Case Report: Novel IL10RB variant causing very early onset-inflammatory bowel disease

Abstract

Background: Very early onset-inflammatory bowel disease (VEO-IBD) can arise from monogenic defects affecting immune regulation. We report a male child with VEO-IBD caused by a homozygous, loss-of-function IL10RB variant (c.562T>G; p.C188G) that has not been previously reported for this disorder.

Case presentation: A male infant of Hispanic descent was admitted to our hospital at the age of 8 months due to intractable colitis, perianal fistulas and growth faltering. Endoscopy at nine months of life revealed pancolitis and gastritis. Despite multiple courses of steroids and use of sulfasalazine, their disease remained active. Standard biologic therapies (infliximab and adalimumab) were trialed in the second year of life without improvement. Given the very early onset and severe phenotype, functional testing by phosflow to evaluate the IL-10 signaling pathway demonstrated the absence of STAT3 phosphorylation in response to IL-10 and follow up genetic testing identified a novel homozygous IL10RB missense variant (c.562T>G; p.C188G). Subsequent protein structure analysis using AlphaFold corroborated this loss-of-function phenotype. The patient's condition was partially controlled with anakinra (IL-1 receptor antagonist) as a bridge therapy. At the age of 3 years, the patient underwent an allogeneic hematopoietic stem cell transplant (HSCT) from an unrelated umbilical cord blood donor; however, they experienced engraftment failure, likely due to persistent hyperinflammation and the choice of cord blood for HSCT. The patient continues to have active disease requiring on-going medical management and supportive care.

Conclusion: We report a novel, loss-of-function IL10RB variant causing VEO-IBD, thus expanding the genotypic spectrum of this condition. This case highlights the diagnostic and therapeutic challenges of IL-10R deficiency-related VEO-IBD. It also underscores the importance of early recognition of monogenic causes of IBD, use of interim immunomodulatory therapies, and the need for optimal timing and donor selection for HSCT.

Keywords: AlphaFold; HSCT; IL-10R; VEO-IBD; phosflow.

Figure 1

The IL10RB (c.562T>G; p. C188G) variant abrogates IL-10 signaling. (A) Schematic representation of the IL-10 signaling pathway [adapted from Schulke, S et al] (6). (B) Assessment of IL-10 signaling in bulk CD3+ T cells. The numerical values in each stacked histogram plot denote the fold change in the median fluorescence intensity (MFI) of the phospho-STAT3 signal following treatment with the signaling input compared to PBS treatment which is normalized to one. The change in the phosphorylation status is additionally depicted by the color of each histogram based on the colorimetric scale placed below the plot. STAT3: Signal Transducer and Activator of Transcription 3; SOCS3: Suppressor of Cytokine Signaling 3; IL-1RN: IL-1 receptor antagonist; JAK1: Janus Kinase 1; Tyk2: Tyrosine kinase 2; MAPK: Mitogen-activated protein kinase; IL-10R: IL-10 Receptor.

Figure 2

The structure of the IL-10Rβ protein implicates C188G in disease pathogenicity. (A) The signal peptide-removed IL-10Rβ AlphaFold structure (AF-Q08334-F1) is composed of multiple domain regions. The two FNIII domains are extracellular and bind directly to the IL-10 ligand. These are followed by a lipid bilayer-embedded transmembrane segment and an unstructured cytosolic region. C188, located on the 2^nd FNIII domain, participates in a disulfide bond with C209. (B) AlphaMissense Pathogenicity scores predict the likelihood that an amino acid change will be disease-causing. The box plots show scores for the 19 natural amino acids changes at each cysteine position in IL-10Rβ. Only the 4 cysteines involved disulfides, which include C188, were predicted to be fully conserved with any change leading to a likely pathogenic protein. A box plot for all amino acid changes for all positions (ALL) was included to show the range of scores throughout the protein. Impairment of disulfide bond formation in the C188G IL-10Rβ protein is predicted to be highly destabilizing and expected to alter its structure and function. The final 17 amino acids were remodeled for illustration purposes.