Chapter 3A - Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency

Abstract

Congenital adrenal hyperplasia (CAH), the most common cause of disorder of sexual development (DSD) in females, refers to a group of autosomal recessive genetic disorders that results in defective steroidogenesis. Approximately 95% of CAH cases arise from 21-hydroxylase deficiency (21OHD). Mutation of the CYP21A2 gene, which encodes the enzyme 21-hydroxylase, leads to impairment of cortisol production and accumulation of its precursor 17-hydroxyprogesterone (17-OHP), and subsequent elevation of androgens. The hallmark of the two classical forms of 21OHD, salt-wasting CAH and simple-virilizing CAH, is genital ambiguity in affected female newborns. In contrast, patients with the non-classical form have normal genitalia, but may present with signs of early sexual development and other symptoms of hyperandrogenemia, such as short stature, hirsutism, acne, and impaired fertility. Hormonal testing is important in making the diagnosis of 21OHD, yet genetic testing is crucial to ascertain the diagnosis. More than 100 pathogenic CYP21A2 variants, which arise from gene conversions, large-scale gene deletions or de novo mutations, have been identified. Notably, whereas a given CYP21A2 mutation may associate with one of the three forms of CAH, there is genotype-phenotype nonconcordance in a significant number of patients.