Refractory very early-onset inflammatory bowel disease associated with cytosolic isoleucyl-tRNA synthetase deficiency: A case report

BACKGROUND Aminoacyl t RNA synthetases/ligases(ARSs) are highly conserved enzymes involved in attaching amino acids to t RNA promoting protein synthesis.Although deficiencies of ARSs localized to the mitochondria classically present with neuropathology, the clinical features of cytosolic ARS deficiencies are more variable. They have previously been associated with neonatal hepatitis, but never with early-onset inflammatory bowel disease.CASE SUMMARY A nine-year-old Bangladeshi boy presented with neonatal liver failure and deranged clotting, transaminitis and cholestasis. His parents were first cousins.Two older brothers and a sister were well. The patient suffered from loose stools from early infancy which became more troublesome and persistent from five years old with ten bloody motions a day. Repeated endoscopies showed persistent pancolitis, which was refractory to mesalazine, corticosteroids,azathioprine, sirolimus and anti-TNF(adalimumab) therapy, but has improved recently with subcutaneous methotrexate.Whole Genome Sequencing revealed a novel pathogenic missense variant(c.290 A > G) in the cytosolic isoleucyl-t RNA synthetase gene, leading to an amino acid substitution(p.Asp97 Gly). Pathogenic variants in other genes associated with inflammatory bowel disease(IBD)(ADAM17, EGFR, FOXP3, IL10 RA, IL10 RB, IL21 R, NCF4, STAT3) were excluded.Cytokine assays demonstrated markedly elevated IL-2, IL-5, IL-13, IL-9 and IL-10 by the patient’s CD4+ T-cells, while IL-17 A, IL-17 F, IFNβ were lower, and TNFαnot significantly different when compared to healthy controls.CONCLUSION This case report provides evidence that recessive mutations in cytosolic isoleucylt RNA synthetase are a novel monogenic cause of IBD, which should be considered, particularly in infants and children with a history of neonatal hepatitis and very early-onset IBD poorly responsive to treatment.