Glucocorticoid-remediable aldosteronism

Glucocorticoid-remediable aldosteronism (GRA) represents a rare, heriditary form of primary aldosteronism which is inherited in an autosomal dominant fashion. GRA is characterized by early onset of moderate to-severe hyperten sion and suppressed plasma renin activity. The family history is often posi tive for a history of early hemorrhagic stroke. However, the clinical and b iochemical features that define mineralcorticoid excess states, such as hyp okalemia, are not consistently present in GRA. Accordingly, recognition of this syndrome can be difficult. In GRA, aldosterone secretion is solely reg ulated by adrenocorticotropin. As a result, the administration of exogenous glucocorticoids will suppress the hypothalamic-pituitary axis and sup, pre ss aldosterone levels, thereby relieving the mineralocorticoid-excess state . GRA is caused by a chimeric gene duplication that results from unequal cr ossing over between the highly homologous 11 beta -hydroxylase (CYP11B1) an d aldosterone synthase (CYP11B2) genes. The chimeric gene represents a fusi on of the 5'adrenocorticotropin-responsive regulatory region of the 11 beta -hydroxylase gene and the 3' coding sequence of the aldosterone synthase g ene. This results in ectopic expression of aldosterone synthase activity in the zona fasciculata, the zone of the adrenal gland that normally secretes cortisol. This mutation explains the physiology and genetics of GRA and pr ovides the basis for a simple direct genetic test for this disorder.