Clinical and radiographic study of 93 patients with a molecularly proven non-lethal type 2 collagen disorder. G. R. Mortier1,23, R. J. A. J. Nievelstein2, E. J. J. Verver3, V. Topsakal3, P. Van Dommelen4, K. Hoornaert5, M. Le Merrer6, A. Zankl7, M. E. H. Simon8, S. F. Smithson9, C. Marcelis10, B. Kerr11, J. Clayton-Smith11, E. Kinning12, S. Mansour13, F. Elmslie13, L. Goodwin14, A. H. van der Hout15, H. E. Veenstra-Knol15, J. C. Herkert15, A. M. Lund16, R. C. M. Hennekam17, A. Mégarbané18, M. M. Lees19, L. C. Wilson19, A. Male19, J. Hurst19,20, N. V. Knoers21, P. Coucke22,23, P. A. Terhal21 1) Dept Medical Genetics, Antwerp Univ Hosp, Antwerp (Edegem), Belgium; 2) Department of Radiology, University Medical Centre Utrecht, The Netherlands; 3) Department of Otorhinolaryngology and Head & Neck Surgery, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands; 4) Department of Life Style, TNO, Leiden, The Netherlands; 5) Department of Ophthalmology, University Hospital Ghent, Ghent, Belgium; 6) Department of Genetics, INSERM UMR_1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Hôpital Necker-Enfants Malades, Paris, France; 7) Discipline of Genetic Medicine,The University of Sydney, Sydney, Australia and Academic Department of Medical Genetics, Sydney Children's Hospital Network (Westmead), Sydney, Australia; 8) Department of Clinical Genetics, Erasmus Medical Centre, University Medical Centre, Rotterdam, The Netherlands; 9) Department of Clinical Genetics, St. Michaels Hospital, Bristol, United Kingdom; 10) Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands; 11) Manchester Centre For Genomic Medicine, University of Manchester, St Mary's Hospital, Manchester M139WL, United Kingdom; 12) Department of Clinical Genetics, Southern General Hospital, Glasgow G51 4TF, United Kingdom; 13) SW Thames Regional Genetics Service, St George's NHS Trust, London, United Kingdom; 14) Department of Genetics, Nepean Hospital, Penrith, Australia; 15) Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands; 16) Centre for Inherited Metabolic Diseases, Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark; 17) Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; 18) Unité de Génétique Médicale et Laboratoire Associé Institut National de la Santé et de la Recherche Médicale UMR-S910, Université Saint-Joseph, Beirut, Lebanon; 19) Department of Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, United Kingdom; 20) Department of Clinical Genetics, Churchill Hospital, Oxford, United Kingdom; 21) Department of Medical Genetics, Division of Biomedical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands; 22) Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium; 23) Ghent University, Ghent, Belgium.

   The type 2 collagenopathies are a clinically heterogeneous group of chondrodysplasias caused by a heterozygous mutation in the COL2A1 gene. With the goal to improve counseling and develop more evidence-based management guidelines, we performed a thorough analysis of the phenotypic features and clinical course in a group of 93 patients with a non-lethal type of spondyloepiphyseal dysplasia due to a heterozygous COL2A1 mutation. The study group included 51 females and 42 males. The identified mutations were 68 missense mutations substituting a glycine residue in the triple helical domain, 9 splice site mutations, 5 arginine-to-cysteine substitutions, 5 in-frame deletions or duplications and 6 mutations in the C-terminal propeptide. The majority of the patients (80/93) had disproportionate short stature with on radiographs features of SEDC (n=66), SEMD (n=5), Kniest dysplasia (n=7) or spondyloperipheral (Torrance-like) dysplasia (n=2). The remaining 13 patients had a mild SED phenotype with premature degenerative joint disease but normal stature, in some cases resembling Stickler syndrome or multiple epiphyseal dysplasia. Cleft palate was present in 22% of the patients. At birth, 9% of the children presented with a clubfoot deformity and 26% of the neonates experienced respiratory problems. Myopia was found in 45% of the patients. In at least two patients, myopia was detected in childhood despite a normal ophthalmological examination in infancy. A spontaneous retinal detachment occurred in 12% of the patients (median age: 14 years; youngest age: 3.5 years). Ophthalmological anomalies tended to be more common and severe in the splice site mutation group, rather mild and infrequent for glycine-to-serine substitutions, and absent in patients with an arginine-to-cysteine mutation. Complaints of hearing loss were reported in 32 cases (37%) of whom 17 needed hearing aids (6 of those patients had a splice site mutation). More than 50% of the patients underwent orthopedic surgery, usually for scoliosis (present in 48% of all patients), hip replacement or femoral osteotomy. Patients with a glycine to a non-serine substitution had generally a more severe skeletal phenotype. Odontoid hypoplasia was present in 56% of the patients. A correlation between odontoid hypoplasia and short stature was observed in our study group. Atlanto-axial instability, found in 28% of the patients who underwent flexion-extension films, rarely resulted in neurological problems.

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