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Pseudohypoaldosteronism type 2 presenting with hypertension and hyperkalaemia due to a novel mutation in the WNK4 gene

A.M. Brooks, M. Owens, J.A. Sayer, M. Salzmann, S. Ellard, B. Vaidya
DOI: http://dx.doi.org/10.1093/qjmed/hcr119 791-794 First published online: 14 July 2011

Case report

A 41-year-old man was found to have high blood pressure of 220/100 mmHg during a routine health check-up for medical insurance. He was asymptomatic, and physical examination was unremarkable apart from a soft ejection systolic murmur heard loudest at the left sternal edge. Initial investigations showed serum sodium 144 mmol/l (reference range 132–144), potassium 6.0 mmol/l (3.5–5.5) and creatinine 100 μmol/l (45–120). There was no evidence of left ventricular hypertrophy on an electrocardiogram, and an echocardiography showed no abnormality apart from trivial tricuspid regurgitation. Renal ultrasound, renal perfusion scan and chest radiograph were also normal.

The patient was given lifestyle advice, and was commenced on atenolol 100 mg once a day. Over the next 7 years, further antihypertensive agents—including amlodipine 10 mg, doxazosin 16 mg and lisinopril 5 mg—were gradually added. During this period, following an episode of renal colic, he was found to have a radio-opaque renal stone and was treated with lithotripsy. Despite multiple antihypertensive agents, his blood pressure was still consistently above 150/90 mmHg. In addition, his serum potassium levels, measured on several occasions, remained high between 5.8 and 6.6 mmol/l. Therefore, the patient was referred to the Endocrine outpatient clinic for further review.

In the Endocrine clinic, it was noted that his mother and his only sister also suffered from hypertension and hyperkalaemia. We excluded pseudohyperkalaemia in our patient by analysing serum potassium level immediately after venesection, and carried out further tests to investigate possible causes for the familial hypertension (Table 1). The investigations revealed that as well as a high serum potassium level, he also had hyperchloraemic metabolic acidosis and marked hypercalciuria. His renal function, renin and aldosterone levels were normal. These results, taken together with the history of familial hypertension and hyperkalaemia, were considered to be consistent with a diagnosis of pseudohypoaldosteronism type 2 (PHA2). Therefore, his antihypertensive agents were switched to bendroflumethiazide 2.5 mg once a day. On this drug, his blood pressure improved and has remained well controlled below 140/80 mmHg. In addition, his hyperkalaemia, hyperchloraemic metabolic acidosis and hypercalciuria have reverted to normal (Table 1).

View this table:
Table 1

Investigations pre and post thiazide treatment

TestsPre-thiazideaPost-thiazideaReference range
Blood tests
    Serum sodium (mmol/l)142138132–145
    Serum potassium (mmol/l)6.24.53.5–5.5
    Creatinine (µmol/l)9610445–120
    Urea (mmol/l)5.57.32.1–6
    Chloride (mmol/l)11310396–106
    Bicarbonate (mmol/l)212622–30
    Glucose fasting (mmol/l)7.26.83.9–5.5
    Calcium (mmol/l)2.172.152.05–2.55
    Albumin (g/l)485035–50
    Phosphate (mmol/l)1.451.010.8–1.45
    Magnesium (mmol/l)0.930.850.7–1
    Urate (µmol/l)388574190–440
    Parathyroid hormone (pmol/l)5.78.31.6–6.9
    Total vitamin D (nmol/l)5736>50
    Renin (ambulant) (mU/l)5.417.52–40
    Aldosterone (ambulant) (ng/l)16314540–310
    Total cholesterol (mmol/l)54.7
    HDL-cholesterol (mmol/l)1.171.250.91–1.42
    LDL-cholesterol (mmol/l)2.122.45
    Total/HDL cholesterol ratio4.33.8
    Triglycerides (mmol/l)3.722.170.84–1.94
Urine tests
    24-h urinary sodium (mmol)212281
    24-h urinary potassium (mmol)112.2122
    24-h urinary creatinine (mmol)1819.6
    24-h urinary calcium (mmol)14.94.82.5–7.5
  • aPre-thiazide and post-thiazide investigations were carried out in summer (August) and winter (December) months, respectively.

