ESPE Abstracts

The contiguous gene deletion syndrome, CAH-X, was reported in an 8.5% of Congenital Adrenal Hyperplasia (CAH) patients with a TNXA/TNXB chimera. This results in deletions of CYP21A2 gene, encoding 21-hydroxylase necessary for cortisol biosynthesis, and TNXB, encoding the extracellular matrix glycoprotein tenascin-X (TNX). There are three TNXA/TNXB chimeras (CH1, CH2, CH3) that differ in the junction site, resulting in TNXB haploinsufficiency or dominant negative effect and an Ehlers Danlos Syndrome (EDS) phenotype. Recently, it has been described a biallelic form of CAH-X syndrome. The aim of this study was to analyze copy number variations and genetic status of TNXB gene in 58 CAH patients due to CYP21A2 deletion to determine the frequency of TNXB alterations in our population. A total of 58 unrelated CAH patients carriers of CYP21A2 gene deletion(65 alleles) were screened for TNXB defects. All the patients were analyzed for the presence of CH1 by MLPA technique evidenced by a 120 bp deletion in TNXB exon 35, and confirmed by exon 35 Sanger sequencing. In addition, all of them were screened for other TNXB alterations related to CH2 and CH3 by exon 40, 41 and 43 Sanger sequencing.

Results: The presence of TNXB deletion due to CH1 was found in 28/65 (43%) alleles carriers of CYP21A2 gene deletion. Moreover, when we analyze the presence of other chimeras (CH2 and CH3) 47/65 (75%) alleles were found to carry a contiguos deletion that extended into TNXB gene. Of 58 patients evaluated for copy number variations, haploinsufficiency of TNXB was found in 39 patients, two patients were homozygous for CH1 (biallelic form) and two patients were compound heterozygous for CH1 and CH2 (biallelic form).

Conclusion: A high frequency of TNXB alterations was found in CYP21A2 deletion carrier alleles in our population. MLPA and Sanger sequencing techniques resulted useful to characterize TNXB deletion. Accurate genotype-phenotype correlation remains to be elucidated in this cohort. Nevertheless, based on the high frequency of TNXB alterations in CYP21A2 deletion carrier alleles found in this study, we recommend to evaluate TNXB status in these patients, warranting assessment of connective tissue dysplasia including cardiologic alterations in positive cases.