Clinical Update on Congenital Adrenal Hyperplasia: Recommendations from a Multidisciplinary Adrenal Program

Abstract

Congenital adrenal hyperplasia (CAH) is a common genetic disorder in endocrinology, especially its milder clinical presentation, often caused by a partial or total deficiency of the 21-hydroxylase enzyme located in the adrenal cortex. CAH is characterized by the overproduction of androgen, along with variable degrees of cortisol and aldosterone deficiency. The age at diagnosis can provide some information about underlying mutations, with those diagnosed at birth/early infancy more likely to have severe enzymatic defects, which may include adrenal insufficiency, sexual development disorders, short stature in adulthood, hirsutism, and a higher risk for metabolic syndrome and infertility. Non-classic CAH, a milder form of CAH, is usually manifested later in life and is a common differential diagnosis of Polycystic Ovary Syndrome and should be actively evaluated during initial studies of clinical or biochemical hyperandrogenism. The main goals of CAH treatment are hormone supplementation for severe cases, controlling adrenal androgen overproduction to minimize long-term side effects, managing fertility and genetic counseling, and optimizing patients' quality of life.

Keywords: congenital adrenal hyperplasia; hyperandrogenism; non-classic CAH; recessive genetic disorder.

Figure 1

Classic adrenal steroidogenesis pathway and alternative pathways in CAH. Light orange denotes early steps of steroidogenesis common to all zones. Gray and light blue, steps that lead to aldosterone synthesis in zona glomerulosa and cortisol synthesis in zona fasciculata respectively, impaired by 21-hydroxilase deficiency. Purple, classic pathway of adrenal- and extra-adrenal androgen synthesis. Orange, “backdoor” pathway that leads to dihydrotestosterone production. Green, CYP11B1 pathway of 11-oxyandrogen production. Adapted from Claahsen-van der Grinten et al. [3].

Figure 2

Deregulated hypothalamic–pituitary–adrenal axis function in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Figure 3

Most frequent pathogenic variants in adrenal hyperplasia due to 21-hydroxylase deficiency.

Figure 4

Clinical manifestations of congenital adrenal hyperplasia due to 21-hydroxylase deficiency at different ages.

Figure 5

Diagnosis algorithm of 21OHD. Reference standards for hormonal diagnosis were derived from Refs. [6,10].