Congenital adrenal hyperplasia due to steroid 21‐hydroxylase deficiency

Cortisol is normally synthesized from cholesterol in the zona fasciculata of the adrenal cortex in five successive enzymatic conversions (Fig. 1). Congenital adrenal hyperplasia (CAH), the inherited inability to synthesize cortisol, may be caused by defective importation of cholesterol into mitochondria (Lin et al., 1995; Boseet al., 1996) or, more commonly, by mutations in steroidogenic enzymes (reviewed in White, 1994a). More than 90% of cases are caused by a deficiency of the 21hydroxylase activity required to convert 17-hydroxyprogesterone to 11-deoxycortisol. This review will focus on our current knowledge of this disorder. Detailed reviews of other deficiencies causing CAH, including 11 b-hydroxylase (White & Speiser, 1994; Whiteet al., 1994b), 17a-hydroxylase (Yanaseet al., 1991; Yanase, 1995) and 3 b-hydroxysteroid dehydrogenase (Simard et al., 1995), have been published. In patients with 21-hydroxylase deficiency, poor synthesis of cortisol results in chronic stimulation of the adrenal cortex by corticotrophin with consequent overproduction of cortisol precursors. Some of these precursors are shunted into the androgen biosynthetic pathway causing signs and symptoms of androgen excess, including ambiguous genitalia in females and rapid somatic growth with accelerated skeletal maturation in both sexes. 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 ‘non-classical’ form that may be asymptomatic or may be associated with signs of androgen excess developing during childhood or at puberty. The salt wasting and simple virilizing forms, collectively referred to as ‘classical’ 21-hydroxylase deficiency, occur in 1/10 000–1/15 000 births in most populations based on newborn screening studies. The frequency of the non-classical form is difficult to determine due to problems of ascertainment. It may be quite frequent in certain populations such as Jews of Eastern European origin (Speiser et al., 1985).