Genetic, biochemical, and clinical studies of patients with A328V or R213Cmutations in 11 beta HSD2 causing apparent mineralocorticoid excess

Apparent mineralocorticoid excess is a recessively inherited hypertensive s yndrome caused by mutations in the 11 beta-hydroxysteroid dehydrogenase typ e 2 gene, which encodes the enzyme normally responsible for converting cort isol to inactive cortisone. Failure to convert cortisol to cortisone in min eralocorticoid-sensitive tissues permits cortisol to bind to and activate m ineralocorticoid receptors, causing hypervolemic hypertension. Typically, t hese patients have increased ratios of cortisol to cortisone and of 5 alpha - to 5 beta-cortisol metabolites in serum and urine. We have studied 3 pati ents in 2 families with severe, apparent mineralocorticoid excess and other family members in terms of their genetic, biochemical, and clinical parame ters, as well as normal controls. Two brothers were homozygous for an A328V mutation and the third patient was homozygous for an R213C mutation in the 11 beta-hydroxysteroid dehydrogenase type 2 gene; both mutations caused a marked reduction in the activity of the encoded enzymes in transfection ass ays. The steroid profiles of the 7 heterozygotes and 2 other family members studied were completely normal. The results of a novel assay used to disti nguish 5 alpha- and 5 beta-tetrahydrometabolites suggest that 5 beta-reduct ase activity is reduced or inhibited in apparent mineralocorticoid excess. In 1 patient undergoing renal dialysis for chronic renal insufficiency, dir ect control of salt and water balance completely corrected the hypertension , emphasizing the importance of mineralocorticoid action in this syndrome.