ESPE Abstracts

Background: Insulin treatment in a very low birth weight neonate having persistent hyperglycemia is challenging. The very recently reported novel human genetic cause of neonatal diabetes due to NKX2.2 pancreatic transcription factor mutations is associated with very low birth weight deliveries.

Objective and hypotheses: To study the diagnostic process, the molecular genetics, the clinical phenotype, and the significant therapeutic challenges in the management of an extremely low birth weight (1.080 Kg) infant of consanguineous Palestinian parents with early severe Neonatal Diabetes (NDM).

Methods: Genetic investigations included homozygosity mapping and sequencing of ABCC8, KCNJ11, INS and EIF2AK3 genes followed by an exome sequencing. Therapeutic trials involved continuous intravenous insulin, sulphonyl urea, subcutaneous Long Acting Insulin Analogues (LAIA) and continuous insulin via insulin pump.

Results: Homozygosity mapping identified three candidate genes, located in small homozygous areas: INS gene, RFX6 gene, and SLC19A2. Sequencing of those genes revealed no pathogenic mutation. Exome sequencing revealed delG, P119fs mutation in the NKX2.2 gene, expressed in the CNS and pancreas and required for the final differentiation of pancreatic beta cells in mice. Therapeutically, the thin subdermal fat tissue in this case limited the use of insulin pump or continuous glucose monitoring. Sulphonylurea treatment showed no benefit. The most optimal glycemic control without extreme fluctuations in glucose monitoring was achieved by 3 daily doses of 0.3 μ/Kg of Long Acting Insulin Analogues (LAIA).

Conclusion: The delG, P119fs mutation in the NKX2.2 gene causes severe NDM associated with very low birth weight infants. Sulphonylureas are not effective and long-acting insulin analogues twice daily were associated with extreme glucose variability. If insulin is required LAIA in three or more daily doses are the optimal choice.