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

Introduction 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. Case Description 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. Discussion 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. Table 1.DiagnosticsValueCytokine panelIL-2 <2.1 (ref range ≤ 2.1)IL-2R 2259.3 (ref range 175.3 - 858.2)IL-12 <1.9 (ref range ≤ 1.9)INF- γ <4.2 (ref range ≤ 4.2)IL-4 <2.2 (ref range ≤ 2.2)IL-5 19.1 (ref range ≤ 2.1)IL-10 11.1 (ref range ≤ 2.8)IL-13 2.5 (ref range ≤ 2.3)IL-17 5.5 (ref range ≤ 5.5)IL-1β <6.5 (ref range ≤ 6.7)IL-6 6.3 (ref range ≤ 2.0)TNF-α 2.5 (ref range ≤ 7.2)ImmunoglobulinsIgA – 69 (ref range 21 – 144)IgE – 4680 (ref range 2 – 524)IgG – 734 (498 – 1332)IgM – 82 (ref range 31 – 63)Lymphocyte subset panelAbsolute CD3 3080 (ref range 1400 – 3700)Absolute CD4 1969 (ref range 700 – 2200)Absolute CD8 876 (ref range 490 – 1300)Absolute CD45RA 1505 (ref range 430 – 1500)Absolute CD45RO 652 (ref range 220 – 660)Absolute HLADR 660 (ref range 50 – 180)Absolute CD19 594 (ref range 390 – 1400)Absolute CD20 552 (ref range)Absolute NK 170 (ref range 130 – 720)EGD/ColonoscopyDuodenum - Intraepithelial lymphocytosisEsophagus mid and distal – esophagitis up to 2 eos/hpfEsophagus upper – esophagitis up to 1 eos/hpfChronic active ileitis with eosinophils (up to 65/hpf)Neutrophil oxidative burstNormal granulocyte dihydrohodamine fluorescence suggesting normal NADPH oxidase activityPrimary immunodeficiency panel1. DUOX2a. c.2922-14_2925del (splice site). Het. Likely pathogenic. GnomAD AC 99. CADD 31.b. c.1528C>T (p.Arg510Trp). Het. VUS. GnomAD AC 3. CADD 25. Peroxidase-like region (mediates peroxidase activity).2. FOXI3a. c.713G>A (p.Arg238Gln). Het. VUS. GnomAD AC 3. CADD 28.8. Associated with T cell lymphopenia. Not clinically relevant.3. MS4A1a. c.352A>C (p.Ile118Leu). Het. VUS. CADD 17.01. Conflicting in silico prediction models. GnomAD AC 71. Associated with CVID. Not clinically relevant.4. POLD1a. c.520C>T (p.Arg174Trp). Het. VUS. Associated with AD mandibular hypoplasia, deafness, progeroid features and lipodystrophy and AR T cell immunodeficiency. GnomAD AC 12. Not clinically relevant.