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Mendelian disorders causing hypertension 

Mendelian disorders causing hypertension
Chapter:
Mendelian disorders causing hypertension
Author(s):

Nilesh J. Samani

and Maciej Tomaszewski

DOI:
10.1093/med/9780199204854.003.161704_update_001

Update:

Expanded discussion of the mechanism of pseudohypoaldosteronism type 2 (Gordon’s syndrome), including its cause by mutations in novel genes.

Updated on 27 Nov 2014. The previous version of this content can be found here.
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Essentials

Several mendelian disorders with hypertension as the predominant manifestation have been characterized at the molecular level. Features that may suggest one of these very rare conditions include a young age of onset, moderate to severe hypertension, strong family history, consanguinity (for the autosomal recessive disorders), and electrolyte abnormalities, particularly of potassium (although this is not invariable).

Glucocorticoid-remediable aldosteronism—an autosomal dominant condition caused by a chimeric gene where the regulatory elements of the 11β‎-hydroxylase gene become attached to the coding region of aldosterone synthase. Hypertension responds to a low daily dose of exogenous glucocorticoid.

Apparent mineralocorticoid excess—an autosomal recessive disorder caused by mutations causing loss of function in the type 2 11β‎-hydroxysteroid dehydrogenase gene that normally inactivates cortisol in the kidney and prevents it binding to the mineralocorticoid receptor. The hypertension responds to spironolactone or amiloride.

Liddle’s syndrome—an autosomal dominant condition, caused by activating mutations in the WNK1 or WNK4 serine-threonine kinases genes, the Kelch-like 3 (KLHL3) gene or the cullin 3 (CUL3) gene. These genes regulate salt reabsorption by the Na-Cl cotransporter (SLC12A3) and the linked process of potassium secretion by the renal outer medullary potassium channel (ROMK). The hypertension and physiological abnormalities are corrected by thiazide diuretics.

Introduction

Several rare mendelian disorders where hypertension is the predominant manifestation have been characterized at the molecular level (Box 16.17.4.1). These include glucocorticoid-remediable aldosteronism, the syndrome of apparent mineralocorticoid excess, Liddle’s syndrome, and Gordon’s syndrome. Hypertension and hypokalaemia are features of 11β‎-hydroxylase and 17β‎-hydroxylase deficiency—two rare recessive gene disorders of adrenal steroid-synthesizing enzymes that, among others, cause congenital adrenal hyperplasia. 11β‎-Hydroxylase deficiency usually presents in infancy or early childhood with virilization of both sexes, while presentation of 17β‎-hydroxylase deficiency may be delayed until adolescence or adulthood. Hypertension due to a phaeochromocytoma may be a feature of multiple endocrine neoplasia type 2 (MEN2, Sipple’s syndrome), which when familial is inherited in an autosomal dominant pattern, or rarely to be a feature of neurofibromatosis (von Recklinghausen’s disease).

Glucocorticoid-remediable aldosteronism

Glucocorticoid-remediable aldosteronism (GRA, OMIM 103900) is a form of mineralocorticoid hypertension that is inherited in an autosomal dominant fashion. The hypertension is accompanied by hypokalaemia (not invariably), a tendency to metabolic alkalosis, an elevated plasma aldosterone level and a suppressed renin level, and it often responds to thiazides or spironolactone. Patients are usually suspected of having primary aldosteronism (Conn’s syndrome, see Chapter 16.17.4), although the age of onset, usually in the first two decades of life, is younger than typical of primary aldosteronism. Intracranial aneurysms are common and the first manifestation may be a presentation with intracranial haemorrhage.

The two hallmark features of GRA are the presence of large amounts of two abnormal steroids—18-hydroxycortisol and 18-oxocortisol—in the urine, and the paradoxical response of the hypertension, with return of plasma aldosterone to a normal level and disappearance of the abnormal steroids, following treatment over a few days with a low daily dose of exogenous glucocorticoid, e.g. 0.5 to 1.0 mg of dexamethasone (hence the name).

