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Pseudohypoaldosteronism type 2
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Conditions

Pseudohypoaldosteronism type 2

Pseudohypoaldosteronism type 2 is a rare condition characterized by high blood pressure and abnormal electrolyte levels, specifically high potassium, caused by genetic mutations affecting kidney function.

Overview

Pseudohypoaldosteronism type 2 (PHA2) is caused by problems that affect the regulation of sodium and potassium in the body. While regulation occurs primarily in the kidneys, people with PHA2 exhibit high blood pressure (hypertension) and high levels of potassium in their blood (hyperkalemia) despite having normal kidney function.

The age of onset is variable, ranging from infancy to adulthood. Hyperkalemia usually occurs first, followed by hypertension later in life. Affected individuals also have high levels of chloride (hyperchloremia) and acid (metabolic acidosis) in their blood. Symptoms may include:

  • Nausea
  • Vomiting
  • Extreme tiredness (fatigue)
  • Muscle weakness
  • High levels of calcium in the urine (hypercalciuria)

Causes

PHA2 is caused by mutations in the WNK1, WNK4, CUL3, or KLHL3 genes, which play a role in blood pressure regulation.

  • WNK1 and WNK4: These proteins help control sodium and potassium levels by regulating channels in the cell membrane of the kidneys. Mutations disrupt this control, leading to hypertension and hyperkalemia.
  • CUL3 and KLHL3: These proteins form a complex called an E3 ubiquitin ligase, which tags WNK1 and WNK4 proteins for breakdown. Mutations in CUL3 or KLHL3 impair the breakdown of WNK4, leading to an excess that disrupts sodium and potassium control.

Inheritance

This condition is usually inherited in an autosomal dominant pattern, where one copy of the altered gene is sufficient to cause the disorder. In most cases involving WNK1, WNK4, or KLHL3, the mutation is inherited from an affected parent. Mutations in CUL3 often result from new mutations in people with no family history. Some cases caused by KLHL3 mutations are inherited in an autosomal recessive pattern, requiring two copies of the mutated gene.

Frequently Asked Questions

PHA2 is inherited in an autosomal‑dominant pattern, so each child has a 50 % chance of inheriting the mutated allele and potentially developing the disorder. Genetic counseling and targeted testing can clarify risk and allow early monitoring.
Diagnosis relies on a combination of clinical findings (persistent hypertension, hyperkalemia, metabolic acidosis) and laboratory tests showing elevated serum potassium, chloride, and bicarbonate with normal renal function. Genetic testing for pathogenic variants in WNK1, WNK4, CUL3, or KLHL3 confirms the diagnosis and guides family counseling.
Thiazide‑type diuretics (e.g., hydrochlorothiazide) are first‑line because they inhibit the NaCl cotransporter that is over‑active in PHA2, lowering both blood pressure and serum potassium. In some cases, a low‑dose potassium‑sparing diuretic (e.g., amiloride) or a calcium‑channel blocker may be added if blood pressure remains high.
Yes. Patients should limit high‑potassium foods such as bananas, oranges, potatoes, tomatoes, and dried fruits. A diet rich in low‑potassium vegetables (e.g., cucumber, lettuce, carrots) and adequate sodium intake (as advised by a nephrologist) can complement medication. Avoiding excessive salt substitutes that contain potassium chloride is also important.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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