The genetics of steroid 21-hydroxylase deficiency

Congenital adrenal hyperplasia (CAH) is a prevalent cause of newborn genital ambiguity and adrenal insufficiency. The most common form of CAH, steroid 21-hydroxylase deficiency, accounts for about 95% of affected individuals. The main forms of this disease are classic salt-wasting, simple virilizing, and nonclassic. Phenotypic variability is attributable to allelic variation in the gene encoding active steroid 21-hydroxylase, CYP21A2. The disease is inherited as an autosomal recessive trait. There are more than 80 known disease-causing mutations, but about 10 mutations comprise 80% to 90% of alleles in most populations. It has become clear that there is a spectrum of disease, ranging from severe to mild, depending on which CYP21A2 mutations a patient carries. Genotyping can be useful in verifying the diagnosis of CAH in newborn screening programs primarily based on hormone assays and is also valuable in prenatal diagnosis.