Interstitial lung disease in children: rare genetic variants beyond surfactant dysfunction

Abstract

Advances in genetic analysis techniques and strategies have enabled the identification of rare novel genetic entities in children's interstitial lung disease (chILD). Aims: To describe an extensive array of demographic, clinical, radiological, and laboratory data from a national registry of children with diffuse lung disease caused by rare and novel genetic variants. Study Design: Retrospective cohort study. Methods: This study used data from the chILD Türkiye (chILD‐TR) registry to analyze rare genetic chILD subtypes, excluding surfactant protein gene variants, ABCA3, and NKX2‐1, between November 2021 and January 2024. Of 671 patients in chILD‐TR, 182 underwent genetic analysis excluding surfactant protein‐related variants, resulting in 37 patients identified with rare genetic variants included in the study. Results: Among the 37 patients with rare genetic variants, 19 (51.4%) were male, and the median age at diagnosis was 40.5 months (IQR 15.5–115.5). Genetic analysis conducted on 15 patients identified COPA, STAT3, STING1, ADA, ZNFX1, PIK3CD, PLCG2, OAS1, CCR2, RNF168 and ATM gene variants, which are associated with immunodeficiency/dysregulation and autoinflammation; 15 NPC1, SMPD1, GBA1, SLC7A7, MARS1, FARSB, and PEPD genes, variants linked to inherent metabolic errors. Seven patients were found with TBX4, SLC34A2, PLG, and SMAD4 gene variants. All patients were born at term, and five (13.5%) of them were small for gestational age. Two patients (5.4%) had previously been on a mechanical ventilator in the neonatal intensive care unit, 25(67.6%) had familial consanguinity, and 23 (62.1%) had comorbid systemic disease. Thirteen patients (35.1%) required oxygen support. All patients underwent chest computed tomography scans at initial assessment, showing ground‐glass opacities in 29 (78.3%), infiltrations in 27 (72.9%), and interlobular septal thickening in 20 (54%). Eight patients (21.6%) received oral steroids, and six (16.2%) received pulse steroids in addition to their primary treatments for systemic diseases. Conclusions: Interstitial lung disease rarely occurs in children, but increased awareness and genetic testing may enable earlier diagnosis. Recognizing that diffuse parenchymal lung disease can occur in rare systemic diseases may improve diagnoses and treatment.