IPEX Syndrome in Siblings with a Novel Variant in FOXP3

Abstract

RATIONALE: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare condition caused by mutations in FOXP3 resulting in defective regulatory T-cells (T regs ). We report two siblings with clinical presentations suggestive of IPEX with a novel variant in FOXP3. METHODS:A 5-year-old male (proband) was evaluated for diarrhea since infancy, intermittent fevers and arthralgias. Fecal calprotectin was markedly elevated and a colonic biopsy revealed findings of nonspecific inflammatory colitis, responsive to high-dose steroids. Family history was notable for type 1 diabetes mellitus in a 14 year-old brother who was subsequently diagnosed with nonspecific inflammatory colitis. Targeted gene sequencing (Invitae, Illumina) was performed in the siblings and parents. FOXP3 expression was evaluated by flow cytometry in CD3 + CD4 + CD25 + T reg cells. In the proband, LRBA expression was assessed in monocytes, T, B and NK cells. Tr1 (CD3 + CD4 + CD45A -CD49b + LAG-3 -) and Tr1/Th3 (CD3 + CD4 + CD25 -CD127 + ) precursor cells were also evaluated. RESULTS: Sequence analysis for both siblings revealed familial variants of uncertain significance (VUS) in FOXP3 [c.1129C>G(p.His377Asp0)]. The proband also had 2 VUS in LRBA [c.3905C>T(p.Thr1302lle) and c.7675G>T(p.Ala2559Ser)]. The same LRBA variants were inherited in cis from the proband's unaffected father and LRBA protein expression was normal in all cells types analyzed. Both siblings had normal or increased percentages CD3 + CD4 + CD25 + FOXP3 + T regs cells. Tr1 and Tr1/Th3 precursor were normal (proband). CONCLUSIONS: These are the first reported cases of IPEX syndrome resulting from this novel FOXP3 variant. FOXP3 expression may be normal in patients with IPEX syndrome. Hematopoietic stem cell transplantation is being considered pending T regs suppression assays.

The Importance of the Transcription Factor Foxp3 in the Development of Primary Immunodeficiencies

“…In many patients, exacerbation of the disease is also observed and caused by infections or food allergens. Subsequently, the main symptoms of the gastrointestinal tract or skin lesions are intensified or exacerbated as well as other disorders related to kidney, digestive, and immune system diseases (Figure 5) [163,178]. Due to such a wide range of symptoms, patients without appropriate treatment (immunosuppressants and bone marrow transplantation) die before reaching the age of 2 [176].…”