Disorders of the aldosterone synthase and steroid 11 beta-hydroxylase deficiencies

The most potent corticosteroids are 11 beta-hydroxylated compounds. In huma ns, two cytochrome P450 isoenzymes with 11 beta-hydroxylase activity, catal ysing the biosynthesis of cortisol and aldosterone, are present in the adre nal cortex. CYP11B1, the gene encoding 11 beta-hydroxylase (P450c11), is ex pressed on high levels in the zona fasciculata and is regulated by ACTH. CY P11B2, the gene encoding aldosterone synthase (P450c11Aldo), is expressed i n the zona glomerulosa under primary control of the renin-angiotensin syste m. Aldosterone synthase has 11 beta-hydroxylase activity as well as 18-hydr oxylase activity and 18-oxidase activity. The substrate for CYP11B2 is 11-d eoxycorticosterone, that of CYP11B1 is 11-deoxycortisol. Mutations in CYP11 B1 cause congenital adrenal hyperplasia (CAH) due to 11 beta-hydroxylase de ficiency. This disorder is characterized by androgen excess and hypertensio n. Mutations in CYP11B2 cause congenital hypoaldosteronism (aldosterone syn thase deficiency) which is characterized by life-threatening salt loss, fai lure to thrive, hyponatraemia and hyperkalaemia in early infancy. Both diso rders have an autosomal recessive inheritance. Classical and nonclassical f orms of 11 beta-hydroxylase deficiency can be distinguished. Studies in het erozygotes for classical 11 beta-hydroxylase deficiency show inconsistent r esults with no or only mild hormonal abnormalities (elevated plasma levels of 11-deoxycortisol after ACTH stimulation). In infants with congenital hyp oaldosteronism, a comparable frequency of 18-hydroxylase deficiency (aldost erone synthase deficiency type I) and of 18-oxidase deficiency (aldosterone synthase deficiency type II) can be found. Molecular genetic studies of th e CYP11B1 and CVP11B2 genes in 11 beta-hydroxylase deficiency or aldosteron e synthase deficiency have led to the identification of several mutations. Transfection experiments showed loss of enzyme activity in vitro. In some o f the patients with 18-oxidase deficiency (aldosterone synthase deficiency type II) no mutations in the CYP11B2 gene were identified. Refined methods for steroid determination are the basis for the diagnosis of inborn errors of steroidogenesis. Molecular genetic studies are complementary; on the one hand, they have practical importance for the prenatal diagnosis of viriliz ing CAH forms and on the other hand, they are of theoretical importance in terms of our understanding of the functioning of cytochrome P450 enzymes. C opyright (C) 1999 S. Karger AG, Basel.