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Terhal P.A.,University Utrecht | Van Dommelen P.,TNO | Le Merrer M.,University of Paris Descartes | Zankl A.,University of Queensland | And 17 more authors.
American Journal of Medical Genetics, Part C: Seminars in Medical Genetics | Year: 2012

From data collected via a large international collaborative study, we have constructed a growth chart for patients with molecularly confirmed congenital spondylo-epiphyseal dysplasia (SEDC) and other COL2A1 related dysplasias. The growth chart is based on longitudinal height measurements of 79 patients with glycine substitutions in the triple-helical domain of COL2A1. In addition, measurements of 27 patients with other molecular defects, such as arginine to cysteine substitutions, splice mutations, and mutations in the C-terminal propeptide have been plotted on the chart. Height of the patients progressively deviate from that of normal children: compared to normal WHO charts, the mean length/height is -2.6 SD at birth, -4.2 SD at 5 years, and -5.8 SD in adulthood. The mean adult height (male and female combined) of patients with glycine substitutions in the triple-helical region is 138.2cm but there is a large variation. Patients with glycine to cysteine substitutions tend to cluster within the upper part of the chart, while patients with glycine to serine or valine substitutions are situated between +1 SD and -1 SD. Patients with carboxy-terminal glycine substitutions tend to be shorter than patients with amino-terminal substitutions, while patients with splice mutations are relatively tall. However, there are exceptions and specific mutations can have a strong or a relatively mild negative effect on growth. The observation of significant difference in adult height between affected members of the same family indicates that height remains a multifactorial trait even in the presence of a mutation with a strong dominant effect. © 2012 Wiley Periodicals, Inc.


Terhal P.A.,University Utrecht | Nievelstein R.J.A.J.,University Utrecht | Verver E.J.J.,University Utrecht | Topsakal V.,University Utrecht | And 56 more authors.
American Journal of Medical Genetics, Part A | Year: 2015

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n=64), others having SEMD (n=5), Kniest dysplasia (n=7), spondyloperipheral dysplasia (n=2), or Torrance-like dysplasia (n=2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders. © 2015 Wiley Periodicals, Inc.


Brice G.,SW Thames Regional Genetics Service | Ostergaard P.,Human Genetics Research Center | Jeffery S.,Human Genetics Research Center | Gordon K.,St George's, University of London | And 2 more authors.
Clinical Genetics | Year: 2013

Oculodentodigital syndrome (ODD; OMIM 164200) is a congenital condition with phenotypic features most commonly affecting the face, eyes, dentition and digits. The condition is caused by mutations in the GJA1 gene on chromosome 6. GJA1 codes for connexin 43, a gap junction protein important in providing cell to cell communication and is expressed in lymphatic valves. We present a patient with a clinical and molecular diagnosis of ODD and lower limb lymphoedema. Sanger sequencing of family members confirmed that the missense, p.K206R, GJA1 mutation segregated with the phenotype suggestive of causality. To our knowledge this association has not been reported previously. This is therefore the second connexin gene associated with a lymphoedema phenotype after the recent publication of GJC2 (connexin 47) as a cause of four limb lymphoedema. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Baple E.L.,SW Thames Regional Genetics Service | Baple E.L.,Salisbury District Hospital | Poole R.L.,University of Southampton | Poole R.L.,Salisbury District Hospital | And 8 more authors.
European Journal of Human Genetics | Year: 2011

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are caused by genetic and epigenetic mutations of the imprinted gene cluster on chromosome 15q13. Although the imprinting mutations causing PWS and AS are essentially opposite in nature, remarkably, a small number of patients have been reported with clinical features of PWS but epigenetic mutations consistent with AS. We report here a patient who presented with clinical features partially consistent with both PWS and Beckwith-Wiedemann syndrome (BWS). Epimutations were found at both the AS/PWS and BWS loci, and additionally at the H19, PEG3, NESPAS and GNAS loci. This patient is therefore the first described case with a primary epimutation consistent with AS accompanied by hypomethylation of other imprinted loci. © 2011 Macmillan Publishers Limited All rights reserved.


PubMed | SW Thames Regional Genetics Service
Type: Case Reports | Journal: European journal of human genetics : EJHG | Year: 2011

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are caused by genetic and epigenetic mutations of the imprinted gene cluster on chromosome 15q13. Although the imprinting mutations causing PWS and AS are essentially opposite in nature, remarkably, a small number of patients have been reported with clinical features of PWS but epigenetic mutations consistent with AS. We report here a patient who presented with clinical features partially consistent with both PWS and Beckwith-Wiedemann syndrome (BWS). Epimutations were found at both the AS/PWS and BWS loci, and additionally at the H19, PEG3, NESPAS and GNAS loci. This patient is therefore the first described case with a primary epimutation consistent with AS accompanied by hypomethylation of other imprinted loci.

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