Measurement of serum tenascin-X in patients with congenital adrenal hyperplasia at risk for Ehlers-Danlos contiguous gene deletion syndrome CAH-X

Abstract

Objective: Approximately 10% of patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency carry a mutation that disrupts CYP21A2 and the flanking TNXB gene resulting in CAH-X, a contiguous gene deletion syndrome. TNXB encodes tenascin-X (TNX), an extracellular matrix glycoprotein that plays an important role in collagen organization. TNXB impairment is associated with Ehlers-Danlos syndrome. Symptoms include joint hypermobility, hernias and cardiac defects. We measured serum TNX using an antibody targeting the amino-terminal of the TNX protein in 161 subjects, including extensively genotyped and phenotyped CAH patients, their relatives, and healthy controls.

Results: We evaluated the potential of serum TNX as a screening tool for CAH-X. CAH-X patients, especially haploinsufficient patients carrying the TNXA-TNXB chimeric gene CAH-X-CH-1 showed reduced TNX levels compared to controls (P < 0.05). TNX levels were similar in all subjects carrying a TNXB mutation. However, CAH patients who did not harbor a TNXB mutation also had reduced TNX compared to controls (P < 0.001). Thus, measuring serum TNX is not an effective screen for CAH-X amongst patients with CAH. TNXB genotyping is recommended for CAH patients who have symptoms of a connective tissue disorder. Epigenetic factors that influence TNX expression require further study.

Keywords: CYP21A2; Congenital adrenal hyperplasia; Ehlers–Danlos syndrome; TNXB; Tenascin-X.

Fig. 1

Serum tenascin-X in healthy volunteers, patients with CAH and different CAH-X patient groups. Box plots represent the median (interquartile range) of absolute serum TNX concentrations. *P < 0.05, **P < 0.001, as determined by Kruskal–Wallis test. Comparisons between other groups were not significant

Fig. 2

Serum tenascin-X according to the CAH phenotype. Box plots represent the median (interquartile range) of absolute serum TNX concentrations. SW: salt-walting, SV: simple virilizing, NC: non-classic