Genetics and Pathophysiology of Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease that manifests clinically in varying forms depending on the degree of enzyme deficiency. CAH is most commonly caused by 21-hydroxylase deficiency (21OHD) due to mutations in the CYP21A2 gene. Whereas there is a spectrum of disease severity, 21OHD is generally categorized into 3 forms. The classic form encompasses salt-wasting and simple virilizing CAH and the least affected form is termed nonclassic CAH. The classic form of 21OHD occurs in ∼1 in 16 000 births with the most severe salt-wasting cases presenting in the neonatal period with cortisol and aldosterone deficiencies and virilization of external female genitalia. Cortisol deficiency removes normal feedback on the hypothalamic-pituitary-adrenal axis leading to elevations in ACTH and adrenal androgen levels, which often accelerate skeletal maturation, leading to premature epiphyseal growth plate closure. Additionally, supraphysiologic doses of glucocorticoids are necessary to suppress androgen levels, adversely affecting final adult height. This paper highlights a brief history of 21OHD and provides an overview of the genetic basis and pathophysiology of 21OHD.