Case Report
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 21, 2020; 26(15): 1841-1846
Published online Apr 21, 2020. doi: 10.3748/wjg.v26.i15.1841
Refractory very early-onset inflammatory bowel disease associated with cytosolic isoleucyl-tRNA synthetase deficiency: A case report
Andrew Fagbemi, William G Newman, Stuart G Tangye, Stephen M Hughes, Edmund Cheesman, Peter D Arkwright
Andrew Fagbemi, Department of Paediatric Gastroenterology, Royal Manchester Children’s Hospital, Manchester M199WL, United Kingdom
William G Newman, Department of Medical Genetics, Manchester University NHS Foundation Trust, Manchester M139WL, United Kingdom
William G Newman, Evolution and Genomic Sciences, University of Manchester, Manchester M139WL, United Kingdom
Stuart G Tangye, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
Stuart G Tangye, St Vincent’s Clinical School, Faculty of Medicine, UNSW Australia, Sydney, NSW 2010, Australia
Stephen M Hughes, Peter D Arkwright, Department of Paediatric Allergy and Immunology, Royal Manchester Children’s Hospital, Manchester M139WL, United Kingdom
Edmund Cheesman, Department of Paediatric Histopathology, St Mary’s Hospital, Manchester M139WL, United Kingdom
Peter D Arkwright, Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M139WL, United Kingdom
Author contributions: Arkwright PD and Newman WG led the study concept and design; all authors were involved in acquisition of data; Arkwright PD, Newman WG, Cheesman E and Tangye SG analysed and interpreted the data; Arkwright PD drafted the manuscript and all authors critically reviewed the manuscript.
Informed consent statement: Informed consent was obtained from the child’s parents for the publication of the report.
Conflict-of-interest statement: The authors have declared no conflicts of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Peter D Arkwright, MD, PhD, Senior Lecturer, Department of Paediatric Allergy and Immunology, Royal Manchester Children’s Hospital, Oxford Road, Manchester M139WL, United Kingdom.
Received: January 6, 2020
Peer-review started: January 6, 2020
First decision: January 19, 2020
Revised: March 26, 2020
Accepted: April 1, 2020
Article in press: April 1, 2020
Published online: April 21, 2020

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.


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, IFNβ were lower, and TNFα not significantly different when compared to healthy controls.


This case report provides evidence that recessive mutations in cytosolic isoleucyl-tRNA 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.

Keywords: Inflammatory bowel disease, Hepatitis, Gene, Cytosolic isoleucine tRNA synthase

Core tip: Consider cytosolic isoleucyl-tRNA synthetase in children presenting with neonatal hepatitis and refractory very early-onset inflammatory bowel disease. This case report provides evidence for a novel monogenic cause of inflammatory bowel disease that should be considered, particularly in patients with very early-onset, poor response to treatment and a history of neonatal hepatitis.