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Pseudohypoaldosteronism type 2
A rare genetic form of hypertension characterized by hyperkalemia, mild hyperchloremic metabolic acidosis, normal or elevated aldosterone, low renin, with normal renal glomerular filtration rate (GFR).
ORPHA:757Classification level: Disorder
- Chloride shunt syndrome
- Familial hyperkalemic hypertension
- Gordon hyperkalemia-hypertension syndrome
- Hyperkalemia-hypertension syndrome, Gordon type
- Hypertensive hyperkalemia
- Mineralocorticoid resistant hyperkalemia
- Spitzer-Weinstein syndrome
- Prevalence: Unknown
- Inheritance: Autosomal dominant or Autosomal recessive
- Age of onset: All ages
- ICD-10: I15.1
- OMIM: 145260 614491 614492 614495 614496
- UMLS: C1449844
- MeSH: -
- GARD: 4553
- MedDRA: -
The prevalence of the disorder is unknown. To date, more than 180 affected individuals and families have been reported.
Patients generally develop hypertension in adulthood. Hyperkalemia, mild hyperchloremic acidosis and low renin are present from a young age and are constant findings. Aldosterone levels may be normal to high. Hypervolemia is frequently observed. Growth failure has been described in some cases. Patients do not present renal failure. Spitzer-Weinstein syndrome is believed to be the early presentation of Pseudohypoaldosteronism type 2 (PHA2) with hypertension associated with other clinical findings such as short stature, muscle weakness, periodic paralysis and dental abnormalities.
There are five etiological subtypes: PHA type 2A has been mapped to chromosome 1q31-q42, but no specific gene has so far been identified. PHA type 2B is due to mutations in WNK4 (17q21.2), PHA type 2C due to mutations in WNK1 (12p13.33), PHA type 2D due to mutations in KLHL3 (5q31.2), and PHA type 2E due to mutations in CUL3 (2q36.2). WNK1 and WNK4 encode serine/threonine-protein kinase WNK1 and WNK4, respectively, which regulate sodium and potassium reabsorption in the distal renal tubule. Disease-causing mutations in these genes lead to increased sodium reabsorption and decreased potassium secretion. The protein products of CUL3 and KLHL3 function together as part of the cullin-RING-based E3 ubiquitin ligase complex, which has a role in ubiquitin-mediated degradation of the proteins produced by WNK1 and WNK4.
Diagnosis is established by the typical constellation of clinical and biochemical findings including hypertension, hyperkalemia (in the setting of normal GFR) with inappropriately low urinary potassium excretion, hyperchloremia, metabolic acidosis, low or suppressed plasma renin activity, hypercalciuria and family history. The diagnosis can be confirmed by genetic testing.
Differential diagnosis includes other causes of hyperkalemia, notably chronic kidney disease. If GFR is normal, differential diagnoses include hyperkalemic renal tubular acidosis, as seen with PHA1, hypoaldosteronism, primary adrenal insufficiency, and hyperkalemia secondary to medication (e.g. potassium-sparing diuretics, nonsteroidal anti-inflammatory drugs, angiotensin inhibitors, trimethoprim, these forms of hyperkalemic RTA are typically associated with hypovolemia and low blood pressure. An acquired form of PHA2 can be seen with calcineurin inhibitors, especially tacrolimus.
Prenatal diagnosis is possible where the genetic mutation has previously been identified in an affected family member.
The pattern of inheritance for PHA2 is typically autosomal dominant; however, PHA2 due to KLHL3 mutations can be inherited in an autosomal recessive or dominant manner. The risk to offspring of inheriting the mutation from an affected parent is 50% for the autosomal dominant forms. Offspring of an individual with autosomal recessive PHA2 are obligate carriers, and typically asymptomatic. Pathogenic variants arising de novo are possible. PHA2 due to CUL3 gene is typically the most severe form. The phenotype of PHA type II due to the WNK1 is typically less severe than PHA2 due to WNK4 or dominant or recessive mutation in the KLHL3 gene.
Management and treatment
Treatment is based on low-dose thiazide diuretics that are very effective in the correction of hypertension (important to prevent secondary complications), hyperkalemia, and hypercalciuria. Exogenous mineralocorticoids do not improve the biochemical abnormalities and likely worsen the hypertension.
Prognosis is good with lifelong therapy. Nephrolithiasis can be a complication of the disease if untreated and hypercalciuria persists.