Patients with GRA have a chimeric gene due to an unequal crossing-over event at meiosis between two adjacent and highly homologous genes involved in adrenocorticosteroid synthesis—aldosterone synthase (CYP11B2) (normally expressed only in the zona glomerulosa, involved in aldosterone synthesis and regulated by angiotensin II) and 11β‎-hydroxylase (CYP11B1) (expressed in the zona fasciculata, involved in glucocorticoid synthesis and regulated by ACTH). In the chimeric gene, the regulatory elements of CYP11B1 have become attached to the aldosterone synthase coding region of CYP11B2 (Fig. 16.17.4.1a). This leads to ACTH-driven production of aldosterone (and the other abnormal hormones) in the zona fasciculata, hence the clinical syndrome and its suppression by glucocorticoids.

Fig. 16.17.4.1 Mechanisms underlying four forms of monogenetic hypertension. (a) Glucocorticoid remediable aldosteronism (GRA). In GRA an unequal crossing event leads to a chimaeric gene where the coding region of aldosterone synthase becomes attached to the regulatory region for 11β‎-hydroxylase. The chimaeric gene produces excess amounts of aldosterone under the regulation of ACTH. (b) Syndrome of apparent mineralocorticoid excess (AME). The mineralocorticoid receptor in the distal renal tubule is normally protected from stimulation by cortisol by the activity of the 11β‎-hydroxysteroid dehydrogenase enzyme. In AME, mutations in the enzyme allow cortisol to gain access to the receptor. (c) Liddle’s syndrome. The trimeric epithelial sodium channel mediates sodium reuptake in the distal renal tubule. In Liddle’s syndrome, mutations in the β‎ and γ‎ subunits of the channel impair its intracellular biodegradation and lead to excessive channel density and activity on the surface of distal renal tubular epithelium. (d) Gordon’s syndrome. WNK1 and WNK4 regulate thiazide-sensitive sodium-chloride cotransporter (NCCT) and potassium secretion via ROMK in the distal nephron. Mutations in WNK1/WNK4 or genes responsible for their intracellular degradation (KLHL3 and CUL3) lead to increased sodium reabsorption via overactive NCCT and impaired potassium secretion through ROMK.
Fig. 16.17.4.1 Mechanisms underlying four forms of monogenetic hypertension. (a) Glucocorticoid remediable aldosteronism (GRA). In GRA an unequal crossing event leads to a chimaeric gene where the coding region of aldosterone synthase becomes attached to the regulatory region for 11β‎-hydroxylase. The chimaeric gene produces excess amounts of aldosterone under the regulation of ACTH. (b) Syndrome of apparent mineralocorticoid excess (AME). The mineralocorticoid receptor in the distal renal tubule is normally protected from stimulation by cortisol by the activity of the 11β‎-hydroxysteroid dehydrogenase enzyme. In AME, mutations in the enzyme allow cortisol to gain access to the receptor. (c) Liddle’s syndrome. The trimeric epithelial sodium channel mediates sodium reuptake in the distal renal tubule. In Liddle’s syndrome, mutations in the β‎ and γ‎ subunits of the channel impair its intracellular biodegradation and lead to excessive channel density and activity on the surface of distal renal tubular epithelium. (d) Gordon’s syndrome. WNK1 and WNK4 regulate thiazide-sensitive sodium-chloride cotransporter (NCCT) and potassium secretion via ROMK in the distal nephron. Mutations in WNK1/WNK4 or genes responsible for their intracellular degradation (KLHL3 and CUL3) lead to increased sodium reabsorption via overactive NCCT and impaired potassium secretion through ROMK.
Fig. 16.17.4.1 Mechanisms underlying four forms of monogenetic hypertension. (a) Glucocorticoid remediable aldosteronism (GRA). In GRA an unequal crossing event leads to a chimaeric gene where the coding region of aldosterone synthase becomes attached to the regulatory region for 11β‎-hydroxylase. The chimaeric gene produces excess amounts of aldosterone under the regulation of ACTH. (b) Syndrome of apparent mineralocorticoid excess (AME). The mineralocorticoid receptor in the distal renal tubule is normally protected from stimulation by cortisol by the activity of the 11β‎-hydroxysteroid dehydrogenase enzyme. In AME, mutations in the enzyme allow cortisol to gain access to the receptor. (c) Liddle’s syndrome. The trimeric epithelial sodium channel mediates sodium reuptake in the distal renal tubule. In Liddle’s syndrome, mutations in the β‎ and γ‎ subunits of the channel impair its intracellular biodegradation and lead to excessive channel density and activity on the surface of distal renal tubular epithelium. (d) Gordon’s syndrome. WNK1 and WNK4 regulate thiazide-sensitive sodium-chloride cotransporter (NCCT) and potassium secretion via ROMK in the distal nephron. Mutations in WNK1/WNK4 or genes responsible for their intracellular degradation (KLHL3 and CUL3) lead to increased sodium reabsorption via overactive NCCT and impaired potassium secretion through ROMK.

