porta, Diana Grauss; Di Rocco, Federico; Legeai-Mallet, Laurence

    2016-07-15

    Activating FGFR3 mutations in human result in achondroplasia (ACH), the most frequent form of dwarfism, where cartilages are severely disturbed causing long bones, cranial base and vertebrae defects. Because mandibular development and growth rely on cartilages that guide or directly participate to the ossification process, we investigated the impact of FGFR3 mutations on mandibular shape, size and position. By using CT scan imaging of ACH children and by analyzing Fgfr3(Y367C/+) mice, a model of ACH, we show that FGFR3 gain-of-function mutations lead to structural anomalies of primary (Meckel's) and secondary (condylar) cartilages of the mandible, resulting in mandibular hypoplasia and dysmorphogenesis. These defects are likely related to a defective chondrocyte proliferation and differentiation and pan-FGFR tyrosine kinase inhibitor NVP-BGJ398 corrects Meckel's and condylar cartilages defects ex vivo. Moreover, we show that low dose of NVP-BGJ398 improves in vivo condyle growth and corrects dysmorphologies in Fgfr3(Y367C/+) mice, suggesting that postnatal treatment with NVP-BGJ398 mice might offer a new therapeutic strategy to improve mandible anomalies in ACH and others FGFR3-related disorders. © The Author 2016. Published by Oxford University Press.

  6. Growth hormone treatment in 35 prepubertal children with achondroplasia: a five-year dose-response trial.

    Science.gov (United States)

    Hertel, Niels Thomas; Eklöf, Ole; Ivarsson, Sten; Aronson, Stefan; Westphal, Otto; Sipilä, Ilkka; Kaitila, Ilkka; Bland, Jon; Veimo, Dag; Müller, Jørn; Mohnike, Klaus; Neumeyer, Lo; Ritzen, Martin; Hagenäs, Lars

    2005-10-01

    Achondroplasia is a skeletal dysplasia with extreme, disproportionate, short stature. In a 5-y growth hormone (GH) treatment study including 1 y without treatment, we investigated growth and body proportion response in 35 children with achondroplasia. Patients were randomized to either 0.1 IU/kg (n = 18) or 0.2 IU/kg (n = 17) per day. GH treatment was interrupted for 12 mo after 2 y of treatment in prepubertal patients to study catch-down growth. Mean height SDS (HSDS) at start was -5.6 and -5.2 for the low- and high-dose groups, respectively, and mean age 7.3 and 6.6 y. Mean growth velocity (baseline 4.5/4.6 cm/y for the groups) increased significantly by 1.9/3.6 cm/y during the first year and by 0.5/1.5 cm/y during the second year. During the third year, a decrease of growth velocity was observed at 1.9/1.3 cm/y below baseline values. HSDS increased significantly by 0.6/0.8 during the first year of treatment and in total by 1.3/1.6 during the 5 y of study. Sitting height SDS improved significantly from -2.1/-1.7 to -0.8/0.2 during the study. Body proportion (sitting height/total height) or arm span did not show any significant change. GH treatment of children with achondroplasia improves height during 4 y of therapy without adverse effect on trunk-leg disproportion. The short-term effect is comparable to that reported in Turner and Noonan syndrome and in idiopathic short stature.

  7. Ser217Cys mutation in the Ig Ⅱ domain of FGFR3 in a Chinese family with autosomal dominant achondroplasia

    Institute of Scientific and Technical Information of China (English)

    ZHANG Shi-rong; ZHOU Xiao-qing; REN Xiang; WANG Tian-tian; YUAN Ming-xiong; WANG Qing; LIU Jing-yu; LIU Mu-gen

    2007-01-01

    @@ Achondroplasia (ACH) is the most common form of skeletal dysplasia characterized by disproportionately short stature, lumbar lordosis, relative macrocephaly and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. The combined frequency of the disease has been estimated to be 1 in 15 000 live births.1 ACH is inherited in autosomal dominant fashion with a complete penetrance, more than 80% of affected individuals have de novo mutations associated with increased paternal age.

  8. Prenatal and postnatal presentation of severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) due to the FGFR3 Lys650Met mutation.

    NARCIS (Netherlands)

    Zankl, A.; Elakis, G.; Susman, R.D.; Inglis, G.; Gardener, G.; Buckley, M.F.; Roscioli, T.

    2008-01-01

    We present prenatal and postnatal features of a patient with severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). Mutation analysis confirmed the clinical diagnosis by detecting the FGFR3 Lys650Met mutation. This case, one of only six with molecular analysis reported in

  9. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta.

    Science.gov (United States)

    Orioli, I M; Castilla, E E; Scarano, G; Mastroiacovo, P

    1995-11-01

    The paternal ages of nonfamilial cases of achondroplasia (AC) (n = 78), thanatophoric dysplasia (TD) (n = 64), and osteogenesis imperfecta (OI) (n = 106), were compared with those of matched controls, from an Italian Indagine Policentrica Italiana sulle Malformazioni Congenite and a South American Estudio Colaborativo Latinoamericano de Malformaciones Congénitas series. The degree of paternal age effect on the origin of these dominant mutations differed among the three conditions. Mean paternal age was highly elevated in AC, 36.30 +/- 6.74 years in the IPIMC, and 37.19 +/- 10.53 years in the ECLAMC; less consistently elevated in TD, 33.60 +/- 7.08 years in the IPIMC, and 36.41 +/- 9.38 years in the ECLAMC; and only slightly elevated in OI in the ECLAMC, 31.15 +/- 9.25 years, but not in the IPIMC, 32.26 +/- 6.07 years. Increased maternal age or birth order in these conditions disappeared when corrected for paternal age. Approximately 50% of AC and TD cases, and only 30% of OI cases, were born to fathers above age 35 years. For AC and TD, the increase in relative incidence with paternal age fitted an exponential curve. The variability of paternal age effect in these new mutations could be due, among other reasons, to the high proportion of germ-line mosaicism in OI parents, or to the localization of the AC gene, mapped to the 4p16.3 region, in the neighborhood of an unstable DNA area.

  10. Acanthosis nigricans and insulin sensitivity in patients with achondroplasia and hypochodroplasia due to FGFR3 mutations.

    Science.gov (United States)

    Alatzoglou, Kyriaki S; Hindmarsh, Peter C; Brain, Caroline; Torpiano, John; Dattani, Mehul T

    2009-10-01

    Acanthosis nigricans (AN) has been reported in association with severe skeletal dysplasias due to activating mutations in FGFR3, including thanatophoric dysplasia, severe achondroplasia (ACH) with developmental delay and AN (SADDAN syndrome), and Crouzon syndrome with AN. There are isolated reports of patients with ACH and AN. In this series, we report clinical and biochemical data on five male patients, four with ACH and one with hypochondroplasia (HCH), who developed AN without SADDAN. We compared the results of a 1.75 g/kg oral glucose tolerance test performed in patients with ACH/HCH and AN with age-, sex-, and puberty-matched short children. Three of the patients were treated with recombinant human GH (dose range, 45-50 microg/kg/d), one patient had discontinued treatment 6 months before presentation, and one had never been treated. All patients had a fasting plasma glucose of less than 6 mmol/liter, and no patient had a plasma glucose greater than 7.8 mmol/liter at 2 h after ingestion of a glucose load. Although body mass index was higher in patients with skeletal dysplasia (28.9 +/- 7.3 vs. 20 +/- 0.6 kg/m(2); P = 0.01), mean fasting plasma insulin concentration was greater in controls (14.4 +/- 4.8 vs. 6.0 +/- 4.5 mU/liter; P = 0.03), as was homeostasis assessment index for insulin resistance (2.5 +/- 0.9 vs. 1.17 +/- 0.8; P = 0.05). Our findings suggest that the development of AN in patients with ACH/HCH is not due to insulin insensitivity either on its own or secondary to treatment with recombinant human GH. Whether the AN is due to altered melanocyte function in these individuals remains to be established.

  11. Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia.

    Science.gov (United States)

    Matsushita, Masaki; Kitoh, Hiroshi; Ohkawara, Bisei; Mishima, Kenichi; Kaneko, Hiroshi; Ito, Mikako; Masuda, Akio; Ishiguro, Naoki; Ohno, Kinji

    2013-01-01

    Achondroplasia (ACH) is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR3 encoding the fibroblast growth factor receptor 3. We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR3 signaling in ACH. We found that meclozine, an anti-histamine drug that has long been used for motion sickness, facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF2-treated rat chondrosarcoma (RCS) cells. Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS-2/8) cells that were infected with lentivirus expressing constitutively active mutants of FGFR3-K650E causing thanatophoric dysplasia, FGFR3-K650M causing SADDAN, and FGFR3-G380R causing ACH. Similarly, meclozine alleviated abnormally suppressed differentiation of ATDC5 chondrogenic cells expressing FGFR3-K650E and -G380R in micromass culture. We also confirmed that meclozine alleviates FGF2-mediated longitudinal growth inhibition of embryonic tibia in bone explant culture. Interestingly, meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF2 treatment. Analyses of intracellular FGFR3 signaling disclosed that meclozine downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells. Similarly, meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK, which suggests that meclozine downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation. We used the C-natriuretic peptide (CNP) as a potent inhibitor of the FGFR3 signaling throughout our experiments, and found that meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling. We propose that meclozine is a potential therapeutic agent for treating ACH and other FGFR3-related skeletal dysplasias.

  12. Maternal administration of meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia.

    Science.gov (United States)

    Matsushita, Masaki; Mishima, Kenichi; Esaki, Ryusaku; Ishiguro, Naoki; Ohno, Kinji; Kitoh, Hiroshi

    2017-01-01

    OBJECTIVE Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum stenosis (FMS) is one of the serious neurological complications in ACH. Through comprehensive drug screening, the authors identified that meclozine, an over-the-counter drug for motion sickness, inhibited activation of FGFR3 signaling. Oral administration of meclozine to the growing ACH mice promoted longitudinal bone growth, but it did not prevent FMS. In the current study, the authors evaluated the effects of maternal administration of meclozine on FMS in ACH mice. METHODS The area of the foramen magnum was measured in 17-day-old Fgfr3(ach) mice and wild-type mice using micro-CT scanning. Meclozine was administered to the pregnant mice carrying Fgfr3(ach) offspring from embryonic Day (ED) 14.5 to postnatal Day (PD) 4.5. Spheno-occipital and anterior intraoccipital synchondroses were histologically examined, and the bony bridges were scored on PD 4.5. In wild-type mice, tissue concentrations of meclozine in ED 17.5 fetuses and PD 6.5 pups were investigated. RESULTS The area of the foramen magnum was significantly smaller in 17-day-old Fgfr3(ach) mice than in wild-type mice (p treatment (p = 0.12). The average tissue concentration of meclozine was significantly higher (508.88 ± 205.16 ng/g) in PD 6.5 mice than in ED 17.5 mice (56.91 ± 20.05 ng/g) (p < 0.005). CONCLUSIONS Maternal administration of meclozine postponed premature closure of synchondroses in some Fgfr3(ach) mice, but the effect on preventing bony bridge formation was not significant, probably due to low placental transmission of the drug. Meclozine is likely to exhibit a marginal effect on premature closure of synchondroses at the cranial base in ACH.

  13. Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia.

    Directory of Open Access Journals (Sweden)

    Masaki Matsushita

    Full Text Available Achondroplasia (ACH is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR3 encoding the fibroblast growth factor receptor 3. We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR3 signaling in ACH. We found that meclozine, an anti-histamine drug that has long been used for motion sickness, facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF2-treated rat chondrosarcoma (RCS cells. Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS-2/8 cells that were infected with lentivirus expressing constitutively active mutants of FGFR3-K650E causing thanatophoric dysplasia, FGFR3-K650M causing SADDAN, and FGFR3-G380R causing ACH. Similarly, meclozine alleviated abnormally suppressed differentiation of ATDC5 chondrogenic cells expressing FGFR3-K650E and -G380R in micromass culture. We also confirmed that meclozine alleviates FGF2-mediated longitudinal growth inhibition of embryonic tibia in bone explant culture. Interestingly, meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF2 treatment. Analyses of intracellular FGFR3 signaling disclosed that meclozine downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells. Similarly, meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK, which suggests that meclozine downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation. We used the C-natriuretic peptide (CNP as a potent inhibitor of the FGFR3 signaling throughout our experiments, and found that meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling. We propose that meclozine is a potential therapeutic agent for treating ACH and other FGFR3-related skeletal dysplasias.

  14. Analysis of the clinical and molecular characteristics of a child with achondroplasia: A case report

    Science.gov (United States)

    LIU, JINGFANG; TANG, XULEI; CHENG, JIANGUO; WANG, LITING; YANG, XIAOMEI; WANG, YAN

    2015-01-01

    Achondroplasia (ACH) is a hereditary dwarfism caused by the disturbed proliferation and differentiation of growth plate chondrocytes, followed by impaired endochondral bone growth. ACH is caused by mutations in the gene encoding the transmembrane receptor, fibroblast growth factor receptor 3 (FGFR3). In total, >90% of patients with ACH have a G1138A mutation in the transmembrane domain of the FGFR3 gene. Patients with ACH usually have no growth hormone (GH) deficiency. The current study presents the case of a four-year-old male with clinical manifestations suggestive of ACH, including a large head, prominent forehead, short upper arms and legs, and short hands with fingers assuming a trident position. The patient showed normal responses to GH provocation tests with L-dopa (peak GH concentration, 42.38 ng/ml) and insulin (peak GH concentration, 23.29 ng/ml during hypoglycemia), but a blunted response to a GH provocation test with arginine (peak GH concentration, 7.31 ng/ml). Furthermore, the GH concentration during exercise was low (4.8 ng/ml). Magnetic resonance imaging revealed a decreased pituitary volume. Thyroid function tests and the levels of sex hormones (follicle stimulating hormone, luteinizing hormone, estradiol, prolactin and progesterone), cortisol and adrenocorticotropic hormone were normal. A heterozygous G1138A mutation within the FGFR3 gene was detected, confirming the diagnosis of ACH. Thus, recombinant human GH therapy (0.1 IU/kg/day) was initiated. At the six-month follow-up, the height, arm span-to-height ratio and lower limb length-to-height ratio of the patient had increased, while the head circumference had decreased. The present results corroborate the finding that the G1138A mutation within FGFR3 is the most common ACH-causing mutation in different populations. GH may be beneficial in the treatment of short stature in ACH patients with subnormal GH secretion. PMID:26136890

  15. New evidence for positive selection helps explain the paternal age effect observed in achondroplasia.

    Science.gov (United States)

    Shinde, Deepali N; Elmer, Dominik P; Calabrese, Peter; Boulanger, Jérôme; Arnheim, Norman; Tiemann-Boege, Irene

    2013-10-15

    There are certain de novo germline mutations associated with genetic disorders whose mutation rates per generation are orders of magnitude higher than the genome average. Moreover, these mutations occur exclusively in the male germ line and older men have a higher probability of having an affected child than younger ones, known as the paternal age effect (PAE). The classic example of a genetic disorder exhibiting a PAE is achondroplasia, caused predominantly by a single-nucleotide substitution (c.1138G>A) in FGFR3. To elucidate what mechanisms might be driving the high frequency of this mutation in the male germline, we examined the spatial distribution of the c.1138G>A substitution in a testis from an 80-year-old unaffected man. Using a technology based on bead-emulsion amplification, we were able to measure mutation frequencies in 192 individual pieces of the dissected testis with a false-positive rate lower than 2.7 × 10(-6). We observed that most mutations are clustered in a few pieces with 95% of all mutations occurring in 27% of the total testis. Using computational simulations, we rejected the model proposing an elevated mutation rate per cell division at this nucleotide site. Instead, we determined that the observed mutation distribution fits a germline selection model, where mutant spermatogonial stem cells have a proliferative advantage over unmutated cells. Combined with data on several other PAE mutations, our results support the idea that the PAE, associated with a number of Mendelian disorders, may be explained primarily by a selective mechanism.

  16. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta

    Energy Technology Data Exchange (ETDEWEB)

    Orioli, I.M. [Universidade Federal do Rio de Janeiro (Brazil); Castilla, E.E. [Centro de Educacion Medica e Investigacion Clinica, Buenos Aires (Argentina); Scarano, G.; Mastroiacovo, P. [Universita Cattolica, Rome (Italy)

    1995-11-06

    The paternal ages of nonfamilial cases of achondroplasia (AC) (n = 78), thanatophoric dysplasia (TD) (n = 64), and osteogenesis imperfecta (OI) (n = 106), were compared with those of matched controls, from an Italian Indagine Policentrica Italiana sulle Malformazioni Congenite (IPIMC) and a South American Estudio Colaborativo Latinoamericano de Malformaciones Congenitas (ECLAMC) series. The degree of paternal age effect on the origin of these dominant mutations differed among the three conditions. Mean paternal age was highly elevated in AC, 36.30 {plus_minus} 6.74 years in the IPIMC, and 37.19 {plus_minus} 10.53 years in the ECLAMC; less consistently elevated in TD, 33.60 {plus_minus} 7.08 years in the IPIMC, and 36.41 {plus_minus} 9.38 years in the ECLAMC; and only slightly elevated in OI in the ECLAMC, 31.15 {plus_minus} 9.25 years, but not in the IPIMC, 32.26 {plus_minus} 6.07 years. Increased maternal age or birth order in these conditions disappeared when corrected for paternal age. Approximately 50% of AC and TD cases, and only 30% of OI cases, were born to fathers above age 35 years. For AC and TD, the increase in relative incidence with paternal age fitted an exponential curve. The variability of paternal age effect in these new mutations could be due, among other reasons, to the high proportion of germ-line mosaicism in OI parents, or to the localization of the AC gene, mapped to the 4p16.3 region, in the neighborhood of an unstable DNA area. 28 refs., 1 fig., 6 tabs.

