Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) refers to a group of genetic disorders responsible for defects in adrenal steroidogenesis and resulting in diminished cortisol production. The leading enzyme deficiency is 21-hydroxylase (P450c21) and results from a mutation in the CYP21A2 gene. This review will focus on CAH resulting from 21-hydroxylase deficiency, with the other causes reviewed in brief.

A deficiency in 21-hydroxylase should be considered in an infant with ambiguous genitalia or a child or adolescent with postnatal virilization. Adrenal crisis with biochemical evidence of salt-wasting may occur if this is not promptly diagnosed and historically has been more common in 46,XY individuals with CAH given lack of genital differences at birth. This can also present later in childhood and should be considered with presentations of premature adrenarche, precocious puberty, irregular menses and hirsutism.

A deficiency of 21-hydroxylase is confirmed by biochemical findings, such as an unequivocally elevated serum concentration of 17-hydroxyprogesterone or follow-up stimulation testing in the case of borderline elevation.

Classical CAH requires lifelong treatment with glucocorticoid replacement therapy and nonclassical CAH requires treatment only in select symptomatic patients.

CAH is a family of inherited enzyme deficiencies that impair normal corticosteroid synthesis by the adrenal cortex. The most common enzyme deficiency is 21-hydroxylase deficiency (21-OHD), which accounts for over 90% of cases.[1]White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000 Jun;21(3):245-91. http://press.endocrine.org/doi/full/10.1210/edrv.21.3.0398 http://www.ncbi.nlm.nih.gov/pubmed/10857554?tool=bestpractice.com ​ CAH due to 21-OHD can be classified as either classical or nonclassical, based on the severity of the enzymatic defect.[2]Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med. 2020 Sep 24;383(13):1248-61. http://www.ncbi.nlm.nih.gov/pubmed/32966723?tool=bestpractice.com ​ The severe or “classical” form of the disease usually presents in infancy, is associated with cortisol deficiency, and in most cases, with additional aldosterone deficiency, and severe adrenal hyperandrogenism. Nonclassical CAH represents a mild phenotype that may present later in life with signs of mild androgen excess.

Rare enzyme deficiencies resulting in CAH include 17-alpha-hydroxylase deficiency, 11-beta-hydroxylase deficiency, 3-beta hydroxysteroid dehydrogenase deficiency, and even more rare - P450SCC deficiency, STAR deficiency and P450 oxidoreductase deficiency.

This topic will focus on the diagnosis and treatment of CAH resulting from 21-OHD.