Glucocorticoid remediable aldosteronism (GRA), also known as familial hyperaldosteronism type I (FH I), was first described by Sutherland et al. in 1966. (7) It is an autosomal dominant form of low renin hypertension characterized by hyperaldosteronism. Aldosterone secretion is controlled by ACTH rather than angiotensin II, and for this reason, the unique distinguishing feature of GRA is the complete and rapid suppression of aldosterone by exogenous glucocorticoid (dexamethasone) administration.

GRA produces a volume expansion, salt-sensitive form of low renin hypertension. Variable presentation is not uncommon; hypertension is invariably present, but hypokalemia and metabolic alkalosis may be absent. The disease is characterized by early onset of moderate to severe hypertension with hyperaldosteronism and low renin values and by high incidence of premature cerebrovascular events. Additionally, children demonstrate normal growth and development, which distinguishes this disorder from 11β-hydroxylase deficiency and apparent mineralocorticoid excess.

Circadian measurement of plasma steroids in GRA patients has not only revealed excessive production of aldosterone following ACTH stimulation, but excessive secretion of two normally rare steroids: 18-hydroxycortisol and 18-oxocortisol. (8) An explanation has been provided by molecular studies that have shown that a chimeric gene is created by misalignment of chromatids and unequal crossing over between genes during meiotic reduction in gametogenesis (9) (Figure 3). This occurs between CYP11B1 and CYP11B2, two genes that reside within a 30-kilobase stretch on chromosome 8. CYP11B1 codes for 11β-hydroxylase, the enzyme that catalyzes the last step in cortisol synthesis in the ZF, and CYP11B2 codes for aldosterone synthase, the enzyme that catalyzes the last step in aldosterone synthesis in the ZG.

In affected individuals, the resulting chimeric gene encodes a protein that has aldosterone synthase enzymatic activity but is regulated by ACTH. Indeed, direct genetic screening for the presence of the chimeric gene can be performed by the long template PCR method with oligonucleotides specific for CYP11B1 and CYP11B2. This test is 100% sensitive and specific, has relatively low cost, and is more rapid and reliable, compared to conventional dexamethasone suppression test. (10) However, both dexamethasone administration and genetic testing are of importance in making diagnosis.

Children with GRA are treated with glucocorticoids, with resolution of their hypertension usually within 2 weeks after initiation of therapy. A sodium-restricted diet is recommended to lower blood pressure because of the salt-sensitive volume expansion; this will also minimize potassium wasting. Normalization of urinary hybrid steroid levels and abolition of ACTH-regulated aldosterone production is not a requisite for hypertension control and, if used as a treatment goal, may unnecessarily increase the risk of Cushingoid side effects. (11) The response to glucocorticoids is variable in adults, often requiring additional use of antihypertensive medications, such as spironolactone, amiloride and triamterene. It has been shown that even in the absence of hypertension, aldosterone excess is associated with increased left ventricular wall thicknesses and reduced diastolic function, initial changes that lead to cardiovascular morbidities. This leads to the recommendation to treat normotensive subjects with FH I. (12)