Abstract-Apparent mineralocorticoid excess is a recessively inherited hypertensive syndrome caused by mutations in the 11␤-hydroxysteroid dehydrogenase type 2 gene, which encodes the enzyme normally responsible for converting cortisol to inactive cortisone. Failure to convert cortisol to cortisone in mineralocorticoid-sensitive tissues permits cortisol to bind to and activate mineralocorticoid receptors, causing hypervolemic hypertension. Typically, these patients have increased ratios of cortisol to cortisone and of 5␣-to 5␤-cortisol metabolites in serum and urine. We have studied 3 patients in 2 families with severe, apparent mineralocorticoid excess and other family members in terms of their genetic, biochemical, and clinical parameters, 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␤-hydroxysteroid dehydrogenase type 2 gene; both mutations caused a marked reduction in the activity of the encoded enzymes in transfection assays. The steroid profiles of the 7 heterozygotes and 2 other family members studied were completely normal. The results of a novel assay used to distinguish 5␣-and 5␤-tetrahydrometabolites suggest that 5␤-reductase activity is reduced or inhibited in apparent mineralocorticoid excess. In 1 patient undergoing renal dialysis for chronic renal insufficiency, direct control of salt and water balance completely corrected the hypertension, emphasizing the importance of mineralocorticoid action in this syndrome. (Hypertension. 1999;34:435-441.)Key Words: hydroxysteroid Ⅲ tetrahydrocortisone Ⅲ hemodialysis Ⅲ mutation Ⅲ hypertension, genetic A pparent mineralocorticoid excess (AME) is a rare and severe form of hypertension characterized by an early age of onset and signs of excess mineralocorticoid activity. 1,2 It has an autosomal recessive mode of inheritance 3 and is caused by mutations in the 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) gene, which result in a deficiency in the activity of the encoded 11␤HSD2 enzyme 4,5 that catalyzes the conversion of cortisol to cortisone and of corticosterone to 11-dehydrocorticosterone. 6 Cortisol and corticosterone are agonists with high affinity for the mineralocorticoid receptor, comparable to the principal mineralocorticoid hormone aldosterone, whereas cortisone and 11-dehydrocorticosterone have a low affinity for the receptor. 7 The catalytic action of 11␤HSD2 ensures, in part, that binding and activation of the mineralocorticoid receptor is effected only by aldosterone, since this steroid is not a substrate for the 11␤HSD2 enzyme.In patients with a hereditary defect of 11␤HSD2 enzymatic activity, cortisol, which circulates at much greater concentrations than aldosterone, acts as a potent mineralocorticoid hormone, inducing hypervolemic hypertension. The AME syndrome has been biochemically characterized by increased cortisol-to-cortisone ratios in serum and urine, or of the urinary cortisol metabolites, 5␤-tetrahydrocortisol (5␤THF) and 5␣-tetrahydr...

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