CONGENITAL HYPOALDOSTERONISM - THE VISSER-COST SYNDROME REVISITED

In 1964, H. K. A. Visser and W. S. Cost were the first to suggest a de fect of the terminal aldosterone (Aldo) biosynthesis in patients with hypoaldosteronism. In the last years, the molecular basis of the termi nal Aldo biosynthesis has been elucidated. Aldo biosynthesis requires 11 beta-hydroxylation of Il-deoxycorticosterone to form corticosterone , hydroxylation at position C-18 to form 18-hydroxycorticosterone (18- OHB), and finally oxidation at position C-18. One single cytochrome P4 50 enzyme (P450aldo) catalyzes all three reactions in the zona glomeru losa The coding gene is termed CYP11B2. Two inborn errors of terminal Aldo biosynthesis characterized by overproduction of corticosterone an d deficient synthesis of Aldo have been described. Corticosterone meth yl oxidase deficiency type I(CMO I) is distinguished by decreased prod uction of 18-OHB while CMO II is characterized by overproduction of 18 -OHB and an elevated ratio of 18-OHB to Aldo. Both disorders are inher ited by an autosomal recessive trait and cause salt-wasting and failur e to thrive in early infancy. Our present series includes 14 CMO defic ient infants diagnosed by multisteroid analysis (RIA after extraction and automated high performance gel chromatography) which provides prec ise biochemical criteria for the differentiation of the two CMO varian ts. So far, three different mutations within the CYP11B2 gene in patie nts with P450aldo deficiency have been described. Introduction of thes es mutations into a CYP11B2 cDNA expression vector construct and subse quent expression in COS cells revealed loss of 11 beta-hydroxylase, 18 -hydroxylase, and 18-dehydrogenase activity of P450aldo. Further molec ular studies on more P450aldo-deficient patients might clarify in the future the still existing discrepancies in CYP11B2 (P450aldo) structur e-function relationship.