  17. Localisation of the gene for achondroplasia to the telomeric region of chromosome 4p

    Energy Technology Data Exchange (ETDEWEB)

    Stoilov, I.; Velinov, M.; Kilpatrick, M.W. [and others

    1994-09-01

    Achondroplasia (ACH), the most common type of genetic dwarfism, is characterized by a variety of skeletal anomalies including disproportionate short stature and rhizomelic shortening of the extremities. The disorder is inherited as an autosomal dominant trait, with a prevalence of 1-15 per 100,000 live births. The etiology of ACH remains unknown, although evidence points to a defect in the maturation of the chondrocytes in the growth plate of the cartilage. To determine the location of the gene responsible for ACH, a panel of 14 families with a total of 43 meioses was genotyped for 40 polymorphic markers for loci randomly distributed throughout the genome. The first significant positive Lod score was obtained for the locus D4S127 (Zmax=3.65 at {theta}=0.03). A series of 20 markers for chromosome 4p16.3 loci were then used to determine the most likely position of the ACH gene. Two additional loci, D4S412 and IDUA, showed strong linkage to the disease (Zmax=3.34 at {theta}=0.03 and Zmax=3.35 at {theta}=0.0, respectively). Multipoint analysis and direct counting of recombinants places the ACH gene in a 2.5 cM region between the marker D4S43 and the chromosome 4p telomere. No evidence was found for genetic heterogeneity. The ACH region contains a number of genes, including that for the fibroblast growth factor receptor FGFR3, which are being evaluated as candidates for the ACH gene. This identification of tightly linked polymorphic markers, as well as being the first step in the characterization of the ACH gene, offers the possibility of DNA based prenatal diagnosis of this disorder.

  18. Analysis of callus pattern of tibia lengthening in achondroplasia and a novel method of regeneration assessment using pixel values

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Suryaudai; Song, Hae-Ryong; Venkatesh, K.P.; Modi, Hitesh N.; Jang, Ki-Mo; Kim, Seung J. [Korea University Guro Hospital, Rare Diseases Institute, Department of Orthopedic Surgery, Seoul (Korea); Park, Man Sik [Korea University, Department of Biostatistics, College of Medicine, Seoul (Korea)

    2010-03-15

    To relate morphology of new bone formation to outcome after tibial lengthening performed in patients with achondroplasia. A retrospective analysis of 60 tibial segments in 30 achondroplasia patients was performed. There were 22 female patients and eight male patients, with a mean age of 9.8 years. New bone formation was classified by shape, homogeneity and density. Pixel values in relation to original bone were measured using a picture-archiving communication system (PACS). Clinical outcome was described by the external fixator and maturation indices. Mean lengthening was 9.2 cm (range 3-12.7 cm). The mean external fixator index was 23.4 (range 15.1-50). The mean maturation index was 12.3 days/cm (range 6-40 days/cm). Homogeneous pathways were associated with the best clinical results (fixator index 20.4, maturation index 10.8), followed by heterogeneous pathway (external fixator index 26.5, maturation index 16.8) and radiolucent pathway (fixator index 31.2, maturation index 21.4). Both cylindrical (external fixator index 25.2, maturation index 14.5) and concave (external fixator index 26.6, maturation index 16.3) callus shapes were favourable. Mineralization of new bone became equal to that of normal bone within 16 weeks (mean) for homogeneous pathway, 12 weeks for heterogeneous pathway and 32 weeks for lucent pathway. The type of new bone formation seen on radiographs is related to clinical outcome, with homogeneous pathways being the most favourable ones. (orig.)

  19. A simple and rapid quantitative method of detection of the common achondroplasia mutation: Analysis in mismatch repair deficient cells

    Directory of Open Access Journals (Sweden)

    Grewal Raji

    2004-01-01

    Full Text Available Achondroplasia is the most common form of dwarfism and has an incidence of approximately 1/7,500. In more than 97% of cases, it is caused by a recurrent point mutation, a G to A substitution at nucleotide position 1138 (G1138A of the fibroblast growth factor receptor 3 gene. Although this is an autosomal dominant condition, more than 90% of all mutations occur sporadically making this one of the most mutagenic sites in the human genome. The reasons for the high spontaneous G1138A mutation rate are not known. This investigation was performed by developing a simple and rapid semi-quantitative allele specific PCR based assay capable of reliably detecting more than 25 mutant G1138A copies in a pool of 300,000 wild type molecules. Using this assay, the G1138A mutation frequency was measured in cell lines deficient in mismatch repair (LoVo, SW48 and comparing it with controls. No differences were found in the frequency of this point mutation between the mismatch repair deficient and wild type cell lines.

  20. Lower limb lengthening in patients with disproportionate short stature with achondroplasia: a systematic review of the last 20 years.

    Science.gov (United States)

    Schiedel, Frank; Rödl, Robert

    2012-01-01

    Parents of children suffering from disproportionate short stature due to achondroplasia may wish to have surgical leg lengthening carried out for the child. The aim is not to increase height, but rather to achieve physiological proportions in the body. In a systematic review of the literature on the topic dating from the last 20 years, the surgical approaches used for this purpose were analyzed in accordance with the Preferred reporting items for systematic reviews and meta-analyses (PRISMA) criteria. Twelve studies show that to date, involvement of the child in decision-making at the start of treatment has been expected and that it is recommended from the age of 12. In highly heterogeneous patient groups, with varying factors involved and different techniques being used, lengthening (often by more than 10 cm) is described. High complication rates are reported, with many setbacks often requiring repeat surgery. Using PALEY'S multiplier method, the expected standing height, sitting height, and leg length can be predicted and an individualized treatment approach can be planned and operative procedures could be started in early childhood as PERETTI suggests. As the patients are unable to be involved in decision-making as young children, these data may provide a basis for offering differentiated advice to parents, who usually consult a pediatric orthopedist at a very early stage in the child's life.

  1. Serum NT-proCNP levels increased after initiation of GH treatment in patients with achondroplasia/hypochondroplasia.

    Science.gov (United States)

    Kubota, Takuo; Wang, Wei; Miura, Kohji; Nakayama, Hirofumi; Yamamoto, Keiko; Fujiwara, Makoto; Ohata, Yasuhisa; Tachibana, Makiko; Kitaoka, Taichi; Takakuwa, Satoshi; Miyoshi, Yoko; Namba, Noriyuki; Ozono, Keiichi

    2016-06-01

    Serum amino-terminal propeptide of C-type natriuretic peptide (NT-proCNP) levels have been proposed as a biomarker of linear growth in healthy children. The usefulness of NT-proCNP in patients with achondroplasia (ACH)/hypochondroplasia (HCH) remains to be elucidated. The objective was to study whether serum NT-proCNP level is a good biomarker for growth in ACH/HCH and other patients of short stature. This was a longitudinal cohort study. Sixteen children with ACH (aged 0·4-4·3 years), six children with HCH (2·7-6·3 years), 23 children with idiopathic short stature (ISS) (2·2-9·0 years), eight short children with GH deficiency (GHD) (2·9-6·8 years) and five short children born small for gestational age (SGA) (2·0-6·6 years). Patients with ACH/HCH received GH treatment for 1 year. Serum NT-proCNP levels and height were measured. NT-proCNP levels positively correlated with height velocity in these short children (P treatment (P treatment for 1 year was positively correlated with the changes in NT-proCNP levels after the initiation of GH (P treatment on growth in patients with ACH/HCH at least in the first year and height velocity in short stature patients. © 2016 John Wiley & Sons Ltd.

  2. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia.

    Science.gov (United States)

    Lorget, Florence; Kaci, Nabil; Peng, Jeff; Benoist-Lasselin, Catherine; Mugniery, Emilie; Oppeneer, Todd; Wendt, Dan J; Bell, Sean M; Bullens, Sherry; Bunting, Stuart; Tsuruda, Laurie S; O'Neill, Charles A; Di Rocco, Federico; Munnich, Arnold; Legeai-Mallet, Laurence

    2012-12-07

    Achondroplasia (ACH), the most common form of dwarfism, is an inherited autosomal-dominant chondrodysplasia caused by a gain-of-function mutation in fibroblast-growth-factor-receptor 3 (FGFR3). C-type natriuretic peptide (CNP) antagonizes FGFR3 downstream signaling by inhibiting the pathway of mitogen-activated protein kinase (MAPK). Here, we report the pharmacological activity of a 39 amino acid CNP analog (BMN 111) with an extended plasma half-life due to its resistance to neutral-endopeptidase (NEP) digestion. In ACH human growth-plate chondrocytes, we demonstrated a decrease in the phosphorylation of extracellular-signal-regulated kinases 1 and 2, confirming that this CNP analog inhibits fibroblast-growth-factor-mediated MAPK activation. Concomitantly, we analyzed the phenotype of Fgfr3(Y367C/+) mice and showed the presence of ACH-related clinical features in this mouse model. We found that in Fgfr3(Y367C/+) mice, treatment with this CNP analog led to a significant recovery of bone growth. We observed an increase in the axial and appendicular skeleton lengths, and improvements in dwarfism-related clinical features included flattening of the skull, reduced crossbite, straightening of the tibias and femurs, and correction of the growth-plate defect. Thus, our results provide the proof of concept that BMN 111, a NEP-resistant CNP analog, might benefit individuals with ACH and hypochondroplasia. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  3. Limb lengthening in achondroplasia

    Directory of Open Access Journals (Sweden)

    Sanjay K Chilbule

    2016-01-01

    Full Text Available Background: Stature lengthening in skeletal dysplasia is a contentious issue. Specific guidelines regarding the age and sequence of surgery, methods and extent of lengthening at each stage are not uniform around the world. Despite the need for multiple surgeries, with their attendant complications, parents demanding stature lengthening are not rare, due to the social bias and psychological effects experienced by these patients. This study describes the outcome and complications of extensive stature lengthening performed at our center. Materials and Methods: Eight achondroplasic and one hypochondroplasic patient underwent bilateral transverse lengthening for tibiae, humeri and femora. Tibia lengthening was carried out using a ring fixator and bifocal corticotomy, while a monolateral pediatric limb reconstruction system with unifocal corticotomy was used for the femur and humerus. Lengthening of each bone segment, height gain, healing index and complications were assessed. Subgroup analysis was carried out to assess the effect of age and bone segment on the healing index. Results: Nine patients aged five to 25 years (mean age 10.2 years underwent limb lengthening procedures for 18 tibiae, 10 femora and 8 humeri. Four patients underwent bilateral lengthening of all three segments. The mean length gain for the tibia, femur and humerus was 15.4 cm (100.7%, 9.9 cm (52.8% and 9.6 cm (77.9%, respectively. Healing index was 25.7, 25.6 and 20.6 days/cm, respectively, for the tibia, femur and humerus. An average of 33.3% height gain was attained. Lengthening of both tibia and femur added to projected height achieved as the 3 rd percentile of standard height in three out of four patients. In all, 33 complications were encountered (0.9 complications per segment. Healing index was not affected by age or bone segment. Conclusion: Extensive limb lengthening (more than 50% over initial length carries significant risk and should be undertaken only after due consideration.

  4. Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia.

    Science.gov (United States)

    Xie, Yangli; Su, Nan; Jin, Min; Qi, Huabing; Yang, Junbao; Li, Can; Du, Xiaolan; Luo, Fengtao; Chen, Bo; Shen, Yue; Huang, Haiyang; Xian, Cory J; Deng, Chuxia; Chen, Lin

    2012-09-15

    Achondroplasia (ACH) and thanatophoric dysplasia (TD) are caused by gain-of-function mutations of fibroblast growth factor receptor 3 (FGFR3) and they are the most common forms of dwarfism and lethal dwarfism, respectively. Currently, there are few effective treatments for ACH. For the neonatal lethality of TD patients, no practical effective therapies are available. We here showed that systemic intermittent PTH (1-34) injection can rescue the lethal phenotype of TD type II (TDII) mice and significantly alleviate the retarded skeleton development of ACH mice. PTH-treated ACH mice had longer naso-anal length than ACH control mice, and the bone lengths of humeri and tibiae were rescued to be comparable with those of wild-type control mice. Our study also found that the premature fusion of cranial synchondroses in ACH mice was partially corrected after the PTH (1-34) treatment, suggesting that the PTH treatment may rescue the progressive narrowing of neurocentral synchondroses that cannot be readily corrected by surgery. In addition, we found that the PTH treatment can improve the osteopenia and bone structure of ACH mice. The increased expression of PTHrP and down-regulated FGFR3 level may be responsible for the positive effects of PTH on bone phenotype of ACH and TDII mice.

  5. Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene.

    Science.gov (United States)

    Matsushita, Masaki; Hasegawa, Satoru; Kitoh, Hiroshi; Mori, Kensaku; Ohkawara, Bisei; Yasoda, Akihiro; Masuda, Akio; Ishiguro, Naoki; Ohno, Kinji

    2015-02-01

    Achondroplasia (ACH) is one of the most common skeletal dysplasias causing short stature owing to a gain-of-function mutation in the FGFR3 gene, which encodes the fibroblast growth factor receptor 3. We found that meclozine, an over-the-counter drug for motion sickness, inhibited elevated FGFR3 signaling in chondrocytic cells. To examine the feasibility of meclozine administration in clinical settings, we investigated the effects of meclozine on ACH model mice carrying the heterozygous Fgfr3(ach) transgene. We quantified the effect of meclozine in bone explant cultures employing limb rudiments isolated from developing embryonic tibiae from Fgfr3(ach) mice. We found that meclozine significantly increased the full-length and cartilaginous primordia of embryonic tibiae isolated from Fgfr3(ach) mice. We next analyzed the skeletal phenotypes of growing Fgfr3(ach) mice and wild-type mice with or without meclozine treatment. In Fgfr3(ach) mice, meclozine significantly increased the body length after 2 weeks of administration. At skeletal maturity, the bone lengths including the cranium, radius, ulna, femur, tibia, and vertebrae were significantly longer in meclozine-treated Fgfr3(ach) mice than in untreated Fgfr3(ach) mice. Interestingly, meclozine also increased bone growth in wild-type mice. The plasma concentration of meclozine during treatment was within the range that has been used in clinical settings for motion sickness. Increased longitudinal bone growth in Fgfr3(ach) mice by oral administration of meclozine in a growth period suggests potential clinical feasibility of meclozine for the improvement of short stature in ACH.

  6. 儿童和青少年软骨发育不全侏儒症双下肢延长术%Bilateral Lengthening of the Lower Limbs in Children and Adolescences with A-chondroplasia

    Institute of Scientific and Technical Information of China (English)

    俞宏亮; 马亮; 赵立登; 席光宝; 劳继军

    1993-01-01

    1984年6月至1990年12月,采用双侧下肢延长术治疗25例软骨发育不全侏儒患者.男16例,女9例.年龄9~15岁,平均12岁.术前身高平均121cm,术后双侧胫骨骨延长长度为4.5~22cm,平均14.5cm.股骨延长长度为16cm.胫骨骨愈合时间为150~421天,其中24例平均214天获骨愈合.股骨骨愈合时间为180天.%From June 1984 to December 1990,bilateral lenthening of the lower limbs was performed on patients with achondroplasia.Among them,16 were males and 9 females,age 9 to 15 years.The preoperative heights ranged from 100 to 135 cms.The tibial length were increased postoperatively from a minimum of 4.5 cms to a maximum of 22 cms,14.5 cms on average.The ratio between the gained length to the original of the tibia was 25% minimum to 147% maximum,75% on average.The femurs were lengthened by 19 cms on average and made the ratio between the gained length to the original being 88%.Bony union of the lengthened tibia appeared from 150 to 721 days.214 days on average,while the bony union of the femur in 270 days averagely.Comlications included:infection of the pin holes in 6 cases (12 holes),equinus deformity in 8 (16 feet),and delayed union in 1 (bilateral tibiae).There was no neurovascular impairment.

