Pseudohypoaldosteronism type 2

Pseudohypoaldosteronism type 2 (PHA2), also known as Gordon syndrome or familial hyperkalemic hypertension, is a rare genetic disorder characterized by hypertension (high blood pressure), hyperkalemia (elevated potassium levels in the blood), and metabolic acidosis, despite normal kidney function. Unlike true hypoaldosteronism, aldosterone levels are typically normal or elevated. The condition results from dysregulation of ion transport in the distal nephron of the kidney, leading to excessive sodium reabsorption and impaired potassium and hydrogen ion excretion. PHA2 is caused by mutations in several genes involved in the WNK kinase signaling pathway, which regulates renal electrolyte handling. Known causative genes include WNK1, WNK4, KLHL3, and CUL3. Mutations in these genes lead to overactivation of the sodium-chloride cotransporter (NCC) in the distal convoluted tubule. The age of onset and severity can vary depending on the specific gene involved; CUL3 mutations tend to cause the most severe phenotype with earlier onset, while WNK1 and WNK4 mutations may present later. Key clinical features include hypertension that may develop in childhood or adulthood, hyperkalemia, hyperchloremic metabolic acidosis, and suppressed renin levels. Some patients may also exhibit short stature, intellectual disability, or dental abnormalities, particularly those with CUL3 mutations. The condition is notably responsive to treatment with thiazide diuretics, which inhibit the NCC transporter and effectively correct the hypertension, hyperkalemia, and acidosis. Dietary sodium restriction may also be beneficial. Early diagnosis and treatment are important to prevent long-term cardiovascular complications associated with uncontrolled hypertension.

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