Monogenic Forms of Low-Renin Hypertension

Vesna D Garovic; Anthony A Hilliard; Stephen T Turner


Nat Clin Pract Nephrol. 2006;2(11):624-630. 

In This Article

Summary and Introduction


Hypertension is an important public health problem affecting more than 50 million individuals in the US alone. The most common form, essential hypertension, results from the complex interplay between genetic predisposition and environmental influences. In contrast, monogenic (mendelian) forms of hypertension are caused by single gene mutations that are influenced little, if at all, by environmental factors. Most monogenic forms of hypertension affect either electrolyte transport in the distal nephron, or the synthesis or activity of mineralocorticoid hormones, leading to the common pathogenic mechanisms of increased distal tubular reabsorption of sodium and chloride, volume expansion and hypertension. In young patients with a family history of hypertension who present with severe or refractory hypertension and characteristic hormonal and biochemical abnormalities, the differential diagnosis should include monogenic forms of hypertension. Genetic testing, which is increasingly available, can facilitate timely diagnosis and treatment of these relatively uncommon disorders, such that the underlying defect can be corrected or ameliorated and the long-term consequences of poorly controlled hypertension prevented.
Review criteria: The following Medical Subject Headings were used to search the MEDLINE database for articles published between 1966 and 2006: "Liddle's syndrome", "congenital adrenal hyperplasia", "mineralocorticoid excess", "Gordon's syndrome", "glucocorticoid-remediable hyperaldosteronism", "hypertension in pregnancy", "familial hyperaldosteronism".


Genetic predisposition has an important role in the pathogenesis of essential hypertension. Published studies have focused upon candidate genes—and their alleles or polymorphisms—that might be associated with hypertension. Another approach has relied on genome-wide scans that might locate genes that increase the risk of hypertension. These attempts have failed to identify a single gene or region that is reproducibly associated with susceptibility to essential hypertension. This failure has lent further support to the view that essential hypertension is a complex polygenic disorder resulting from multiple gene—gene and gene—environment interactions.[1,2] Advances in genomic techniques have, however, facilitated identification of rare monogenic forms of hypertension. Inherited in a mendelian fashion, these disorders affect either electrolyte transport in the distal tubule or the synthesis and/or activity of mineralocorticoid hormones.

Mineralocorticoid hormones produced by the adrenal cortex have a major role in homeostasis of blood volume and pressure by promoting renal sodium, chloride and water reabsorption. Aldosterone accounts for almost 90% of the mineralocorticoid activity of steroids produced by the adrenal glands; other adrenal steroids that contribute to mineralocorticoid activity are cortisol, corticosterone and deoxycorticosterone. In monogenic hypertensive disorders, single gene mutations lead to either a primary increase in the rate of sodium and chloride reabsorption in the distal nephron or enhancement of the effects of hormones with mineralocorticoid activity. Hypertension develops as a consequence of increased sodium, chloride and water reabsorption and subsequent plasma volume expansion. Low plasma renin activity due to volume expansion is a feature common to these disorders; the disorders can be characterized further into syndromes of increased or decreased aldosterone synthesis. Seven single gene mutations known to cause hypertension have been identified ( Table 1 ). These genetic defects, their associated laboratory findings, and recommended treatments are discussed below.


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