  7. 软骨发育不全家系产前诊断与基因突变分析%Prenatal diagnosis and mutation analysis of fibroblast growth factor receptor 3 gene in achondroplasia

    Institute of Scientific and Technical Information of China (English)

    郝胜菊; 闫有圣; 李静; 郑雷; 张钏; 梁济慈; 陈雪

    2016-01-01

    Objective To explore the value of prenatal genetical diagnosis by mutation analysis of achondroplasia (ACH) fibroblast growth factor receptor 3 (FGFR3) gene.Methods Genomic DNA from nine ACH patients and their parents in Gansu Maternal and Child Health Hospital from July,2010 to December,2014 was prepared for polymerase chain reaction.Direct sequencing revealed the samples were performed after amplification of exon 10 of FGFR3 containing the potential mutation.Fetal DNA was extracted from cells in both amniotic fluid and umbilical cord,and then exon 10 of FGFR3 was also tested.Three fetuses with short-limb dysplasia were also included and prenatal diagnosis was offered to them through amniocentesis or cordocentesis.Results Prenatal ultrasonography test showed shorter femoral length,which was less than 2-3 standard deviation of normal reference dysplasia fetal performance for femoral short.Femur length is lower than 2-3 standard deviation minus normal value,and discrepancy in biparietal diameter compared with fetuses at the same gestational age.In the four families with one ACH parent,c.1138G > A heterozygous mutation was detected in all of the four mothers,while two fetuses among them showed c.1138G > A heterozygous mutation mutation and the other two were normal.There were other two fetuses with c.1138G > A heterozygous mutation from other two families,one's father had c.1138G > A heterozygous mutations,but not the mother,the other had c.1138G > A heterozygous mutations in both the mother and father.Among the three families with unaffected parents but each had a de novo c.1138G > A mutation child,no mutation of c.1138G > A genotype was detected in their fetuses,neither in the three fetus with short limb dysplasia.Four fetuses with a c.1138G > A mutation and three with short-limb dysplasia were terminated.The other five fetuses whose genotype was normal were born and healthy with normal phenotype at one-year-old follow-up.Conclusion FGFR3 genetic

  8. HDAC6 deficiency or inhibition blocks FGFR3 accumulation and improves bone growth in a model of achondroplasia.

    Science.gov (United States)

    Ota, Sara; Zhou, Zi-Qiang; Romero, Megan P; Yang, Guang; Hurlin, Peter J

    2016-10-01

    Mutations that cause increased and/or inappropriate activation of FGFR3 are responsible for a collection of short-limbed chondrodysplasias. These mutations can alter receptor trafficking and enhance receptor stability, leading to increased receptor accumulation and activity. Here, we show that wildtype and mutant activated forms of FGFR3 increase expression of the cytoplasmic deacetylase HDAC6 (Histone Deacetylase 6) and that FGFR3 accumulation is compromised in cells lacking HDAC6 or following treatment of fibroblasts or chondrocytes with small molecule inhibitors of HDAC6. The reduced accumulation of FGFR3 was linked to increased FGFR3 degradation that occurred through a lysosome-dependent mechanism. Using a mouse model of Thanatophoric Dysplasia Type II (TDII) we show that both HDAC6 deletion and treatment with the small molecule HDAC6 inhibitor tubacin reduced FGFR3 accumulation in the growth plate and improved endochondral bone growth. Defective endochondral growth in TDII is associated with reduced proliferation and poor hypertrophic differentiation and the improved bone growth was associated with increased chondrocyte proliferation and expansion of the differentiation compartment within the growth plate. These findings further define the mechanisms that control FGFR3 accumulation and contribute to skeletal pathology caused by mutations in FGFR3. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. ANÁLISIS MUTACIONAL DE LA ACONDROPLASIA EN 20 PACIENTES COLOMBIANOS Mutational analysis of achondroplasia in 20 Colombian patients

    OpenAIRE

    Ángela Castro; Andrés Gutiérrez; Luisa Fernanda Rodríguez; Pineda Tatiana; Harvy Velasco; Clara Arteaga; Hugo Sotomayor; Alejandro Giraldo

    2010-01-01

    Antecedentes. La acondroplasia es la más común de las displasias esqueléticas. Se trata de una enfermedad autosómica dominante con penetrancia completa. Esta enfermedad se debe a una mutación en el gen del receptor 3 del factor de crecimiento fibroblástico (FGFR3). El 90% o más de los casos se deben a mutaciones nuevas que se originan en las células germinales de padres sanos, asociada a una edad incrementada. Se ha calculado una frecuencia al nacimiento de 1:10.000 a 1:30.000. En la mayoría ...

  10. Effects of diadenosine tetraphosphate on FGF9-induced chloride flux changes in achondroplastic chondrocytes

    OpenAIRE

    Huete, Fernando; Guzman-Aranguez, Ana; Ortín, Javier; Hoyle, Charles H. V.; Pintor, Jesús

    2011-01-01

    Achondroplasia, the most common type of dwarfism, is characterized by a mutation in the fibroblast growth factor receptor 3 (FGFR3). Achondroplasia is an orphan pathology with no pharmacological treatment so far. However, the possibility of using the dinucleotide diadenosine tetraphosphate (Ap4A) with therapeutic purposes in achondroplasia has been previously suggested. The pathogenesis involves the constitutive activation of FGFR3, resulting in altered biochemical and physiological processes...

  11. Impairment of the transition from proliferative stage to prehypertrophic stage in chondrogenic differentiation of human induced pluripotent stem cells harboring the causative mutation of achondroplasia in fibroblast growth factor receptor 3

    Directory of Open Access Journals (Sweden)

    Naohiro Horie

    2017-06-01

    Conclusions: These results suggested that chondrocyte maturation was impaired between the proliferative stage and prehypertrophic stage in the chondrocytes of ACH. The development of chemical compounds which affect the specific maturation stage of chondrocytes is expected to contribute to the ACH treatment, and FGFR3 genome-edited hiPSCs will be a valuable tool in such research studies.

  12. 501 Case studies.indd

    African Journals Online (AJOL)

    grade of I. The mentohyoid and mentothyroid distance were unremarkable. ... PVC endotracheal tube. The endotracheal tube was fixed ... intubation in achondroplasia have been reported.13–17. Short stature ... of known predictors. Fibreoptic ...

  13. Polyhydramnios

    Science.gov (United States)

    ... system problems, such as anencephaly and myotonic dystrophy Achondroplasia Beckwith-Wiedemann syndrome It can also happen if ... health of the mother and baby and give treatment if needed. Images Polyhydramnios References Carlo WA. High- ...

  14. Short stature

    Science.gov (United States)

    ... condition. Bone or skeletal disorders, such as: Rickets Achondroplasia Chronic diseases, such as: Asthma Celiac disease Congenital ... growth seems slow or your child seems small. TREATMENT Your child's short stature may affect her self- ...

  15. SAJCH 448 NEW.indd

    African Journals Online (AJOL)

    Holistic care for patients involves not only treating their biological or physical ... However, if one parent has achondroplasia, there is a 50% risk in each pregnancy ... immense benefit such activities have for families with rare genetic conditions.

  16. Genetic inactivation of ERK1 and ERK2 in chondrocytes promotes bone growth and enlarges the spinal canal

    OpenAIRE

    Sebastian, Arjun; Matsushita, Takehiko; Kawanami, Aya; Mackem, Susan; Landreth, Gary; Murakami, Shunichi

    2010-01-01

    Activating mutations in FGFR3 cause the most common forms of human dwarfism: achondroplasia and thanatophoric dysplasia. In mouse models of achondroplasia, recent studies have implicated the ERK MAPK pathway, a pathway activated by FGFR3, in creating reduced bone growth. Our recent studies have indicated that increased Fgfr3 and ERK MAPK signaling in chondrocytes also causes premature synchondrosis closure in the cranial base and vertebrae, accounting for the sometimes fatal stenosis of the f...

  17. FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway

    OpenAIRE

    Matsushita, Takehiko; Wilcox, William R.; Chan, Yuk Yu; Kawanami, Aya; Bükülmez, Hülya; Balmes, Gener; Krejci, Pavel; Mekikian, Pertchoui B.; Otani, Kazuyuki; Yamaura, Isakichi; Warman, Matthew L.; Givol, David; Murakami, Shunichi

    2008-01-01

    Activating mutations in FGFR3 cause achondroplasia and thanatophoric dysplasia, the most common human skeletal dysplasias. In these disorders, spinal canal and foramen magnum stenosis can cause serious neurologic complications. Here, we provide evidence that FGFR3 and MAPK signaling in chondrocytes promote synchondrosis closure and fusion of ossification centers. We observed premature synchondrosis closure in the spine and cranial base in human cases of homozygous achondroplasia and thanatoph...

  18. FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway

    Science.gov (United States)

    Matsushita, Takehiko; Wilcox, William R.; Chan, Yuk Yu; Kawanami, Aya; Bükülmez, Hülya; Balmes, Gener; Krejci, Pavel; Mekikian, Pertchoui B.; Otani, Kazuyuki; Yamaura, Isakichi; Warman, Matthew L.; Givol, David; Murakami, Shunichi

    2009-01-01

    Activating mutations in FGFR3 cause achondroplasia and thanatophoric dysplasia, the most common human skeletal dysplasias. In these disorders, spinal canal and foramen magnum stenosis can cause serious neurologic complications. Here, we provide evidence that FGFR3 and MAPK signaling in chondrocytes promote synchondrosis closure and fusion of ossification centers. We observed premature synchondrosis closure in the spine and cranial base in human cases of homozygous achondroplasia and thanatophoric dysplasia as well as in mouse models of achondroplasia. In both species, premature synchondrosis closure was associated with increased bone formation. Chondrocyte-specific activation of Fgfr3 in mice induced premature synchondrosis closure and enhanced osteoblast differentiation around synchondroses. FGF signaling in chondrocytes increases Bmp ligand mRNA expression and decreases Bmp antagonist mRNA expression in a MAPK-dependent manner, suggesting a role for Bmp signaling in the increased bone formation. The enhanced bone formation would accelerate the fusion of ossification centers and limit the endochondral bone growth. Spinal canal and foramen magnum stenosis in heterozygous achondroplasia patients, therefore, may occur through premature synchondrosis closure. If this is the case, then any growth-promoting treatment for these complications of achondroplasia must precede the timing of the synchondrosis closure. PMID:18923003

  19. An achondroplasic case with foramen magnum stenosis, hydrocephaly, cortical atrophy, respiratory failure and sympathetic dysfunction.

    Science.gov (United States)

    Ozcetin, Mustafa; Arslan, Mehmet Tayip; Karapinar, Bulent

    2012-03-01

    Achondroplasia is a relatively frequent genetic disorder that may lead to limb weakness, motor-mental retardation, hydrocephaly, and respiratory disorders. In this pathology, foramen magnum stenosis and accompanying disorders like respiratory depression is well documented. A 2.5 year-old child with the diagnosis of achondroplasia admitted to our clinic with severe respiratory depression, limb weakness, and motor mental retardation as well as sympathetic dysfunction. In radiologic evaluations, severe foramen magnum stenosis was detected. The patient was operated and posterior fossa decompression was accomplished to prevent compression of respiratory centers and neurons. This case is unique with the narrowest foramen magnum reported up to date and the sympathetic dysfunction which is not reported as a complication in achondroplasic patients. The authors review the relevant literature, focusing on the indications for cervicomedullary decompression in infants with achondroplasia.

  20. Disease: H00505 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H00505 FGFR3-related short limb skeletal dysplasias, including: Achondroplasia; Hypochondroplasia...; Thanatophoric dysplasia, type 1; Thanatophoric dysplasia, type 2; Severe achondroplasia with... developmental delay and acanthosis nigricans (SADDAN) FGFR3-related short limb skeletal dysplasias are a gr...ause these conditions by disrupting endochondral bone growth. Skeletal dysplasia FGFR3 [HSA:2261] [KO:K05094...] ICD-10: Q77.4 MeSH: D013796 OMIM: 100800 146000 187600 187601 PMID:12357475 (description, gene) Cohen MM Jr Some chondrodysplasia

  1. Dwarfism and gigantism in historical picture postcards.

    Science.gov (United States)

    Enderle, A

    1998-05-01

    A collection of 893 historical picture postcards from 1900 to 1935, depicting dwarfs and giants, was analysed from medical and psychosocial viewpoints. In conditions such as 'bird headed dwarfism', achondroplasia, cretinism, so-called Aztecs or pinheads, Grebe chondrodysplasia, and acromegalic gigantism, the disorder could be diagnosed easily. In hypopituitary dwarfism, exact diagnosis was more difficult because of heterogeneity. The most common conditions depicted were pituitary dwarfism and achondroplasia. Most of those with gigantism had pituitary gigantism and acromegaly. Brothers and sisters or parents and their children provided evidence of mendelian inheritance of some of these disorders. The cards suggest that being put on show provided, at least in some cases, social benefits.

  2. 77 FR 52619 - Make Inoperative Exemptions; Retrofit On-Off Switches for Air Bags

    Science.gov (United States)

    2012-08-30

    ... crashes, they were found to cause a small number of fatalities, especially to unrestrained, out-of-position children, in relatively low speed crashes.\\2\\ To address this problem, NHTSA developed a plan that... passenger because of scoliosis, osteoporosis/arthritis; driver because of achondroplasia; or passenger...

  3. 77 FR 33998 - Make Inoperative Exemptions; Retrofit On-Off Switches for Air Bags

    Science.gov (United States)

    2012-06-08

    ... agency. This regulation is only available for motor vehicles manufactured before September 1, 2012. In..., osteoporosis/arthritis; driver because of achondroplasia; or passenger because of Down syndrome and... vehicles. There have been two confirmed air-bag- related adult fatalities in model year 2004 or...

  4. Expert’s comment concerning Grand Rounds case entitled “Surgical treatment of a 180° thoracolumbar fixed kyphosis in a young achondroplastic patient: a one stage ‘in situ’ combined fusion and spinal cord translocation” (by J. C. Aurégan, T. Odent, M. Zerah, J.-P. Padovani and C. Glorion)

    Science.gov (United States)

    2010-01-01

    Abstact An expert comment is provided for the case of an 18-year-old male achondroplastic patient with a severe thoracolumbar kyphosis and spinal stenosis managed with a five level hemilaminotomy, a decancellation osteotomy of the three apical vertebrae and circumferential fusion. A review incidence, presenting symptoms and treatment options for thoracolumbar kyphosis in adults with achondroplasia, is provided. PMID:20798961

  5. FGFR4 Downregulation of Cell Adhesion in Prostate Cancer

    Science.gov (United States)

    2008-09-01

    in Figure 1, all constructs were stably incorporated into 293-RXR cells and were inducible upon treatment with Ponasterone A. Though we had created...through the transmembrane domain, similar to the FGFR3 Gly380Arg mutation responsible for human dwarfism, or achondroplasia . In this model, the FGFR4

  6. Veterans Affairs: Health Care and Benefits for Veterans Exposed to Agent Orange

    Science.gov (United States)

    2010-09-22

    pharynx (including tonsils), or nasal cavity (including ears and sinuses); cancers of the pleura, mediastinum, and other unspecified sites within the...1) Achondroplasia; (2) Cleft lip and cleft palate; (3) Congenital heart disease; (4) Congenital talipes equinovarus (clubfoot); (5) Esophageal and

  7. Preserved fertility in a non-mosaic Klinefelter patient with a mutation in the fibroblast growth factor receptor 3 gene

    DEFF Research Database (Denmark)

    Juul, A; Aksglaede, L; Lund, A M;

    2007-01-01

    receptor 3 (FGFR3) gene, which is a gain-of-function mutation resulting in achondroplasia. The patient had phenotypic characteristics of achondroplasia (e.g. short limbed dwarfism and frontal bossing). Testicular volume was 8 ml at 27 years of age and repeated semen samples showed sperm concentrations of 0...... a child from a spontaneous pregnancy. The observed testicular size and function in our patient contrast the typical findings in classical Klinefelter syndrome. We speculate that the alteration of FGFR3 protein function in our Klinefelter patient alleviated the destruction of the seminiferous tubules...... and may suggest that the fibroblast growth factor family has a pleiotrophic function in human spermatogonia, which physiologically express FGFR3....

  8. Dwarfism and gigantism in historical picture postcards.

    Science.gov (United States)

    Enderle, A

    1998-01-01

    A collection of 893 historical picture postcards from 1900 to 1935, depicting dwarfs and giants, was analysed from medical and psychosocial viewpoints. In conditions such as 'bird headed dwarfism', achondroplasia, cretinism, so-called Aztecs or pinheads, Grebe chondrodysplasia, and acromegalic gigantism, the disorder could be diagnosed easily. In hypopituitary dwarfism, exact diagnosis was more difficult because of heterogeneity. The most common conditions depicted were pituitary dwarfism and achondroplasia. Most of those with gigantism had pituitary gigantism and acromegaly. Brothers and sisters or parents and their children provided evidence of mendelian inheritance of some of these disorders. The cards suggest that being put on show provided, at least in some cases, social benefits. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:9764085

  9. Den molekylaergenetiske baggrund for en raekke arvelige kraniosynostoser og kondrodysplasier

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; juncker, Inger; Christensen, L

    2001-01-01

    genes encoding fibroblast growth factor receptors have been identified, and mutations in three of these, FGFR1, FGFR2, and FGFR3, can cause different congenital, autosomal dominant disorders affecting the craniofacial and skeletal development: craniosynostosis and chondrodysplasias. The craniosynostosis......, ACS. The same mutation can cause different syndromes, and the same syndrome can be caused by mutations in different genes. The chondrodysplasias: achondroplasia, hypochondroplasia, and thanatophoric dysplasia are all caused by mutations in FGFR3....

