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Cited by 122Connective tissue disorders researchProteoglycans and glycosaminoglycans researchCongenital limb and hand anomalies

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

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Malfait, Fransiska, Syx, Delfien, Vlummens, Philip, Symoens, Sofie, Nampoothiri, Sheela, Hermanns-Lê, Trinh, Van Laer, Lut, De Paepe, Anne·2010·Human Mutation
DOI 10.1002/humu.21355
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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.

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  • Malfait et al. [2010] concluded that patients with ATCS or EDS Kosho type had a single clinical condition, termed Musculocontractural EDS (MCEDS).

    “The authors concluded that these patients and those diagnosed with ATCS or EDS, Kosho type had a single clinical condition, which they termed “Musculocontractural EDS (MCEDS)””

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al., 2010

  • EDS caused by D4ST1 deficiency was initially reported as three independent conditions, ATCS, EDS Kosho Type, and musculocontractural EDS, all now concluded to be a single clinical entity.

    “EDS caused by D4ST1 deficiency has initially been reported as three independent conditions: A rare type of arthrogryposis syndrome, “adducted thumbclubfoot syndrome (ATCS)”; a specific type of EDS, “EDS, Kosho Type (EDSKT)”; and a subset of kEDS without lysyl hydroxylase deficiency, “musculocontractural EDS (MCEDS),” all of which are now concluded to be a single clinical entity”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al., 2010

  • Malfait et al. [2010] found mutations in CHST14 through homozygosity mapping in two Turkish sisters and an Indian girl, both with parental consanguinity.

    “Malfait et al. [2010] found mutations in CHST14 through homozygosity mapping in two Turkish sisters and an Indian girl, both with parental consanguinity.”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al., 2010

  • Hydronephrosis was caused by renal ptosis in one patient, who underwent laparoscopic placement of a ureteral stent, complicated by severe hemorrhage due to tissue fragility.

    “It was caused by renal ptosis in one patient, who underwent laparoscopic placement of a ureteral stent, complicated by severe hemorrhage due to tissue fragility [Malfait et al., 2010].”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al., 2010

  • Complications associated with gastrointestinal malformations included a common mesentery, spontaneous volvulus of the small intestine associated with absent gastrocolic omentum, and duodenal obstruction due to malrotation.

    “Complications associated with gastrointestinal malformations included a common mesentery, spontaneous volvulus of the small intestine associated with absent gastrocolic omentum [Janecke et al., 2001], and duodenal obstruction due to malrotation [Malfait et al., 2010].”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al., 2010

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Authors
Malfait, F., Syx, D., Vlummens, P., Symoens, S., Nampoothiri, S., Hermanns-Lê, T., Van Laer, L., & De Paepe, A.
Affiliations
  • Ghent University Hospital (BE)
  • Amrita Institute of Medical Sciences and Research Centre (IN)
Corresponding author
Malfait, Fransiska
ORCID
Venue
Human Mutation
Publisher
Wiley
Published
2010-10-28
Volume
31
Issue
11
Pages
1233-1239
ISSN
1059-7794 (ISSN-L)
DOI
10.1002/humu.21355
OpenAlex
W2066747545
Cited by
122
References
8
Citations by year
2026: 3 · 2025: 4 · 2024: 4 · 2023: 7 · 2022: 8 · 2021: 12 · 2020: 9 · 2019: 5 · 2018: 8 · 2017: 7 · 2016: 3 · 2015: 10 · 2014: 9 · 2013: 12 · 2012: 12
FWCI
5.94
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 1769 d)
Locations
  • Human Mutation (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
  • ORBi (University of Liège) (submittedVersion)
  • Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
Funders
  • Fonds Wetenschappelijk Onderzoek
  • Universiteit Gent
  • Vlaamse regering
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
Keywords
loss-of-function mutations, homozygous frameshift mutation, consanguineous family, phenotypic continuum, kyphoscoliosis, joint contractures, collagen self-assembly, genotype-phenotype correlation
MeSH terms
Abnormalities, Multiple, Adolescent, Base Sequence, Child, Clubfoot, Consanguinity, Contracture, DNA Mutational Analysis, Ehlers-Danlos Syndrome, Eye Abnormalities, Female, Genes, Recessive, Humans, Joint Instability, Male, Pedigree, Phenotype, Skin Abnormalities, Thumb, Sulfotransferases, Mutagenesis, Insertional, Frameshift Mutation, Sequence Deletion, DNA, Complementary, Young Adult

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