Monogenic Forms of Low-Renin Hypertension

Vesna D Garovic; Anthony A Hilliard; Stephen T Turner

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

Summary and Introduction

Summary

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".

Introduction

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 ( ). These genetic defects, their associated laboratory findings, and recommended treatments are discussed below.

Table 1.  Characteristics of and Treatments for Monogenic Forms of Low-renin Hypertension

Disorder Age of onset Pattern of inheritance Aldosterone level Serum potassium level Genetic test (reference) Treatmenth
FH-I (GRA)a Second or third decade Autosomal dominant High Decreased in 50% of cases; marked decrease with thiazides Commercial Glucocorticoids
FH-IIa Middle Autosomal dominant High Low to normal Research (11) Spironolactone, eplerenone
DOC oversecretion due to CAHb,c Childhood Autosomal recessive Low Low to normal Research (25) Glucocorticoids
Activating MCR mutation exacerbated by pregnancyd Second or third decade Unknown Low Low to normal Research (14,15) Delivery of fetus
AMEb,e Childhood Autosomal recessive Low Low to normal Commercial Spironolactone, dexamethasone
Liddle syndromef Third decade Autosomal dominant Low Low to normal Commercial Amiloride, triamterene
Gordon's syndromeg Second or third decade Autosomal dominant Low High Research (22) Thiazide diuretic, low-sodium diet

aDue to hyperaldosteronism.
bDue to production of non-aldosterone mineralocorticoids.
cAcquired forms due to DOC-producing tumors.
dDue to increased activity of MCRs.
eAcquired forms due to either licorice ingestion or ectopic ACTH secretion.
fDue to increased activity of sodium channels.
gDue to increased activity of Na-Cl co-transporter in the distal tubule.
hSpecific for underlying mechanisms (other forms of treatment, including different antihypertensive medications = might be needed to adequately control blood pressure).
Abbreviations: ACTH = adrenocorticotropic hormone; AME = apparent mineralocorticoid excess; CAH = congenital adrenal hyperplasia; DOC = deoxycorticosterone; FH-I = familial hyperaldosteronism type I; FH-II = familial hyperaldosteronism type II; GRA = glucocorticoid-remediable aldosteronism; MCR = mineralocorticoid receptor.

Familial Hyperaldosteronism Type I

Primary hyperaldosteronism, commonly due to either an aldosterone-producing adrenal adenoma or bilateral adrenal hyperplasia, is one of the most common causes of secondary hypertension. One report estimates that primary aldosteronism affects 8% and 13% of individuals with hypertension grades 2 and 3, respectively.[3] Familial forms are much less common, with literature reports limited to several pedigrees, small series, and isolated case reports.

The recommended screening test for both familial and non-familial forms of primary hyperaldosteronism is the ratio of plasma aldosterone concentration to plasma renin activity.[4] A ratio higher than 30, together with a plasma aldosterone concentration of at least 0.42 nmol/l (15 ng/dl), is widely accepted as a positive screening-test result. The diagnostic accuracy of this approach is only fair, with reported sensitivities of 73-78% and specificities of 74-83%.[5,6] Confirmation of the diagnosis is dependent upon measurement of urinary aldosterone in a 24 h urine collection. Aldosterone values greater than 14 ng/day in the setting of a high sodium diet (indicated by urine sodium excretion exceeding 200 mEq/day and plasma renin activity <1.0 ng/dl/h) is a positive confirmatory-test result for primary hyperaldosteronism.

Familial hyperaldosteronism type I (FH-I)—also known as glucocorticoid-remediable aldosteronism—was the first form of monogenic hypertension to be recognized as a single-gene hypertensive disorder. The genetic defect is characterized by the presence of a hybrid or chimeric gene on chromosome 8q (Figure 1) consisting of the regulatory region of the 11β-hydroxylase gene, CYP11B1, coupled with the structural region of the aldosterone synthase gene, CYP11B2.[7] Its mode of inheritance is autosomal dominant with complete penetrance.

Figure 1.

 

Familial hyperaldosteronism type I (also known as glucocorticoid-remediable aldosteronism). The genetic defect that causes this disorder is characterized by the presence of a hybrid or chimeric gene on chromosome 8q consisting of the regulatory region of the 11β-hydroxylase gene coupled to the coding sequence of the aldosterone synthase gene. Abbreviations: ACTH = adrenocorticotropic hormone; Ang II = angiotensin II.

