Congenital adrenal hyperplasia: focus on the molecular basis of 21-hydroxylase deficiency

Abstract

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by defects in one of several steroidogenic enzymes involved in the synthesis of cortisol from cholesterol in the adrenal glands. More than 90% of cases are caused by 21-hydroxylase deficiency, and the severity of the resulting clinical symptoms varies according to the level of 21-hydroxylase activity. 21-Hydroxylase deficiency is usually caused by mutations in theCYP21A2gene, which is located on the RCCX module, a chromosomal region highly prone to genetic recombination events that can result in a wide variety of complex rearrangements, such as gene duplications, gross deletions and gene conversions of variable extensions. Molecular genotyping ofCYP21A2and the RCCX module has proved useful for a more accurate diagnosis of the disease, and prenatal diagnosis. This article summarises the clinical features of 21-hydroxylase deficiency, explains current understanding of the disease at the molecular level, and highlights recent developments, particularly in diagnosis.

Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations

“…Also, precursors prior to the 21-OH block are accumulated and redirected to the adrenal androgen production. The excess of androgens ultimately affects sexual differentiation in females and causes advanced somatic development in both sexes in childhood [2]. Depending on the severity of enzymatic defect, CAH can be categorized into two major phenotypes: a severe classical form revealed at birth, consisting of salt-wasting (SW-CAH) and simple virilizing form (SV-CAH), and a mild non-classical form (NC-CAH) with late-onset symptoms.…”

Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency

“…Thus, affected patients usually manifest hyponatraemia, hyperkalaemia and vomiting during the first 4 weeks of life. In the female foetus, the excess of androgen causes variable degrees of external genital virilisation, and consequently, newborn females have genital ambiguity (1,7,8). The residual activity of 21OH (aldosterone is synthetized) results in SV-CAH with external genital virilisation in females and also results in signs of precocious pseudopuberty which develop by 8 years of age in female and male patients (1,8,9).…”

“…In the female foetus, the excess of androgen causes variable degrees of external genital virilisation, and consequently, newborn females have genital ambiguity (1,7,8). The residual activity of 21OH (aldosterone is synthetized) results in SV-CAH with external genital virilisation in females and also results in signs of precocious pseudopuberty which develop by 8 years of age in female and male patients (1,8,9). NC-CAH is associated with a moderate deficiency in 21OH and manifests in later childhood or adolescence with hirsutism and decreased fertility or precocious pseudopuberty (8).…”

“…The residual activity of 21OH (aldosterone is synthetized) results in SV-CAH with external genital virilisation in females and also results in signs of precocious pseudopuberty which develop by 8 years of age in female and male patients (1,8,9). NC-CAH is associated with a moderate deficiency in 21OH and manifests in later childhood or adolescence with hirsutism and decreased fertility or precocious pseudopuberty (8). Patients with NC-CAH secrete aldosterone normally and most of the male patients diagnosed after puberty are entirely asymptomatic (1,10).…”

“…The milder, non-classical form of CAH is much more common, with a prevalence of 1/100 in the general population (8). As CYP21A2 analysis has been made available in many countries, studies on CYP21A2 mutations in large national patient series have provided an insight into specific mutation distributions.…”