Pediatric Atrophic Metaplastic Gastritis: A Rare Presentation of IPEX Syndrome

Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by mutations in the FOXP3 gene. Due to the variable expression of IPEX syndrome can be misdiagnosed and underestimated, especially in those with an incomplete clinical picture or late onset. We report a rare case of severe active gastritis and mild active duodenitis initially managed with infliximab (IFX) for presumed gastro-duodenal Crohn’s disease (CD). One year after initiating IFX, surveillance endoscopy, and colonoscopy found refractory gastro-duodenitis, evolving pyloric stricture, and new findings of autoimmune atrophic metaplastic gastritis with intestinal metaplasia. Workup for very early onset inflammatory bowel disease (VEO-IBD) revealed IPEX syndrome. Methods: Case of a 10-year-old male referred to the Pediatric Gastroenterology clinic two years ago due to intermittent abdominal pain, mouth ulcers, iron deficiency anemia, elevated fecal calprotectin (FC), and poor weight gain with concerns for IBD. Initial endoscopy showed chronic severe active gastritis, normal colon, and MRE. The patient was treated with omeprazole and iron supplements. After 3 months, he continued with poor weight gain; FC was trending up, with low ferritin. Interval endoscopy 4 months later showed mild active duodenitis, persistent chronic active and atrophic gastritis, and colon remained normal. Crohn’s disease in the small bowel was suspected by capsule endoscopy. He started IFX 10 mg/kg with low IFX levels and completed 3 months of budesonide. IFX levels reached therapeutic levels with IFX 15 mg/kg every 4 weeks, showing partial clinical and laboratory response. Results: After 1 year of diagnosis, endoscopy showed refractory gastric and proximal small bowel involvement with concerns for an evolving pyloric stricture. Intermittent abdominal pain, chronic constipation, and poor weight gain continued. Labs showed mild vitamin B12 deficiency, elevated FC, and persistent iron deficiency anemia. Interval biopsy showed findings resembling autoimmune metaplastic atrophic gastritis. Diagnostic workup included negative autoimmune gastritis antibodies and thyroid antibodies. Omeprazole was discontinued due to absent parietal cells. A genetic panel for primary immunodeficiencies and VEO-IBD detected heterozygous mutation in the FOXP3 gene associated with IPEX syndrome. The patient was referred to Immunology, Hematology/Oncology, and Genetics for further evaluation and possible hematopoietic stem cell transplantation (HSCT) versus change in biological therapy from IFX to sirolimus. Conclusions: A monogenic etiology for VEO-IBD should be considered in patients with treatment-resistant IBD, which could result in a definitive cure. This report highlights the variability of the genotype-phenotype correlation of IPEX syndrome with an atypical case of a late-onset of symptoms, single organ involvement, and a mild phenotype caused by a pathogenic variant in FOXP3 – c.1190G>A (p. R397Q) presenting with atrophic metaplastic gastritis and constipation rather than diarrhea and dermatitis seen previously in patients with the same mutation. There is no standardized therapeutic approach to IPEX syndrome. Immunosuppressive treatments are potential options to control his disease phenotype; however, at the moment, HSCT is the only available definitive cure. Treatment options require an individualized approach to address specific organ involvement based on the onset and severity of the disease, considering the risks, benefits, and long-term quality of life.