Pulmonary surfactant biology: produced by alveolar type II pneumocytes; reduces alveolar surface tension preventing collapse. Composition - 90% lipids (DPPC dominant), 10% proteins (SP-A, SP-B, SP-C, SP-D). SP-B (SFTPB) - essential for tubular myelin formation and lamellar body packaging; loss-of-function mutations are lethal in neonates. SP-C (SFTPC) - misfolded mutant protein triggers ER stress and apoptosis (autosomal dominant; variable penetrance). ABCA3 - lamellar body lipid transporter; mutations impair surfactant lipid composition. NKX2-1 (TTF-1) - transcription factor for thyroid, lung, and basal ganglia; haploinsufficiency causes brain-thyroid-lung syndrome.
Clinical presentation by gene: 1) SP-B deficiency - presents at birth (term infant) with severe progressive respiratory failure unresponsive to surfactant; uniformly fatal without lung transplant; 2) ABCA3 deficiency - severe form (homozygous null) similar to SP-B; milder forms (missense mutations) present in infancy with chronic respiratory disease; 3) SP-C deficiency - variable presentation from neonatal RDS to childhood ILD to adult-onset pulmonary fibrosis; family history common; 4) NKX2-1 (brain-thyroid-lung syndrome) - benign hereditary chorea (movement disorder), congenital hypothyroidism, ILD; ranges from neonatal to adult presentation. Diagnostic workup - surfactant protein analysis from BAL or lung biopsy, genetic testing (NGS panel), HRCT (ground-glass, septal thickening, cysts), histology (PAP-like, alveolar simplification, fibrosis).
Management strategies: 1) Acute neonatal respiratory failure - intubation, mechanical ventilation, surfactant replacement (limited efficacy in genetic disorders), high-frequency oscillatory ventilation, ECMO bridge to diagnosis or transplant; 2) SP-B and severe ABCA3 - lung transplantation is only definitive treatment; bilateral lobar transplant in infants; 5-year survival 50-65%; 3) SP-C and milder forms - immunomodulatory/anti-inflammatory therapy: hydroxychloroquine (most evidence; 10 mg/kg/day), systemic corticosteroids, IV pulse methylprednisolone, azithromycin (anti-inflammatory); 4) Supportive - oxygen, nutritional support, growth optimization, RSV prophylaxis (palivizumab), influenza/pneumococcal vaccines, prevention of viral exacerbations; 5) Genetic counseling for family and prenatal diagnosis in subsequent pregnancies; 6) Multidisciplinary follow-up at ChILD specialist center.