title: 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.
abstract: 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.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. Fransiska.Malfait@UGent.be
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
authors.forename: Delfien
authors.initials: D
authors.lastname: Syx
authors.forename: Philip
authors.initials: P
authors.lastname: Vlummens
authors.forename: Sofie
authors.initials: S
authors.lastname: Symoens
authors.forename: Sheela
authors.initials: S
authors.lastname: Nampoothiri
authors.forename: Trinh
authors.initials: T
authors.lastname: Hermanns-Lê
authors.forename: Lut
authors.initials: L
authors.lastname: Van Laer
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000293:Adolescent; D001483:Base Sequence; D002648:Child; D003025:Clubfoot / Q000235:genetics; D003241:Consanguinity; D003286:Contracture / Q000235:genetics; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D004535:Ehlers-Danlos Syndrome / Q000235:genetics*; D005124:Eye Abnormalities; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D006801:Humans; D007593:Joint Instability / Q000151:congenital; D008297:Male; D016254:Mutagenesis, Insertional; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion; D012868:Skin Abnormalities; D015238:Sulfotransferases / Q000235:genetics*; D013933:Thumb / Q000002:abnormalities; D055815:Young Adult
chemical_list: D018076:DNA, Complementary; D015238:Sulfotransferases; C438013:dermatan-4-sulfotransferase-1