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

Background: The Ehlers-Danlos syndrome is a heritable connective-tissue dis order caused by defects in fibrillar-collagen metabolism. Mutations in the type V collagen genes account for up to 50 percent of cases of classic Ehle rs-Danlos syndrome, but many other cases are unexplained. We investigated w hether 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, hype rmobility, or vascular types of the Ehlers-Danlos syndrome; 75 patients wit h psoriasis; 93 patients with rheumatoid arthritis; and 21 healthy persons for the presence of tenascin-X and tenascin-C by enzyme-linked immunosorben t assay. We examined the expression of tenascins and type V collagen in ski n by immunohistochemical methods and sequenced the tenascin-X gene. Results: Tenascin-X was present in serum from all normal subjects, all pati ents with psoriasis, all patients with rheumatoid arthritis, and 146 of 151 patients with the Ehlers-Danlos syndrome. Tenascin-X was absent from the s erum of the five remaining patients with Ehlers-Danlos syndrome, who were u nrelated. Tenascin-X deficiency was confirmed in these patients by analysis of skin fibroblasts and by immunostaining of skin. The expression of tenas cin-C and type V collagen was normal in these patients. All five of these p atients had hypermobile joints, hyperelastic skin, and easy bruising, witho ut 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 tr uncating 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 oth er 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. (N Engl J Med 2001;345:1167-75.) Copyright (C) 2001 Ma ssachusetts Medical Society.