Tim Van Damme1, Alain Colige2, Delfien Syx1, Cecilia Giunta3, Uschi Lindert3, Marianne Rohrbach3, Omid Aryani4, Yasemin Alanay5, Pelin Özlem Simsek-Kiper6, Hester Y Kroes7, Koen Devriendt8, Marc Thiry9, Sofie Symoens1, Anne De Paepe1, Fransiska Malfait1. 1. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. 2. Laboratory of Connective Tissues Biology, Tour de Pathologie, GIGA-Cancer, University of Liège, Liège, Belgium. 3. Division of Metabolism, Connective Tissue Unit, University Children's Hospital and Children's Research Centre, Zurich, Switzerland. 4. Department of Medical Genetics, Special Medical Center, Tehran, Iran. 5. Pediatric Genetics Unit, Department of Pediatrics, Acibadem University School of Medicine, Istanbul, Turkey. 6. Department of Pediatric Genetics, Faculty of Medicine, Hacettepe University, Ankara, Turkey. 7. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 8. Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium. 9. 9Laboratory of Cell and Tissue Biology, GIGA-Neurosciences, University of Liège, Liège, Belgium.
Abstract
PURPOSE: The Ehlers-Danlos syndrome (EDS), dermatosparaxis type, is a recessively inherited connective tissue disorder caused by deficient activity of ADAMTS-2, an enzyme that cleaves the aminoterminal propeptide domain of types I, II, and III procollagen. Only 10 EDS dermatosparaxis patients have been reported, all presenting a recognizable phenotype with characteristic facial gestalt, extreme skin fragility and laxity, excessive bruising, and sometimes major complications due to visceral and vascular fragility. METHODS: We report on five new EDS dermatosparaxis patients and provide a comprehensive overview of the current knowledge of the natural history of this condition. RESULTS: We identified three novel homozygous loss-of-function mutations (c.2927_2928delCT, p.(Pro976Argfs*42); c.669_670dupG, p.(Pro224Argfs*24); and c.2751-2A>T) and one compound heterozygous mutation (c.2T>C, p.? and c.884_887delTGAA, p.(Met295Thrfs26*)) in ADAMTS2 in five patients from four unrelated families. Three of these displayed a phenotype that was strikingly milder than that of previously reported patients. CONCLUSION: This study expands the clinical and molecular spectrum of the dermatosparaxis type of EDS to include a milder phenotypic variant and stresses the importance of good clinical criteria. To address this, we propose an updated set of criteria that accurately captures the multisystemic nature of the dermatosparaxis type of EDS.Genet Med 18 9, 882-891.
PURPOSE: The Ehlers-Danlos syndrome (EDS), dermatosparaxis type, is a recessively inherited connective tissue disorder caused by deficient activity of ADAMTS-2, an enzyme that cleaves the aminoterminal propeptide domain of types I, II, and III procollagen. Only 10 EDS dermatosparaxis patients have been reported, all presenting a recognizable phenotype with characteristic facial gestalt, extreme skin fragility and laxity, excessive bruising, and sometimes major complications due to visceral and vascular fragility. METHODS: We report on five new EDS dermatosparaxis patients and provide a comprehensive overview of the current knowledge of the natural history of this condition. RESULTS: We identified three novel homozygous loss-of-function mutations (c.2927_2928delCT, p.(Pro976Argfs*42); c.669_670dupG, p.(Pro224Argfs*24); and c.2751-2A>T) and one compound heterozygous mutation (c.2T>C, p.? and c.884_887delTGAA, p.(Met295Thrfs26*)) in ADAMTS2 in five patients from four unrelated families. Three of these displayed a phenotype that was strikingly milder than that of previously reported patients. CONCLUSION: This study expands the clinical and molecular spectrum of the dermatosparaxis type of EDS to include a milder phenotypic variant and stresses the importance of good clinical criteria. To address this, we propose an updated set of criteria that accurately captures the multisystemic nature of the dermatosparaxis type of EDS.Genet Med 18 9, 882-891.
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