Normally, aldosterone is produced by the zona glomerulosa via angiotensin-II-mediated stimulation of CYP11B2, and cortisol is produced by the zona fasciculata via adrenocorticotropic hormone (ACTH)-mediated stimulation of CYP11B1. In FH-I, ectopic secretion of aldosterone and 18-OH corticosterone metabolites in the zona fasciculata is positively regulated by ACTH and is not affected by angiotensin II and potassium. Plasma renin activity is typically suppressed while aldosterone levels are increased, although normokalemia is present in nearly half of all FH-I cases. Patients with this genetic defect typically present with a family history of severe hypertension with moderate to severe hypertension usually occurring before the age of 21 years, and are at particularly high risk for hemorrhagic strokes due to ruptured aneurysms.[8] Therefore, all patients with genetically proven FH-I should undergo a cerebral MR angiogram at puberty, and subsequently every 5 years. Preferred treatment is low-dose glucocorticoids, amiloride, and spironolactone, which blocks binding of aldosterone to the mineralocorticoid receptor (MCR). Thiazide diuretics are not the recommended first-line treatment, but might improve control of blood pressure when used concurrently with spironolactone. Thiazide diuretics can cause marked hypokalemia secondary to increased sodium delivery to the cortical collecting duct.[9]

Familial Hyperaldosteronism Type II

Initially described in 1991 in 13 patients from five families whose primary hyperaldosteronism was not suppressed by a dexamethasone challenge (distinguishing it from FH-I), familial hyperaldosteronism type II (FH-II) is now recognized as another rare cause of secondary hypertension.[10] Patients with FH-II are clinically indistinguishable from those with sporadic forms of primary hyperaldosteronism due to bilateral adrenal hyperplasia. The genetic abnormality causing FH-II has been localized to chromosome 7p22.[11] In patients with a family history of hypertension who present with hypertension and hypokalemia, one should consider screening for genetic causes of primary hyperaldosteronism.

While both FH-I and FH-II are rare, it is important to differentiate between the two causes of familial hyperaldosteronism as they require vastly different treatments. Direct genetic testing for the presence of the chimeric gene is available and has been shown to have 100% sensitivity and specificity for diagnosing FH-I.[12] In FH-I, glucocorticoids ameliorate overproduction of aldosterone, thus diminishing ACTH release and subsequently blood pressure. By contrast, hypertension in FH-II is unresponsive to glucocorticoids, but spironolactone is effective.

Congenital Adrenal Hyperplasia

The term 'congenital adrenal hyperplasia' (CAH) describes a group of syndromes caused by defects in cortisol biosynthesis. CAH is inherited in an autosomal recessive manner. When 21-hydroxylase (CYP21A2) is deficient—the most common cause of CAH—patients are normotensive.[13] In 11β-hydroxylase (CYP11B1) and 17α-hydroxylase (CYP17) deficiencies, production of deoxycorticosterone (DOC), which has mineralocorticoid activity, is increased, leading to hypertension. Defects in CYP11B1 and CYP17 cause inhibition of cortisol production (Figure 2) with a subsequent reduction in feedback inhibition of ACTH secretion by the anterior pituitary and hypothalamus. Increased ACTH secretion then stimulates production of steroid precursors proximal to the 'blocked' step, leading to excessive levels of DOC.

Figure 2.

 

Adrenal steroid synthesis. Deficiency in 11β-hydroxylase (CYP11B1) results in accumulation of DOC and consequent hypertension; increased androgen synthesis leads to virilization in girls and precocious puberty in boys (black bar). Deficiency in 17α-hydroxylase (CYP17) also causes DOC accumulation and hypertension; sex hormone synthesis is blocked leading to delayed sexual development in girls and ambiguous genitalia in boys (gray bar). Abbreviation: DOC, deoxycorticosterone.

