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The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations.
Am J Med Genet A. 2016 Jan; 170A(1):103-15.AJ

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+Show Affiliations

Department of Pediatrics I, Innsbruck Medical University, Innsbruck, Austria. Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria.Department of Pediatrics, Division of Genetics, University of California, San Francisco, California.Translational Medicine Branch NHLBI-NIH, Bethesda, Maryland.Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria.Division of Metabolism, Connective Tissue Unit and Children's Research Center, University Children's Hospital, Zurich, Switzerland.Department of Pediatrics I, Innsbruck Medical University, Innsbruck, Austria.Department of Pediatrics I, Innsbruck Medical University, Innsbruck, Austria.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.Developmental Neurobiology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.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.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.Division of Medical Genetics, Department of Pediatrics, Stanford University Medical Center, Stanford, California.Division of Biology and Genetics, Department of Molecular and Translational Medicine, Medical Faculty, University of Brescia, Brescia, Italy.Developmental Neurobiology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.Division of Metabolism, Connective Tissue Unit and Children's Research Center, University Children's Hospital, Zurich, Switzerland.Department of Pediatrics, Division of Genetics, University of California, San Francisco, California.Division of Metabolism, Connective Tissue Unit and Children's Research Center, University Children's Hospital, Zurich, Switzerland.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26373698

Citation

Janecke, Andreas R., et al. "The Phenotype of the Musculocontractural Type of Ehlers-Danlos Syndrome Due to CHST14 Mutations." American Journal of Medical Genetics. Part A, vol. 170A, no. 1, 2016, pp. 103-15.
Janecke AR, Li B, Boehm M, et al. The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations. Am J Med Genet A. 2016;170A(1):103-15.
Janecke, A. R., Li, B., Boehm, M., Krabichler, B., Rohrbach, M., Müller, T., Fuchs, I., Golas, G., Katagiri, Y., Ziegler, S. G., Gahl, W. A., Wilnai, Y., Zoppi, N., Geller, H. M., Giunta, C., Slavotinek, A., & Steinmann, B. (2016). The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations. American Journal of Medical Genetics. Part A, 170A(1), 103-15. https://doi.org/10.1002/ajmg.a.37383
Janecke AR, et al. The Phenotype of the Musculocontractural Type of Ehlers-Danlos Syndrome Due to CHST14 Mutations. Am J Med Genet A. 2016;170A(1):103-15. PubMed PMID: 26373698.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations. AU - Janecke,Andreas R, AU - Li,Ben, AU - Boehm,Manfred, AU - Krabichler,Birgit, AU - Rohrbach,Marianne, AU - Müller,Thomas, AU - Fuchs,Irene, AU - Golas,Gretchen, AU - Katagiri,Yasuhiro, AU - Ziegler,Shira G, AU - Gahl,William A, AU - Wilnai,Yael, AU - Zoppi,Nicoletta, AU - Geller,Herbert M, AU - Giunta,Cecilia, AU - Slavotinek,Anne, AU - Steinmann,Beat, Y1 - 2015/09/16/ PY - 2014/11/11/received PY - 2015/09/03/accepted PY - 2015/9/17/entrez PY - 2015/9/17/pubmed PY - 2016/10/14/medline KW - Ehlers-Danlos syndrome KW - N-acetylgalactosamine 4-O-sulfotransferase KW - adducted thumb KW - arthrogryposis KW - clubfoot KW - connective tissue KW - deficiency KW - dermatan sulfate KW - dermatan sulfate epimerase KW - myopathy KW - proteoglycan SP - 103 EP - 15 JF - American journal of medical genetics. Part A JO - Am J Med Genet A VL - 170A IS - 1 N2 - 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. SN - 1552-4833 UR - https://www.unboundmedicine.com/medline/citation/26373698/The_phenotype_of_the_musculocontractural_type_of_Ehlers_Danlos_syndrome_due_to_CHST14_mutations_ L2 - https://doi.org/10.1002/ajmg.a.37383 DB - PRIME DP - Unbound Medicine ER -