Pseudohypoaldosteronism type 2

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Pseudohypoaldosteronism type 2 (PHA2) is caused by problems that affect regulation of the amount of sodium and potassium in the body. Sodium and potassium are important in the control of blood pressure, and their regulation occurs primarily in the kidneys.

People with PHA2 have high blood pressure (hypertension) and high levels of potassium in their blood (hyperkalemia) despite having normal kidney function. The age of onset of PHA2 is variable and difficult to pinpoint; some affected individuals are diagnosed in infancy or childhood, and others are diagnosed in adulthood. Hyperkalemia usually occurs first, and hypertension develops later in life. Affected individuals also have high levels of chloride (hyperchloremia) and acid (metabolic acidosis) in their blood (together, referred to as hyperchloremic metabolic acidosis). People with hyperkalemia, hyperchloremia, and metabolic acidosis can have nonspecific symptoms like nausea, vomiting, extreme tiredness (fatigue), and muscle weakness. People with PHA2 may also have high levels of calcium in their urine (hypercalciuria).

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

PHA2 can be caused by mutations in the WNK1, WNK4, CUL3, or KLHL3 gene. These genes play a role in the regulation of blood pressure.

The proteins produced from the WNK1 and WNK4 genes help control the amount of sodium and potassium in the body by regulating channels in the cell membrane that control the transport of sodium or potassium into and out of cells. This process primarily occurs in the kidneys. Mutations in either of these genes disrupt control of these channels, leading to abnormal levels of sodium and potassium in the body. As a result, affected individuals develop hypertension and hyperkalemia.

The proteins produced from the CUL3 gene (called cullin-3) and the KLHL3 gene help control the amount of WNK1 and WNK4 protein available. Cullin-3 and KLHL3 are two pieces of a complex, called an E3 ubiquitin ligase, that tags certain other proteins with molecules called ubiquitin. This molecule acts as a signal for the tagged protein to be broken down when it is no longer needed. E3 ubiquitin ligases containing cullin-3 and KLHL3 are able to tag the WNK1 and WNK4 proteins with ubiquitin, leading to their breakdown. Mutations in either the CUL3 or KLHL3 gene impair breakdown of the WNK4 protein. (The effect of these mutations on the WNK1 protein is unclear.) An excess of WNK4 likely disrupts control of sodium and potassium levels, resulting in hypertension and hyperkalemia.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is usually inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases caused by mutations in the WNK1, WNK4, or KLHL3 gene, an affected person inherits the mutation from one affected parent. While some cases caused by CUL3 gene mutations can be inherited from an affected parent, many result from new mutations in the gene and occur in people with no history of the disorder in their family.

Some cases caused by mutations in the KLHL3 gene are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

PHA2 is a rare condition; however, the prevalence is unknown.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Hyperkalemia · Very frequent (99-80%)

The concentration of potassium(1+) in the blood circulation is above the upper limit of normal.

Hypertension · Very frequent (99-80%)

The presence of chronic increased pressure in the systemic arterial system.

Nausea and vomiting · Frequent (79-30%)

Nausea is a commonly encountered symptom that has been defined as an unpleasant painless subjective feeling that one will imminently vomit. Vomiting has been defined as the forceful expulsion of the contents of the stomach, duodenum, or jejunum through the oral cavity. While nausea and vomiting are often thought to exist on a temporal continuum, this is not always the case. There are situations when severe nausea may be present without emesis and less frequently, when emesis may be present without preceding nausea.

Abnormality of dental enamel · Occasional (29-5%)

An abnormality of the dental enamel.

Abnormality of the dentition · Occasional (29-5%)

Any abnormality of the teeth.

Growth delay · Occasional (29-5%)

A deficiency or slowing down of growth pre- and postnatally.

Muscle weakness · Occasional (29-5%)

Reduced strength of muscles.

Periodic paralysis · Occasional (29-5%)

Episodes of muscle weakness.

Other findings in the same source

From: Orphanet

Additional reported features include Short stature (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Pseudohypoaldosteronism type 2 is Nephrology, with a nephrologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• How is kidney function being assessed over time?
• Are any current medicines or supplements relevant to kidney safety?
• Is there an individual recommendation about fluids, diet or blood pressure?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Pseudohypoaldosteronism type 2. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.