Biallelic DUOX2 Variants and the Link to Very Early-Onset IBD

Very early-onset inflammatory bowel disease (VEO-IBD) involves children less than 6 years of age presenting with IBD. These patients are more likely to have inborn errors of immunity. We present a child with VEO-IBD, found to have compound heterozygous variants in the DUOX2 gene that expands on the rare association of VEO-IBD with DUOX2 insufficiency.

A 5-year-old male presented with six months of watery diarrhea, with labs notable for thrombocytosis, elevated CRP, and fecal calprotectin to 1430 [ref ≤ 49 μg/g]. Endoscopy and colonoscopy with biopsy revealed intraepithelial lymphocytosis in the duodenum, eosinophilic infiltrate in the stomach, esophagitis without eosinophilia, and chronic active ileitis with eosinophils of 65/hpf in the terminal ileum, consistent with a diagnosis of Crohn’s disease. The patient underwent immune phenotyping given his young age, which revealed elevated sIL2R, IL-17, IL-5, IL-13, IL-10, and IL-6, T cell lymphocytosis, and a normal neutrophil oxidative burst. Targeted genetic sequencing revealed two heterozygous variants in the DUOX2 gene: one maternally inherited likely pathogenic splice site variant, c.2922-14_2925del; and one paternally inherited variant of uncertain significance (VUS), c.1528C>T (p.Arg510Trp). The VUS is within the peroxidase-like region of the gene, which plays a crucial role in enzyme function, has a high CADD score of 25, and has a GnomAD allelic frequency of only 0.001%, suggesting possible pathogenicity. The patient is currently doing well on infliximab, with interval normalization of his cytokines.

The DUOX2 gene encodes for dual NADPH oxidase (DUOX), which is responsible for the release of hydrogen peroxide as part of the innate immune defense of gut epithelial cells. In mice, DUOX2 has been shown to play an integral role in maintaining immune homeostasis in the gut biome, with knockout models showing elevated IL-17C levels in the ileum. There are few reported cases describing the association of compound heterozygous variants in DUOX2 in patients with VEO-IBD, with this being the fourth patient, to the best of our knowledge. This case highlights the importance of further research to better understand the role of this gene in the development of inflammatory bowel disease.