P292 Neonatal diabetes in a tertiary centre; genetics dictating management. (June 2019)

• Record Type: Journal Article
• Authors: McCarron, Laura; Burke, Eleanor; O'Donnell, Gillian; Carolan, Eirin; Murphy, Nuala; McDonnell, Ciara
• Is Part Of: Archives of disease in childhood. Volume 104:Supplement 3(2019)
• Page Start: A274
• Page End: A274
• Publication Date: 2019-06
• Subjects: Infants -- Diseases -- Periodicals; Newborn infants -- Diseases -- Periodicals; Fetus -- Diseases -- Periodicals; 618.920105
• DOI: 10.1136/archdischild-2019-epa.642
• Languages: English
• ISSNs: 1359-2998

Abstract

Abstract : Background: Neonatal diabetes mellitus is a rare condition with one case per 300, 000 to 500, 000 live births. It presents with marked hyperglycaemia in the first six months of life and is commonly of generic origin. Approximately half of cases are transient (TNDM) with the reminder being permanent (PNDM). The majority of Permanent Diabetes Mellitus (PNDM) cases are secondary to genetic mutations in K-ATP channel genes. Case: We report two infants who presented in the neonatal period with hyperglycaemia and were subsequently diagnosed with neonatal diabetes. The first infant presented at 22 hours of life with blood glucose of 44.3 mmol/L and in ketoacidosis. He was born by LSCS at 34 weeks gestation due to IUGR with a birth weight of 1.36 kg. He received an IV insulin infusion for two months with frequent dose titration due to challenging glycaemic control. He was then successfully transitioned to a subcutaneous insulin infusion pump. Genetic analysis confirmed homozygous INS non sense variant, p(ARf43Ter). The second infant presented at six weeks of age in severe diabetic ketoacidosis with a blood glucose of 60 mmol/L. She was born at term weighing 2.46 kg following induction of labour for IUGR. She presented with lethargy and vomiting for 24 hours on a background of failure to thrive and chronic candidiasis from birth. She was managed with an IV insulin infusion in the ICU before transitioning to a subcutaneous insulin pump. Genetic analysis revealed a de novo KCNJ11 gene mutation. She was then successfully transitioned to oral Glibenclamide which optimised her glycaemic control and resulted in complete withdrawal of subcutaneous insulin. Discussion: These are two cases of NDM with identified genetic mutations. The INS mutation is localised to amino acid residues affecting cleavage and/or folding of pre-proinsulin and pro-insulin which leads to prolonged ER stress and subsequent B-cell apoptosis. The KCJN11 gene mutation identified in our second patient results in K-ATP channel overactivity. The K-ATP channel is at the end of the glycolytic pathway and has a KIR amino terminus responsible for channel gating. Its deletion results in channels that are continuously closed reducing sensitivity to inhibitory ATP and resulting in dramatic hyperglycaemia. Oral glibenclamide inhibits K-ATP channel activity with resultant normoglycaemia. Early identification is essential for optimal management and targeted therapy.