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Musculocontractural Ehlers‐Danlos Syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan‐4‐sulfotransferase 1 encoding CHST14 gene
Author(s) -
Malfait Fransiska,
Syx Delfien,
Vlummens Philip,
Symoens Sofie,
Nampoothiri Sheela,
HermannsLê Trinh,
Van Laer Lut,
De Paepe Anne
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21355
Subject(s) - joint hypermobility , frameshift mutation , ehlers–danlos syndrome , missense mutation , genetics , biology , exome sequencing , sanger sequencing , disease gene identification , phenotype , medicine , endocrinology , dermatology , mutation , gene , anatomy
We present clinical and molecular findings of three patients with an EDS VIB phenotype from two consanguineous families. The clinical findings of EDS kyphoscoliotic type (EDS type VIA and B) comprise kyphoscoliosis, muscular hypotonia, hyperextensible, thin and bruisable skin, atrophic scarring, joint hypermobility and variable ocular involvement. Distinct craniofacial abnormalities, joint contractures, wrinkled palms, and normal urinary pyridinoline ratios distinguish EDS VIB from EDS VIA. A genome‐wide SNP scan and sequence analyses identified a homozygous frameshift mutation (NM_130468.2:c.145delG, NP_569735.1:p.Val49*) in CHST14 , encoding dermatan‐4‐sulfotransferase 1 (D4ST‐1), in two Turkish siblings. Subsequent sequence analysis of CHST14 identified a homozygous 20‐bp duplication (NM_130468.2:c.981_1000dup, NP_569735.1:p.Glu334Glyfs*107) in an Indian patient. Loss‐of‐function mutations in CHST14 were recently reported in adducted thumb–clubfoot syndrome (ATCS). Patients with ATCS present similar craniofacial and musculoskeletal features as the EDS VIB patients reported here, but lack the severe skin manifestations. By identifying an identical mutation in patients with EDS VIB and ATCS, we show that both conditions form a phenotypic continuum. Our findings confirm that the EDS‐variant associated with CHST14 mutations forms a clinical spectrum, which we propose to coin as “musculocontractural EDS” and which results from a defect in dermatan sulfate biosynthesis, perturbing collagen assembly. Hum Mutat 31:1–7, 2010. © 2010 Wiley‐Liss, Inc.