  10. Not all hypochondroplasia families are linked to chromosome 4p16.3

    Energy Technology Data Exchange (ETDEWEB)

    Rousseau, F.; Munnich, A.; Merrer, M.Le. [INSERM, Paris (France)] [and others

    1994-09-01

    Achondroplasia (ACH, MIM 100800) and hypochondroplasia (HCH, MIM 146000) are short limb dwarfism with enlarged head sharing some specific radiological features. Inter- and intrafamilial clinical variability and histolopathological aspects of the growth cartilage suggested that ACH and HCH are allelic disorders. Recently, the gene for achondroplasia was mapped to chromosome 4p and no recombinants were found in 9 families with hypochondroplasia between D4S111 and the telomere (Zmax=1.70, {theta}=0). By using an additional polymorphic DNA marker which detects VNTR-like polymorphism at the D4S227 locus and a new microsatellite at locus D4S? (AFM163yc1), we observed recombinant events with markers of the chromosome 4p16.3 in 3/10 hypochondroplasia families, indicating that not all hypochondroplasia families are linked to chromosome 4p. A fibroblast growth factor receptor (FGFR3) expressed in chondrocytes during endochondral ossification which is located in the 2.5 Mb candidate region for achondroplasia was regarded as a good candidate gene. No major rearrangement of the FGFR3 gene was detected by Southern blot analysis using an FGFR3 cDNA probe. Further investigations will be required to conclude as to the possible involvement of this gene in ACH.

  11. Skeletal dysplasia in ancient Egypt.

    Science.gov (United States)

    Kozma, Chahira

    2008-12-01

    The ancient Egyptian civilization lasted for over 3000 years and ended in 30 BCE. Many aspects of ancient Egyptian culture, including the existence of skeletal dysplasias, and in particular achondroplasia, are well known through the monuments and records that survived until modern times. The hot and dry climate in Egypt allowed for the preservation of bodies and skeletal anomalies. The oldest dwarf skeleton, the Badarian skeleton (4500 BCE), possibly represents an epiphyseal disorder. Among the remains of dwarfs with achondroplasia from ancient Egypt (2686-2190 BCE), exists a skeleton of a pregnant female, believed to have died during delivery with a baby's remains in situ. British museums have partial skeletons of dwarfs with achondroplasia, humeri probably affected with mucopolysaccharidoses, and a skeleton of a child with osteogenesis imperfecta. Skeletal dysplasia is also found among royal remains. The mummy of the pharaoh Siptah (1342-1197 BCE) shows a deformity of the left leg and foot. A mummified fetus, believed to be the daughter of king Tutankhamun, has scoliosis, spina bifida, and Sprengel deformity. In 2006 I reviewed the previously existing knowledge of dwarfism in ancient Egypt. The purpose of this second historical review is to add to that knowledge with an expanded contribution. The artistic documentation of people with skeletal dysplasia from ancient Egypt is plentiful including hundreds of amulets, statues, and drawing on tomb and temple walls. Examination of artistic reliefs provides a glance of the role of people with skeletal dysplasia and the societal attitudes toward them. Both artistic evidence and moral teachings in ancient Egypt reveal wide integration of individuals with disabilities into the society.

  12. Sleep Disorders in Childhood Neurogenetic Disorders

    Directory of Open Access Journals (Sweden)

    Laura Beth Mann Dosier

    2017-09-01

    Full Text Available Genetic advances in the past three decades have transformed our understanding and treatment of many human diseases including neurogenetic disorders. Most neurogenetic disorders can be classified as “rare disease,” but collectively neurogenetic disorders are not rare and are commonly encountered in general pediatric practice. The authors decided to select eight relatively well-known neurogenetic disorders including Down syndrome, Angelman syndrome, Prader–Willi syndrome, Smith–Magenis syndrome, congenital central hypoventilation syndrome, achondroplasia, mucopolysaccharidoses, and Duchenne muscular dystrophy. Each disorder is presented in the following format: overview, clinical characteristics, developmental aspects, associated sleep disorders, management and research/future directions.

  13. Thanatophoric dwarfism. Two case reports and survey of the literature.

    Science.gov (United States)

    Nissenbaum, M; Chung, S M; Rosenberg, H K; Buck, B E

    1977-08-01

    Thanatophoric dwarfism is a severe form of short-limbed dwarfism in which cardiorespiratory failure uniformly results in death in the neonatal period. Its radiographic features include markedly flattened vertebral bodies with a typical U-shaped deformity, a flat squat pelvis, and short, bowed extremities with flaring and irregularity of the metaphyses. These characteristic features distinguish this entity from the two other most commonly confused congenital short-limbed forms of dwarism--achondroplasia and achondrogenesis. The distinctions are discussed in the text.

  14. Selfish spermatogonial selection

    DEFF Research Database (Denmark)

    Lim, Jasmine; Maher, Geoffrey J; Turner, Gareth D H

    2012-01-01

    The dominant congenital disorders Apert syndrome, achondroplasia and multiple endocrine neoplasia-caused by specific missense mutations in the FGFR2, FGFR3 and RET proteins respectively-represent classical examples of paternal age-effect mutation, a class that arises at particularly high...... frequencies in the sperm of older men. Previous analyses of DNA from randomly selected cadaveric testes showed that the levels of the corresponding FGFR2, FGFR3 and RET mutations exhibit very uneven spatial distributions, with localised hotspots surrounded by large mutation-negative areas. These studies imply...

  15. Pediatric aspects of skeletal dysplasia.

    Science.gov (United States)

    Ozono, Keiichi; Namba, Noriyuki; Kubota, Takuo; Kitaoka, Taichi; Miura, Kohji; Ohata, Yasuhisa; Fujiwara, Makoto; Miyoshi, Yoko; Michigami, Toshimi

    2012-10-01

    Skeletal dysplasia is a disorder of skeletal development characterized by abnormality in shape, length, a number and mineral density of the bone. Skeletal dysplasia is often associated with manifestation of other organs such as lung, brain and sensory systems. Skeletal dysplasias or dysostosis are classified with more than 400 different names. Enchondral bone formation is a coordinated event of chondrocyte proliferation, differentiation and exchange of terminally maturated chondrocyte with bone. Impaired enchondral bone formation will lead to skeletal dysplasia, especially associated with short long bones. Appropriate bone volume and mineral density are achieved by balance of bone formation and bone resorption and mineralization. The gene encoding fibroblast growth factor receptor 3 is responsible for achondroplasia, representative skeletal dysplasia with short stature. The treatment with growth hormone is approved for achondroplasia in Japan. Osteogenesis imperfecta is characterized by low bone mineral density and fragile bone. Data on the beneficial effect of bisphosphonate for osteogenesis imperfecta are accumulating. Osteopetrosis has high bone mineral density, but sometimes show bone fragility. In Japan as well as other countries, pediatrician treat larger numbers of patients with skeletal dysplasia with short stature and fragile bones compared to 20 years ago.

  16. Acute obstructive hydrocephalus complicating decompression surgery of the craniovertebral junction

    Science.gov (United States)

    Ohya, Junichi; Chikuda, Hirotaka; Nakatomi, Hirofumi; Sakamoto, Ryuji; Saito, Nobuhito; Tanaka, Sakae

    2016-01-01

    Obstructive hydrocephalus has been described as a rare complication following foramen magnum decompression for Chiari malformation. However, there are few reports of obstructive hydrocephalus after spinal surgery for other pathologies of the craniovertebral junction (CVJ). The authors herein report a 52-year-old female with achondroplasia presenting with an 8-month history of myelopathy due to spinal cord compression at CVJ. She underwent resection of the C1 posterior arch and part of the edge of the occipital bone. A computed tomography (CT) scan obtained 1-week after the surgery revealed bilateral infratentorial fluid collection. The patient was first managed conservatively; however, on the 17th day, her consciousness level showed sudden deterioration. Emergency CT demonstrated marked hydrocephalus due to obstruction of the cerebral aqueduct. Acute obstructive hydrocephalus can occur late after decompression surgery at the CVJ, and thus should be included in the differential diagnosis of a deteriorating mental status. PMID:27366268

  17. Chondroectodermal dysplasia (Ellis van Creveld syndrome: A report of three cases with review of literature

    Directory of Open Access Journals (Sweden)

    Kurian K

    2007-01-01

    Full Text Available Chondroectodermal dysplasia is a rare mesenchymal - ectodermal dysplasia first described in 1940 by Richard W.B. Ellis and Simon van Creveld now known as Ellis van Creveld syndrome. It is also known as Mesvectodermal dysplasia. Majority of cases were characteristically seen in one particular inbred population from the Amish community of Lancaster County, Pennsylvania, U.S.A. The syndrome manifests with several skeletal anomalies, oral mucosal and dental anomalies, congenital cardiac defects and nail dysplasia. Ellis van Creveld syndrome may be differentiated from other chondrodystrophies like achondroplasia, chondroplasia punctata, asphyxiating thorasic dystrophy and Morquio′s syndrome. The presence of oral mucosal and dental alterations like notching of the lower alveolar process, fusion of the upper lip with gingival mucosal margin, occasional presence of neonatal teeth, oligodontia and conical shape of anterior teeth will confirm the diagnosis of Ellis van Creveld syndrome and hence its importance to dentists.

  18. Livebirth prevalence and follow-up of malformation syndromes in 27,472 newborns.

    Science.gov (United States)

    Higurashi, M; Oda, M; Iijima, K; Iijima, S; Takeshita, T; Watanabe, N; Yoneyama, K

    1990-01-01

    The results of a survey of the birth prevalence of congenital anomalies among 27,472 consecutive newborn babies at a large maternity hospital in Tokyo are reported. There were 29 cases with trisomy-21; 5 cases with trisomy-13 syndrome; 5 with trisomy-18 syndrome; 2 with cri-du-chat syndrome; and one each with partial monosomy 4p, partial trisomy 5p, partial trisomy 6p, partial trisomy 9p, partial trisomy 9q, partial monosomy 10p, and partial monosomy 13q. Single cases of the following were observed: the Hallermann-Streiff syndrome, the Treacher-Collins syndrome, achondroplasia, arthrogryposis, the Beckwith-Wiedemann syndrome, the asplenia syndrome, the Klippel-Trenaunay-Weber syndrome, the Marfan syndrome, the Carpenter syndrome, the Goldenhar syndrome, and the Pierre Robin syndrome. The results of follow-ups to determine the life-prognosis of each patient with an autosomal aberration are reported.

  19. Perceval S aortic valve implantation in an achondroplastic Dwarf

    Directory of Open Access Journals (Sweden)

    Nikolaos G Baikoussis

    2016-01-01

    Full Text Available Despite cardiovascular disease in patients with dwarfism is not rare; there is a lack of reports referring to cardiac interventions in such patients. Dwarfism may be due to achondroplasia or hormonal growth disorders. We present a 58-year-old woman with episodes of dyspnea for several months. She underwent on transthoracic echocardiography, and she diagnosed with severe aortic valve stenosis. She referred to our department for surgical treatment of this finding. In accordance of her anthropometric characteristics and her very small aortic annulus, we had the dilemma of prosthesis selection. We decided to implant a stentless valve to optimize her effective orifice area. Our aim is to present the successful Perceval S valve implantation and the descriptions of the problems coming across in operating on these special patients. To our knowledge, this is the first case patient in which a Perceval S valve is implanted according to the international bibliography.

  20. Interpretation and value of MR CSF flow studies for paediatric neurosurgery

    Directory of Open Access Journals (Sweden)

    Samukelisiwe Sithembile Mbonane

    2013-03-01

    Full Text Available Imaging techniques may be underutilised when clinicians are unaware of the technique or do not recognise its potential. Phase-contrast MR imaging (PC-MRI is a rapid, simple and non-invasive technique that is sensitive to CSF flow. It demonstrates a mechanical coupling between cerebral blood and CSF flow throughout the cardiac cycle. Neurosurgeons should be able to request this procedure routinely as part of an MRI request. This paper gives an overview of the indications, technical requirements, technique and interpretation, using image examples. Indications for CSF flow studies include assessment and functionality of shunt treatment in patients with hydrocephalus; hydrocephalus associated with achondroplasia; Chiari I malformation; confirmation of aqueductal stenosis; and determining patency of a third ventriculostomy.

  1. Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations.

    Science.gov (United States)

    Wilkie, Andrew O M

    2005-04-01

    The discovery in 1994 that highly specific mutations of fibroblast growth factor (FGF) receptor 3 caused the most common form of human short-limbed dwarfism, achondroplasia, heralded a new era in FGF receptor (FGFR) biology. A decade later, the purpose of this review is to survey how the study of humans with FGFR mutations continues to provide insights into FGFR function in health and disease, and the clinical applications of these findings. Amongst the most interesting recent discoveries have been the description of novel phenotypes associated with FGFR1 and FGFR3 mutations; identification of fundamental differences in the cellular mechanisms of mutant FGFR2 and FGFR3 action; and the direct identification of FGFR2 and FGFR3 mutations in sperm. These clinical observations illustrate the pleiotropism of FGFR action and fuel ongoing efforts to understand the rich biology and pathophysiology of the FGF signalling system.

  2. Advances on circulating fetal DNA in maternal plasma

    Institute of Scientific and Technical Information of China (English)

    FU Xian-hu; CHEN Han-ping

    2007-01-01

    @@ The discovery of cell-free fetal DNA in maternal plasma in 1997 has opened up new possibilities for noninvasive diagnosis.1 By RT-PCR, circulating fetal DNA can be detected in the plasma of pregnant women,even in the first trimester of pregnancy,2,3 and thus can be used for noninvasive prenatal diagnosis of sex-linked disorders,4-6 the RhD status of fetuses,7 and single gene disorders such as beta-thalassaemia,8,9 congenital adrenal hyperplasia,10 and achondroplasia.11 In addition,quantitative aberrations of circulating fetal DNA may indicate various pregnancy-associated disorders,including1 Preeclampsia,12-14 preterm labor15,16 and fetal trisomy 21.17

  3. The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16

    Energy Technology Data Exchange (ETDEWEB)

    Polymeropoulos, M.H.; Ide, S.E. [National Institute of Health, Bethesda, MD (United States); Wright, M. [Univ. of Newcastle Upon Tyne (United Kingdom)] [and others

    1996-07-01

    Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by disproportionate dwarfism, polydactyly, and congenital heart disease. This rare disorder is found with increased frequency among the Old Order Amish community in Lancaster County, Pennsylvania. We have used linkage analysis to localize the gene responsible for the EVC phenotype in nine interrelated Amish pedigrees and three unrelated families from Mexico, Ecuador, and Brazil. We now report the linkage for the Ellisvan Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Z{sub max} = 6.91 at {theta} = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype. 17 refs., 2 figs., 1 tab.

  4. Paleopathological Study of Dwarfism-Related Skeletal Dysplasia in a Late Joseon Dynasty (South Korean) Population.

    Science.gov (United States)

    Woo, Eun Jin; Lee, Won-Joon; Hu, Kyung-Seok; Hwang, Jae Joon

    2015-01-01

    Skeletal dysplasias related to genetic etiologies have rarely been reported for past populations. This report presents the skeletal characteristics of an individual with dwarfism-related skeletal dysplasia from South Korea. To assess abnormal deformities, morphological features, metric data, and computed tomography scans are analyzed. Differential diagnoses include achondroplasia or hypochondroplasia, chondrodysplasia, multiple epiphyseal dysplasia, thalassemia-related hemolytic anemia, and lysosomal storage disease. The diffused deformities in the upper-limb bones and several coarsened features of the craniofacial bones indicate the most likely diagnosis to have been a certain type of lysosomal storage disease. The skeletal remains of EP-III-4-No.107 from the Eunpyeong site, although incomplete and fragmented, provide important clues to the paleopathological diagnosis of skeletal dysplasias.

  5. Germline Stem Cell Competition, Mutation Hot Spots, Genetic Disorders, and Older Fathers.

    Science.gov (United States)

    Arnheim, Norman; Calabrese, Peter

    2016-08-31

    Some de novo human mutations arise at frequencies far exceeding the genome average mutation rate. Examples include the common mutations at one or a few sites in the genes that cause achondroplasia, Apert syndrome, multiple endocrine neoplasia type 2B, and Noonan syndrome. These mutations are recurrent, provide a gain of function, are paternally derived, and are more likely to be transmitted as the father ages. Recent experiments have tested whether the high mutation frequencies are due to an elevated mutation rate per cell division, as expected, or to an advantage of the mutant spermatogonial stem cells over wild-type stem cells. The evidence, which includes the surprising discovery of testis mutation clusters, rules out the former model but not the latter. We propose how the mutations might alter spermatogonial stem cell function and discuss how germline selection contributes to the paternal age effect, the human mutational load, and adaptive evolution.

