Abstract

Primary aldosteronism is the most common form of secondary arterial hypertension, affecting up to 10% of hypertensive patients. It is responsible for treatment resistance and increased risk of cardiovascular complications. Due to the difficulty of its diagnosis, PA is frequently missed, and as a result, treatment of the condition is either delayed by many years after the onset of hypertension, or is not initiated at all. Over the past 10 years, important discoveries have been made regarding the genetic basis of aldosterone producing adenoma and familial forms of primary aldosteronism. In most cases, genetic abnormalities are found in genes coding for ion channels (KCNJ5, CACNA1D, CACNA1H, CLCN2) as well as ion pumps (ATP1A1, ATP2B3). They occur as somatic mutations in aldosterone producing adenoma and as germline mutations in familial forms of the disease. Mutations in these genes affect intracellular ion homeostasis and/or cell membrane potential, leading to increased intracellular calcium concentrations and activation of calcium signalling, which is the main regulator of aldosterone biosynthesis. In addition, double mutations in CTNNB1 and GNAQ/GNA11 have been identified in aldosterone producing adenoma presenting in puberty, pregnancy and menopause. Genetic studies have opened interesting diagnostic and treatment opportunities. While surrogate biomarkers of the mutation status may facilitate diagnosis and subtype identification in primary aldosteronism, innovative therapies are currently studied targeting mutated proteins. Finally, recent evidence suggests a continuum between unilateral and bilateral forms of primary aldosteronism, with somatic mutations being found in aldosterone producing cell clusters and aldosterone producing adenoma in patients with bilateral forms. We have recently identified genetic risk loci for primary aldosteronism through genome wide association studies, which may explain shared susceptibility and reveal new mechanisms involved in adrenal gland function and the development of aldosterone producing adenoma and bilateral adrenal hyperplasia.

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