Pseudohypoaldosteronism Type II

Excerpt

Clinical characteristics: Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia despite normal glomerular filtration rate (GFR) and frequently by hypertension. Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels. Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion). Hypercalciuria is well described.

Diagnosis/testing: The diagnosis of PHAII is established in a proband:

1. With hyperkalemia (in the setting of normal glomerular filtration), hypertension, metabolic acidosis, hyperchloremia, and suppressed plasma renin levels;

   AND/OR

2. By the identification of a heterozygous pathogenic variant in CUL3, WNK1, or WNK4 or a heterozygous pathogenic variant or biallelic pathogenic variants in KLHL3.

Management: Treatment of manifestations: Electrolyte and blood pressure abnormalities of PHAII in children and adults are often corrected with thiazide diuretics.

Prevention of secondary complications: Control of blood pressure is important to reduce the risk of cardiovascular and renal disease and stroke.

Surveillance: Routine electrolyte and blood pressure measurements.

Agents/circumstances to avoid: Untreated individuals with PHAII should avoid excessive intake of foods high in salt and potassium as these may exacerbate hypertension and hyperkalemia.

Evaluation of relatives at risk: Measurement of serum potassium concentration and blood pressure or identification of the known familial CUL3, KLHL3, WNK1, and WNK4 pathogenic variant(s) in first-degree relatives of individuals with PHAII allows for early diagnosis and treatment .

Pregnancy management: Affected pregnant women should undergo routine monitoring of electrolytes and blood pressure, with adjustments to antihypertensive medication dosage as needed. Some antihypertensive medications, including thiazide diuretics, have been associated with adverse fetal outcome, especially when taken during the first trimester of pregnancy; referral to an obstetrics group with expertise in high-risk pregnancies should be considered.

Genetic counseling: PHAII is frequently inherited in an autosomal dominant manner; PHAIID (caused by pathogenic variants in KLHL3) may also be inherited in an autosomal recessive manner. Many pathogenic variants in CUL3 arise de novo and are not inherited from a parent. Each child of an individual with autosomal dominant PHAII has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant(s) in the family are known.