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Familial hyperaldosteronism type III
Familial hyperaldosteronism type III (FH-III) is a rare heritable form of primary aldosteronism (PA) that is characterized by early-onset severe hypertension, non glucocorticoid-remediable hyperaldosteronism, overproduction of 18-oxocortisol and 18-hydroxycortisol, and profound hypokalemia.
ORPHA:251274Classification level: Disorder
Seven families with FH-III have been reported to date.
Severe hypertension associated with profound hypokalemia generally manifests during early childhood. It can be accompanied with polydipsia, polyuria, nausea, vomiting and headaches. Marked bilateral adrenal hyperplasia has been described. In exceptional cases, a mild form of FH-III, resembling to FH type II (see this term) has been reported, with normal appearing adrenals and treatable with medical therapy.
FH-III is due to heterozygous missense mutations of the KCNJ5 gene (11q24), encoding the G-protein-activated inward rectifier potassium channel GIRK-4. These mutations result in loss of channel selectivity, membrane depolarization of the zona glomerulosa cells of the adrenal cortex, opening of voltage-activated calcium channels, and activation of the calcium signaling pathway that trigger saldosterone biosynthesis. There is a genotype-phenotype correlation, with the mild phenotype observed in patients with the p.G151E and p.Y152C mutations.
Blood and urinary tests show profound hypokalemia, an abnormal aldosterone/renin ratio with increased aldosterone levels not suppressible by dexamethasone, suppressed plasma renin activity, and elevated levels of the hybrid steroids 18-oxo- and 18-hydroxycortisol. Diagnosis is confirmed by genetic testing.
The clinical presentation resembles that of the other familial forms of hyperaldosteronism (FH-I, FH-II) (see these terms).
Transmission is autosomal dominant.
Management and treatment
FH-III does not respond to glucocorticoid treatment. Severe cases require bilateral adrenalectomy to normalize blood pressure and hypokalemia, whereas mild cases are treated with medical therapy with aldosterone antagonists and/or other antihypertensive drugs if required.
In severe cases treated with bilateral adrenalectomy, life-long glucocorticoid and mineralocorticoid replacement therapy is required. In mild cases, prognosis is good with medical treatment.