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 hypertension and suppressed plasma renin activity. The family history is often positive for a history of early hemorrhagic stroke. However, the clinical and biochemical features that define mineralcorticoid excess states, such as hypokalemia, are not consistently present in GRA. Accordingly, recognition of this syndrome can be difficult. In GRA, aldosterone secretion is solely regulated by adrenocorticotropin. As a result, the administration of exogenous glucocorticoids will suppress the hypothalamic-pituitary axis and suppress aldosterone levels, thereby relieving the mineralocorticoid-excess state. GRA is caused by a chimeric gene duplication that results from unequal crossing over between the highly homologous 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. The chimeric gene represents a fusion of the 5´ adrenocorticotropin-responsive regulatory region of the 11β-hydroxylase gene and the 3´ coding sequence of the aldosterone synthase gene. 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 provides the basis for a simple direct genetic test for this disorder.