Fig. 16.17.4.1
Mechanisms underlying four forms of monogenetic hypertension. (a) Glucocorticoid remediable aldosteronism (GRA). In GRA an unequal crossing event leads to a chimaeric gene where the coding region of aldosterone synthase becomes attached to the regulatory region for 11β‎-hydroxylase. The chimaeric gene produces excess amounts of aldosterone under the regulation of ACTH. (b) Syndrome of apparent mineralocorticoid excess (AME). The mineralocorticoid receptor in the distal renal tubule is normally protected from stimulation by cortisol by the activity of the 11β‎-hydroxysteroid dehydrogenase enzyme. In AME, mutations in the enzyme allow cortisol to gain access to the receptor. (c) Liddle’s syndrome. The trimeric epithelial sodium channel mediates sodium reuptake in the distal renal tubule. In Liddle’s syndrome, mutations in the β‎ and γ‎ subunits of the channel impair its intracellular biodegradation and lead to excessive channel density and activity on the surface of distal renal tubular epithelium. (d) Gordon’s syndrome. WNK1 and WNK4 regulate thiazide-sensitive sodium-chloride cotransporter (NCCT) and potassium secretion via ROMK in the distal nephron. Mutations in WNK1/WNK4 or genes responsible for their intracellular degradation (KLHL3 and CUL3) lead to increased sodium reabsorption via overactive NCCT and impaired potassium secretion through ROMK.

The mainstay of treatment for GRA is glucocorticoids, with physiological doses (or only slightly higher, e.g. 0.125 mg of dexamethasone or 2.5 mg of prednisolone daily) sufficing. Response can be monitored by measuring the suppression of aldosterone production. Selective mineralocorticoid receptor blockers, such as spironolactone, can provide useful adjunctive treatment.

Syndrome of apparent mineralocorticoid excess

The syndrome of apparent mineralocorticoid excess (AME, OMIM 218030) is an autosomal recessive disorder that usually presents in childhood with hypertension, hypokalaemia, and low renin activity. Despite the clinical features of mineralocorticoid excess, levels of all known mineralocorticoid hormones are low, yet the hypertension responds to spironolactone or amiloride. Patients with the disorder cannot metabolize cortisol to its inactive metabolite cortisone normally, resulting in a prolonged half-life of cortisol and a characteristic increase in urinary cortisol (compound F) compared with cortisone (compound E) ratio.

Elucidating the defect causing AME first required the solution of another paradox—why cortisol, which circulates at a level several-fold greater than aldosterone, does not overwhelmingly activate the renal mineralocorticoid receptor in vivo despite the two having equal affinity in vitro. The reason relates to the enzyme 11β‎-hydroxysteroid dehydrogenase (11β‎-HSD), which has two isoforms. Type 1 11β‎-HSD is located in the liver, adipose tissue, muscle, pancreaticislets, and gonad and converts cortisone to cortisol. Type 2 11β‎-HSD is expressed in the mineralocorticoid target tissues—kidney, colon, and salivary gland—and inactivates cortisol to cortisone. In the kidney the enzyme plays the crucial role of protecting the mineralcorticoid receptor on the distal tubule from activation by cortisol. In subjects with AME a variety of loss-of-function mutations in the type 2 11β‎-HSD gene cause a deficiency of the enzyme, allowing cortisol access to the mineralocorticoid receptor (Fig. 16.17.4.1b).

