A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency

N Engl J Med. 2001 Oct 18;345(16):1167-75. doi: 10.1056/NEJMoa002939.


Background: The Ehlers-Danlos syndrome is a heritable connective-tissue disorder caused by defects in fibrillar-collagen metabolism. Mutations in the type V collagen genes account for up to 50 percent of cases of classic Ehlers-Danlos syndrome, but many other cases are unexplained. We investigated whether the deficiency of the tenascins, extracellular-matrix proteins that are highly expressed in connective tissues, was associated with the Ehlers-Danlos syndrome.

Methods: We screened serum samples from 151 patients with the classic, hypermobility, or vascular types of the Ehlers-Danlos syndrome; 75 patients with psoriasis; 93 patients with rheumatoid arthritis; and 21 healthy persons for the presence of tenascin-X and tenascin-C by enzyme-linked immunosorbent assay. We examined the expression of tenascins and type V collagen in skin by immunohistochemical methods and sequenced the tenascin-X gene.

Results: Tenascin-X was present in serum from all normal subjects, all patients with psoriasis, all patients with rheumatoid arthritis, and 146 of 151 patients with the Ehlers-Danlos syndrome. Tenascin-X was absent from the serum of the 5 remaining patients with Ehlers-Danlos syndrome, who were unrelated. Tenascin-X deficiency was confirmed in these patients by analysis of skin fibroblasts and by immunostaining of skin. The expression of tenascin-C and type V collagen was normal in these patients. All five of these patients had hypermobile joints, hyperelastic skin, and easy bruising, without atrophic scarring. Tenascin-X mutations were identified in all tenascin-X-deficient patients; one patient had a homozygous tenascin-X gene deletion, one was heterozygous for the deletion, and three others had homozygous truncating point mutations, confirming a causative role for tenascin-X and a recessive pattern of inheritance.

Conclusions: Tenascin-X deficiency causes a clinically distinct, recessive form of the Ehlers-Danlos syndrome. This finding indicates that factors other than the collagens or collagen-processing enzymes can cause the syndrome and suggests a central role for tenascin-X in maintaining the integrity of collagenous matrix.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Arthritis, Rheumatoid / blood
  • DNA Mutational Analysis
  • Ehlers-Danlos Syndrome / blood
  • Ehlers-Danlos Syndrome / genetics*
  • Ehlers-Danlos Syndrome / pathology
  • Female
  • Gene Deletion
  • Genes, Recessive*
  • Humans
  • Male
  • Pedigree
  • Point Mutation
  • Psoriasis / blood
  • Reference Values
  • Skin / pathology
  • Tenascin / blood
  • Tenascin / deficiency*
  • Tenascin / genetics


  • Tenascin
  • tenascin X