Molecular Diagnosis of CYP21 Mutations in Congenital Adrenal Hyperplasia

Abstract

Congenital adrenal hyperplasia (CAH) is an inherited disorder of steroid biosynthesis most often attributable to mutations in CYP21 (also termed CYP21A2) encoding the active steroid 21-hydroxylase enzyme. This review focuses on clinical and genetic aspects of CAH, and updates the reader on current methodology and applications for molecular genetic diagnosis. Genotyping patients with CAH has revealed > 50 mutations within CYP21, yet only 10 mutations account for approximately 95% of affected alleles. Many CYP21 mutations are gene conversions arising via transfer of gene sequences between the non-functional CYP21 pseudogene and CYP21. Phenotype is generally well-correlated with genotype. Historically, CAH has been divided into 3 types of disease: classic salt-wasting, classic simple virilizing (non-salt-wasting), and nonclassic. Recent findings support the notion that rather than discrete phenotypic categories, CAH is better represented as a continuum of phenotypes, from severe to mild. Molecular genetic diagnosis is most effectively employed now in prenatal diagnosis of classic CAH. As newborn screening for CAH becomes more widespread, genotyping may be implemented to resolve diagnostic difficulties encountered with hormonal testing. As automated methods of DNA diagnosis such as microarrays or gene chips are refined, it is likely that genetic screening will become less expensive and more readily available. The clinician should be aware of the potential for both false negatives and false positives with PCR-based gene screening. In short, whereas molecular genetic diagnosis is a valuable tool, it cannot replace clinical acumen and hormonal assays.

<b><i>CYP21A2</i></b> Gene Pathogenic Variants: A Multicenter Study on Genotype–Phenotype Correlation from a Portuguese Pediatric Cohort

“…An interesting finding is that we have detected a very low number of deletions or large conversions (6.7%) compared to the previously published in general population, 25% [3, 8], but once again similar to Spain [18]. …”

“…The conversion can involve more than 1 pseudogene variant, or “microconversions,” limited to a single-point variant. The remaining 20–25% of CAH may be due to recombination owing to unequal crossing over during meiosis that can lead to gene duplications and gross gene deletions involving CYP21A2 and other contiguous genes [3, 8]. …”

“…Several studies have shown a high correlation between genotype and phenotype in 21OHD [8-11], predominantly for the most severe and milder genotypes [12-14]. However, the largest and most heterogeneous cohort of CAH patients, who comprises data from 1507 families with at least 1 member diagnosed with CAH, found around 39% of nonconcordance between genotype and phenotype [13].…”

Mild Cutaneous Manifestation in Two Young Women with Extraordinary Hyperandrogenemia

“…It is often mistaken for idiopathic precocious pubarche in children or polycystic ovary syndrome in young women [22]. A boy with acne fulminans was described to have androgen excess derived from late-onset CAH [23].…”

Congenital Adrenal Hyperplasia, the Origin of Combined Infertility: A Case Report and a Review of Literature

“…However, the correlation between the genotype and the virilization phenotype assessed by Prader genital stages is less pronounced [6]. In addition, this association is weaker in cases of compound heterozygotes for two different mutations or those carrying mutations of intermediate severity and as a result prediction of phenotype from genotype tends to become more difficult [25][26][27][28][29][30][31].…”