Diverse Clinical and Immunological Profiles in Patients with IPEX Syndrome: A Multicenter Analysis

Abstract Purpose: Immunodysregulation, Polyendocrinopathy, Enteropathy, and X-linked syndrome (IPEX), caused by FOXP3 mutations, is a rare autoimmune disorder with diverse clinical features, including early-onset diabetes, eczema, and enteropathy. Atypical cases show milder symptoms and unique signs, requiring different treatments. Therefore, there are ambiguities in the accurate diagnosis and management of IPEX. We sought to present clinical, genetic, and immunological assessments of 12 IPEX patients with long-term follow-up to facilitate the diagnosis and management of the disease. Methods: Clinical findings and treatment options of the patients were collected over time. Lymphocyte subpopulations, protein expressions, regulatory T (Treg) and circulating T follicular helper (cTFH) cells, and T-cell proliferation were analyzed. Results: Predominant presentations included chronic diarrhea (75%), failure to thrive (66.7%), and eczema (58.3%). There were four classical and eight atypical IPEX individuals. Strikingly, the classical triad of IPEX was observed only in one patient. Allergic manifestations were more common in atypical patients. Notably, infections and chronic diarrhea demonstrated heightened severity compared to other manifestations. Four patients (33.3%) demonstrated eosinophilia, and nine (75%) showed high serum IgE levels. Most patients showed normal percentages of Treg cells with reduced CD25, FOXP3, and CTLA-4 expressions. Compared to healthy controls, the TH2-like skewing accompanied by reduced TH17-like responses was observed in cTFH and Treg cells of patients. The impaired immune responses were corrected after hematopoietic stem cell transplantation (HSCT). Overall, nine patients (75%) received immunosuppressants (ISs), and six (50%) underwent HSCT, which was the only treatment revealing sustained control. Commonly used ISs included corticosteroids and sirolimus, but severe side effects led to therapy discontinuation in six patients. Conclusions: This comprehensive analysis of clinical features and treatment responses contributes valuable insights for the improved diagnosis and management of IPEX syndrome, particularly emphasizing the atypical presentations and the efficacy of HSCT in achieving sustained control.