Congenital Adrenal Hyperplasia and Ehlers-Danlos Syndrome.

Roxana Marino,Angélica Moresco,Alicia Belgorosky,Pablo Ramirez,Natalia Perez Garrido

doi:10.3389/fendo.2022.803226

Roxana Marino, Angélica Moresco + Show 3 more

Open Access

https://doi.org/10.3389/fendo.2022.803226

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Abstract

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.

Highlights

Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive enzymatic disorders, caused by a deficiency of one of the enzymes required for cortisol biosynthesis in the adrenal cortex
At present three different TNXA/TNXB chimeras have been described- CH1, CH2 and CH3-that differ in the junction site
Different studies on the CYP21A2 gene have improved our knowledge on TNXB-related disorders

Summary

INTRODUCTION

Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive enzymatic disorders, caused by a deficiency of one of the enzymes required for cortisol biosynthesis in the adrenal cortex. Most patients with the monoallelic form of CAH-X syndrome present with the clinical spectrum of hEDS with variable expression at different stages of life, predominantly characterized by GJH, mild skin hyperextensibility, and soft velvety skin, without abnormal scarring Related musculoskeletal complications, such as recurrent joint dislocations, pes planus, and chronic arthralgias, have been reported. Compared to TNXB haploinsufficiency caused by CAH-X CH1, a dominant negative effect related to CAH-X CH2 causes a more severe phenotype with increased joint and skin manifestations [12, 20] Gastrointestinal disorders, such as chronic gastroesophageal reflux and irritable bowel syndrome, hernias, and organ prolapse, are more frequently reported in patients that are heterozygous for CAHX CH2 than in those with CAH-X CH1. Further TNXB and CAH-X studies are necessary to define detailed surveillance guidelines for these and other long-term complications and to develop prevention strategies

CONCLUSIONS

Findings

ETHICS STATEMENT