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Pseudohypoaldosteronism type 2

Orpha number ORPHA757
Synonym(s) Chloride shunt syndrome
Familial hyperkalemic hypertension
Gordon hyperkalemia-hypertension syndrome
Hyperkaliemia - hypertension, Gordon type
Hypertensive hyperkalemia
Mineralocorticoid resistant hyperkalemia
PHA2
PHAII
Spitzer-Weinstein syndrome
Prevalence Unknown
Inheritance
  • Autosomal dominant
  • Autosomal recessive
Age of onset Variable
ICD-10
  • I15.1
OMIM
UMLS
  • C1449844
MeSH -
MedDRA -
SNOMED CT
  • 15689008

Summary

Pseudohypoaldosteronism type 2 (PHA2) is a rare inherited form of hypertension characterized by hyperkalemia, hyperchloremic metabolic acidosis, normal or elevated aldosterone, low renin, and normal renal function. Prevalence is unknown. Around 80 families have been reported in the literature, but only 10 are genetically confirmed cases. Patients under the age of 20 generally have normal blood pressure, but then develop hypertension in adulthood. Hyperkalemia, mild hyperchloremic acidosis and low renin are present from a young age and are constant findings. Growth failure has been described in some cases. Patients do not present renal failure. Spitzer-Weinstein syndrome (or adolescent hyperkalemic syndrome) is believed to be the early presentation of PHA2 with hypertension associated with other clinical findings such as short stature, muscle weakness, and periodic paralysis. Pseudohypoaldosteronism type 2 is due to mutations in the genes WNK1 (PHA2C) on chromosome 12 and WNK4 (PHA2B) on chromosome 17 encoding the with-no-lysine kinases WNK1 and WNK4 that regulate the Na-Cl and Na-K-Cl cotransporters (NCC and NKCC2, respectively) and the renal outer medullary potassium (ROMK) channel in the distal renal tubule. Mutations in these genes lead to increased NaCl reabsorption and decreased potassium secretion. Additional genetic heterogeneity exists since another locus in chromosome 1 has been suggested (PHA2A). Transmission is autosomal dominant. Diagnosis is based on biochemical examinations that show hyperkalemia, hyperchloremic acidosis, low or suppressed plasma renin activity and normal to high levels of aldosterone. Glomerular filtration rate is normal. Hypervolemia is frequently observed. Hypercalciuria and low bone mineral density is present in the case of WNK4 mutations. Differential diagnosis includes hyperkalemic renal tubular acidosis, hypoaldosteronism and dehydrated hereditary stomatocytosis (DHS) (see these terms), a rare dominant formof hereditary hemolytic anemia associated with pseudohyperkalemia. Treatment is based on low-dose thiazide diuretics that are very effective in the correction of hypertension, hyperkalemia, and hypercalciuria. PHA2 patients with WNK4 mutations show a better response to thiazide diuretics than patients with WNK1 mutations. PHA2 does not respond to exogenous mineralocorticoids. Patients must follow a low sodium diet. Prognosis is good with lifelong therapy. Nephrolithiasis can be a complication of the disease if hypercalciuria is present.

Expert reviewer(s)

  • Dr Rosa VARGAS-POUSSOU

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Detailed information

Summary information
Clinical genetics review
  • EN (2014)
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