Expanding the phenotypic spectrum of FARSA-related interstitial lung disease: a pediatric case series and literature review.

The FARSA gene encodes the catalytic α-subunit of cytoplasmic phenylalanyl-tRNA synthetase (FARS1), a key enzyme in protein biosynthesis. Biallelic pathogenic variants cause a rare multisystemic disorder of variable severity, usually characterized by early-onset interstitial lung disease (ILD) with neurological and hepatic involvement. We present two genetically confirmed cases of FARSA deficiency and one additional patient with FARSA-related ILD carrying two rare heterozygous variants of uncertain significance and compare their phenotypes with previously reported patients. Clinical, radiologic, laboratory, and genetic features of three pediatric patients were retrospectively reviewed. Whole-exome sequencing confirmed the molecular diagnosis in two patients and identified two rare candidate FARSA variants in one putative case. The results were systematically compared with published cases. Two patients carried homozygous R295W variants, whereas Case 3 carried two rare heterozygous candidate variants, p.Ala90Val and p.Gln341Arg, with unconfirmed phase. Cases 1 and 2 developed ILD during early infancy, whereas Case 3 developed interstitial lung disease after severe RSV pneumonia at 15 months. Imaging showed diffuse ground-glass opacities with interlobular septal thickening in Cases 1 and 2 and a mosaic perfusion pattern in Case 3. Neurologic features included hypotonia, corpus callosum hypoplasia, and periventricular cysts. Liver abnormalities ranged from persistent hypoalbuminemia to intermittent enzyme elevations. Cases 1 and 2 showed persistently elevated inflammatory markers independent of infection. Corticosteroids were ineffective. Rituximab and ruxolitinib were associated with variable clinical benefit: partial stabilization in the severe cases and sustained clinical improvement in the milder pulmonary case. Overall, these patients illustrate a broad phenotypic spectrum of FARSA-related disease, ranging from severe, ventilator-dependent multisystem disease to a milder, lung-dominant form with sustained stabilization.

conclusionsFARSA-related disease is characterized by severe early-onset ILD, persistent inflammatory activity, and multisystem involvement, but with poor response to current therapies. Our cases emphasize that the pathogenesis probably involves both impaired protein synthesis and chronic inflammatory mechanisms. International collaboration and longitudinal studies are needed to refine the genotype-phenotype correlation and develop innovative treatment strategies that could ultimately improve prognosis and survival. WHAT IS KNOWN: • FARSA deficiency is a rare cause of pediatric interstitial lung disease with multisystem involvement, and only a limited number of cases have been reported. WHAT IS NEW: • We report two genetically confirmed cases and one putative FARSA-related ILD case, together with an updated literature review demonstrating the broad phenotypic spectrum and current therapeutic experience.