New Genetic Insights in Familial Hyperaldosteronism

Abstract

Aldosterone, the major circulating mineralocorticoid, particiates in blood volume and serum potassium homeostasis. Primary aldosteronism is a disorder characterized by hypertension and, in more severe form, hypokalemia, due to autonomous aldosterone secretion from the adrenocortical zona glomerulosa. Improved screening techniques, particularly application of the plasma aldosterone: plasma renin activity ratio, has led to renewed interest in Conn's original proposal that primary aldosteronism may be the cause of increased blood pressure in about 10% of adults with hypertension. Glucocorticoid-remediable aldosteronism (GRA) was the first described familial form of hyperaldosteronism. The disorder is characterized by aldosterone secretory function regulated chronically by ACTH. Hence, aldosterone hypersecretion can be chronically suppressed by exogenous glucocorticoids such as dexamethasone in physiologic-range doses. This autosomal dominant disorder has been shown to be caused by a hybrid gene mutation formed by a cross-over of genetic material between the ACTH-responsive regulatory portion of the 11b-hydroxylase (CYP11B1) gene and the coding region of the aldosterone synthase (CYP11B2) gene. Familial hyperaldosteronism type II (FH-II), so named to distinguish the disorder from GRA or familial hyperaldosteronism type I (FH-I), is characterized by inheritance consistent with an autosomal dominant pattern of autonomous aldosterone hypersecretion which is not suppressible by dexamethasone. Linkage analysis in a single large kindred, and direct mutation screening, has shown that this disorder is unrelated to mutations in the genes for aldosterone synthase or the angiotensin II receptor. A recent genome-wide search has identified a genetic linkage between FH-II in this single large kindred and polymorphic gene markers on chromosome 7 in a region that corresponds to cytogenetic band 7p22. This is the first identified locus for FH-II. Several possible candidate genes have been localized to the 7p22 region. The precise genetic cause of FH-II remains to be elucidated.

An update on novel mechanisms of primary aldosteronism

“…In the hypertensive adult population, FH1 accounts for 0.5 to 1.0% of PA and occurs equally among women and men (Jackson et al 2002, Pizzolo et al 2005, Mulatero et al 2011Figure 2). However, in the pediatric population, a recent study has described a prevalence of 3% of the chimeric CYP11B1/CYP11B2 gene in hypertensive children (Aglony et al 2011).…”

Minireview: Primary Aldosteronism—Changing Concepts in Diagnosis and Treatment

“…18-hydroxycortisol and 18-oxocortisol), and suppressibility with exogenous glucocorticoids (2). FH type II refers to the familial occurrence of APA or IHA or both (3).…”

Pathophysiology, Diagnosis, and Treatment of Mineralocorticoid Disorders

“…Patients with familial hyperaldosteronism make up a small subset of patients with PA and with some exceptions, should be managed with medical therapy. The first syndrome to be described, familial hyperaldosteronism type I (FH-I; also known as GRA) is inherited in an autosomal dominant pattern and accounts for ≤1% of all cases of PA (157). In this form of PA, aldosterone secretion is regulated by ACTH rather than by Ang II and potassium.…”