title: Extracellular matrix and platelet function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in the CHST14 gene.
abstract: We report on a consanguineous, Afghani family with two sisters affected with characteristic facial features, multiple contractures, progressive joint and skin laxity, hemorrhagic diathesis following minor trauma and multisystem fragility-related manifestations suggestive of a diagnosis of musculocontractural Ehlers-Danlos syndrome (EDS). This novel form of connective tissue disorder was recently reported in patients of Japanese, Turkish, and Indian descent who were formerly classified as having EDS type VIB and has now been recognized to be a part of spectrum including patients previously classified as having adducted thumb-clubfoot syndrome. We identified a previously unreported mutation in the CHST14 gene, which codes for the enzyme dermatan 4-O-sulfotransferase. We discuss the prenatal presentation, detailed clinical manifestations, and neurological findings in two sisters with this newly described musculocontractural EDS-CHST14 type. We demonstrate that fibroblasts from one of our patients produce more chondroitin sulfate than normal and show lower than normal deposition of collagens I and II and fibrillin 1-containing microfibrills. These findings suggest that the imbalance in the glycosaminoglycan content in developing tissues might interfere with normal deposition of other extracellular matrix components and ultimately contribute to the development of the phenotype observed in these patients. Furthermore, we ruled out the contribution of intrinsic platelet factors to the bleeding diathesis observed in some affected individuals.
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada. roberto.mendoza@sickkids.ca
authors.forename: Roberto
authors.initials: R
authors.lastname: Mendoza-Londono
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Walter H A
authors.initials: WH
authors.lastname: Kahr
authors.forename: Aleksander
authors.initials: A
authors.lastname: Hinek
authors.forename: Susan
authors.initials: S
authors.lastname: Blaser
authors.forename: Lucie
authors.initials: L
authors.lastname: Dupuis
authors.forename: Elaine
authors.initials: E
authors.lastname: Goh
authors.forename: Ramses
authors.initials: R
authors.lastname: Badilla-Porras
authors.forename: Andrew
authors.initials: A
authors.lastname: Howard
authors.forename: Laureane
authors.initials: L
authors.lastname: Mittaz
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafe
mesh_terms: D001792:Blood Platelets / Q000378:metabolism* / Q000648:ultrastructure; D002648:Child; D002675:Child, Preschool; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D019066:Facies; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007223:Infant; D009154:Mutation; D010641:Phenotype; D010974:Platelet Aggregation; D010976:Platelet Count; D015238:Sulfotransferases / Q000235:genetics*
chemical_list: D015238:Sulfotransferases; C438013:dermatan-4-sulfotransferase-1