In both disorders, patients present with hypertension and hypokalemia early in life. Signs of androgen excess distinguish the two disorders; 11β-hydroxylase deficiency causes virilization in girls and precocious puberty in boys, whereas 17α-hydroxylase deficiency results in sex hormone deficiency, primary amenorrhea and delayed sexual development in girls, and ambiguous genitalia in boys. Genetic diagnosis of both conditions relies on testing for mutations that either severely depress or abolish enzyme activity. Both conditions can be effectively treated with exogenous glucocorticoids, which normalize ACTH secretion and ACTH-mediated build-up of cortisol precursors proximal to the enzymatic deficiency, including DOC. Acquired forms of the conditions caused by DOC-producing tumors typically present later in life.

Activating Mineralocorticoid Receptor Mutation

Approximately 6% of pregnancies are associated with hypertension, and it is well established that hypertension in pregnancy increases the risk of morbidity and mortality to the mother and fetus. Whereas the pathophysiologic cause for pregnancy-related hypertension is largely unknown, Lifton et al.[14] described a single gene mutation that caused early-onset hypertension in a family. All family members with this missense mutation had severe hypertension with low renin and aldosterone levels, and presented prior to the age of 21 years. Members of the family without this mutation were normotensive. The mutation—a leucine for serine substitution at codon 810—occurs in the hormone-binding domain of the MCR. The mutation causes the receptor to be constitutively active and alters its specificity such that the steroid hormones, which lack a 21-hydroxyl group and are normally antagonistic (including progesterone and cortisone), act as agonists (Figure 3A).

Figure 3.

 

Single gene disorders that affect the distal nephron and cause hypertension. (A) Mutation that changes specificity of the MCR and leads to hypertension exacerbated by pregnancy (progesterone). (B) Deficiency of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2)—either inherited (AME) or acquired (licorice)—leads to elevated levels of cortisol, stimulation of MCR and hypertension. (C) Liddle syndrome. Mutations in the β- or γ-subunit of the ENaC prevent binding to Nedd4, a repressor factor, leading to constitutive expression of sodium channels, volume expansion and hypertension. (D) Gordon's syndrome. Mutations in WNK cause: (Da ) increased NCCT activity in DCT, sodium and chloride reabsorption with volume expansion and hypertension; and (Db ) inhibition of ROMK activity in CCT and hyperkalemia. Abbreviations: AME, apparent mineralocorticoid excess; CCT, cortical collecting tubule; DCT, distal convoluted tubule; ENaC, amiloride-sensitive sodium channel; MCR, mineralocorticoid receptor; NCCT, Na-Cl co-transporter; PT, proximal tubule; ROMK, renal outer medullary potassium channel; WNK, serine-threonine kinase.

Hypertension in females harboring this mutation was markedly exacerbated during pregnancy. The 100-fold increase in progesterone during pregnancy is thought to underlie this marked exacerbation, causing avid retention of sodium and blood volume expansion.[14] These occurrences create a virtual state of hyperaldosteronism in which both plasma renin activity and serum aldosterone levels are suppressed. The exact mechanism by which the missense mutation becomes activated is unknown. Recent data have shown that cortisone, the main metabolite of cortisol in the kidney, can activate the mutation, conferring a potential permanent increase in renal sodium reabsorption—a possible explanation for the severe hypertension evident in young males and in non-pregnant females.[15]

Treatment of this condition differs from those described above. With its low levels of aldosterone, this condition is refractory to standard medical management aimed at reducing aldosterone levels. In fact, spironolactone actually worsens hypertension in affected individuals. The cases reported to date have not been associated with proteinuria, edema or neurological changes, which distinguish them from cases of pre-eclampsia. Nonetheless, the treatment for both of these conditions is the same—delivery of the fetus, which markedly reduces progesterone levels and, subsequently, blood pressure. While delivery improves the hypertension in pregnancy, no definitive therapeutic algorithm has been described for males or non-pregnant females.

Syndrome of Apparent Mineralocorticoid Excess

Both cortisol and aldosterone are potent activators of renal MCRs. In vitro, cortisol is a tenfold more potent activator of the MCR than aldosterone. In the kidney, 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2) converts cortisol to cortisone, which does not activate the renal MCR. This mechanism thereby protects the collecting tubules from inappropriate activation of the MCR by circulating cortisol. The autosomal recessive syndrome of apparent mineralocorticoid excess causes severe hypertension through mutations in the 11β-HSD-2 gene (Figure 3B), which render the enzyme ineffective.[16] This allows cortisol, which circulates at much higher concentrations than aldosterone, to saturate the MCR and induce hypertension and hypokalemia.

