Primary
aldosteronism is characterized by at least partially autonomous production of the adrenal
steroid hormone aldosterone and is the most common cause of secondary
hypertension. The most frequent subforms are idiopathic
hyperaldosteronism and
aldosterone-producing
adenoma. Rare causes include unilateral
hyperplasia,
adrenocortical carcinoma and Mendelian forms (
familial hyperaldosteronism). Studies conducted in the last eight years have identified somatic driver mutations in a substantial portion of
aldosterone-producing
adenomas, including the genes KCNJ5 (encoding
inwardly rectifying potassium channel GIRK4), CACNA1D (encoding a subunit of L-type voltage-gated
calcium channel CaV1.3), ATP1A1 (encoding a subunit of Na+/K+-
ATPase), ATP2B3 (encoding a Ca2+-
ATPase), and CTNNB1 (encoding ß-
catenin). In addition,
aldosterone-producing cells were recently reported to form small clusters (
aldosterone-producing cell clusters) beneath the adrenal
capsule. Such clusters accumulate with age and appear to be more frequent in individuals with idiopathic
hyperaldosteronism. The fact that they are associated with somatic mutations implicated in
aldosterone-producing
adenomas also suggests a precursor function for
adenomas. Rare germline variants of
CYP11B2 (encoding
aldosterone synthase), CLCN2 (encoding voltage-gated
chloride channel ClC-2), KCNJ5, CACNA1H (encoding a subunit of T-type voltage-gated
calcium channel CaV3.2), and CACNA1D have been reported in different subtypes of
familial hyperaldosteronism. Collectively, these studies suggest that primary
aldosteronism is largely due to genetic mutations in single genes, with potential implications for diagnosis and
therapy.