Mutations in ITCH, which encodes an E3 ubiquitin-protein ligase, can result in systemic autoimmunity and immunodeficiency. The clinical phenotype and mechanism of disease have not been fully characterized, resulting in a paucity of therapeutic options for this potentially fatal disease.
We aimed to: (1) expand the understanding about the phenotype of human ITCH deficiency (2) further characterize the associated immune dysregulation and (3) report the first successful hematopoietic cell transplant (HCT) in a patient with ITCH deficiency.
Disease profiling was performed in a patient with multi-system immune dysregulation. Whole exome sequencing (WES) with trio analysis and functional validation of candidate disease variants were performed, including mRNA and protein expression. Analyses to further delineate the immunophenotype included quantitative evaluation of lymphoid and myeloid subsets with flow cytometry and mass cytometry.
A patient with multi-system immune dysregulation presenting with growth failure, very early onset inflammatory bowel disease (VEO-IBD), arthritis, uveitis, psoriasis and type 1 diabetes mellitus underwent WES, which identified novel compound heterozygous mutations in ITCH. Reduced expression of ITCH mRNA and absent ITCH protein were found. Abnormalities in both lymphoid and myeloid lineages were identified. The patient underwent HCT. He demonstrated excellent immune reconstitution and resolution of many manifestations of his systemic disease.
Here we report ITCH deficiency with unique clinical features of colonic VEO-IBD, arthritis and uveitis in the setting of immune dysregulation and further characterize the underlying immune dysregulation. We demonstrate that HCT can be an effective, and potentially curative, therapy for ITCH deficiency.

Copyright © 2021. Published by Elsevier Inc.