Congenital Adrenal Hyperplasia Owing to 21-Hydroxylase Deficiency

Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations

“…It is worth noting that mutation detection rate was higher in the classic forms of CAH than in NC-CAH, suggesting that heterozygotes might have been included in NC-CAH group [18]. On the other hand, the reason for not detecting the second diseasecausing mutation in patients with CYP21A2 deficiency could be additional CYP21A1P/CYP21A2 chimeras detectable only by Southern blotting and MLPA [19] or unidentified genetic variants located in the promoter region, deep intronic regions or at the polyadenylation sites [6]. It has been suggested that there is a necessity for evaluation of CYP21A2 regulatory regions and that CYP21A2 sequencing should be extended to −2000 bp to identify mutations in transcriptional regulatory region [20].…”

“…It was suggested that in some cases non-paternity could be responsible for this phenomenon [6]. The most frequent de novo mutation was c.290-13A/C>G, a mutation prevalently described as de novo mutation [33], but also a mutation that is most frequently found in Serbia.…”

“…These two genes, together with neighboring genes encoding complement proteins (C4A, C4B), serine/threonine nuclear proteins (RP1 and RP2) and tenascin (TNXA and B), are tandemly organized most frequently as an RCCX (RP-C4-CYP21-TNX) bimodule [5]. Complex structure of CYP21A2 locus, as well as the proximity and high sequence homology (96-98 %) between the active gene and the pseudogene, predisposes this region to frequent recombination errors resulting in unequal crossing over and gene conversions which transfer CYP21A1P mutations into the CYP21A2 gene [6]. Mutations created by mechanism of gene conversion account for up to 75 % of all CYP21A2 mutations, approximately 25 % are CYP21A1P/CYP21A2 chimeras resulting from unequal crossing over, while sporadic mutations, not copied from the pseudogene, are rare.…”

Clinical Outcome, Hormonal Status, Gonadotrope Axis, and Testicular Function in 219 Adult Men Born With Classic 21-Hydroxylase Deficiency. A French National Survey

“…So-called classic 21OHD is subclassified into salt-wasting (SW) and simple virilizing (SV) forms, depending on whether or not a clinical episode of salt-wasting dehydration occurs during the neonatal period (1)(2)(3)(4)(5)(6). Clinical manifestations of 21OHD are due to a combination of cortisol and aldosterone deficiency and accumulation of steroid precursors that are shunted into the androgen synthesis pathway (1,3,6), resulting in an androgen excess. In females, 21OHD causes prenatal masculinization of the external genitalia, resulting in more or less severe sexual ambiguity (1, 3, 6 -11).…”

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

“…The most prevalent form of CAH arises from steroid 21-hydroxylase enzyme deficiency, accounting for ∼90-95% of all cases (1,2). In contrast, CAH caused by steroid 11β-hydroxylase deficiency is considerably rare, with a prevalence of 5-8% (3), from which we estimate an overall frequency of 1 in 100,000 live births.…”