Surfactant protein disorders are a group of rare genetic diseases affecting components of the pulmonary surfactant system, which reduces alveolar surface tension and is essential for normal lung function. Pulmonary surfactant consists of phospholipids (mainly phosphatidylcholine) and four surfactant-associated proteins (SP-A, SP-B, SP-C, SP-D). Mutations in genes encoding these proteins or their processing/trafficking machinery cause distinct clinical syndromes.
Major disorders include: SFTPB (surfactant protein B) deficiency—autosomal recessive, complete deficiency causes lethal neonatal respiratory failure unresponsive to surfactant replacement, requiring lung transplantation for survival; ABCA3 (ATP-binding cassette transporter A3) deficiency—autosomal recessive, broad phenotypic spectrum from neonatal lethal to childhood/adult ILD; SFTPC (surfactant protein C) mutations—usually autosomal dominant with variable penetrance, presenting as childhood ILD or adult familial pulmonary fibrosis with characteristic mutations including I73T (the most common); NKX2-1 (TTF-1) mutations—causing 'brain-lung-thyroid syndrome' with variable triad of choreoathetosis, hypothyroidism, and lung disease; rarer disorders include SFTPA1/SFTPA2 mutations causing familial pulmonary fibrosis often with lung cancer predisposition.
Diagnostic approach combines clinical features (neonatal respiratory failure, childhood ILD with diffuse ground-glass opacities, family history of ILD), high-resolution chest CT (ground-glass, septal thickening, cysts), lung biopsy showing pulmonary alveolar proteinosis (PAP) pattern, type II pneumocyte hyperplasia, foamy macrophages, fibrosis, and characteristic electron microscopy findings (lamellar body abnormalities). Genetic testing with comprehensive ILD gene panels has become essential. Treatment is challenging—high-dose corticosteroids, hydroxychloroquine, azithromycin, and IVIG have been used with variable response; lung transplantation is the only definitive treatment for severe cases (lethal SFTPB requires transplantation in infancy; advanced SFTPC/ABCA3 disease may benefit at later stages). Avoidance of viral infections and aggressive vaccination, supportive care with oxygen, and genetic counseling for families are important. Emerging gene therapies and CFTR-modulator-like small molecules for specific mutations are investigational.