This disorder typically presents in childhood with hypertension, hypokalemia, and suppressed renin and aldosterone levels. An increased ratio of cortisol-to-cortisone metabolites in the urine is the hallmark of the syndrome. Treatment consists of spironolactone, which blocks binding of both cortisol and aldosterone to the MCR. Adjunctive treatments are potassium supplementation and a low-sodium diet. Dexamethasone can sometimes correct hypokalemia by suppressing cortisol formation via feedback inhibition of ACTH, but this agent lacks a consistent antihypertensive effect.[8]

There are several acquired forms of apparent mineralocorticoid excess that are more common than congenital forms, and therefore need to be considered in the differential diagnosis. A component of black licorice, glycyrrhetinic acid, inhibits 11β-dehydrogenase, thereby increasing levels of cortisol and saturating the MCR.[17] Conditions associated with ectopic ACTH release, such as small cell lung cancer, might cause apparent mineralocorticoid excess by inducing such high cortisol levels that the capacity of the 11β-dehydrogenase enzyme to convert cortisol to cortisone is exceeded.[18] Affected individuals typically present with hypertension and hypokalemic alkalosis; cushingoid features are usually absent due to malignant cachexia. A dexamethasone suppression test might lead to the diagnosis by demonstrating nonsuppressible hypersecretion of ACTH and cortisol. The prognosis in these patients is ultimately dependent on progression of the underlying malignancy. Commonly, the prognosis is grave, as ectopic ACTH syndrome, like other paraneoplastic syndromes, is frequently associated with advanced disease.

Liddle Syndrome

Liddle syndrome is an autosomal dominant disorder caused by hyperactivity of the amiloride-sensitive sodium channel (ENaC) of the principal cell of the cortical collecting tubule. In 1963, Liddle described a family in which multiple siblings developed early-onset severe hypertension and hypokalemia. Genetic studies have revealed mutations in the genes coding the beta or gamma subunits of ENaC (chromosome 16p) that cause deletions of proline-rich regions.[19,20] These regions are important to regulation of ENaC activity as they facilitate binding of Nedd4, a regulatory repressor that promotes channel degradation. The inability of beta and gamma subunits to bind Nedd4 results in constitutive expression of sodium channels at the apical surface of principal cells, leading to increased rates of sodium reabsorption, volume expansion and hypertension (Figure 3C).

The typical presentation of patients with Liddle syndrome includes early-onset severe hypertension, hypokalemia, metabolic alkalosis in the setting of low plasma renin and aldosterone, low rates of urinary aldosterone excretion, and a family history of hypertension.[21] Hypokalemia and metabolic alkalosis develop in response to reabsorption of cationic sodium in the absence of an anion. This creates a lumen-negative electrical gradient, which promotes secretion of potassium and hydrogen ions into the collecting tubule. In untreated patients, cardiovascular complications are common.

Treatment of Liddle syndrome with amiloride or triamterene lowers blood pressure and corrects the hypokalemia and acidosis. These agents effectively block the constitutively active ENaC in the collecting tubule. Spironolactone is not an effective treatment as the increased activity of the ENaC is not mediated by aldosterone (as reflected by the low plasma and urinary aldosterone levels).

Gordon's Syndrome

Recently identified mutations of WNK1 and WNK4 (members of a family of serine-threonine kinases) have been shown to cause the rare familial autosomal dominant disease, Gordon's syndrome (also known as pseudohypoaldosteronism type II).[22] Wild-type WNK1 and WNK4 inhibit the thiazide-sensitive Na-Cl co-transporter in the distal tubule. Mutations of these proteins are associated with gain of function (Figure 3Da) and increased co-transporter activity, excessive chloride and sodium reabsorption, and volume expansion.[23] This syndrome is characterized by short stature, intellectual impairment, dental abnormalities, muscle weakness, severe hypertension by the third decade of life, low fractional excretion of sodium, normal renal function, hyperchloremic metabolic acidosis, and low renin and aldosterone levels. Hyperkalemia, another hallmark of this syndrome, might be a function of diminished sodium delivery to the cortical collecting tubule (sodium reabsorption provides the driving force for potassium excretion, which is mediated by the renal outer medullary potassium channel ROMK). Alternatively, the same mutations in WNK4 that result in a gain of function of the Na-Cl co-transporter, might inhibit ROMK activity (Figure 3Db), resulting in hyperkalemia, as suggested by recent genetic studies.[24] Treatment consists of either a low-salt diet or thiazide diuretics, aimed at decreasing chloride intake and blocking Na-Cl co-transporter activity, respectively.

