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.