Hereditary pulmonary alveolar proteinosis

Hereditary pulmonary alveolar proteinosis (hereditary PAP) is a rare genetic lung disorder characterized by the abnormal accumulation of surfactant — a lipoprotein substance that normally lines the alveoli (air sacs) and helps keep the lungs open — within the alveolar spaces. This accumulation impairs gas exchange, leading to progressive respiratory insufficiency. Hereditary PAP is caused by mutations in genes involved in surfactant metabolism or granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, most notably biallelic mutations in the CSF2RA or CSF2RB genes encoding the GM-CSF receptor alpha or beta chains, respectively. Mutations in SFTPB, SFTPC, ABCA3, and NKX2-1 (TTF1) can also cause hereditary forms of pulmonary surfactant dysfunction that overlap with PAP. The disease primarily affects the respiratory system. Key symptoms include progressive dyspnea (shortness of breath), cough (often nonproductive), fatigue, and in severe cases cyanosis and respiratory failure. In neonatal-onset forms, particularly those caused by SFTPB or ABCA3 mutations, the disease can present as severe respiratory distress shortly after birth and may be rapidly fatal without intervention. Later-onset forms associated with GM-CSF receptor mutations may present in childhood or adolescence with more gradual respiratory decline. Chest imaging typically reveals bilateral ground-glass opacities and a characteristic "crazy paving" pattern on high-resolution CT. The primary treatment for hereditary PAP is whole lung lavage (WLL), a procedure in which the lungs are physically washed to remove accumulated surfactant material. While WLL can provide symptomatic relief, it does not address the underlying genetic defect and must often be repeated. For neonatal forms caused by surfactant protein B deficiency, lung transplantation may be the only definitive treatment option. Emerging therapies under investigation include inhaled GM-CSF supplementation (primarily for autoimmune PAP but studied in some hereditary contexts) and gene therapy approaches. Supportive care including supplemental oxygen and management of secondary infections is also important. Genetic counseling is recommended for affected families.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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