Genetic Disorders of Surfactant Metabolism

Genetic disorders affecting surfactant protein production and function can result in respiratory distress and severe respiratory failure in late-preterm and term neonates. Pathogenic variants in surfactant pulmonary-associated protein B (SFTPB) are typically loss-of-function and disrupt surfactant protein B (SP-B) production and surfactant function. Dominant variants in surfactant pulmonary-associated protein C (SFTPC) generally result in a toxic gain-of-function with disruption of surfactant protein C (SP-C) processing and trafficking in the alveolar epithelial type 2 cells. Adenosine triphosphate binding cassette transporter A3 (ABCA3) variants include loss-of-function or "null" variants in which no ABCA3 protein is made or missense variants that disrupt intracellular trafficking of ABCA3 or impair phospholipid transport. Pathogenic variants and deletions of the NK2 homeobox 1 gene (NKX2-1) result in haploinsufficiency and alter transcription of surfactant-associated genes as well as genes for brain and thyroid development. Diagnosis of these disorders requires a high index of clinical suspicion because presentations may vary between and within diseases. Prognosis is highly variable, ranging from requiring supportive care with improvement in respiratory status over time to severe disease with early mortality without lung transplantation. Neonatologists and pulmonologists alike should recognize early presentations of these rare genetic disorders of surfactant metabolism to identify and care for affected infants and to counsel families regarding prognosis, treatment options, recurrence risk, and risk assessment for other family members.