The severe form of AME, due to disabling mutations in type 2 11β‎-HSD, usually presents in childhood. Recently a milder form, termed AME type II, has been described, which is characterized by a later age of presentation (>30 years), a more variable degree of hypertension, and less impact on biochemical parameters. These patients have alterations in 11β‎-HSD2 that produce a partial rather than absolute decrease in enzymatic activity, hence classification into distinct subcategories may be inappropriate, with AME best regarded as a spectrum of mineralocorticoid hypertension with severity reflecting the underlying genetic defect. The mainstay of treatment of AME is spironolactone. A low-salt diet is also important.

AME resembles the syndrome observed in subjects ingesting large amounts of liquorice or taking the now redundant antiulcer drug carbenoxolone, both of which contain glycyrrhetinic acid, an inhibitor of type 2 11β‎-HSD, thus explaining the hypertension and hypokalaemia observed with these compounds. Spillover access of cortisol to the mineralocorticoid receptor may also, at least partly, explain the hypertension accompanying some forms of Cushing’s syndrome and glucocorticoid resistance.

Liddle’s syndrome

Liddle described a family in which the siblings were affected by early-onset hypertension and hypokalaemia, but with low renin and aldosterone levels (OMIM 177200). The clue to the nature of the molecular defect underlying this autosomal dominant disorder came from the observation that the hypertension does not respond to spironolactone, the mineralocorticoid receptor antagonist, but does respond to direct inhibitors (such as triamterene or amiloride) of the trimeric epithelial sodium channel,—a key channel responsible for sodium reabsorption in the distal nephron. Subsequent work revealed activating mutations in genes (SCNN1B, SCNN1G) encoding the β‎- or γ‎-subunits of the channel (Fig. 16.17.4.1c). All mutations so far identified cause an alteration or deletion of a proline-rich (PY) motif in the C-terminal cytoplasmic tails of the subunits that is necessary for regulatory proteins such as Nedd4 to bind and internalize the channel. When this mechanism is impaired, the number of channels located in the apical membrane is increased, leading to over-reabsorption of sodium and water.

Mendelian disorders causing hypertensionPseudohypoaldosteronism type 2 (Gordon’s syndrome)

Pseudohypoaldosteronism type 2 (PHA2, OMIM 145260) also known as Gordon’s syndrome, is an autosomal dominant disorder that causes elevated blood pressure accompanied by hyperkalaemia, despite normal renal glomerular filtration. Mild hyperchloraemia, metabolic acidosis, and suppressed plasma renin activity are common associated findings. Hypercalciuria can also be a feature, leading to osteopenia, osteoporosis, and kidney stone disease. The hypertension and biochemical abnormalities are corrected by thiazide diuretics.

Mutations in at least four genes are recognized causes of PHA2. Initially some cases of PHA2 were linked to mutations in two genes, WNK1 and WNK4, members of the WNK family of serine-threonine kinases. The genetic defects in both WNK1 and WNK4, by increasing their expression/activity in the distal nephron, lead to enhanced phosphorylation of two other enzymes, STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1). Both SPAK and OSR1 are key regulators of the Na-Cl cotransporter, NCCT (encoded by the SLC12A3 gene), which is responsible for sodium reabsorption in the distal convoluted tubule and the linked process of potassium secretion by the renal outer medullary potassium channel (ROMK). Na-Cl cotransporter overactivity is the chief biochemical abnormality of the syndrome and the primary driver of enhanced sodium reabsorption, volume expansion, inhibition of renin secretion, and hypertension.

