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

查看全文 作　　者：Andrew [1]Fagbemi;William G [2,3]Newman;Stuart G [4,5]Tangye;Stephen M [6]Hughes;Edmund [7]Cheesman;Peter D [8]Arkwright 高影响力作者 机构地区：[1]Department of Paediatric Gastroenterology,Royal Manchester Children’s Hospital,Manchester M199WL,United Kingdom;[2]Department of Medical Genetics,Manchester University NHS Foundation Trust,Manchester M139WL,United Kingdom;[3]Evolution and Genomic Sciences,University of Manchester,Manchester M139WL,United Kingdom;[4]Garvan Institute of Medical Research,Darlinghurst,NSW 2010,Australia;[5]St Vincent’s Clinical School,Faculty of Medicine,UNSW Australia,Sydney,NSW 2010,Australia;[6]Department of Paediatric Allergy and Immunology,Royal Manchester Children’s Hospital,Manchester M139WL,United Kingdom;[7]Department of Paediatric Histopathology,St Mary’s Hospital,Manchester M139WL,United Kingdom;[8]Lydia Becker Institute of Immunology and Inflammation,University of Manchester,Manchester M139WL,United Kingdom高影响力机构 出　　处：《World Journal of Gastroenterology》索引2020年第26卷第15期,共6页高影响力期刊 摘　　要：BACKGROUND Aminoacyl tRNA synthetases/ligases(ARSs)are highly conserved enzymes involved in attaching amino acids to tRNA 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.290A>G)in the cytosolic isoleucyl-tRNA synthetase gene,leading to an amino acid substitution(p.Asp97Gly).Pathogenic variants in other genes associated with inflammatory bowel disease(IBD)(ADAM17,EGFR,FOXP3,IL10RA,IL10RB,IL21R,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-17A,IL-17F,IFNβwere lower,and TNFαnot significantly different when compared to healthy controls.CONCLUSION This case report provides evidence that recessive mutations in cytosolic isoleucyltRNA 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. 关 键 词：Inflammatory BOWEL disease Hepatitis Gene CYTOSOLIC ISOLEUCINE TRNA SYNTHASE
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