Telomere biology disorders in childhood interstitial lung disease: new insights from the chILD-EU cohort

Greiner-Mai et al. expand recognition of telomere biology disorder (TBD)-associated interstitial lung disease (ILD) in children, demonstrating heterogenous radiographic and ILD subtypes in combination with variable extrapulmonary phenotypes, even in the absence of ultrashort peripheral blood telomere length (TL).While their findings highlight some of the limitations of current TL testing methods, they introduce critical questions regarding family screening and the role of antifibrotic and telomeredirected therapies in children with TBD-related ILD.Despite being first described in children, the pulmonary manifestations of telomere biology disorders (TBDs) have been better studied in adults with interstitial lung disease (ILD).Between 15%-30% of adults with familial ILD have short telomeres (<10th age adjusted percentile), pathogenic or likely pathogenic telomere maintenance gene variants, or both (Table 1). 1) In contrast, the association between TBD and childhood ILD has been less well described.In this setting, the cohort study from Greiner-Mai et al. adds a significant international perspec tive. 2)Using the chILD-EU database, the authors measured telomere length (TL) by quantitative polymerase chain reaction (qPCR) and completed exome sequencing to identify pediatric patients with TBD-related ILD, which they characterized as the presence of a pathogenic variant or variant of unknown significance (VUS), with phenotypic manifestations of a TBD, with or without TL <10th percentile.This inclusive definition captures the complexity of genotype-phenotype relationships in TBDs, including that ultrashort TL can be inherited independently of the causative genetic variant and that TL can be shorter in affected tissues, even if peripheral blood mononuclear cells (PBMC) have TL>10th percentile.Greiner-Mai et al. 2) identified 10 pediatric patients within chILD-EU with TBD ILD.While the denominator is not reported, given the size of the data base presented