title: The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations.
abstract: The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with bi-allelic mutations identified in CHST14 and DSE, respectively, encoding two enzymes necessary for dermatan sulfate (DS) biosynthesis. We report seven additional patients with MC-EDS from four unrelated families, including the follow-up of a sib-pair originally reported with the kyphoscoliotic type of EDS in 1975. Brachycephaly, a characteristic facial appearance, an asthenic build, hyperextensible and bruisable skin, tapering fingers, instability of large joints, and recurrent formation of large subcutaneous hematomas are always present. Three of seven patients had mildly elevated serum creatine kinase. The oldest patient was blind due to retinal detachment at 45 years and died at 59 years from intracranial bleeding; her affected brother died at 28 years from fulminant endocarditis. All patients in this series harbored homozygous, predicted loss-of-function CHST14 mutations. Indeed, DS was not detectable in fibroblasts from two unrelated patients with homozygous mutations. Patient fibroblasts produced higher amounts of chondroitin sulfate, showed intracellular retention of collagen types I and III, and lacked decorin and thrombospondin fibrils compared with control. A great proportion of collagen fibrils were not integrated into fibers, and fiber bundles were dispersed into the ground substance in one patient, all of which is likely to contribute to the clinical phenotype. This report should increase awareness for MC-EDS.
authors.affiliation: Department of Pediatrics I, Innsbruck Medical University, Innsbruck, Austria.|Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.affiliation: Department of Pediatrics, Division of Genetics, University of California, San Francisco, California.
authors.forename: Ben
authors.initials: B
authors.lastname: Li
authors.affiliation: Translational Medicine Branch NHLBI-NIH, Bethesda, Maryland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Krabichler
authors.affiliation: Division of Metabolism, Connective Tissue Unit and Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Rohrbach
authors.affiliation: Department of Pediatrics I, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.affiliation: Department of Pediatrics I, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Irene
authors.initials: I
authors.lastname: Fuchs
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, and Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Golas
authors.affiliation: Developmental Neurobiology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Katagiri
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, and Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Shira G
authors.initials: SG
authors.lastname: Ziegler
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, and Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Stanford University Medical Center, Stanford, California.
authors.forename: Yael
authors.initials: Y
authors.lastname: Wilnai
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, Medical Faculty, University of Brescia, Brescia, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Zoppi
authors.affiliation: Developmental Neurobiology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Geller
authors.affiliation: Division of Metabolism, Connective Tissue Unit and Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giunta
authors.affiliation: Department of Pediatrics, Division of Genetics, University of California, San Francisco, California.
authors.forename: Anne
authors.initials: A
authors.lastname: Slavotinek
authors.affiliation: Division of Metabolism, Connective Tissue Unit and Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Steinmann
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003240:Connective Tissue Diseases / Q000235:genetics / Q000473:pathology*; D020405:Dermis / Q000378:metabolism / Q000473:pathology*; D004535:Ehlers-Danlos Syndrome / Q000235:genetics / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D015238:Sulfotransferases / Q000235:genetics*; D055815:Young Adult
chemical_list: D015238:Sulfotransferases; C438013:dermatan-4-sulfotransferase-1
keywords: Ehlers-Danlos syndrome; N-acetylgalactosamine 4-O-sulfotransferase; adducted thumb; arthrogryposis; clubfoot; connective tissue; deficiency; dermatan sulfate; dermatan sulfate epimerase; myopathy; proteoglycan