Decreased potassium excretion leading to hyperkalaemia in PHA2 results from two processes. Firstly, increased Na-Cl cotransporter activity, by increasing sodium reabsorption in the distal convoluted tubule, leads to reduced sodium delivery to the connecting tubule, which results in a drop in electrochemical gradient necessary to maintain activity of ROMK channels that transfer K+ from blood to urine across the distal tubule epithelium. Secondly, enhanced internalization of ROMK channels in PHA2 leads to their decreased expression/activity on the surface of tubular epithelium.

More recently, mutations in two novel genes, Kelch-like 3 (KLHL3) and Cullin 3 (CUL3), were reported to account for a majority (≈80%) of causal genetic defects in patients with PHA2. The mutations are inherited in either autosomal dominant (KLHL3 and CUL3) or recessive (KLHL3) manner. The products of both genes are a part of ubiquitin ligase complex responsible for intracellular degradation of more than 50 proteins, including WNKs. The most likely molecular mechanism by which genetic defects in these genes lead to PHA2 is disruption of WNKs intracellular degradation and accumulation of WNK4/WNK1 and subsequent changes in the activity of Na-Cl cotransporter /ROMK channel.

The Na-Cl transporter is the target for thiazide diuretics, which explains the specific clinical response of PHA2 to this class of drugs.

Defects in the Na-Cl cotransporter lead to the salt-losing Gitelman’s syndrome, which as described below is the mirror image of PHA2.

Other monogenetic forms of hypertension

A missense mutation in the ligand-binding domain of the mineralocorticoid receptor has been found to cause an autosomal dominant form of hypertension that is markedly accelerated in pregnancy. The mutation, MR S810L, causes partial, aldosterone-independent activation of the receptor, causing carriers to develop hypertension before age 20. Compounds such as progesterone that normally bind to but do not activate the mineralocorticoid receptor are all potent agonists of the mutant receptor, hence MR S810L carriers have dramatic acceleration of hypertension during pregnancy stimulated by the 100-fold rise in progesterone. Although the MR S810L mutation is extremely rare, the finding does raise the question of whether related mechanisms may underlie other forms of hypertension in pregnancy.

Genetic defects causing hypotension

A number of mendelian syndromes where hypotension is a feature have recently been characterized at the molecular level (Table 16.17.4.1). Many are mirror images of the genetic abnormalities causing the mendelian forms of hypertension described above.

Table 16.17.4.1 Biochemical and therapeutic characteristics of glucocorticoid-remediable aldosteronism (GRA), syndrome of apparent mineralocorticoid excess (AME), Liddle’s syndrome, and Gordon’s syndrome

GRA

AME

Liddle’s

Gordon’s

Plasma electrolytes

↑Na ↓K

↑Na ↓K

↑Na ↓K

↑Na ↑K

Plasma aldosterone

↑↓

Plasma renin

Specific treatment

Dexamethasone

Spironolactone

Amiloride

Thiazide

Note that while the biochemical changes are characteristic, they are not invariably present.

Pseudohypoaldosteronism type 1 (PHA1) occurs in two forms, autosomal recessive and autosomal dominant. Both are characterized by life-threatening dehydration in the neonatal period, hypotension, salt wasting, hyperkalaemia, metabolic acidosis, and marked elevation of renin and aldosterone. The autosomal recessive form (OMIM 264350) is due to inactivating mutations (compare with Liddle’s syndrome) in one of the genes SCNN1A, SCCN1B or SCNN1G, encoding (respectively) the α‎, β‎, and γ‎ subunits of the epithelial sodium channel, while the autosomal dominant form (OMIM 177735) is due to loss-of-function mutations in the gene NR3C2 encoding the mineralocorticoid receptor.

Gitelman’s syndrome (OMIM 263800) is an autosomal recessive disorder characterized by hypotension, neuromuscular abnormalities, hypokalaemia, hypomagnesaemia, hypocalciuria, metabolic alkalosis, and an activated renin–angiotensin system. It arises due to inactivating mutations in the gene encoding the renal thiazide-sensitive Na-Cl cotransporter (SLC12A3), and typically presents in adolescence or early adulthood with neuromuscular signs and symptoms.

