Genetic basis of endocrine disease 2: congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Abstract

Most cases of congenital adrenal hyperplasia, the inherited inability to synthesize cortisol, are caused by a deficiency of the 21-hydroxylase activity required to convert 17-hydroxyprogesterone to 11-deoxycortisol. Poor synthesis of cortisol results in chronic stimulation of the adrenal cortex by corticotropin with consequent overproduction of cortisol precursors. Some of these precursors are shunted into the androgen biosynthetic pathway causing the signs and symptoms of androgen excess seen in this disorder. The disease occurs in a wide spectrum of clinical variants, including a severely affected form with a concurrent defect in aldosterone biosynthesis (“salt wasting” type), a form with apparently normal aldosterone biosynthesis (“simple virilizing” type) and a mild “nonclassic” form that may be asymptomatic or may be associated with symptoms of androgen excess developing during childhood or at puberty (1). The disorder is inherited as a monogenic autosomal recessive trait located within the HLA major histocompatibility complex on chromosome 6~21.3. There are a number of associations between the different forms of 21-hydroxylase deficiency and specific combinations of HLA antigens, or haplotypes. In particular, the unusual haplotype A3;Bw47;DR7 is associated with about 10% of classic (i.e. salt wasting or simple virilizing) 21-hydroxylase deficiency alleles, whereas HLA-B14;DRl is associated with 70% of alleles for nonclassic disease. Based on these associations and on studies of pedigrees containing patients with the different forms of the disease, it appears that these forms are inherited as allelic variants. Classic disease occurs in approximately l/10,000 births, whereas nonclassic disease occurs in approximately 1% of the general population (2). The molecular genetic basis of 21-hydroxylase deficiency has been thoroughly studied. The 21-hydroxylase enzyme is a microsomal cytochrome P450 termed P45OXXI or P45Oc21. The structural gene encoding