A New Form of Hereditary Primary Aldosteronism: Familial Hyperaldosteronism Type III

Abstract

Primary aldosteronism (PA) is the most frequent form of secondary hypertension accounting for up to 5–10% of all hypertensive patients (1–3). The diagnosis of this form of hypertension is fundamental because, compared with essential hypertensives with similar risk profiles, patients with PA are more prone to stroke, myocardial infarction, and atrial fibrillation (4) and display an increase in cardiovascular damage and metabolic complications (5). Two familial forms of primary aldosteronism [familial hyperaldosteronism (FH)] have been described so far, referred to as FH-I, also known as glucocorticoid-remediable aldosteronism (GRA), and FH-II (5–7). In this issue of the Journal, Geller et al. (8) report a newly described Mendelian form of familial hyperaldosteronism with distinctive clinical and biochemical features from previously described forms. FH-I/GRA is transmitted as an autosomal dominant disease and is characterized by hypertension, elevated ACTH-dependent aldosterone secretion, renin suppression, and high levels of the hybrid steroids, 18OHcortisol (18OHF) and 18oxo-cortisol (18oxoF). Despite the state of hyperaldosteronism, hypokalemia is uncommon (7, 9). The genetic defect leading to FH-I/GRA is an unequal genetic recombination between CYP11B1 (11 -hydroxylase) and CYP11B2 (aldosterone synthase), generating a chimeric CYP11B gene containing CYP11B1 sequences (including the promoter) at its 5 end and CYP11B2 sequences at its 3 end (7, 9). Because CYP11B1 expression is regulated by ACTH, the hybrid gene encodes a chimeric enzyme with aldosterone synthase activity and ACTH-dependent expression throughout the adrenal cortex. Hence, in FH-I/GRA patients, aldosterone levels are persistently suppressed by glucocorticoid administration. Most affected individuals develop severe hypertension in early life, but patients with mild hypertension or blood pressure in the normal range are described in many families, some of them displaying a notably milder clinical phenotype (10, 11). FH-II is a nonglucocorticoid remediable familial form of PA (6). Patients affected by FH-II present a family history of PA caused by either an adrenal adenoma or hyperplasia. Each single case of FH-II is clinically, biochemically, and morphologically indistinguishable from apparently sporadic forms of PA. In most families, a vertical transmission suggests an autosomal dominant inheritance. The diagnosis of FH-II is based on the demonstration of PA in at least two members from the same family. Unfortunately, the genetic background of FH-II remains unknown, and thus, the diagnosis is made by the finding of a consistently high Aldosterone Renin Ratio (ARR) (without interfering medications) with a positive confirmatory test (saline load fludrocortisone) and lack of the hybrid gene responsible for FH-I/GRA (6). This strategy of studying first-degree relatives in FH-I/GRA and FH-II families allowed the diagnosis of PA in normotensive individuals, indicating a different penetrance of the disease, even within the same family (10, 12). A linkage study involving one large Australian family demonstrated linkage between FH-II and a locus at chromosome 7p22 (13). Subsequently this locus has been shown to be in linkage with FH-II in a second Australian family, a South American family, and more recently two Italian families (12). Recent evidence from the Framingham Offspring Study (14) has emphasized the importance of aldosterone in the development of hypertension. This study found a significant relationship between ARR and both blood pressure progression and hypertension development among Framingham study participants and significant heritability of the ARR (15). Intriguingly, in a linkage analysis that included 1225 genotyped individuals from 328 families, the most striking locus of linkage for logARR in the multivariable adjusted model was at chromosome 7p (15). In the study by Geller et al. (8), the authors could not identify the genetic alteration responsible for the disease. However, they excluded the involvement of potential candidate genes such as CYP11B1 and CYP11B2; the angiotensin II and ACTH receptors, DAX-1, which has been implicated in congenital adrenal