Congenital Adrenal Hyperplasia and Ehlers-Danlos Syndrome

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.

Keywords: CAH-X; CYP21A2; Ehlers-Danlos Syndrome; TNXB; congenital adrenal hyperplasia.

Figure 1

Genomic organization of the CYP21 locus on chromosome 6p21.1-21.3: The functional CYP21A2 gene and its non-functional CYP21A1P pseudogene are arranged in tandem repeat with the two C4 genes that encode factor four of the complement system, the serine–threonine nuclear protein kinase active gene RP1 (STK19) and a truncated pseudogene RP2 (STK19P). The functional TNXB and the TNXA pseudogene are located on the complement strand. Schematic representation of a 30-kb deletion as a result of unequal crossover during meiosis and the formation of the three described TNXA/TNXB chimeras (CH1, CH2 and CH3), which differ in the junction site. CH1 is characterized by a 120-bp deletion in exon and intron 35 carried over from TNXA pseudogene sequences. CH2 lacks this deletion but contains a pseudogene-derived variant c.12174C>G (p.Cys4058Trp) in TNXB exon 40. CH3 is characterized by the presence of any variant of a cluster of three pseudogene-derived variants (exon 41: c.12218G>A, p.Arg4073His; exon 43: c.12514G>A, p.Asp4172Asn and c.12524G>A, p.Ser4175Asn). These three pseudogene-derived variants do not always co-segregate in the three chimeras. TNXB gene exons are represented in cyan and TNXA gene exons in purple. The red arrow indicates a 120-bp deletion in exon 35 and grey arrows indicate different pseudogene-derived variants. CH1: TNXA/TNXB chimera 1. CH2: TNXA/TNXB chimera 2. CH3: TNXA/TNXB chimera 3.

Figure 2

Clinical evaluation of CAH-X Syndrome patients: (A) Generalized joint hypermobility Beighton score: 1) fifth finger extension test, 2) wrist flexion thumb abduction test, 3) elbow extension test, 4) trunk and hip flexion test, and 5) knee extension test. (B) Skin extensibility can be measured by lifting the cutaneous and subcutaneous layers of the skin and is considered hyperextensible if it can be stretched over 1.5 cm at the forearm and the dorsum of hands, and 3 cm for neck, elbow, and knees. Photographs shown belong to a biallelic CAH-X patient (compound heterozygous for CH1 and CH2).