Abstract

Objective: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics and clinical phenotype of FOXP3 mutations in a large cohort with permanent neonatal diabetes (PNDM).

Research Design and Methods: The eleven coding exons and the polyadenylation region of FOXP3 were sequenced in 26 male subjects with diabetes diagnosed before 6 months of age in whom common genetic causes of PNDM had been excluded. Ten cases had at least one additional immune-related disorder and the remaining 16 had isolated diabetes.

Results: We identified four hemizygous FOXP3 mutations in 6/10 patients with associated immune related disorders and 0/16 of those with isolated diabetes (p=0.002). Three patients with two novel mutations (R337Q and P339A) and the previously reported L76QfsX53 developed classical IPEX syndrome and died within the first 13 months. The novel mutation V408M was found in three cases from 2 unrelated families and had a mild phenotype with hypothyroidism and autoimmune enteropathy (n=2) or nephrotic syndrome (n=1) and survival until 12 to 15 years.

Conclusions: FOXP3 mutations result in approximately 4% of cases of males with permanent diabetes diagnosed before 6 months. Patients not only have the classical IPEX syndrome but, unexpectedly, may have a more benign phenotype. FOXP3 sequencing should be performed in any male patient diagnosed with diabetes in the first 6 months who develops other possible autoimmune associated conditions, even in the absence of the full IPEX syndrome.