background children's interstitial lung diseases (chilD) cover many rare entities, frequently not diagnosed or studied in detail. there is a great need for specialised advice and for internationally agreed subclassification of entities collected in a register. Our objective was to implement an international management platform with independent multidisciplinary review of cases at presentation for long-term follow-up and to test if this would allow for more accurate diagnosis. also, quality and reproducibility of a diagnostic subclassification system were assessed using a collection of 25 complex chilD cases. Methods a web-based chilD management platform with a registry and biobank was successfully designed and implemented. results Over a 3-year period, 575 patients were included for observation spanning a wide spectrum of chilD. in 346 patients, multidisciplinary reviews were completed by teams at five international sites (Munich 51%, london 12%, Hannover 31%, ankara 1% and Paris 5%). in 13%, the diagnosis reached by the referring team was not confirmed by peer review. among these, the diagnosis initially given was wrong (27%), imprecise (50%) or significant information was added (23%). the ability of nine expert clinicians to subcategorise the final diagnosis into the chilD-eU register classification had an overall exact inter-rater agreement of 59% on first assessment and after training, 64%. Only 10% of the 'wrong' answers resulted in allocation to an incorrect category. Subcategorisation proved useful but training is needed for optimal implementation. Conclusions We have shown that chilD-eU has generated a platform to help the clinical assessment of chilD. Trial registration number results, nct02852928.

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The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities. Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases. Unlike dominantly inherited gain-of-function mutations, recessive loss-of-function mutations can potentially elucidate ex-translational activities. We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alpha2beta2 phenylalanine-tRNA synthetase (FARS). Collectively, the mutant alleles encompass a 5′-splice junction non-coding variant (SJV) and six missense variants, one of which is shared by unrelated individuals. The clinical condition is characterized by interstitial lung disease, cerebral aneurysms and brain calcifications, and cirrhosis. For the SJV, we confirmed exon skipping leading to a frameshift associated with noncatalytic activity. While the bi-allelic combination of the SJV with a p.Arg305Gln missense mutation in two individuals led to severe disease, cells from neither the asymptomatic heterozygous carriers nor the compound heterozygous affected individual had any defect in protein synthesis. These results support a disease mechanism independent of tRNA synthetase activities in protein translation and suggest that this FARS activity is essential for normal function in multiple organs.

PIG is associated with alveolar growth abnormalities and has to be considered in all newborns with unexplained respiratory distress. Apparent treatment benefit of glucocorticosteroids needs to be evaluated systematically.

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