Neonatal respiratory distress beyond common causes: surfactant dysfunction disorders and other etiologies of childhood interstitial lung disease

Background Neonatal interstitial lung disease (ILD) encompasses a heterogeneous group of rare disorders, among which surfactant dysfunction disorders represent a clinically distinct and severe subgroup. Diagnosis is challenging because presentation frequently overlaps with common neonatal respiratory conditions, and classification in neonates remains particularly difficult. Objectives To describe the clinical characteristics, genetic spectrum, and outcomes of neonatal-onset childhood interstitial lung disease (chILD), with a focus on etiology-related differences in clinical presentation between surfactant dysfunction disorders and other chILD subtypes. Methods This retrospective study included 14 patients with neonatal-onset chILD diagnosed between 2019 and 2025. Patients underwent a standardized evaluation protocol and were stratified by surfactant dysfunction mutation status to explore etiology-related differences in clinical presentation and outcome. Results Fourteen patients were included (50% male; 42.9% consanguineous; 50% premature). Pathogenic or likely pathogenic variants were identified in 7/14 patients (50%), most commonly in ABCA3 (21.4%) and NKX2-1 (14.3%). Patients with surfactant dysfunction mutations presented earlier (symptom onset <24 h in 100% vs. 77.8%) and required higher peak oxygen support (median FiO₂ 100% vs. 55%), whereas those with other etiologies had a longer but less fatal course. Pulmonary hypertension was present in 42.9%. Mortality was 21.4% after a median follow-up of 36 months. Conclusions In this small cohort, surfactant dysfunction disorders showed numerically earlier symptom onset, higher oxygen requirements, and higher mortality compared with other etiologies, although between-group differences did not reach statistical significance. Repeated surfactant requirements or failure to wean from respiratory support should prompt early systematic clinical, radiological, and genetic evaluation, particularly in preterm infants, in whom diagnostic delay may occur due to clinical overlap with respiratory distress syndrome.