  6. Lumbar gibbus in storage diseases and bone dysplasias

    Energy Technology Data Exchange (ETDEWEB)

    Levin, T.L. [Department of Radiology, Division of Pediatric Radiology, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital of New York, NY (United States); Berdon, W.E. [Department of Radiology, Division of Pediatric Radiology, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital of New York, NY (United States); Lachman, R.S. [International Skeletal Dysplasia Registry, Los Angeles, CA (United States); Anyane-Yeboa, K. [Department of Pediatrics, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital of New York, NY (United States); Ruzal-Shapiro, C. [Department of Radiology, Division of Pediatric Radiology, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital of New York, NY (United States); Roye, D.P. Jr. [Department of Orthopedic Surgery, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital of New York, NY (United States)

    1997-04-01

    Objective. The objective of this study was to review the problem of lumbar gibbus in children with storage diseases and bone dysplasias utilizing plain films and MR imaging. Materials and methods. Clinical histories and radiographic images in five patients with storage diseases [four mucopolysaccharidosis (MPS) and one mucolipidosis] and two with achondroplasia were reviewed. The International Skeletal Dysplasia Registry (Los Angeles, Calif.), surveyed for all patients with lumbar gibbus and skeletal dysplasias, provided 12 additional cases. Results. All patients had localized gibbus of the upper lumbar spine, characterized by anterior wedging and posterior displacement of the vertebrae at the apex of the curve, producing a beaked appearance. The curve, exaggerated in the sitting or standing position, was most severe in the two patients with MPS-IV (one of whom died). Both developed severe neurologic signs and symptoms requiring surgical intervention. In four patients, MR images demonstrated the apex of the curve to be at or below the conus. Two patients demonstrated anterior herniation of the intervertebral discs at the apex of the curve, though the signal intensity of the intervertebral discs was normal. Conclusion. Lumbar gibbus has important neurologic and orthopedic implications, and is most severe in patients with MPS. The etiology of the gibbus with vertebral beaking is multifactorial and includes poor truncal muscle tone, weight-bearing forces, growth disturbance and anterior disc herniation. The curve is generally at or below the conus. Neurologic complications are unusual, although orthopedic problems can arise. Due to their longer survival, patients with achondroplasia or Morquio`s disease are more vulnerable to eventual gibbus-related musculoskeletal complications. (orig.). With 6 figs., 2 tabs.

  7. The time of onset of abnormal calcification in spondylometaepiphyseal dysplasia, short limb-abnormal calcification type

    Energy Technology Data Exchange (ETDEWEB)

    Tueysuez, Beyhan [Istanbul University, Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul (Turkey); Gazioglu, Nurperi [Istanbul University, Department of Neurosurgery, Cerrahpasa Medical School, Istanbul (Turkey); Uenguer, Savas [Istanbul University, Department of Pediatric Radiology, Cerrahpasa Medical School, Istanbul (Turkey); Aji, Dolly Yafet [Istanbul University, Department of Pediatrics, Cerrahpasa Medical School, Istanbul (Turkey); Tuerkmen, Seval [Istanbul University, Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul (Turkey); Universitatsklinikum Berlin, Charite Virchow-Klinik, Berlin (Germany)

    2009-01-15

    A 1-month-old boy with shortness of extremities on prenatal US was referred to our department with a provisional diagnosis of achondroplasia. His height was normal but he had short extremities and platyspondyly, premature carpal epiphyses on both hands, and short tubular bones with irregular metaphyses on radiographs. Re-evaluation of the patient at the age of 1 year revealed very short height and premature calcification of the costal cartilages and epiphyses. Spondylometaepiphyseal dysplasia (SMED), short limb-abnormal calcification type was diagnosed. This condition is a very rare autosomal recessively inherited disorder, and most of the patients die in early childhood due to neurological involvement. At the age of 2 years and 5 months, a CT scan showed narrowing of the cervical spinal canal. One month later he died suddenly because of spinal cord injury. In conclusion early diagnosis is very important because the recurrence risk is high and patients may die due to early neurological complications. The time of onset of abnormal calcifications, a diagnostic finding of the disease, is at the age of around 1 year in most patients. When abnormal calcifications are not yet present, but radiological changes associated with SMED are present, this rare disease must be considered. (orig.)

  8. Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes.

    Science.gov (United States)

    Gudernova, Iva; Vesela, Iva; Balek, Lukas; Buchtova, Marcela; Dosedelova, Hana; Kunova, Michaela; Pivnicka, Jakub; Jelinkova, Iva; Roubalova, Lucie; Kozubik, Alois; Krejci, Pavel

    2016-01-01

    Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) cause the most common genetic form of human dwarfism, achondroplasia (ACH). Small chemical inhibitors of FGFR tyrosine kinase activity are considered to be viable option for treating ACH, but little experimental evidence supports this claim. We evaluated five FGFR tyrosine kinase inhibitors (TKIs) (SU5402, PD173074, AZD1480, AZD4547 and BGJ398) for their activity against FGFR signaling in chondrocytes. All five TKIs strongly inhibited FGFR activation in cultured chondrocytes and limb rudiment cultures, completely relieving FGFR-mediated inhibition of chondrocyte proliferation and maturation. In contrast, TKI treatment of newborn mice did not improve skeletal growth and had lethal toxic effects on the liver, lungs and kidneys. In cell-free kinase assays as well as in vitro and in vivo cell assays, none of the tested TKIs demonstrated selectivity for FGFR3 over three other FGFR tyrosine kinases. In addition, the TKIs exhibited significant off-target activity when screened against a panel of 14 unrelated tyrosine kinases. This was most extensive in SU5402 and AZD1480, which inhibited DDR2, IGF1R, FLT3, TRKA, FLT4, ABL and JAK3 with efficiencies similar to or greater than those for FGFR. Low target specificity and toxicity of FGFR TKIs thus compromise their use for treatment of ACH. Conceptually, different avenues of therapeutic FGFR3 targeting should be investigated.

  9. Ellis-van Creveld syndrome associated with chronic intestinal pseudo-obstruction.

    Science.gov (United States)

    Iwakura, Hideo; Fujii, Katsunori; Furutani, Yoshiyuki; Takatani, Tomozumi; Ebata, Ryota; Nakanishi, Toshio; Mitsunaga, Tetsuya; Saito, Takeshi; Kishimoto, Takashi; Yoshida, Hideo; Shimojo, Naoki

    2016-01-01

    Ellis-van Creveld (EVC) syndrome is a rare autosomal recessive disorder characterized by hypoplastic nails, polydactyly, and achondroplasia. Patients usually exhibit normal cognitive function and no remarkable developmental delay. We herein present an unusual case of EVC syndrome. A Japanese 2-year-old boy was born at term, but immediately developed severe respiratory failure due to thorax deformity, postaxial polydactyly and nail hypoplasia. We identified a novel pattern of germinal compound heterozygous nonsense EVC2 mutations of c.1814C > A (p. S605X) and c.2653C > T (p. R885X), leading to the diagnosis of EVC syndrome. Interestingly, he also had severe developmental delay, and suddenly developed excessive abdominal distension at the age of 2. On surgery, extensive necrotic bowel with chronic intestinal pseudo-obstruction was noted. This is, to our knowledge, a most severe phenotype of EVC syndrome, illustrating that the specific pattern of EVC2 compound heterozygous mutations may cause severe developmental delay and intestinal malfunction.

  10. The time of onset of abnormal calcification in spondylometaepiphyseal dysplasia, short limb-abnormal calcification type.

    Science.gov (United States)

    Tüysüz, Beyhan; Gazioğlu, Nurperi; Ungür, Savaş; Aji, Dolly Yafet; Türkmen, Seval

    2009-01-01

    A 1-month-old boy with shortness of extremities on prenatal US was referred to our department with a provisional diagnosis of achondroplasia. His height was normal but he had short extremities and platyspondyly, premature carpal epiphyses on both hands, and short tubular bones with irregular metaphyses on radiographs. Re-evaluation of the patient at the age of 1 year revealed very short height and premature calcification of the costal cartilages and epiphyses. Spondylometaepiphyseal dysplasia (SMED), short limb-abnormal calcification type was diagnosed. This condition is a very rare autosomal recessively inherited disorder, and most of the patients die in early childhood due to neurological involvement. At the age of 2 years and 5 months, a CT scan showed narrowing of the cervical spinal canal. One month later he died suddenly because of spinal cord injury. In conclusion early diagnosis is very important because the recurrence risk is high and patients may die due to early neurological complications. The time of onset of abnormal calcifications, a diagnostic finding of the disease, is at the age of around 1 year in most patients. When abnormal calcifications are not yet present, but radiological changes associated with SMED are present, this rare disease must be considered.

  11. Morphological and ultrasonographic study of fetuses with cervical hygroma. A cases series.

    Science.gov (United States)

    Munteanu, Octavian; Cîrstoiu, Monica Mihaela; Filipoiu, Florin Mihail; BohîlŢea, Roxana Elena; Bulescu, Ioan Alexandru; Berceanu, Costin

    2016-01-01

    Cystic cervical hygroma or cervical cystic lymphangioma is a congenital benign disease of the lymphatic system that is characterized by the accumulation of lymph in the jugular lymphatic sacs of the nuchal region. The factor that causes this pathology is not clarified yet but the physiopathological mechanism seems to be multifactorial. The incidence and prevalence of cervical hygroma are increased in patients with Turner syndrome, Down syndrome, Klinefelter syndrome, Edwards syndrome, Patau syndrome, Noonan syndrome, pterygium syndrome, Cantrell pentalogy, Fryns syndrome, Apert syndrome, Pena-Shokeir syndrome and achondroplasia. The gold standard method in establishing the antenatal diagnosis is ultrasonography, a non-invasive and low-cost procedure. We report four cases of fetuses who were diagnosed antepartum with cervical hygroma in the Department of Obstetrics and Gynecology of the University Emergency Hospital in Bucharest, Romania. Two products of conception were send to the Department of Anatomy of the "Carol Davila" University of Medicine and Pharmacy, Bucharest, for an extensive morphological analysis. Cervical cystic hygroma is a congenital condition of variable expression in terms of both morphology and chronology. A complete ultrasound examination, performed by an experimented specialist in maternal-fetal medicine is essential in establishing the diagnosis of cervical hygroma. Screening for aneuploidies, between the 11th and 14th weeks of pregnancy is also mandatory due to the frequent association between cervical hygroma and congenital anomalies.

  12. Hypochondroplasia, Acanthosis Nigricans, and Insulin Resistance in a Child with FGFR3 Mutation: Is It Just an Association?

    Directory of Open Access Journals (Sweden)

    Manal Mustafa

    2014-01-01

    Full Text Available FGFR3 mutations cause wide spectrum of disorders ranging from skeletal dysplasias (hypochondroplasia, achondroplasia, and thanatophoric dysplasia, benign skin tumors (epidermal nevi, seborrhaeic keratosis, and acanthosis nigricans, and epithelial malignancies (multiple myeloma and prostate and bladder carcinoma. Hypochondroplasia is the most common type of short-limb dwarfism in children resulting from fibroblast growth factor receptor 3 (FGFR3 mutation. Acanthosis nigricans might be seen in severe skeletal dysplasia, including thanatophoric dysplasia and SADDAN syndrome, without a biochemical evidence of hyperinsulinemia. Insulin insensitivity and acanthosis nigricans are uncommonly seen in hypochondroplasia patients with FGFR3 mutations which may represent a new association. We aim to describe the association of hypochondroplasia, acanthosis nigricans, and insulin resistance in a child harboring FGFR3 mutation. To our knowledge, this is the first case report associating the p.N540 with acanthosis nigricans and the second to describe hyperinsulinemia in hypochondroplasia. This finding demonstrates the possible coexistence of insulin insensitivity and acanthosis nigricans in hypochondroplasia patients.

  13. The acrophysis: a unifying concept for understanding enchondral bone growth and its disorders. II. Abnormal growth

    Energy Technology Data Exchange (ETDEWEB)

    Oestreich, Alan E. [Department of Radiology, Cincinnati Children' s Hospital Medical Center, 3333 Burnet Avenue, OH 45229-3039, Cincinnati (United States)

    2004-03-01

    In order to discuss and illustrate the effects common to normal and abnormal enchondral bone at the physes and at all other growth plates of the developing child, the term ''acrophysis'' was proposed. Acrophyses include the growth plates of secondary growth centers including carpals and tarsals and apophyses, and the growth plates at the nonphyseal ends of small tubular bones. Abnormalities at acrophyseal sites are analogous to those at the physeal growth plates and their metaphyses. For example, changes relating to the zone of provisional calcification (ZPC) are often important to the demonstration of such similarities. Lead lines were an early example of the concept of analogy from abnormality due to physeal and to acrophyseal disturbance. The ZPC is a key factor in understanding patterns of rickets and its healing. Examples (including hypothyroidism, scurvy and other osteoporosis, Ollier disease, achondroplasia, and osteopetrosis, as well as the family of frostbite, Kashin-Beck disease, and rat bite fever) illustrate the acrophysis principle and in turn their manifestations are explained by that principle. (orig.)

  14. Respiratory sinus arrhythmia of brainstem lesions.

    Science.gov (United States)

    DiMario, F J; Bauer, L; Baxter, D

    1999-04-01

    In this pilot study we investigated the hypothesis that intrinsic and extrinsic brainstem lesions situated within the pontomedullary region would effect the integrity of respiratory sinus arrhythmia. The study sample consisted of three patients with anatomic brainstem abnormalities associated with isolated Chiari I malformation, Chiari II malformation with syringobulbia, and achondroplasia with cervicomedullary compression. They were compared to an age- and sex-matched control group of nine patients. Each subject's electrocardiogram was recorded in a quiet room and digitized by a personal computer during five 1-minute periods. R-R intervals within each 1-minute period were converted to heart rate in 120 successive 0.5-second intervals. The resultant heartrate time series was converted to its underlying frequency composition by a fast Fourier transform and averaged across minutes. Respiratory sinus arrhythmia was defined as the variability in the time series over a frequency range (0.096 to 0.48 Hz) corresponding to a range of respiratory rates from 6 to 30 breaths per minute. Analysis revealed a significant reduction in respiratory sinus arrhythmia (P < .05), defined as the summated area under the curve, with a mean for controls of 35.42+/-28.13 SD and for subjects of 17.20+/-11.50 SD. There was a gradient of abnormality noted, with the mildest deviation in respiratory sinus arrhythmia for the patient with isolated Chiari I malformation and maximum deviation seen in the patient with extrinsic cervicomedullary compression.

  15. A systematic review of genetic skeletal disorders reported in Chinese biomedical journals between 1978 and 2012

    Directory of Open Access Journals (Sweden)

    Cui Yazhou

    2012-08-01

    Full Text Available Abstract Little information is available on the prevalence, geographic distribution and mutation spectrum of genetic skeletal disorders (GSDs in China. This study systematically reviewed GSDs as defined in “Nosology and Classification of genetic skeletal disorders (2010 version” using Chinese biomedical literature published over the past 34 years from 1978 to 2012. In total, 16,099 GSDs have been reported. The most frequently reported disorders were Marfan syndrome, osteogenesis imperfecta, fibrous dysplasia, mucopolysaccharidosis, multiple cartilaginous exostoses, neurofibromatosis type 1 (NF1, osteopetrosis, achondroplasia, enchondromatosis (Ollier, and osteopoikilosis, accounting for 76.5% (12,312 cases of the total cases. Five groups (group 8, 12, 14, 18, 21 defined by “Nosology and Classification of genetic skeletal disorders” have not been reported in the Chinese biomedical literature. Gene mutation testing was performed in only a minor portion of the 16,099 cases of GSDs (187 cases, 1.16%. In total, 37 genes for 41 different GSDs were reported in Chinese biomedical literature, including 43 novel mutations. This review revealed a significant imbalance in rare disease identification in terms of geographic regions and hospital levels, suggesting the need to create a national multi-level network to meet the specific challenge of care for rare diseases in China.

  16. Molecular, Phenotypic Aspects and Therapeutic Horizons of Rare Genetic Bone Disorders

    Directory of Open Access Journals (Sweden)

    Taha Faruqi

    2014-01-01

    Full Text Available A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.

  17. Anatomic Considerations for Radical Retropubic Prostatectomy in an Achondroplastic Dwarf

    Directory of Open Access Journals (Sweden)

    Dennis Gyomber

    2009-01-01

    Full Text Available This is the first report of a radical retropubic prostatectomy (RRP in an achondroplastic dwarf. We highlight the pelvic anatomy, precluding laparoscopic or robotic prostatectomy, and making open surgery extremely difficult. We review relevant literature regarding general, urological, and orthopedic abnormalities of achondroplasia (ACH and present a clinical case. No reports of RRP in achondroplastic dwarfs exist, with only one case of an abandoned RRP due to similar pelvic anatomy in a patient with osteogenesis imperfecta. Significant lumbar lordosis found in ACH results in a short anteroposterior dimension, severely limiting access to the prostate. We present a case of a 62-year-old achondroplastic dwarf who had Gleason 3+4 disease on transrectal ultrasound-guided biopsy in four from 12 cores. Surgery was difficult due to narrow anteroposterior pelvic dimension, but achievable. Histological analysis revealed multifocal prostate cancer, with negative surgical margins and no extraprostatic extension. RRP in ACH patients, although possible, should be approached with caution due to the abnormal pelvic dimensions, and discussions regarding potential abandonment of surgery should be included during informed consent. This case highlights the preoperative use of computed tomography to assist in the surgical planning for patients with difficult pelvic anatomy.

  18. Pneumomediastinum, Subcutaneous Emphysema, and Tracheal Tear in the Early Postoperative Period of Spinal Surgery in a Paraplegic Achondroplastic Dwarf

    Directory of Open Access Journals (Sweden)

    Sinan Kahraman

    2013-01-01

    Full Text Available Achondroplasia was first described in 1878 and is the most common form of human skeletal dysplasia. Spinal manifestations include thoracolumbar kyphosis, foramen magnum, and spinal stenosis. Progressive kyphosis can result in spinal cord compression and paraplegia due to the reduced size of spinal canal. The deficits are typically progressive, presenting as an insidious onset of paresthesia, followed by the inability to walk and then by urinary incontinence. Paraplegia can be the result of direct pressure on the cord by bone or the injury to the anterior spinal vessels by a protruding bone. Surgical treatment consists of posterior instrumentation, fusion with total wide laminectomy at stenosis levels, and anterior interbody support. Pedicle screws are preferred for spinal instrumentation because wires and hooks may induce spinal cord injury due to the narrow spinal canal. Pedicle lengths are significantly shorter, and 20–25 mm long screws are appropriate for lower thoracic and lumbar pedicles in adult achondroplastic There is no information about the appropriate length of screws for the upper thoracic pedicles. Tracheal injury due to inappropriate pedicle screw length is a rare complication. We report an extremely rare case of tracheal tear due to posterior instrumentation and its management in the early postoperative period.

