Saga of Familial Hyperaldosteronism: Yet a New Channel

In 1953, Litynski1 reported in a Polish journal the first case of an adrenocortical adenoma associated with hypertension and hypokalemia that was cured by adrenalectomy. Three years later, Conn2 reported a similar case and described the full characterization of the syndrome of primary aldosteronism (PA). Compelling evidence is now established that PA, albeit deceiving diagnosis in the majority of the cases because of the lack of hypokalemia, is the most common endocrine cause of hypertension. Moreover, if adrenal vein sampling is systematically used, PA is surgically curable in about two thirds of the cases.3,4 Exceptions to this rule entail the familial cases of PA because of germline mutations that, by definition, involve both adrenals and, therefore, cannot be cured by unilateral adrenalectomy. The familial occurrence of PA has been known for decades since the discovery of PA in 1966 by Sutherland et al.5 Of note, they reported that in some pedigrees of patients with PA, the syndrome could be corrected by glucocorticoids, which led them to define this condition glucocorticoid-remediable aldosteronism5—a condition today redefined as familial hyperaldosteronism (FH) type 1 (FH-1). The molecular mechanisms of FH-1 remained unknown until 1992 when a chimeric gene deriving from unequal crossing over of the CYP11B1 and CYP11B2 genes was identified as the culprit of FH-1.6 Genetic testing for this form based on long polymerase chain reaction7 rapidly followed, which allowed the identification of familial cases of PA without the chimeric gene that by default were provisionally classified as FH type 2. A long quest for responsible genes was unsuccessful8 until a few months ago. Moreover, an impressive amount of research work in the past 6 years has allowed the discovery of additional germline mutations in multiple genes and to a new classification …