Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Congenital Adrenal Hyperplasia (CAH) [E25.09]

OMIM numbers: 201910, 613815 (CYP21A2), 202010, 610613 (CYP11B1)

Dipl.-Biol. Wolfgang Rupprecht, Dr. med. Dagmar Wahl

Scientific Background

Congenital adrenal hyperplasia (CAH) is an autosomal recessive inherited deficiency of cortisol and has a prevalence of approximately 1:10,000–1:16,000 (classical CAH) and 1:500–1:1,000 (non-classical or late-onset CAH). The main cause of the disease are mutations in the 21-hydroxylase gene (CYP21A2) on chromosome 6p21.3. There is a clinical differentiation between the classical CAH and the late-onset or non-classical CAH.

The classical CAH is caused by mutations that lead to a severe reduction of enzyme activity of the 21-hydroxylase. Reduced enzymatic hydroxylation of progesterone and therefore a deficiency of desoxycortisol are the consequence. The metabolic block causes a negativ feedback, leading to increased release of ACTH. This results in a secondary adrenal cortical hyperplasia with formation of male steroid metabolites leading to an impaired female sex differentiation. Already prenatally, affected girls exhibit virilization and formation of ambiguous genitalia. If not treated, an additionally occurring aldosterone deficiency results in life-threatening saltwasting syndrome, which may also occur in boys; pubertas praecox may arise later on. In the course of the disease, affected children show accelerated skeletal maturation, which at first makes them appear too tall, but due to early closing of the physis, are later too small. If the parents are known carriers, virilization of female fetuses can be prevented by administering dexamethasone during pregnancy.

The non-classical or late-onset CAH is characterized by a mild hyperandrogenemia that can manifest in signs such as hirsutism, disorders of the menstrual cycle, low voice and acne. It is caused by homozygosity of a “mild” mutation or combined heterozygosity of a “mild” and a “severe” mutation or two “mild” mutations in the 21-hydroxylase gene.

Mutations in the 11-β-hydroxylase gene (CYP11B1) are responsible for approx. 5-8% of all classic CAH cases. The resulting metabolic block also leads to increased formation of male steroid metabolites and impaired female sex differentiation. A salt-wasting syndrome does usually not occur. In a few cases, mutations in the CYP11B1 gene were detected in women with late-onset CAH.