Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia

Hum Mutat. 2016 Sep;37(9):893-7. doi: 10.1002/humu.23028. Epub 2016 Jul 8.


Some variants that cause autosomal-recessive congenital adrenal hyperplasia (CAH) also cause hypermobility type Ehlers-Danlos syndrome (EDS) due to the monoallelic presence of a chimera disrupting two flanking genes: CYP21A2, encoding 21-hydroxylase, necessary for cortisol and aldosterone biosynthesis, and TNXB, encoding tenascin-X, an extracellular matrix protein. Two types of CAH tenascin-X (CAH-X) chimeras have been described with a total deletion of CYP21A2 and characteristic TNXB variants. CAH-X CH-1 has a TNXB exon 35 120-bp deletion resulting in haploinsufficiency, and CAH-X CH-2 has a TNXB exon 40 c.12174C>G (p.Cys4058Trp) variant resulting in a dominant-negative effect. We present here three patients with biallelic CAH-X and identify a novel dominant-negative chimera termed CAH-X CH-3. Compared with monoallelic CAH-X, biallelic CAH-X results in a more severe phenotype with skin features characteristic of classical EDS. We present evidence for disrupted tenascin-X function and computational data linking the type of TNXB variant to disease severity.

Keywords: CAH-X; Ehlers-Danlos syndrome; biallelic; congenital adrenal hyperplasia; tenascin-X.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adrenal Hyperplasia, Congenital / genetics*
  • Adrenal Hyperplasia, Congenital / metabolism
  • Adult
  • Alleles
  • Collagen / metabolism
  • Ehlers-Danlos Syndrome / genetics*
  • Ehlers-Danlos Syndrome / metabolism
  • Female
  • Fibrillin-1 / metabolism
  • Gene Deletion*
  • Humans
  • Male
  • Pedigree
  • Steroid 21-Hydroxylase / genetics*
  • Tenascin / genetics*
  • Tenascin / metabolism
  • Young Adult


  • FBN1 protein, human
  • Fibrillin-1
  • Tenascin
  • tenascin X
  • Collagen
  • CYP21A2 protein, human
  • Steroid 21-Hydroxylase