ESPE Abstracts

Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder caused by loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor. This factor plays a key role in the differentiation and function of CD4+ CD25+ regulatory T cells, essential for the establishment and maintenance of natural tolerance.

Objective: To describe clinical, biochemical and genetic characteristics in two siblings with neonatal diabetes and a novel FOXP3 mutation.

Method: Genomic DNAs were extracted from peripheral blood leukocytes from both patients and their parents with informed consent for genetic studies. Sanger sequencing.

Results: Patient 1: male, born at term, birth weight 3,050 kg. Neonatal diabetes diagnosed with DKA at 1 month old. Glycemia 5,11 g/L. HbA1c 4%. C-peptide 0,1 ng/mL. Anti-insulin Antibodies 13,4 U/mL. Ig E 7710 IU/mL. Treatment with NPH and aspartic insulin led to variable glycemic control. Enteropathy with severe and persistent diarrhea was confirmed by endoscopy and biopsy and required exclusive parenteral nutrition. IPEX syndrome was suspected based on neonatal diabetes, enteropathy and eczema. Multiple infectious diseases associated with autoimmune cytopenias. Died cachectic at 6 months old because of sepsis after 5 months at hospital. Sequence analysis confirmed he was hemizygous for a novel FOXP3 frameshift variant resulting in loss of the stop codon, p.(Thr428fs). Evidence up to that moment suggested that the variant was likely pathogenic, consistent with IPEX syndrome. His mother is heterozygous for the mentioned variant, being a carrier.

Patient 2: male, born at term, birth weight 1,720 kg. Given his older brother's record, patient 2's glycemia was controlled since birth. He showed hyperglycemia 6 hours after he was born. Glycemia 2,5 g/L. HbA1c 4%. C-peptide 0,1 ng/mL. GADA 11,1 U/mL. IgE 2,3 IU/mL. Insulin requirement since his first day of life. He received aspartic, glargine and finally lispro administered by insulin pump. Variable glycemic control. He has received hydrolyzed formula since birth. Hospital discharge at 43 days of life. No persistent enteral symptoms at present (3 months old). He underwent a Rotavirus infection requiring a short hospitalization. Adecuate weight gain. His genetic testing showed patient 1's same variant. He is close to receive bone marrow transplant.

Conclusion: Distinctive manifestations have been described in two siblings with neonatal diabetes as first diagnosis with a novel variant in FOXP3's Sanger sequence. Their mother is the carrier of the X-linked mutation.