Congenital Adrenal Hyperplasia and Ehlers-Danlos Syndrome.

Congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency is an autosomal recessive disorder. The 21-hydroxylase enzyme P450c21 is encoded by the CYP21A2 gene located on chromosome 6p21.33 within the HLA major histocompatibility complex. This locus also contains the CYP21A1P, a non-functional pseudogene, that is highly homologous to the CYP21A2 gene. Other duplicated genes are C4A and C4B, that encode two isoforms of complement factor C4, the RP1 gene that encodes a serine/threonine protein kinase, and the TNXB gene that, encodes the extracellular matrix glycoprotein tenascin-X (TNX). TNX plays a role in collagen deposition by dermal fibroblasts and is expressed in the dermis of the skin and the connective tissue of the heart and skeletal muscle. During meiosis, misalignment may occur producing large gene deletions or gene conversion events resulting in chimeric genes. Chimeric recombination may occur between TNXB and TNXA. Three TNXA/TNXB chimeras have been described that differ in the junction site (CH1 to CH3) and result in a contiguous CYP21A2 and TNXB gene deletion, causing CAH-X syndrome. TNXB deficiency is associated with Ehlers Danlos syndrome (EDS). EDS comprises a clinically and genetically heterogeneous group of connective tissue disorders. As molecular analysis of the TNXB gene is challenging, the TNX-deficient type EDS is probably underdiagnosed. In this minireview, we will address the different strategies of molecular analysis of the TNXB-gene, as well as copy number variations and genetic status of TNXB in different cohorts. Furthermore, clinical features of EDS and clinical recommendations for long-term follow-up are discussed.

Ehlers-Danlos Syndrome: Molecular and Clinical Characterization of TNXA/TNXB Chimeras in Congenital Adrenal Hyperplasia.

CONTEXT: The syndrome CAH-X is due to a contiguous gene deletion of CYP21A2 and TNXB resulting in TNXA/TNXB chimeras. OBJECTIVE: To analyze TNXB gene status and to clinically evaluate the Ehlers-Danlos syndrome phenotype in a large cohort of Argentine congenital adrenal hyperplasia (CAH) patients to assess the prevalence of this condition in our population. METHODS: TNXB gene analysis was performed in 66 nonrelated CAH patients that were carriers of the CYP21A2 gene deletion. A molecular strategy based on multiplex ligation-dependent probe amplification and Sanger sequencing analysis was developed allowing for the detection of different, previously described TNXA/TNXB chimeras, named CH1, CH2, and CH3. The main outcome measures were TNXB status of CAH patients that were carriers of the CYP21A2 deletion in the homozygous or heterozygous state. RESULTS: TNXA/TNXB CH1 was found in 41%, CH2 in 29%, and CH3 in 1% of nonrelated alleles carrying the CYP21A2 deletion. Thus, overall 71% of alleles were found to carry a contiguous gene deletion. Sixty-seven percent of patients analyzed had a monoallelic form and 6% a biallelic form. All patients with the biallelic form had severe skin hyperextensibility and generalized joint hypermobility. CONCLUSION: Based on the high frequency of TNXB alterations found in CYP21A2 deletion carrier alleles, we recommend evaluating TNXB status in these patients, and assessing connective tissue dysplasia, including cardiologic alterations in positive cases. The number of patients undergoing cardiological evaluation should be expanded to determine the incidence of structural and functional abnormalities in this cohort.