Background Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, is a rare, X-linked recessive, genetic immune dysregulatory disorder affecting approximately 1 in 1-1.6 million individuals. The syndrome is classically characterized by the triad of severe enteritis and food allergy, infantile endocrinopathy (infantile diabetes or thyroiditis) and eczema. Symptoms usually start in the first month of life. The prognosis is poor, with most children dying in early childhood. In most cases, IPEX syndrome is caused by mutations in the FOXP3 gene, which leads to impairment of regulatory T cells. As a result, this immune dysregulation manifests as severe multi-organ autoimmunities.

Case Presentation A 12-month-old male with eczema presented with a one-month history of non-bloody diarrhea. Parents reported 7-8 episodes of diarrhea per day without fevers or emesis. The patient was admitted for severe dehydration and malnutrition. His albumin and potassium levels were low (1.7g/dL and 2.8mmol/L respectively). Fecal occult blood test was positive. Additional workup guided by the gastroenterology service revealed multiple allergies on food allergy panel. IgA, tissue transglutaminase, fecal calprotectin and GI pathogen panel were negative. The differential diagnosis included food allergy, malabsorption, and autoimmune enteritis including IPEX. Our patient was started on an amino acid formula, but no improvement in symptoms occurred. Biopsy results from an esophagogastroduodenoscopy and colonoscopy showed complete villous atrophy in the duodenum and chronic lymphocytic inflammation and apoptosis in the colon. Autoimmune screening labs including celiac disease panel, thyroid panel, anti-islet, anti-thyroglobulin, insulin antibodies, anti-TPO were all negative. Considering persistent symptoms, steroid therapy was initiated while awaiting genetic testing. A likely pathogenic variant FOXP3 mutation (chrX, 767t>C hemizygous mutation) was identified. Steroid therapy yielded limited improvement, and our patient was transferred to a specialized facility for further management and potential hematopoietic stem cell transplant.

Discussion The case highlights diagnostic challenges in recognizing atypical IPEX syndrome presentations. Our patient had a delayed onset and had 2 out of the 3 classic systems enteropathy, dermatitis, endocrinopathy involved with IPEX syndrome. The severity and persistence of symptoms led us to pursue genetic testing, which revealed a FOXP3 mutation. IPEX can manifest later in life; the eldest known onset was at 12 years old. Enteropathy typically precedes endocrinopathies in late-onset cases. Effective management of IPEX involves a combination of immune suppression and dietary adjustments, with Hematopoietic Cell Transplantation (HCT) offering the sole curative option. This case suggests that IPEX should always be considered in the differential diagnosis of intractable diarrhea, especially in a child with eczema and/or endocrinopathies.