Focus area: Physicians
Genetic causes and clinical management of pediatric interstitial lung diseases
The knowledge of chILD has been improving in recent years thanks to the possibility of carrying out increasingly accurate genetic studies.
Interstitial lung disease (ILD) in children (chILD) is an umbrella term for a heterogeneous group of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. Disease pathogenesis is complex and involves various molecular mechanisms that contribute to inflammatory and fibrotic changes of the lung parenchyma. Patient presentation at diagnosis is highly variable and the clinical course of the chILD patients is unpredictable, with various regimens of lung function decline punctuated by episodes of acute exacerbation. Since the first descriptions by Nogee et al. of lung diseases due to deficiencies in surfactant protein (SP)-B, a number of studies have established the important contribution of surfactant disorders in the development of various forms of chILD. More recently, other disease-causing genes have been identified. For example SFTPC is a 3.5-kb gene located on chromosome 8 (Surfactant protein-C defects); ABCA3 is a 80-kb gene located on chromosome 16 (ABCA3 defects); NKX2-1 is located on chromosome 14q13 (NKX2-1 defects, lung-tyroid-brain disease); SFTPA1 and SFTPA2, with a pseudo gene (SFTPA3) in between are on chromosome 10 (Surfactant protein-A defects). Mutations in the CSF2RA and the CSF2RB genes have been identified in several forms of lung diseases in children and adults (Granulocyte macrophage colony-stimulating factor receptors defects). To date, genetic defects have been mostly reported in genes encoding the methionyl-tRNA synthetase (MARS), the stimulator of interferon (STING), also known as transmembrane protein 173 (TMEM173), and the nonclathrin-coated vesicular coat proteins (COPs), mainly the alpha-COP COPA. MARS is an ubiquitary enzyme that catalyzes the ligation of methionine to tRNA, is encoded by MARS, which is located on chromosome 12. STING, a stimulator of interferon genes, plays an important role in innate immunity. It is encoded by TMEM173, a gene containing 8 exons and located on chromosome 5. COPA is a protein involved in the retrograde transport of the cargo proteins between the golgi and the endoplasmic reticulum. It is encoded by a gene containing 33 exons and located on chromosome 1.
In conclusion genetic factors are important contributors to chILD pathogenesis. In the coming years, the development of next generation sequencing capacities along with novel bioinformatics approaches will broaden the genetic landscape of chILD, allowing to progress in the understanding of the underlying mechanisms. As such, it is expected that newly identified molecular defects and markers will help predicting disease courses and tailoring individual therapies.
Nathan N, Borensztajn K, Clement A, Genetic causes and clinical management of pediatric interstitial lung diseases. Curr Opin Pulm Med. 2018;24(3):253-259