Familial hyperaldosteronism type III

Familial hyperaldosteronism type III (FH-III) is a rare inherited form of primary aldosteronism caused by gain-of-function mutations in the KCNJ5 gene, which encodes the potassium channel Kir3.4 (GIRK4). These mutations alter the ion selectivity of the channel, leading to chronic depolarization of adrenal glomerulosa cells and massive overproduction of aldosterone. The condition primarily affects the endocrine and cardiovascular systems. It was first described in a father and two daughters with severe hypertension refractory to medical therapy, markedly elevated aldosterone levels, and bilateral adrenal hyperplasia. Key clinical features include severe early-onset hypertension, very high serum aldosterone levels, low plasma renin activity, and hypokalemia (low potassium). Patients may also develop end-organ damage related to uncontrolled hypertension, including cardiac hypertrophy and renal complications. The adrenal glands are typically massively enlarged bilaterally. Unlike familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism), FH-III does not respond to dexamethasone suppression. Treatment depends on the severity of the disease. In the most severe forms, bilateral adrenalectomy may be necessary to control aldosterone excess and hypertension, followed by lifelong glucocorticoid and mineralocorticoid replacement therapy. In milder phenotypes associated with certain KCNJ5 variants, medical management with mineralocorticoid receptor antagonists such as spironolactone or eplerenone, along with antihypertensive medications, may be sufficient to control blood pressure and electrolyte abnormalities. Genetic testing for KCNJ5 mutations is important for confirming the diagnosis and guiding family screening.

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