17α-Hydroxylase/17,20-Lyase Deficiency: From Clinical Investigation to Molecular Definition*

THE term congenital adrenal hyperplasia (CAH) defines a group of syndromes resulting from inherited defects in any one of the five enzymes involved in the steps leading to cortisol biosynthesis from cholesterol. These include four distinct forms of cytochrome P450: P450scc, P450C21, P45011β, and P45017α, as well as 3β- hydroxysteroid dehydrogenase. Pathologically, CAH is characterized by hyperplastic growth of the adrenal stimulated by ACTH. A blockage in any one of the steps in normal steroid hormone synthesis leads to decreased synthesis of the steroid hormones and accumulation of intermediates, giving rise to the various clinical symptoms. The most common form of CAH, 21-hydroxylase deficiency, accounts for 90–95% of CAH (1). The high frequency of 21-hydroxylase deficiency is related to the structure of the P450C21 (CYP21) genes of which there are two, closely linked, a functional gene and a pseudo-gene (2, 3). Understanding of this unique gene structure and its location in the HLA locus has led to the definition of the molecular basis of a number of cases of 21-hydroxylase deficiency (4).