Beyond the Classical Triad: Atypical Presentations and Regulatory T Cell Phenotyping in a Cohort of IPEX Patients

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked(IPEX) syndrome caused by FOXP3 mutations is rare. FOXP3 is a transcription factor required for the regulatory T cell (Treg) development/function.

We aimed to characterize the clinical, immunologic, and genetic features of a single-center cohort of IPEX syndrome.

We present the clinical/immunological/genetic features of 12 patients with IPEX syndrome. We used whole exome and Sanger sequencing for the diagnosis/familial segregation. We performed immunophenotyping and measured Treg percentage and FOXP3 expression in peripheral blood by flow cytometric analysis.

Median age at diagnosis was 2.5 years (range: 0.3-22 years). Common clinical manifestations were infections (n = 9, 75%), allergies (n = 8, 67%), autoimmunity (n = 7, 58%), enteropathy (n = 7, 58%), and lymphoproliferation (n = 3, 25%). Atypical initial presentations included class IV lupus nephritis, a SCID-like immunophenotype (CD3⁺ T cells: 4% [100/µL]; CD4⁺ T cells: 3%, CD8⁺ T cells: 1%, CD19⁺ B cells: 81%, CD16/56⁺ NK cells: 13%), and isolated hypogammaglobulinemia persisting for years during follow-up. At the time of diagnosis, three (25%) patients had leukopenia, six (50%) had lymphopenia and two (17%) had neutropenia. Eosinophilia was observed in 42% of patients (25% mild, 17% moderate). Six different variants in FOXP3 were characterized in 12 patients from nine unrelated families. Four (33%) patients underwent hematopoietic stem cell transplantation (HSCT). Overall, three (25%) patients died due to infections. One patient died due to HSCT-related catheter complications, one patient died in an accident. Among the transplanted patients, two are alive and well. Among the non-transplanted patients, five are alive and are being followed up at our center. Treg (CD4⁺CD127^-/lowCD25⁺Foxp3⁺) percentage was low in eight patients compared to healthy controls (p < 0.001). FOXP3 expression was low in all the patients compared to healthy controls.

Atypical presentations make the diagnosis of IPEX syndrome challenging. This study expands the current knowledge of IPEX syndrome by describing a single-center cohort with certain atypical manifestations and by confirming previously reported rare phenotypes. Elucidating the genetic basis of immunodeficiency diseases contributes to improving diagnostic approaches and patient management.