Familial Varieties Of Primary Aldosteronism

Abstract

1. Improved approaches to screening and diagnosis have revealed primary aldosteronism (PAL) to be much more common than previously thought, with most patients normokalaemic. The spectrum of this disorder has been further broadened by the study of familial varieties. 2. Familial hyperaldosteronism type I (FH-I) is a glucocorticoid-remediable form of PAL caused by the inheritance of an adrenocorticotrophic hormone (ACTH)- regulated, hybrid CYP11B1/CYP11B2 gene. Diagnosis has been greatly facilitated by the advent of genetic testing. The severity of hypertension varies widely in FH-I, even among members of the same family, and has demonstrated relationships with gender, degree of biochemical disturbance and hybrid gene crossover point position. Hormone "day curve" studies show that the hybrid gene dominates over wild-type CYP11B2 in terms of aldosterone regulation. This may be due, in part, to a defect in wild-type CYP11B2-induced aldosterone production. Control of hypertension in FH-I requires only partial suppression of ACTH and much smaller glucocorticoid doses than previously recommended. 3. Familial hyperaldosteronism type II (FH-II) is not glucocorticoid remediable and is not associated with the hybrid gene mutation. Familial hyperaldosteronism type II is clinically, biochemically and morphologically indistinguishable from apparently non-familial PAL. Linkage studies in one informative family did not show segregation of FH-II with the CYP11B2, AT1 or MEN1 genes, but a genome-wide search has revealed linkage with a locus in chromosome 7. As has already occurred in FH-I, elucidation of causative mutations is likely to facilitate earlier detection of PAL.

Integrating Genetics and Genomics in Primary Aldosteronism

“…22 FH-2 also reflects autosomal dominant transmission, but not associated with a hybrid gene and with hyperaldosteronism not suppressible by dexamethasone. 23 The phenotype is variable from APA to BAH, with a variable response of aldosterone to angiotensin II (Ang II). Clinical and biological features of FH-2 are indistinguishable from sporadic PA, and FH-2 is diagnosed on the basis of Ն2 affected members in a family, however, with phenotypic variability within affected families typical for the disease.…”

“…Clinical and biological features of FH-2 are indistinguishable from sporadic PA, and FH-2 is diagnosed on the basis of Ն2 affected members in a family, however, with phenotypic variability within affected families typical for the disease. 20,21 The prevalence of FH-2 is estimated to be between 2.8% and 6.0% in adult populations with PA. 20,21,23 In a large family with FH-2, a locus associated with the disease has been mapped to chromosome 7p22, 24 although no causal mutations have been identified in any of the genes located in the linkage area thus far. We have explored in depth the family history of 350 index cases in our PA database.…”

Human adipocytes secrete mineralocorticoid-releasing factors

“…Aldosterone is the most potent mineralocorticoid secreted by the adrenal cortex, promoting sodium retention and elevation of arterial pressure. Hypertension is caused by primary aldosteronism (32), and increased serum aldosterone levels have been linked to the development of obesity hypertension (33), a common disorder related to obesity. It is therefore not surprising that, in a large prospective study, high sodium intake was significantly associated with increased cardiovascular disease risk in obese compared with nonobese subjects (34,35).…”

Pathophysiology, Diagnosis, and Treatment of Mineralocorticoid Disorders

“…Studies in a large kindred with FH-II indicate linkage to a locus at chromosome 7p22 but no definite mutations have been discovered thus far (160). The prevalence of FH-II is reported to be in the 2.8% to 6.0% range of adults with PA (210,233,354) and is the most common familial form of hyperaldosteronism. Mineralocorticoid blockers are the main treatment option in this disorder.…”