Generalized pseudohypoaldosteronism type 1

Generalized pseudohypoaldosteronism type 1 (generalized PHA1), also known as systemic pseudohypoaldosteronism type 1 or autosomal recessive PHA1, is a severe inherited disorder of mineralocorticoid resistance. It is caused by loss-of-function mutations in genes encoding subunits of the epithelial sodium channel (ENaC), specifically SCNN1A, SCNN1B, or SCNN1G. Unlike the milder renal form of PHA1, the generalized form affects multiple organ systems because ENaC is expressed in the kidneys, lungs, sweat glands, salivary glands, and colon. The condition presents in the neonatal period with life-threatening salt wasting, hyperkalemia (high potassium levels), and metabolic acidosis, despite markedly elevated levels of aldosterone in the blood. Key clinical features include severe dehydration, failure to thrive, vomiting, and potentially fatal hyperkalemia in early infancy. Affected individuals also commonly experience recurrent lower respiratory tract infections and excessive skin rashes due to abnormal sweat gland function with high sodium content in sweat. Unlike the renal form of PHA1, the generalized form does not improve with age and requires lifelong management. There is no cure for generalized PHA1. Treatment is supportive and focuses on aggressive sodium chloride supplementation (often requiring very high oral doses), correction of hyperkalemia with potassium-binding resins such as sodium polystyrene sulfonate, and management of respiratory complications. Patients require careful monitoring of electrolytes throughout life. Dietary salt supplementation must be maintained continuously, and acute episodes of salt wasting—often triggered by illness—may require emergency intravenous saline administration. With early diagnosis and diligent management, survival and quality of life can be significantly improved, though the disease remains a serious lifelong condition.

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