Fetal-onset IPEX: Report of two families and review of literature

- IPEX clinical features may manifest already in fetal life.
- Premature labor and intrauterine growth restriction occur commonly in fetal IPEX.
- IPEX may cause miscarriage, sometimes due to hydrops.
- The mutations c.1189C > T and c.319_320delTC are associated with severe IPEX phenotype.

Early-life autoimmunity is an IPEX characteristic, however intrauterine forms had not yet been described. Here, two unrelated families with clear evidence of fetal-onset IPEX are reported. One had 5 miscarriages of males in two generations, and a newborn presenting type-1 diabetes mellitus immediately after birth, diarrhea, thrombocytopenia, eczematous dermatitis, eosinophilia, high IgE levels and autoantibodies to pancreatic islet antigens at 4-days-old. Maternal serology was negative. He presented a FOXP3 mutation, c.1189C > T, p.Arg397Trp, previously described only in another family with IPEX at birth. The second family had several miscarriages of males in three consecutive generations and a novel FOXP3 c.319_320delTC mutation was observed in two miscarried monochorionic twin male fetuses. These twins died at 21 weeks of gestation due to hydrops, and CD3 + infiltrating lymphocytes were found in their pancreas. We demonstrate that: i) IPEX may develop in fetal life; and ii) c.1189C > T and c.319_320delTC mutations are associated with early-onset phenotype.