Conclusion

In monogenic hypertensive disorders, three distinct mechanisms leading to the common final pathway of increased sodium reabsorption, volume expansion and low plasma renin activity are recognized. The first mechanism relates to mutations in and consequent hyperactivity of sodium and chloride transporters, or of mineralocorticoid receptors that can mimic a state of mineralocorticoid excess, leading to hypertension (e.g. Liddle syndrome, Gordon's syndrome, activating MCR mutation in hypertension exacerbated by pregnancy). The second mechanism involves deficiencies of enzymes that regulate adrenal steroid synthesis and activity, resulting in a build-up of precursors with potent mineralocorticoid activity and consequent hypertension (e.g. CAH, syndrome of apparent mineralocorticoid excess). Increased rates of sodium and water reabsorption leading to plasma volume expansion, hypertension and suppression of both renin and aldosterone levels are common to these two mechanisms. By contrast, the third mechanism is characterized by excessive aldosterone synthesis that escapes normal regulatory mechanisms, and gives rise to volume-dependent hypertension that, in turn, suppresses renin release (FH-I and FH-II). Hormonal studies coupled with genetic testing can help in the early diagnosis of these disorders ( ). Treatment strategies aim to correct the underlying defect and, for most of these disorders, are readily available and successful.

Table 1.  Characteristics of and Treatments for Monogenic Forms of Low-renin Hypertension

Disorder Age of onset Pattern of inheritance Aldosterone level Serum potassium level Genetic test (reference) Treatmenth
FH-I (GRA)a Second or third decade Autosomal dominant High Decreased in 50% of cases; marked decrease with thiazides Commercial Glucocorticoids
FH-IIa Middle Autosomal dominant High Low to normal Research (11) Spironolactone, eplerenone
DOC oversecretion due to CAHb,c Childhood Autosomal recessive Low Low to normal Research (25) Glucocorticoids
Activating MCR mutation exacerbated by pregnancyd Second or third decade Unknown Low Low to normal Research (14,15) Delivery of fetus
AMEb,e Childhood Autosomal recessive Low Low to normal Commercial Spironolactone, dexamethasone
Liddle syndromef Third decade Autosomal dominant Low Low to normal Commercial Amiloride, triamterene
Gordon's syndromeg Second or third decade Autosomal dominant Low High Research (22) Thiazide diuretic, low-sodium diet

aDue to hyperaldosteronism.
bDue to production of non-aldosterone mineralocorticoids.
cAcquired forms due to DOC-producing tumors.
dDue to increased activity of MCRs.
eAcquired forms due to either licorice ingestion or ectopic ACTH secretion.
fDue to increased activity of sodium channels.
gDue to increased activity of Na-Cl co-transporter in the distal tubule.
hSpecific for underlying mechanisms (other forms of treatment, including different antihypertensive medications = might be needed to adequately control blood pressure).
Abbreviations: ACTH = adrenocorticotropic hormone; AME = apparent mineralocorticoid excess; CAH = congenital adrenal hyperplasia; DOC = deoxycorticosterone; FH-I = familial hyperaldosteronism type I; FH-II = familial hyperaldosteronism type II; GRA = glucocorticoid-remediable aldosteronism; MCR = mineralocorticoid receptor.


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Sidebar: Key Points

  • Monogenic hypertension is caused by single gene mutations and accounts for a spectrum of familial forms of elevated blood pressure

  • Monogenic forms of hypertension share a common pathway of increased reabsorption of sodium and chloride in distal tubules and volume expansion, which suppresses plasma renin activity

  • These disorders should be suspected in young patients with a familyhistory of hypertension who present with severe or refractory hypertension and characteristic hormonal and biochemical abnormalities

  • Timely diagnosis using genetic tests might enhance the success of therapies that target the underlying defects and thus prevent long-term consequences of uncontrolled hypertension

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