Glucocorticoid-remediable Aldosteronism (GRA) is a rare form of primary aldosteronism in which aldosterone secretion is solely under the control of Adrenocorticotropic hormone (ACTH). GRA is caused by a chimeric gene in which the the ACTH- responsive 5'-promoter of the 11Beta-hydroxylase gene is fused to coding sequences of the aldosterone synthase gene. This results in ectopic expression of aldosterone synthase activity in zona fasciculata cells of the adrenal cortex under the regulation of ACTH, with resultant hyperaldosteronism and suppression of angiotensin II-stimulated aldosterone production in the zona glomerulosa.
The most common presentation of GRA is the discovery of asymptomatic severe hypertension, especially in infancy or early adulthood. A strong family history of hypertension, often associated with early death of affected family members due to cerebrovascualr accidents, characteristically is seen in some GRA families. An important clinical clue is the age of onset of hypertension, with GRA patients typically diagnosed with high blood pressure as children; this is in contrast to patients with other mineralocorticoid excess states, such as aldosterone producing adenomas and idiopathic hyperplasia, who usually are diagnosed in the third through sixth decades of life. As expected plasma-renin activity is typically very low, and plasma aldosterone concentration high in those with GRA. Hypokalemia is often seen, but not the norm.
GRA, a hereditary cause of hypertension, is passed on in an autosomal dominant inheritance pattern. Genetic testing is 100% sensitive and specific for the diagnosis of GRA. (See Screening Information for information on how to have a patient screened). A dexamethasone suppression test (DST) is highly indicative of GRA, and easy to administer, but lacks the absolute specificity of the genetic test. (see Publications, "Evaluation of the dexamethasone suppression test for the diagnosis of GRA", Litchfield, et al.) The DST should be used in patients with biochemical primary hyperaldosteronism, who have a suggestive clinical history, and negative CT imaging of the adrenals. However, a positive DST should not displace the primacy of direct genetic testing in the diagnosis of GRA.
GRA may be more common in the hypertensive population than had been previously estimated. We encourage those with a clinical and/or family history indicative of GRA to be genetically screened for the disorder.
Please email: Erin.Loring@yale.edu for more information
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