Genetic testing

Genomic DNA was initially screened for mutations in exons 7 and 17 of the WNK4 gene (MIM 601844) since all reported mutations associated with PHA2 are located within these two exons.1–4 We used standard PCR conditions, exon-specific primers (sequences available on request) and automated sequencing (ABI 3730 with analysis using Mutation Surveyor). Sequencing analysis identified a novel heterozygous missense mutation, p.Glu560Gly (c.1679A>G) in exon 7 of the WNK4 gene (Figure 1). This substitution was not found in dbSNP (build 132) nor identified through the 1000 genomes project (March 2010 update). The amino acid is conserved across species (to Opossum, considering 10 species). In silico analysis using SIFT, Polyphen-2 and AlignGVGD predicted this substitution to be pathogenic (accessed through Alamut Mutation Interpretation Software, version 2.0).

Figure 1.

Heterozygous mutation in exon 7 of the WNK4 gene. (A) the wild type sequence. (B) sequencing result for patient showing heterozygous change, p.Glu560Gly; c.1679A>G (indicated by arrow)

Discussion

We report a case of pseudohypoaldosteronism type 2 (PHA2) associated with a novel heterozygous mutation in the WNK4 gene. PHA2—also known as Gordon's syndrome—is a rare, autosomal dominant disease characterized by hypertension, hyperkalaemia and hyperchloraemic metabolic acidosis with a normal glomerular filtration rate.5 Plasma renin and aldosterone levels are low or normal. As in our patient, hypercalciuria may be present, with an increased risk of urolithiasis. The condition has been described as the ‘mirror image’ of Gitelman's syndrome, in which the subjects have low blood pressure, hypokalaemia, hypochloraemic metabolic alkalosis and hypocalciuria.

PHA2 has been found to be associated with mutations in genes encoding WNK1 and WNK4 kinases,1 which belong to kinases characterized by the absence of a lysine residue found in the catalytic domain of all other known serine–threonine kinases.6 The WNK1 gene is located on chromosome 12 and the WNK4 gene on chromosome 17. Identification of the molecular basis of PHA2 has made it possible to confirm the diagnosis in a patient by genetic analysis, and to screen family members when genetic mutation is found in the patient. As hypercalciuria typically occurs in PHA2 associated with mutations in the WNK4 gene,7 we screened for this gene first in our patient. Sequence analysis identified a novel heterozygous missense mutation in exon 7, resulting in the substitution of glycine for glutamic acid at codon 560 (p.Glu560Gly). The glutamic acid residue is located within a motif of 10 amino acids (557EPEEPEADQH566) that is conserved across all of the WNK genes.1 This acid motif is thought to play an important structural and functional role in the protein molecule.3 This evidence supports the likely pathogenicity of the mutation. However, samples from the mother and sister of this patient were not available to confirm that the mutation co-segregated with the disease in this family.

WNK4 is exclusively expressed in the distal renal tubule, and is a negative regulator of the thiazide sensitive Na-Cl co-transporter (NCC) in the distal renal tubule.8 Inactivating mutations of the WNK4 gene lead to defective WNK4 kinase function, resulting in uninhibited NCC activity. The result is an excess of sodium and chloride reabsorption, which is associated with volume expansion, hypertension and hyperchloraemia. Furthermore, WNK4 mutations also inhibit the aldosterone sensitive renal outer medullary potassium (ROMK) channels present on the apical membrane of the distal renal tubule. This results in decreased potassium secretion via these channels to cause hyperkalaemia.8,9 The exact mechanism of hypercalciuria in patients with PHA2 due to WNK4 mutations remains uncertain, although it is thought to be related to the uninhibited NCC activity as there is an inverse relationship between sodium and calcium absorption from the distal renal tubule.7 Consistent with the human PHA2 phenotype, mice studies have shown that transgenes engineered to manufacture mutant WNK4 kinases resulted in hypertension, hyperkalaemia and hypercalciuria.10

The importance of making a diagnosis of PHA2 is that thiazide diuretics effectively reverse the hypertension and hyperkalaemia.11 The NCC affected by the WNK1 and WNK4 gene mutations is the molecular target of thiazides, and hypertension in patients with PHA2 is estimated to be six times more sensitive to thiazide treatment than in individuals with essential hypertension.7 Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers should not be used to treat hypertension in PHA2 as they may worsen the hyperkalaemia. In our patient, hypertension management was improved with thiazide treatment and also reversed the biochemical abnormalities of hyperkalaemia, hyperchloraemic metabolic acidosis and hypercalciuria. In particular, the patient had marked hypercalciuria, and normalization of urinary calcium was important in view of the history of renal stones.

In conclusion, pseudohypoaldosteronism type 2 should be considered in a patient presenting with hypertension and hyperkalaemia, particularly if there is a positive family history. The diagnosis is important as thiazides are effective in controlling hypertension and reversing biochemical abnormalities in this condition.

Conflict of interest: None declared.

References

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