Bartter’s syndrome is caused by mutations in one or more of the genes that encode regulators of chloride transport within the thick ascending limb of nephron. There are several types of Bartter’s syndrome. The gene defects responsible are in genes encoding bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2 (SLC12A1) (type 1, OMIM 601678), ATP-regulated potassium channel ROMK (KCNJ1) (type 2, OMIM 241200), chloride channel Kb (CLCNKB) (type 3, OMIM 607364), barttin (BSDN) (type 4a, OMIM 602522), and both CLCNKA and CLCNKB genes (type 4b, OMIM 613090).

The manifestation of these autosomal recessive disorders is heterogeneous, but the most typical clinical presentations include early onset (infancy or childhood), hypovolaemia and polyuria, low or normal blood pressure, elevated prostaglandin levels and nephrocalcinosis. The recently identified Bartter-like syndrome occurring in subjects with mutations in the CASR gene (which encodes extracellular basolateral calcium sensing receptor) manifests as hypocalcemic hypercalciuria. For further discussion of Gitelman’s and Bartter’s syndromes, see Chapter 21.2.2.

Does my patient have a recognized form of monogenetic hypertension?

Identification that a patient has GRA, AME, Liddle’s syndrome, or Gordon’s syndrome has important consequences for treatment (Table 16.17.4.1) and family screening. Phenotypic expression is highly variable, but all of the syndromes are extremely rare and suspicion will usually go unrewarded. Features that may suggest a diagnosis of mendelian hypertension include a young age of onset, moderate to severe hypertension, strong family history, consanguinity (for the autosomal recessive disorders), and electrolyte abnormalities, particularly of potassium (although this is not invariable). A good starting point, as described in Chapter 16.17.4, is the measurement of plasma renin activity and plasma aldosterone. If the aldosterone is significantly elevated then the differential diagnosis lies between the various forms of Conn’s syndrome and GRA. Diagnosis of GRA would be supported by the finding of elevated 18-hydroxycortisol and 18-oxocortisol in the urine, and a positive dexamethasone suppression test, suppression of plasma aldosterone levels to less than 4 ng/dl with 0.75 to 2.0 mg/day for at least 2 days being reported to have a greater than 90% specificity and sensitivity for the diagnosis, and GRA can now also be relatively easily confirmed by finding a chimeric gene fragment with DNA testing.

If the aldosterone level is suppressed, then finding an increased ratio of cortisol/cortisone metabolites in the urine would support a diagnosis of AME. The presence of hyperkalaemia, hyperchloraemia, and metabolic acidosis would suggest a diagnosis of Gordon’s syndrome. No biochemical abnormalities specifically support a diagnosis of Liddle’s syndrome, but it typically presents with hyporeninaemic hypoaldosteronism. Ultimately, diagnosis of AME, Liddle’s syndrome, and Gordon’s syndrome also requires DNA confirmation, but this is not as straightforward as it is with GRA since several different mutations can give rise to each syndrome.

Further reading

Boyden LM, et al. (2012). Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature, 482, 98–102.Find this resource:

    Geller DS, et al. (2000). Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science, 289, 119–23.Find this resource:

    Lifton RP, et al. (1992). A chimaeric 11ß-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature, 355, 262–65.Find this resource:

    Lifton RP, et al. (2001). Molecular mechanisms of human hypertension. Cell, 104, 545–56.Find this resource:

    Mune T, et al. (1995). Human hypertension caused by mutations in the kidney isozyme of 11β‎-hydroxysteroid dehydrogenase. Nat Genet, 10, 394–9.Find this resource:

    Shimkets RA, et al. (1994). Liddle’s syndrome: Heritable human hypertension caused by mutations in the β‎ subunit of the epithelial sodium channel. Cell, 79, 407–14.Find this resource:

    Wilson FH, et al. (2001). Human hypertension caused by mutations in WNK kinases. Science, 293, 1107–12.Find this resource: