Molecular Genetics of Congenital Adrenal Hyperplasia

Abstract Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders causing an impairment of cortisol biosynthesis. The phenotypic expression of different CAH forms depends on the underlying enzymatic defect. Steroid 21‐hydroxylase (CYP21A2) and 11β‐hydroxylase (CYP11B1) deficiencies only affect adrenal steroidogenesis, whereas 17α‐hydroxylase (CYP17A1) and 3β‐hydroxysteroid dehydrogenase type 2 (HSD3B2) also impair gonadal steroid biosynthesis. P450 oxidoreductase deficiency (PORD) manifests with apparent combined CYP17A1–CYP21A2 deficiency. In contrast to other CAH forms, PORD also causes skeletal malformations and genital ambiguity in both sexes. Three additional enzymatic defects have been traditionally classified as CAH. Steroidogenic acute regulatory protein (StAR) deficiency results in congenital lipoid adrenal hyperplasia (CLAH), and has the unique feature of adrenal and gonadal lipid accumulation. P450 side‐chain cleavage (CYP11A1) deficiency resembles the CLAH phenotype, but patients have normal‐sized or absent adrenals. Aldosterone synthase (CYP11B2) deficiency manifests with isolated aldosterone deficiency and normal cortisol synthesis. Key Concepts: Congenital adrenal hyperplasia (CAH) is one of the most common inherited metabolic disorders and comprises a group of autosomal recessive conditions. Molecular genetic analysis of the CYP21A2 gene is challenging due to a high rate of conversions and a multitude of possible complex rearrangements. Common mutations in CYP21A2 account for the majority of cases including gene deletions, chimeric genes, seven single point mutations, an eight base‐pair deletions and a cluster of point mutations. CYP21A2 gene duplications have to be considered in carriers of the p.Gln318X mutation to provide the correct molecular genetic diagnosis. Other forms of CAH are less often caused by common mutations, which are only found in specific populations. The genotype correlates overall well with the adrenal phenotype in all CAH forms, CLAH, CYP11A1 and CYP11B2 deficiencies. Although a trend exists, correlation between genotype and genital development is weaker, and it is particularly poor in CYP11A1 or 3β‐hydroxysteroid dehydrogenase type 2 deficiencies. Mutations in POR and CYP17A1 genes can be associated with clinically isolated 17,20‐lyase deficiency. CYP11A1 deficiency and CLAH due to StAR deficiency can manifest with a phenotype resembling familial glucocorticoid deficiency. Molecular genetic diagnosis is essential to provide the correct diagnosis and allow for appropriate clinical and genetic counselling.