Adulthood interstitial lung disease due to variants in surfactant related genes: A systematic review.

Abstract

Background: Surfactant-related gene (SRG) variants are an emerging cause of interstitial lung disease/pulmonary fibrosis (ILD/PF). Accurate recognition of these disorders is relevant for diagnosis, genetic counselling, and clinical management.Reaserch question: How do SRG-associated ILD/PF present in adults, and what clinical, radiological, and histopathological features characterize their phenotype?Study design and methods: We performed a systematic review (PROSPERO CRD42024517610) to describe the clinical features, management, and outcomes of adults with SRG-related ILD/PF. PubMed, Embase, and Web of Science were searched from January 2000 to December 2024 for studies reporting adults (≥18 years) with genetically confirmed SRG variants and ILD/PF. Demographic, clinical, radiological, histological, functional, treatment, and lung transplantation (LT) data were extracted.Results: Thirty-eight studies included 162 adults carrying class 3-5 variants in SFTPA1/2 (61), SFTPC (52), ABCA3 (31), NKX2-1 (16), and SFTPB (2), including 35 novel variants. Age at diagnosis ranged from 19 to 79 years. Familial ILD predominated in SFTPA1/2, frequently associated with personal or familial lung cancer, whereas NKX2-1 variants showed thyroid and neurological involvement. Lung function typically demonstrated mild-to-moderate restriction with impaired diffusing capacity. Chest CT findings were heterogeneous and often indeterminate, while usual interstitial pneumonia was the predominant histological pattern except in ABCA3-related disease. Treatment approaches varied considerably; LT provided favourable outcomes in selected patients.Conclusion: Adult SRG-related ILD/PF is likely under-recognised because of variable penetrance, wide age at onset, and non-specific imaging features. International registries are needed to improve genotype-phenotype correlations and guide personalised management.