  19. Fibroblast growth factor (FGF) signaling in development and skeletal diseases.

    Science.gov (United States)

    Teven, Chad M; Farina, Evan M; Rivas, Jane; Reid, Russell R

    2014-12-01

    Fibroblast growth factors (FGF) and their receptors serve many functions in both the developing and adult organism. Humans contain 18 FGF ligands and four FGF receptors (FGFR). FGF ligands are polypeptide growth factors that regulate several developmental processes including cellular proliferation, differentiation, and migration, morphogenesis, and patterning. FGF-FGFR signaling is also critical to the developing axial and craniofacial skeleton. In particular, the signaling cascade has been implicated in intramembranous ossification of cranial bones as well as cranial suture homeostasis. In the adult, FGFs and FGFRs are crucial for tissue repair. FGF signaling generally follows one of three transduction pathways: RAS/MAP kinase, PI3/AKT, or PLCγ. Each pathway likely regulates specific cellular behaviors. Inappropriate expression of FGF and improper activation of FGFRs are associated with various pathologic conditions, unregulated cell growth, and tumorigenesis. Additionally, aberrant signaling has been implicated in many skeletal abnormalities including achondroplasia and craniosynostosis. The biology and mechanisms of the FGF family have been the subject of significant research over the past 30 years. Recently, work has focused on the therapeutic targeting and potential of FGF ligands and their associated receptors. The majority of FGF-related therapy is aimed at age-related disorders. Increased understanding of FGF signaling and biology may reveal additional therapeutic roles, both in utero and postnatally. This review discusses the role of FGF signaling in general physiologic and pathologic embryogenesis and further explores it within the context of skeletal development.

  20. A single nucleotide mutation in Nppc is associated with a long bone abnormality in lbab mice

    Directory of Open Access Journals (Sweden)

    Roe Bruce A

    2007-04-01

    Full Text Available Abstract Background The long bone abnormality (lbab mouse is a new autosomal recessive mutant characterized by overall smaller body size with proportionate dwarfing of all organs and shorter long bones. Previous linkage analysis has located the lbab mutation on chromosome 1 between the markers D1Mit9 and D1Mit488. Results A genome-based positional approach was used to identify a mutation associated with lbab disease. A total of 122 genes and expressed sequence tags at the lbab region were screened for possible mutation by using genomic DNA from lbabl/lbab, lbab/+, and +/+ B6 mice and high throughput temperature gradient capillary electrophoresis. A sequence difference was identified in one of the amplicons of gene Nppc between lbab/lbab and +/+ mice. One-step reverse transcriptase polymerase chain reaction was performed to validate the difference of Nppc in different types of mice at the mRNA level. The mutation of Nppc was unique in lbab/lbab mice among multiple mouse inbred strains. The mutation of Nppc is co-segregated with lbab disease in 200 progenies produced from heterozygous lbab/+ parents. Conclusion A single nucleotide mutation of Nppc is associated with dwarfism in lbab/lbab mice. Current genome information and technology allow us to efficiently identify single nucleotide mutations from roughly mapped disease loci. The lbab mouse is a useful model for hereditary human achondroplasia.

  1. Spell Checking Nature: Versatility of CRISPR/Cas9 for Developing Treatments for Inherited Disorders.

    Science.gov (United States)

    Wojtal, Daria; Kemaladewi, Dwi U; Malam, Zeenat; Abdullah, Sarah; Wong, Tatianna W Y; Hyatt, Elzbieta; Baghestani, Zahra; Pereira, Sergio; Stavropoulos, James; Mouly, Vincent; Mamchaoui, Kamel; Muntoni, Francesco; Voit, Thomas; Gonorazky, Hernan D; Dowling, James J; Wilson, Michael D; Mendoza-Londono, Roberto; Ivakine, Evgueni A; Cohn, Ronald D

    2016-01-01

    Clustered regularly interspaced short palindromic repeat (CRISPR) has arisen as a frontrunner for efficient genome engineering. However, the potentially broad therapeutic implications are largely unexplored. Here, to investigate the therapeutic potential of CRISPR/Cas9 in a diverse set of genetic disorders, we establish a pipeline that uses readily obtainable cells from affected individuals. We show that an adapted version of CRISPR/Cas9 increases the amount of utrophin, a known disease modifier in Duchenne muscular dystrophy (DMD). Furthermore, we demonstrate preferential elimination of the dominant-negative FGFR3 c.1138G>A allele in fibroblasts of an individual affected by achondroplasia. Using a previously undescribed approach involving single guide RNA, we successfully removed large genome rearrangement in primary cells of an individual with an X chromosome duplication including MECP2. Moreover, removal of a duplication of DMD exons 18-30 in myotubes of an individual affected by DMD produced full-length dystrophin. Our findings establish the far-reaching therapeutic utility of CRISPR/Cas9, which can be tailored to target numerous inherited disorders.

  2. Pseudoachondroplasia: A case report

    Directory of Open Access Journals (Sweden)

    Radlović Vladimir

    2013-01-01

    Full Text Available Introduction. Pseudoachondroplasia (PSACH is an autosomal dominant osteochondrodysplasia due to mutations in the gene encoding cartilage oligomeric matrix protein. It is characterized by rhizomelic dwarfism, limb and vertebral deformity, joint laxity and early onset osteoarthrosis. We present the girl with the early expressed and severe PSACH born to clinically and radiographically unaffected parents. Case Outline. A 6.5-year-old girl presented with short-limbed dwarfism (body height 79.5 cm, achondroplasia-like rhizomelic dwarfism recognized by the absence of abnormality at birth, normal craniofacial appearance, characteristic epiphyseal and metaphyseal radiographic finding and joint hyperlaxity.

  3. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease.

    Science.gov (United States)

    Goriely, Anne; Wilkie, Andrew O M

    2012-02-10

    Advanced paternal age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term "paternal age effect" (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the paternal age effect lies in the dysregulation of spermatogonial cell behavior, an effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time-explaining the observed paternal age effect associated with these disorders-and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition.

  4. Paleodysmorphology and paleoteratology: Diagnosing and interpreting congenital conditions of the skeleton in anthropological contexts.

    Science.gov (United States)

    Oostra, Roelof-Jan; Boer, Lucas; van der Merwe, Alie E

    2016-10-01

    Most congenital conditions have low prevalence, but collectively they occur in a few percent of all live births. Congenital conditions are rarely encountered in anthropological studies, not least because many of them have no obvious effect on the skeleton. Here, we discuss two groups of congenital conditions that specifically affect the skeleton, either qualitatively or quantitatively. Skeletal dysplasias (osteochondrodysplasias) interfere with the histological formation, growth and maturation of skeletal tissues leading to diminished postural length, but the building plan of the body is unaffected. Well- known skeletal dysplasias represented in the archeological record include osteogenesis imperfecta and achondroplasia. Dysostoses, in contrast, interfere with the building plan of the body, leading to e.g. missing or extraskeletal elements, but the histology of the skeletal tissues is unaffected. Dysostoses can concern the extremities (e.g., oligodactyly and polydactyly), the vertebral column (e.g., homeotic and meristic anomalies), or the craniofacial region. Conditions pertaining to the cranial sutures, i.e., craniosynostoses, can be either skeletal dysplasias or dysostoses. Congenital conditions that are not harmful to the individual are known as anatomical variations, several of which have a high and population-specific prevalence that could potentially make them useful for determining ethnic origins. In individual cases, specific congenital conditions could be determinative in establishing identity, provided that ante-mortem registration of those conditions was ensured. Clin. Anat. 29:878-891, 2016. © 2016 The Authors Clinical Anatomy published by Wiley Periodicals, Inc. on behalf of American Association of Clinical Anatomists.

  5. Atlantoaxial subluxation. Radiography and magnetic resonance imaging correlated to myelopathy

    Energy Technology Data Exchange (ETDEWEB)

    Yamashita, Y.; Takahashi, M.; Sakamoto, Y.; Kojima, R.

    Twenty-nine patients with atlantoaxial subluxation (18 with rheumatoid arthritis, 2 due to trauma, 4 with os odontoideum, and one each with polyarteritis nodosa, rheumatic fever, Klippel-Feil syndrome, achondroplasia, and cause unknown) were evaluated using a 0.22 tesla resistive MRI unit. Cord compression was classified into four grades according to the degree on magnetic resonance imaging. There were 7 patients with no thecal sac compression (grade 0), 10 with a minimal degree of subarachnoid space compression without cord compression (grade 1), 7 with mild cord compression (grade 2), and 5 with severe cord compression or cord atrophy (grade 3). Although the severity of myelopathy showed poor correlation with the atlantodental interval on conventional radiography, high correlation was observed between MR grading and the degree of myelopathy. The high signal intensity foci were observed in 7 or 12 patients with cord compression (grades 2 and 3) on T2 weighted images. Other frequently observed findings in rheumatoid arthritis included soft tissue masses of low to intermediate signal intensity in the paraodontoid space, erosions of the odontoid processes, and atlanto-axial impaction on T1 and T2 weighted images.

  6. Dwarfism and early death in mice lacking C-type natriuretic peptide

    Science.gov (United States)

    Chusho, Hideki; Tamura, Naohisa; Ogawa, Yoshihiro; Yasoda, Akihiro; Suda, Michio; Miyazawa, Takashi; Nakamura, Kenji; Nakao, Kazuki; Kurihara, Tatsuya; Komatsu, Yasato; Itoh, Hiroshi; Tanaka, Kiyoshi; Saito, Yoshihiko; Katsuki, Motoya; Nakao, Kazuwa

    2001-01-01

    Longitudinal bone growth is determined by endochondral ossification that occurs as chondrocytes in the cartilaginous growth plate undergo proliferation, hypertrophy, cell death, and osteoblastic replacement. The natriuretic peptide family consists of three structurally related endogenous ligands, atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP), and is thought to be involved in a variety of homeostatic processes. To investigate the physiological significance of CNP in vivo, we generated mice with targeted disruption of CNP (Nppc−/− mice). The Nppc−/− mice show severe dwarfism as a result of impaired endochondral ossification. They are all viable perinatally, but less than half can survive during postnatal development. The skeletal phenotypes are histologically similar to those seen in patients with achondroplasia, the most common genetic form of human dwarfism. Targeted expression of CNP in the growth plate chondrocytes can rescue the skeletal defect of Nppc−/− mice and allow their prolonged survival. This study demonstrates that CNP acts locally as a positive regulator of endochondral ossification in vivo and suggests its pathophysiological and therapeutic implication in some forms of skeletal dysplasia. PMID:11259675

  7. Current insights into the molecular genetic basis of dwarfism in livestock.

    Science.gov (United States)

    Boegheim, Iris J M; Leegwater, Peter A J; van Lith, Hein A; Back, Willem

    2017-06-01

    Impairment of bone growth at a young age leads to dwarfism in adulthood. Dwarfism can be categorised as either proportionate, an overall size reduction without changes in body proportions, or disproportionate, a size reduction in one or more limbs, with changes in body proportions. Many forms of dwarfism are inherited and result from structural disruptions or disrupted signalling pathways. Hormonal disruptions are evident in Brooksville miniature Brahman cattle and Z-linked dwarfism in chickens, caused by mutations in GH1 and GHR. Furthermore, mutations in IHH are the underlying cause of creeper achondroplasia in chickens. Belgian blue cattle display proportionate dwarfism caused by a mutation in RNF11, while American Angus cattle dwarfism is caused by a mutation in PRKG2. Mutations in EVC2 are associated with dwarfism in Japanese brown cattle and Tyrolean grey cattle. Fleckvieh dwarfism is caused by mutations in the GON4L gene. Mutations in COL10A1 and COL2A1 cause dwarfism in pigs and Holstein cattle, both associated with structural disruptions, while several mutations in ACAN are associated with bulldog-type dwarfism in Dexter cattle and dwarfism in American miniature horses. In other equine breeds, such as Shetland ponies and Friesian horses, dwarfism is caused by mutations in SHOX and B4GALT7. In Texel sheep, chondrodysplasia is associated with a deletion in SLC13A1. This review discusses genes known to be involved in these and other forms of dwarfism in livestock. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. All Madelung deformities are not endocrine

    Directory of Open Access Journals (Sweden)

    Ajay Kumar

    2013-01-01

    Full Text Available Madelung deformity is a rare inherited disorder associated with endocrine disorders like Turner′s syndrome, pseudohypoparathyroidism, but can be seen with short stature homeobox deficiency conditions such as Leri-Weill dyschondrosteosis (LWD and Langers mesomelic dysplasia. It has also been reported following trauma to the distal radius epiphysis neoplasia mucopolysaccharidosis (MPS and achondroplasia. Madelung deformity is an abnormality of distal radial epiphysis where in progressive ulnar and volar tilt of the articular surface occurring in association with distal subluxation of ulna. A 13-year-old girl was referred to us for evaluation of bilateral deformity of wrist and short stature. There was ulnar deviation and dorsal tilt of bilateral hands without history of pain to the joint trauma and family history of similar illness. On X-ray, wrist showed malformed distal radial epiphysis with dorsal and ulnar shift and with increased length of phalanges suggestive of Madelung deformity. X-ray spine was normal. Ultrasound abdomen showed normal uterus and ovary and her follicle stimulating hormone. Luteinizing hormone was normal and so was urine MPS screening. Based on the above points the diagnosis of LWD was made.

  9. Complex oncologic reconstruction of a mandibular and floor of mouth defect with a fibula free flap in an achondroplastic patient.

    Science.gov (United States)

    García-Rozado, Alvaro; Martín Sastre, Roberto J; López Cedrún, José L

    2003-01-01

    The fibular free flap is seen as one of the foremost technical options in mandibular reconstruction, especially in those defects where long bone is required. Cases with squamous-cell carcinoma of the floor of the mouth with mandibular spread and subsequent segmentary mandibular removal are the cornerstone examples. A case of squamous-cell carcinoma of the whole floor of the mouth with mandibular invasion is reported. Radical resection of the floor of the mouth and bilateral mandibular horizontal ramus was performed, with a bony defect extending from angle to angle. The patient revealed an achondroplastic condition, with remarkable dwarfism and long-bone morphological alterations, that minimized the potential fibular length to transfer. A microsurgical reconstruction with an osteocutaneous fibular free flap was undertaken. The flap design was technically compromised by the forward bowing of the fibula and the ossification of the interosseous membrane. Specific intraoperative strategies for dealing with anatomic variations are discussed. The fibular free flap is an excellent technique for mandibular reconstruction. Morphological deviations can modify the design of the flap. Achondroplasia is not a deterrent in successful use of the free fibula flap for reconstruction of the head and neck in adequately selected cases.

  10. SHORT STATURE: WHA T IS THE CAUSE IN OUR POPULATION.

    Science.gov (United States)

    Ullah, Fahim; Ghaffar, Tahir; Afridi, Ayesha Khan; Ali, Ashfaq; Aamir, Aziz ul hasan

    2016-01-01

    Globally children and adolescents with growth failure are referred to specialized units for evaluation and management. We designed this study to determine the cause of short stature in children and adolescents referred to our endocrine unit for evaluation and further management. This descriptive cross sectional study was performed in the Department of Endocrine, Diabetes and Metabolic Diseases, Hayatabad Medical Complex, Peshawar. Children and adolescents between 2-20 years with height below 2 SDS or less then 3rd percentile for their age and gender were included while those with kyphoscoliosis, thalassemia major, diabetes mellitus type-1 were excluded. Detailed history was obtained followed by detailed physical examination and a pre-set penal of investigations. Seventy-three children with mean chronological age of 11.75.3 ± 4.06 years, 56.31% boys and 43.83% girls (p < 0.05) were included. Mean height was 117.28 ± 17.55 cm, -4.23 ± 2.06 SDS below for this population age group. Mean parental height was 156.87 ± 11.82 cm, mean bone age was 8.56 ± 4.03 years while mean bone age delay was 3.23 ± 1.94 years. Common causes found were variants of normal growth present in 38.35%. Constitutional Delay of Growth and Puberty (CDGP) were found in 13.7%, Familial Short Stature (FSS) in 11.0% while overlapping features of both in other 13.7%. Isolated Growth Hormone Deficiency (GHD) was found in 23.3%, primary hypothyroidism in 9.6% and pan- hypopituitarism in 2.7%. Common non endocrine causes found were Turner's syndrome, rickets, chronic anaemia, bronchial asthma and achondroplasia. Isolated GHD, CDGP and FSS, primary hypothyroidism and Turner's syndrome are the most common causes of short stature in our set up.

  11. New insight on FGFR3-related chondrodysplasias molecular physiopathology revealed by human chondrocyte gene expression profiling.

    Directory of Open Access Journals (Sweden)

    Laurent Schibler

    Full Text Available Endochondral ossification is the process by which the appendicular skeleton, facial bones, vertebrae and medial clavicles are formed and relies on the tight control of chondrocyte maturation. Fibroblast growth factor receptor (FGFR3 plays a role in bone development and maintenance and belongs to a family of proteins which differ in their ligand affinities and tissue distribution. Activating mutations of the FGFR3 gene lead to craniosynostosis and multiple types of skeletal dysplasia with varying degrees of severity: thanatophoric dysplasia (TD, achondroplasia and hypochondroplasia. Despite progress in the characterization of FGFR3-mediated regulation of cartilage development, many aspects remain unclear. The aim and the novelty of our study was to examine whole gene expression differences occurring in primary human chondrocytes isolated from normal cartilage or pathological cartilage from TD-affected fetuses, using Affymetrix technology. The phenotype of the primary cells was confirmed by the high expression of chondrocytic markers. Altered expression of genes associated with many cellular processes was observed, including cell growth and proliferation, cell cycle, cell adhesion, cell motility, metabolic pathways, signal transduction, cell cycle process and cell signaling. Most of the cell cycle process genes were down-regulated and consisted of genes involved in cell cycle progression, DNA biosynthesis, spindle dynamics and cytokinesis. About eight percent of all modulated genes were found to impact extracellular matrix (ECM structure and turnover, especially glycosaminoglycan (GAG and proteoglycan biosynthesis and sulfation. Altogether, the gene expression analyses provide new insight into the consequences of FGFR3 mutations in cell cycle regulation, onset of pre-hypertrophic differentiation and concomitant metabolism changes. Moreover, impaired motility and ECM properties may also provide clues about growth plate disorganization. These

  12. Prevalence of dominant mutations in Spain: effect of changes in maternal age distribution.

    Science.gov (United States)

    Martínez-Frías, M L; Herranz, I; Salvador, J; Prieto, L; Ramos-Arroyo, M A; Rodríguez-Pinilla, E; Cordero, J F

    1988-12-01

    We studied the birth prevalence of autosomal dominant mutations in Spain and estimated how a decrease in maternal age distribution may lead to reduction in dominant mutations. The data were collected by the Estudio Colaborativo Español de Malformaciones Congénitas from April, 1976, to December, 1985. Among 553,270 liveborn infants monitored during the period, 66 infants with autosomal dominant conditions were identified. These included Apert, Crouzon, Hay-Wells, Treacher-Collins, Robinow, Stickler, Adams-Oliver, and the blepharophimosis syndromes, achondroplasia, cleidocranial dysostosis, and thanatophoric dysplasia. The overall rate of autosomal dominant conditions was 1.2 per 10,000 liveborn infants. Thirteen (20%) had an affected relative, and 52 (79%) had a negative family history. One case was excluded because of insufficient family data. The rate of autosomal dominant mutations was 0.9 per 10,000 liveborn infants, or 47 per 1 million gametes. A reduction in the maternal age distribution of mothers age 35 years and older from the current 10.8% to 4.9%, as in Atlanta, Georgia, would reduce the rate of Down syndrome in Spain by 33% and through a change in parternal age distribution may lead to a reduction in dominant mutations of about 9.6%. This suggests that a public health campaign to reduce older maternal age distribution in Spain may also lead to a reduction in dominant mutations and emphasizes the potential that a direct campaign for fathers to complete their families before age 35 years may have a small, but measurable, effect in the primary prevention of dominant mutations.

  13. Dwarfs in ancient Egypt.

    Science.gov (United States)

    Kozma, Chahira

    2006-02-15

    Ancient Egypt was one of the most advanced and productive civilizations in antiquity, spanning 3000 years before the "Christian" era. Ancient Egyptians built colossal temples and magnificent tombs to honor their gods and religious leaders. Their hieroglyphic language, system of organization, and recording of events give contemporary researchers insights into their daily activities. Based on the record left by their art, the ancient Egyptians documented the presence of dwarfs in almost every facet of life. Due to the hot dry climate and natural and artificial mummification, Egypt is a major source of information on achondroplasia in the old world. The remains of dwarfs are abundant and include complete and partial skeletons. Dwarfs were employed as personal attendants, animal tenders, jewelers, and entertainers. Several high-ranking dwarfs especially from the Old Kingdom (2700-2190 BCE) achieved important status and had lavish burial places close to the pyramids. Their costly tombs in the royal cemeteries and the inscriptions on their statutes indicate their high-ranking position in Egyptian society and their close relation to the king. Some of them were Seneb, Pereniankh, Khnumhotpe, and Djeder. There were at least two dwarf gods, Ptah and Bes. The god Ptah was associated with regeneration and rejuvenation. The god Bes was a protector of sexuality, childbirth, women, and children. He was a favored deity particularly during the Greco-Roman period. His temple was recently excavated in the Baharia oasis in the middle of Egypt. The burial sites and artistic sources provide glimpses of the positions of dwarfs in daily life in ancient Egypt. Dwarfs were accepted in ancient Egypt; their recorded daily activities suggest assimilation into daily life, and their disorder was not shown as a physical handicap. Wisdom writings and moral teachings in ancient Egypt commanded respect for dwarfs and other individuals with disabilities.

  14. Thyroid hormones regulate fibroblast growth factor receptor signaling during chondrogenesis.

    Science.gov (United States)

    Barnard, Joanna C; Williams, Allan J; Rabier, Bénédicte; Chassande, Olivier; Samarut, Jacques; Cheng, Sheue-Yann; Bassett, J H Duncan; Williams, Graham R

    2005-12-01

    Childhood hypothyroidism causes growth arrest with delayed ossification and growth-plate dysgenesis, whereas thyrotoxicosis accelerates ossification and growth. Thyroid hormone (T(3)) regulates chondrocyte proliferation and is essential for hypertrophic differentiation. Fibroblast growth factors (FGFs) are also important regulators of chondrocyte proliferation and differentiation, and activating mutations of FGF receptor-3 (FGFR3) cause achondroplasia. We investigated the hypothesis that T(3) regulates chondrogenesis via FGFR3 in ATDC5 cells, which undergo a defined program of chondrogenesis. ATDC5 cells expressed two FGFR1, four FGFR2, and one FGFR3 mRNA splice variants throughout chondrogenesis, and expression of each isoform was stimulated by T(3) during the first 6-12 d of culture, when T(3) inhibited proliferation by 50%. FGFR3 expression was also increased in cells treated with T(3) for 21 d, when T(3) induced an earlier onset of hypertrophic differentiation and collagen X expression. FGFR3 expression was reduced in growth plates from T(3) receptor alpha-null mice, which exhibit skeletal hypothyroidism, but was increased in T(3) receptor beta(PV/PV) mice, which display skeletal thyrotoxicosis. These findings indicate that FGFR3 is a T(3)-target gene in chondrocytes. In further experiments, T(3) enhanced FGF2 and FGF18 activation of the MAPK-signaling pathway but inhibited their activation of signal transducer and activator of transcription-1. FGF9 did not activate MAPK or signal transducer and activator of transcription-1 pathways in the absence or presence of T(3). Thus, T(3) exerted differing effects on FGFR activation during chondrogenesis depending on which FGF ligand stimulated the FGFR and which downstream signaling pathway was activated. These studies identify novel interactions between T(3) and FGFs that regulate chondrocyte proliferation and differentiation during chondrogenesis.

  15. Genetic drift. The ancient Egyptian dwarfs of the pyramids: the high official and the female worker.

    Science.gov (United States)

    Kozma, Chahira; Sarry El Din, Azza Mohamed; El Shafy El Banna, Rokia Abd; El Samie Kandeel, Wafaa Abd; Lachman, Ralph

    2011-08-01

    The existence of dwarfism is amply documented in ancient Egypt due to the rich biological and artistic legacies. In previous articles published in this journal, I discussed the roles of people with skeletal dysplasia in ancient Egyptian civilization. In this article I, along with my Egyptian and American colleagues, describe two skeletons of dwarfs that date to 2700-2184 BCE and were unearthed from a funerary complex near the Great Pyramids in Giza. The first skeleton belongs to a high official, Per-ni-ankh-w, who died between 45 and 50 years of age. His statue is on display in the Egyptian Museum of Cairo. The second skeleton belongs to a pregnant female worker found with a fetus in situ. Her estimated age at death was 25-30 years. She most likely died during childbirth due to a small pelvic outlet as supported by her narrow sacrum. The fetal bones appear normal. Radiological examination of both skeletons confirmed the clinical diagnosis of achondroplasia. Ancient Egyptians concerned themselves with the search for spiritual fulfillment through the tradition of moral teachings. Amenemope, a wise man who lived during the reign of Amenhotep III (1391-1354 BCE), advocated respect toward individuals with disabilities: Do not jeer at a blind man nor tease a dwarf, Neither interfere with the condition of a cripple. Do not taunt a man who is in the hand of God, Nor scowl at him if he errs. In summary, artistic, biological, and written resources indicate that dwarfs were well integrated in ancient Egyptian society.

  16. Cellular evidence for selfish spermatogonial selection in aged human testes.

    Science.gov (United States)

    Maher, G J; Goriely, A; Wilkie, A O M

    2014-05-01

    Owing to a recent trend for delayed paternity, the genomic integrity of spermatozoa of older men has become a focus of increased interest. Older fathers are at higher risk for their children to be born with several monogenic conditions collectively termed paternal age effect (PAE) disorders, which include achondroplasia, Apert syndrome and Costello syndrome. These disorders are caused by specific mutations originating almost exclusively from the male germline, in genes encoding components of the tyrosine kinase receptor/RAS/MAPK signalling pathway. These particular mutations, occurring randomly during mitotic divisions of spermatogonial stem cells (SSCs), are predicted to confer a selective/growth advantage on the mutant SSC. This selective advantage leads to a clonal expansion of the mutant cells over time, which generates mutant spermatozoa at levels significantly above the background mutation rate. This phenomenon, termed selfish spermatogonial selection, is likely to occur in all men. In rare cases, probably because of additional mutational events, selfish spermatogonial selection may lead to spermatocytic seminoma. The studies that initially predicted the clonal nature of selfish spermatogonial selection were based on DNA analysis, rather than the visualization of mutant clones in intact testes. In a recent study that aimed to identify these clones directly, we stained serial sections of fixed testes for expression of melanoma antigen family A4 (MAGEA4), a marker of spermatogonia. A subset of seminiferous tubules with an appearance and distribution compatible with the predicted mutant clones were identified. In these tubules, termed 'immunopositive tubules', there is an increased density of spermatogonia positive for markers related to selfish selection (FGFR3) and SSC self-renewal (phosphorylated AKT). Here we detail the properties of the immunopositive tubules and how they relate to the predicted mutant clones, as well as discussing the utility of

  17. Education and related support from medical specialists for Japanese patients with major skeletal dysplasias.

    Science.gov (United States)

    Haga, Nobuhiko; Kosaki, Keisuke; Takikawa, Kazuharu; Tanaka, Hiroshi; Okada, Keita; Nakahara, Yasuo; Ogata, Naoshi

    2013-10-01

    Skeletal dysplasias manifest various clinical symptoms. Age at onset, severity, and progression of symptoms differ even among individuals with the same diagnosis. Though necessary support in education is presumed to differ among patients with different disorders, few articles report on education in patients with skeletal dysplasias. To clarify what types of schools children with major skeletal dysplasias attend, what kind of support they needed at schools, and how the advice on such support was conveyed from medical specialists to schools. Questionnaire study on patients with achondroplasia or hypochondroplasia (A/HCH), and osteogenesis imperfecta (OI). In A/HCH childhood locomotion ability was high and most patients had received general education, irrespective of their generation. Children with OI showed a lower level of locomotion ability; only about half of them had received general education. In selecting schools, the patients received advice from pediatricians, physiatrists, and orthopedic surgeons. The degree of necessity and content of support at the schools differed between A/HCH and OI. Remodeling of the lavatory, washbasin, and chair and support during swimming lessons were common in A/HCH patients. Support in school for OI patients was more frequent and included propelling wheelchairs, assisting in the use of the bathroom, and remodeling the lavatory. Most children were restricted from participating in physical education classes. Locomotion ability and the necessary support at school differed between A/HCH and OI. Support and advice from medical specialists who recognize disability of patients with skeletal dysplasias may improve patients' participation and education in schools. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. The etiology of short stature affects the clinical outcome of lower limb lengthening using external fixation. A systematic review of 18 trials involving 547 patients.

    Science.gov (United States)

    Kim, Seung-Ju; Pierce, Wendy; Sabharwal, Sanjeev

    2014-04-01

    Distraction osteogenesis (DO) has been used to gain height in short statured individuals. However, there have been no studies comparing the clinical outcome of limb lengthening based on the etiology of the short stature. We assessed whether different underlying diagnoses are associated with varied clinical outcomes in these patients. We performed a systematic review of the literature pertaining to lower limb lengthening using external fixation for short stature. Clinical outcomes including amount of lengthening, healing index (HI), and complications based on the underlying diagnosis for the short stature were documented. 18 clinical studies were included, with 547 patients who underwent 1,581 lower limb segment lengthening procedures. Mean follow-up was 4.3 years. The average age at lengthening was less for individuals with achondroplasia/hypochondroplasia (A/H) (14.5 years) than for those with Turner's syndrome (TS) (18.2 years) or with constitutional short stature (CSS) (21.7 years). Mean height gained was greater in patients with A/H (9.5 cm) than in those with TS (7.7 cm) or CSS (6.1 cm) group. The HI was better in A/H (30.8 days/cm) and CSS (32 days/cm) than in TS (45.1 days/cm). The reported complication rate per segment was lower for A/H (0.68) and TS (0.71) than for CSS (1.06). Patients with A/H tolerated larger amounts of lengthening with fewer complications than those with other diagnoses.

  19. Volume reduction of the jugular foramina in Cavalier King Charles Spaniels with syringomyelia

    Directory of Open Access Journals (Sweden)

    Schmidt Martin

    2012-09-01

    Full Text Available Abstract Background Understanding the pathogenesis of the chiari-like malformation in the Cavalier King Charles Spaniel (CKCS is incomplete, and current hypotheses do not fully explain the development of syringomyelia (SM in the spinal cords of affected dogs. This study investigates an unconventional pathogenetic theory for the development of cerebrospinal fluid (CSF pressure waves in the subarachnoid space in CKCS with SM, by analogy with human diseases. In children with achondroplasia the shortening of the skull base can lead to a narrowing of the jugular foramina (JF between the cranial base synchondroses. This in turn has been reported to cause a congestion of the major venous outflow tracts of the skull and consequently to an increase in the intracranial pressure (ICP. Amongst brachycephalic dog breeds the CKCS has been identified as having an extremely short and wide braincase. A stenosis of the JF and a consequential vascular compromise in this opening could contribute to venous hypertension, raising ICP and causing CSF jets in the spinal subarachnoid space of the CKCS. In this study, JF volumes in CKCSs with and without SM were compared to assess a possible role of this pathologic mechanism in the development of SM in this breed. Results Computed tomography (CT scans of 40 CKCSs > 4 years of age were used to create three-dimensional (3D models of the skull and the JF. Weight matched groups (7–10 kg of 20 CKCSs with SM and 20 CKCSs without SM were compared. CKCSs without SM presented significantly larger JF -volumes (median left JF: 0.0633 cm3; median right JF: 0.0703 cm3; p 3; median right JF: 0.0434 cm3; p Conclusion A stenosis of the JF and consecutive venous congestion may explain the aetiology of CSF pressure waves in the subarachnoid space, independent of cerebellar herniation, as an additional pathogenetic factor for the development of SM in this breed.

  20. Caracterización patogénica de los recién nacidos con malformaciones múltiples

    Directory of Open Access Journals (Sweden)

    Francisca Alonso Lotti

    1998-06-01

    Full Text Available El Registro Cubano de Malformaciones Congénitas (RECUMAC ha analizado 520 578 recién nacidos en 36 hospitales ginecobstétricos de 13 provincias de Cuba en un período de 12 años (de marzo de 1985 a diciembre de 1996, en el cual la prevalencia de malformaciones congénitas al nacimiento es de 179,8 por 10 000 nacimientos. El 24,6 % de los casos presentó 2 ó más malformaciones asociadas entre sí. Se realizó la clasificación de los multimalformados y los síndromes resultaron ser los más frecuentes. Entre los cromosómicos, el síndrome de Down ocupó el primer lugar, con una prevalencia al nacimiento de 7,8 por 10 000 nacimientos. En relación con los monogénicos heredados con modelos autosómicos dominante y recesivo la acondroplasia y el albinismo presentaron el mayor número de casos para una prevalencia al nacimiento de 0,44 y 0,21 por 10 000 nacimientos, respectivamente.The Cuban Registry of Congenital Malformations (CRCM has analyzed 520 578 newborns at 36 gynecobstetric hospitals in 13 provinces af Cuba for 12 years (from March, 1985 to December, 1996, in which the prevalence of malformations at birth is of 179.8 per 10 000 births. 24.6 % of the cases presented 2 or more malformations associated among themselves. The classification of those suffering from multimalformation was carried out and syndromes proved to be the most frequent. Within the cromosomic syndromes the Down´s syndrome was in the first place with a prevalence at birth of 7.8 per 10 000 births´. In connection with monogenic syndromes inherited with dominant and recessive autosomal models, achondroplasia and albinism had the highest number of cases for a prevalence at birth of 0.44 and 0.21 per 10 000 births, respectively.

  1. 胎儿肢骨发育异常18例产前诊断%Prenatal diagnose of abnormalities of fetal limb bone

    Institute of Scientific and Technical Information of China (English)

    宋晶; 王欣

    2010-01-01

    Objective To discuss the prenatal diagnosis of abnormalities of fetal limb bone.Methods We selected 18 cases which long bone of fetus less than 2SD of average volume of gestational weeks or long bone changed into angle or other fetus's abnormalities by first B-mode ultrasonic. All above cases was delivered at Capital Medical University of Obstetric and Gynecological Hospital during Jan. 2006 to Dec. 2009. We B-mode ultrasonic was used to measure fetus's biparietal diameter (BPD) ,femur length (FL) ,abdominal circumference(AC) ,head circumference(HC) ,humerus length (HL) ,amniotic fluid index (AFI) and structures of organ and calculated FL/AC, growth speed of long bone. The standard of achondroplasia is that FL and HL are less than 4SD of average of gestational weeks or FL/AC less than 0. 16. The standard of Osteogenesis Imperfecta is fetal long bone of fetus shows short and thick, curves into angle, fracture in uterus by X-ray, or skull shows thin or sink by X-ray. Results (1) By B-mode ultrasonic and X-ray exam of all 18 cases: 7 cases shows that HC >2SD, 10 cases shows too much amniotic fluid, 12 cases shows AFI > 18.0, 9 cases shows abnormalities of narrow cavitas thoracis, disordered vertebral column, or unusual architecture of heart. For cases 1 to 14 are achondroplasia, among which,11 cases are FL<4SD and HL<4SD, 2 cases are FL <3SD and HL <4SD, 1 case is not only FL <2SD and HL <3SD but also hydroncus all over the body of fetus. The growth velocity of long bone of fetus in all the 14 cases is more slowly than the normal rate. For all the above 14 cases, 12 cases FL/AC <0. 16, 1 case FL/AC =0. 19, 1 case FL/AC =0. 20. The length of femur or humerus is shorter than the normal rate and have other abnormalities the above last two cases. For case 15 and 16, they don't show any abnormalities of bone growth though one year's follow up studying. For case 17 and 18, they are osteogenesis imperfecta. (2) The result of fetal perinatal period fate and

  2. Seqüestro pulmonar extralobar: análise anatomopatológica de dois casos em natimortos e revisão da literatura Extralobar pulmonary sequestration: anatomical analysis of two cases in stillbirths and review of literature

    Directory of Open Access Journals (Sweden)

    Ítalo Martins de Oliveira

    2008-06-01

    Full Text Available O seqüestro pulmonar é definido como uma massa anormal de tecido pulmonar sem comunicação com a árvore brônquica. É anomalia rara, responsável por 0,15-6,45% das malformações pulmonares congênitas. Quando possui revestimento pleural próprio, chama-se seqüestro pulmonar extralobar (SPE. Este trabalho descreve dois casos de SPE em natimortos (NM com 32 (1 e 34 (2 semanas de gestação com diagnóstico clínico de hipoxia intra-uterina e adenomatose cística, respectivamente, e faz revisão da literatura. O diagnóstico envolveu análise ultra-sonográfica, sindrômica, macroscópica e microscópica dos NM. Foi observada massa supradiafragmática no hemitórax esquerdo ligada à aorta torácica (1 e ao diafragma (2. As MFs associadas foram agenesia tímica (2, hipoplasia pulmonar (2, pé torto congênito (1 e acondroplasia de membros (2. A microscopia evidenciou, nos dois casos, tecido pulmonar imaturo e pedículo vascularizado e inervado.Pulmonary sequestration represents an abnormal pulmonary mass that does not communicate with the tracheobronchial tree. It is a rare malformation (MF, accountable for 0.15%-6.45% of pulmonary congenital MFs. When it has its own pleural covering, it is called extralobar (EBPS. This work describes two cases of EBPS in stillbirths (SB, at 32 (1 and 34 (2 weeks' gestation, with clinical diagnosis of intrauterine hypoxia and cystic adenomatosis, respectively. It also reviews the literature on the subject. The diagnosis involved ultrasonographic, syndromic, macroscopic and microscopic analysis. The macroscopy showed a supradiaphragmatic mass in the left hemithorax linked to thoracic aorta (1 and diaphragm (2. The associated MFs were: thymic agenesis (2, pulmonary hypoplasia (2, clubfoot (1 and achondroplasia (2. Microscopy demonstrated, in both cases, immature pulmonary tissue and vascularized and innervated pedicle.

  3. Fibroblast growth factor expression in the postnatal growth plate.

    Science.gov (United States)

    Lazarus, Jacob E; Hegde, Anita; Andrade, Anenisia C; Nilsson, Ola; Baron, Jeffrey

    2007-03-01

    Fibroblast growth factor (FGF) signaling is essential for endochondral bone formation. Mutations cause skeletal dysplasias including achondroplasia, the most common human skeletal dysplasia. Most previous work in this area has focused on embryonic chondrogenesis. To explore the role of FGF signaling in the postnatal growth plate, we quantitated expression of FGFs and FGF receptors (FGFRs) and examined both their spatial and temporal regulation. Toward this aim, rat proximal tibial growth plates and surrounding tissues were microdissected, and specific mRNAs were quantitated by real-time RT-PCR. To assess the FGF system without bias, we first screened for expression of all known FGFs and major FGFR isoforms. Perichondrium expressed FGFs 1, 2, 6, 7, 9, and 18 and, at lower levels, FGFs 21 and 22. Growth plate expressed FGFs 2, 7, 18, and 22. Perichondrial expression was generally greater than growth plate expression, supporting the concept that perichondrial FGFs regulate growth plate chondrogenesis. Nevertheless, FGFs synthesized by growth plate chondrocytes may be physiologically important because of their proximity to target receptors. In growth plate, we found expression of FGFRs 1, 2, and 3, primarily, but not exclusively, the c isoforms. FGFRs 1 and 3, thought to negatively regulate chondrogenesis, were expressed at greater levels and at later stages of chondrocyte differentiation, with FGFR1 upregulated in the hypertrophic zone and FGFR3 upregulated in both proliferative and hypertrophic zones. In contrast, FGFRs 2 and 4, putative positive regulators, were expressed at earlier stages of differentiation, with FGFR2 upregulated in the resting zone and FGFR4 in the resting and proliferative zones. FGFRL1, a presumed decoy receptor, was expressed in the resting zone. With increasing age and decreasing growth velocity, FGFR2 and 4 expression was downregulated in proliferative zone. Perichondrial FGF1, FGF7, FGF18, and FGF22 were upregulated. In summary, we have

  4. Prenatal craniofacial development: new insights on normal and abnormal mechanisms.

    Science.gov (United States)

    Johnston, M C; Bronsky, P T

    1995-01-01

    multifactorial etiology. Genetic variations in TGF alpha s, RAR alpha s, NADH dehydrogenase, an enzyme involved in oxidative metabolism, and cytochrome P-450, a detoxifying enzyme, have been implicated as contributing genetic factors. Cigarette smoking, with the attendant hypoxia, is a probable contributing environmental factor. It seems likely that few clefts involve single major genes. In most cases, the pathogenesis appears to involve inadequate contact and/or fusion of the facial prominences or palatal shelves. Specific mutations in genes for different FGF receptor molecules have been identified for achondroplasia and Crouzon's syndrome, and in a regulatory gene (Msx2) for one type of craniosynostosis. Poorly co-ordinated control of form and size of structures, or groups of structures (e.g., teeth and jaws), by regulatory genes should do much to explain the very frequent "mismatches" found in malocclusions and other dentofacial "deformities". Future directions for research, including possibilities for prevention, are discussed.

  5. From Horus the child to Hephaestus who limps: a romp through history.

    Science.gov (United States)

    Aterman, K

    1999-03-01

    The question of why Hephaestus, the Greek god of smiths, limped has been the subject of much debate, mainly on mythological grounds. This debate extended also into the field of medical diagnosis, with attempts at defining the nature of the deformity that made the crippled Hephaestus the buffoon of the other Olympic gods. One problem encountered in these debates was the changes to which the ugly young Hephaestus was subjected with the passing of time-from a limping deformed youth to the later dignified and normal man. While some authors, largely influenced by poetic Greek texts and vase paintings, attributed the limp to talipes (club-feet), others pointed to certain features suggestive of achondroplasia. Since the image of the early Hephaestus is based mainly on the much earlier concept of the Egyptian god Ptah, who as the triune god of the resurrection sometimes is depicted as an achondroplastic dwarf (Ptah-Pataikos), the suggestion of the possible achondroplastic dwarf-like nature of the early Hephaestus is not implausible. It is supported by similarities in the image of Hephaestus to some features in other Egyptian gods, such as the domestic god Bes, the guardian of the new-born, and the Horus the Child or Harpocrates (Greek), yet another protector of youth and "the symbol of everything that is young and vigorous" [Budge, 1969: The Gods of the Egyptians, or Studies in Egyptian Mythology. Volume I.]. The characteristic feature of this child-god is the "lock of Harpocrates" on the right side of his head. That this lock can sometimes also be seen not only on the head of Ptah-Pataikos and of Bes but also on the young Hephaestus is highly suggestive of the Egyptian influence on his image. Recently, however, another interesting explanation of Hephaestus's limp has been suggested that may explain why the Egyptian influenced image of the early achondroplastic Hephaestus changed to the later, more Grecian view of the smith-god who hobbled because of club

  6. Estudo comparativo do nível de qualidade de vida entre sujeitos acondroplásicos e não-acondroplásicos Comparative study of quality of life level between achondroplasics and non-achondroplasics subjects

    Directory of Open Access Journals (Sweden)

    Mariana Pereira Cervan

    2008-01-01

    Full Text Available A acondroplasia é caracterizada como um distúrbio genético autossômico dominante que afeta a ossificação endocondral, constituindo uma das causas de nanismo. Entre as características está presente principalmente a baixa estatura e desproporção tronco/membros. Diante disso, o acondroplásico poderá se mostrar inferiorizado e insatisfeito com sua aparência física, influenciando, juntamente a outros fatores, na qualidade de vida (QV dessa população. OBJETIVO: Comparar o nível de QV entre sujeitos acondroplásicos e não-acondroplásicos. MÉTODO: Foram avaliados 21 indivíduos acondroplásicos, sendo nove homens e 13 mulheres, pareados por idade e gênero, a 21 não-acondroplásicos. O nível de QV foi estimado por meio do questionário WHOQOL-BREF. RESULTADOS: Na comparação entre sujeitos acondroplásicos e não acondroplásicos do gênero feminino constatou-se que no domínio físico as mulheres acondroplásicas apresentaram escore médio significativamente menor, enquanto na comparação entre os gêneros, o grupo de mulheres acondroplásicas apresentou escore médio significativamente menor que os homens acondroplásicos no domínio psicológico. CONCLUSÃO: No presente estudo, a QV não apresentou diferença entre os grupos, entretanto, nos domínios físico e psicológico, as mulheres acondroplásicas demonstraram menor satisfação com sua condição.Achondroplasia is characterized as an autosomal dominant genetic disturbance which affects the endochondral ossification which is a common cause of dwarfism syndrome. Among the characteristics the most common are the short stature and disproportional trunk/limbs. Thus, the achondroplasic subjects can face themselves inferior and not satisfied with their physical appearance, influencing, among other factors, the quality of life of this population. OBJECTIVE: To compare the quality of life level between achondroplasic and non-achondroplasic subjects. METHODS: Study with 21

  7. Desbalance redox en la infertilidad masculina Lack of Redox balance in male sterility

    Directory of Open Access Journals (Sweden)

    Akel Mallok

    2011-06-01

    between generation of reactive oxygen species and the antioxidants that may to cause damages or deformities in the spermatozoa and eventually male sterility. The reactive oxygen species are produced due to different mechanisms present in semen, motionless spermatozoa or with motility disorders, leukocytes and morphologically normal spermatozoa but functionally abnormal. Among these damages it is present the lipid peroxidation to spermatic membrane and the nuclear and mitochondrial DNA fragmentation. The damages of oxidative stress on DNA may also to cause disorders in offspring including cancer and achondroplasia. Lipid peroxidation leads to an alteration in the membrane affecting its structure and function. The human spermatozoon membrane contains a high proportion of poly-non-saturated fatty acids therefore its oversensitivity to lipid peroxidation is very high. The reactive oxygen species have different effects on spermatic cells, being a very controversial topic. The aim of present paper was to update readers on some of the biochemical features related to the production of reactive oxygen species and the diagnostic methods used to detect the human sterility.

  8. MANAGEMENT OF LUMBAR SPINAL CANAL STENOSIS

    Directory of Open Access Journals (Sweden)

    Mukhergee G. S

    2016-06-01

    Full Text Available BACKGROUND Spinal stenosis is one of the most common conditions in the elderly. It is defined as a narrowing of the spinal canal. The term stenosis is derived from the Greek word for narrow, which is “Stenos”. The first description of this condition is attributed to Antoine portal in 1803. Verbiest is credited with coining the term spinal stenosis and the associated narrowing of the spinal canal as its potential cause. [1-10] Kirkaldy–Willis subsequently described the degenerative cascade in the lumbar spine as the cause for the altered anatomy and pathophysiology in spinal stenosis. [11-15] If compression does not occur, the canal should be described as narrow but not stenotic. Some studies defined lumbar spinal stenosis as a “narrowing of the osteoligamentous vertebral canal and/or the intervertebral foramina causing compression of the thecal sac and/or the caudal nerve roots; at a single vertebral level, narrowing may affect the whole canal or part of it” (Postacchini 1983. This definition distinguished between disc herniation and stenosis. [16] . The most common type of spinal stenosis is caused by degenerative arthritis of the spine. Hypertrophy and ossification of the posterior longitudinal ligament which usually are confined to the cervical spine, and diffuse idiopathic skeletal hyperostosis (DISH syndrome also may result in an acquired form of spinal stenosis. Congenital forms caused by disorders such as achondroplasia and dysplastic spondylolisthesis are much less common. Congenital spinal stenosis usually is central and is evident or imaging studies. Idiopathic congenital narrowing usually involves the anteroposterior dimension of the canal secondary to short pedicles; the patient otherwise is normal. In contrast, in achondroplasia, the canal is narrowed in the anteroposterior plane owing to shortened pedicles and in lateral dimension because of diminished interpedicular distance. Acquired forms of spinal stenosis usually are

  9. Anestesia em anã acondroplásica obesa mórbida para gastroplastia redutora Anestesia en enana acondroplásica obesa mórbida para gastroplastia reductora Anesthesia for bariatric surgery in an achondroplastic dwarf with morbid obesity

    Directory of Open Access Journals (Sweden)

    Maria Angélica Abrão

    2009-02-01

    í la conducción de la anestesia.BACKGROUND AND OBJECTIVES: Achondroplasia is the most common

  10. Bloqueio bilateral do nervo pudendo para hemorroidectomia em paciente acondroplásico: relato de caso Bloqueo bilateral del nervio pudendo para hemorroidectomía en paciente acondroplásico: relato de caso Bilateral blockade of the pudend nerve to hemorrhoidectomy in achondroplasic patient: case report

    Directory of Open Access Journals (Sweden)

    Bruno Salomé de Morais

    2006-04-01

    ética espontánea. La anestesia de esos pacientes presenta varias particularidades. El objetivo del presente relato fue el de describir un caso de paciente acondroplásico, con previo historial de intervención quirúrgica de la columna para descompresión medular, sometido a Hemorroidectomía a través de bloqueo bilateral de los nervios pudendos. RELATO DEL CASO: Paciente del sexo masculino, 47 años, acondroplásico, que fue ingresado para la realización de hemorroidectomía.Al hacérsele el examen físico presentaba el cuello acortado con extensión limitada de la cabeza, Mallampati clase IV, distancia tireomentoniana de 6 cm y abertura de la boca de 3,5 cm. La columna vertebral presentaba cifosis torácica y lordosis lumbar acentuada, además de cicatriz quirúrgica en la región lumbar. Fue realizado el bloqueo bilateral de los nervios pudendos con ropivacaina a 1%, por vía transperineal, con una aguja aislada de 0,8 mm x 100 mm 21G (Stimuplex A100 BBraun, Melsungen, Germany conectada al estimulador de nervios periféricos (Stimuplex-DIG, BBraun.El paciente fue colocado en decúbito ventral y la cirugía iniciada después de 15 minutos da administración del anestésico. Durante todo el procedimiento, el paciente permaneció consciente y no relató ningún dolor o incomodidad. Hasta el momento del alta hospitalaria (22h después de la realización del bloqueo, el paciente no refirió dolor, incomodidad, náusea, vómito, bloqueo motor, retención o incontinencia urinaria. Después del alta, evolucionó bien presentando evacuación después de 31 horas de efectuada la cirugía. CONCLUSIONES: El caso mostró el uso del bloqueo bilateral de los nervios pudendos, con el auxilio del neuroestimulador como técnica anestésica aislada para la hemorroidectomía.BACKGROUND AND OBJECTIVES: The achondroplasic dwarfism or achondroplasia is the most common form of dwarfism and occurs, in most of the cases, as a result of spontaneous genetic alteration. The anesthesia in these