title: Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia.
abstract: BACKGROUND
  The contiguous gene deletion syndrome (CAH-X) was described in a subset (7%) of congenital adrenal hyperplasia (CAH) patients with a TNXA/TNXB chimera, resulting in deletions of CYP21A2, encoding 21-hydroxylase necessary for cortisol biosynthesis, and TNXB, encoding the extracellular matrix glycoprotein tenascin-X (TNX). This TNXA/TNXB chimera is characterized by a 120-bp deletion in exon 35 and results in TNXB haploinsufficiency, disrupted TGF-β signaling, and an Ehlers Danlos syndrome phenotype.
  
  
  OBJECTIVE
  The objective of the study was to determine the genetic status of TNXB and resulting protein defects in CAH patients with a CAH-X phenotype but not the previously described TNXA/TNXB chimera. Design, Settings, Participants, and Intervention: A total of 246 unrelated CAH patients were screened for TNXB defects. Genetic defects were investigated by Southern blotting, multiplex ligation-dependent probe amplification, Sanger, and next-generation sequencing. Dermal fibroblasts and tissue were used for immunoblotting, immunohistochemical, and coimmunoprecipitation experiments.
  
  
  METHODS
  The genetic and protein status of tenascin-X in phenotypic CAH-X patients was measured.
  
  
  RESULTS
  Seven families harbor a novel TNXB missense variant c.12174C>G (p.C4058W) and a clinical phenotype consistent with hypermobility-type Ehlers Danlos syndrome. Fourteen CAH probands carry previously described TNXA/TNXB chimeras, and seven unrelated patients carry the novel TNXB variant, resulting in a CAH-X prevalence of 8.5%. This highly conserved pseudogene-derived variant in the TNX fibrinogen-like domain is predicted to be deleterious and disulfide bonded, results in reduced dermal elastin and fibrillin-1 staining and altered TGF-β1 binding, and represents a novel TNXA/TNXB chimera. Tenascin-X protein expression was normal in dermal fibroblasts, suggesting a dominant-negative effect.
  
  
  CONCLUSIONS
  CAH-X syndrome is commonly found in CAH due to 21-hydroxylase deficiency and may result from various etiological mechanisms.
authors.affiliation: Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Rachel
authors.initials: R
authors.lastname: Morissette
authors.affiliation: Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Wuyan
authors.initials: W
authors.lastname: Chen
authors.affiliation: Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Ashley F
authors.initials: AF
authors.lastname: Perritt
authors.affiliation: Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Dreiling
authors.affiliation: Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Arai
authors.affiliation: Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Vandana
authors.initials: V
authors.lastname: Sachdev
authors.affiliation: Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Hwaida
authors.initials: H
authors.lastname: Hannoush
authors.affiliation: Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Mallappa
authors.affiliation: Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Nazli B
authors.initials: NB
authors.lastname: McDonnell
authors.affiliation: Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Martha
authors.initials: M
authors.lastname: Quezado
authors.affiliation: Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Deborah P
authors.initials: DP
authors.lastname: Merke
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000150:complications* / Q000453:epidemiology / Q000235:genetics; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004535:Ehlers-Danlos Syndrome / Q000145:classification* / Q000150:complications* / Q000453:epidemiology / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D055815:Young Adult