Familial hyperaldosteronism type I

Familial hyperaldosteronism type I (FH-I), also known as glucocorticoid-remediable aldosteronism (GRA) or dexamethasone-suppressible hyperaldosteronism, is a rare inherited form of primary aldosteronism. It is caused by a chimeric gene duplication resulting from an unequal crossing-over between the CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) genes on chromosome 8q24. This fusion gene places aldosterone synthase activity under the regulatory control of adrenocorticotropic hormone (ACTH) rather than the renin-angiotensin system, leading to ectopic production of aldosterone and hybrid steroids (18-oxocortisol and 18-hydroxycortisol) in the zona fasciculata of the adrenal cortex. The condition primarily affects the cardiovascular and renal systems. Patients typically present with early-onset hypertension, which can range from mild to severe. Hypokalemia may be present but is not a consistent finding, and some patients have normal potassium levels. A hallmark and serious complication of FH-I is an increased risk of hemorrhagic stroke, often due to intracranial aneurysms, which can occur at a young age. Other features may include headaches, muscle weakness, and fatigue related to hypertension and electrolyte imbalances. The defining feature of FH-I is that aldosterone production is suppressible by exogenous glucocorticoids. Treatment typically involves low-dose glucocorticoid therapy (such as dexamethasone or prednisone) to suppress ACTH and thereby reduce aldosterone secretion. The lowest effective dose should be used to avoid Cushingoid side effects, particularly in children. Alternatively, or in addition, mineralocorticoid receptor antagonists such as spironolactone or eplerenone can be used to manage hypertension. Early diagnosis and treatment are important to prevent cardiovascular complications, including stroke. Genetic testing for the chimeric CYP11B1/CYP11B2 gene is the gold standard for diagnosis and is recommended for at-risk family members.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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