New type of Ehlers-Danlos Syndrome (EDS) in Patients With Congenital Adrenal Hyperplasia.

New type of Ehlers-Danlos Syndrome (EDS) in Patients With Congenital Adrenal Hyperplasia

Rachel Morissette*, Wuyan Chen*, Ashley F. Perritt, Jennifer L. Dreiling, Andrew E. Arai, Vandana Sachdev, Hwaida Hannoush, Ashwini Mallappa, Zhi Xu, Nazli B. McDonnell, Martha Quezado, and Deborah P. Merke
Address all correspondence and requests for reprints to: Rachel Morissette, PhD, National Institutes of Health Clinical Center, Building 10, Room 1-2610, 10 Center Drive, Bethesda, MD 20892-1932. E-mail:
*R.M. and W.C. contributed equally to this work.
Received: May 08, 2015
Accepted: June 10, 2015
First Published Online: June 15, 2015

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.
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.
Main Outcome Measures:
The genetic and protein status of tenascin-X in phenotypic CAH-X patients was measured.
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.
CAH-X syndrome is commonly found in CAH due to 21-hydroxylase deficiency and may result from various etiological mechanisms.
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