Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia.

Abstract

CONTEXT:

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.

MAIN OUTCOME MEASURES:

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: 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, Deborah P Merke
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 100 Issue 8 Pg. E1143-52 (Aug 2015) ISSN: 1945-7197 [Electronic] United States
• PMID: 26075496 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Topics

• Adolescent
• Adrenal Hyperplasia, Congenital (complications, epidemiology, genetics)
• Adult
• Aged
• Child
• Child, Preschool
• Cohort Studies
• Ehlers-Danlos Syndrome (classification, complications, epidemiology, genetics)
• Female
• Humans
• Infant
• Male
• Middle Aged
• Phenotype
• Young Adult