6q24 methylation defects are the most common cause of Transient Neonatal Diabetes Mellitus (TNDM). The clinical picture is one of impaired insulin secretion, small for gestational age and diabetes mellitus aged <6 months. This case illustrates the fluctuation between both hyper- and hypoglycaemia that can been seen in 6q24 methylation defects. A term, small for gestational age baby boy was noted to have hypoglycaemia (BSL 1.8 mmol/l) at 1.5 h of life which resolved with oral formula and iv dextrose. Then on day 9 whilst tolerating breast milk feeds 160 ml/kg per day (glucose utilisation rate (GUR) 8 mg/kg per min) he was noted to have hyperglycaemia (BSL 22.7 mmol/l). Fluctuating hyper/normoglycaemia continued between days 913 of life; nadir BSL 2.9 mmol/l on day 11. On day 14, after 24 h of persistent hyperglycaemia IV insulin infusion was commenced, and DNA sent for investigation of Neonatal Diabetes Mellitus. Insulin was weaned over 6 days and ceased completely following 48 h of normoglycaemia on combination enteral feeds and IV dextrose (GUR 9.5 mg/kg per min). At 4 weeks of age the baby was again noted to be hypoglycaemic (BSL 2.8 mmol/l), with suppressed ketones 3-hydroxybutyrate 0.04 mmol/l (RR 00.61) and inappropriately recordable insulin 1.2 mU/l. Treatment with diazoxide was considered, however normoglycaemia was achieved on large-volume breastmilk feeds (TFI 280 ml/kg per day, GUR 12.4 mg/kg per min). He was discharged home on day 35 with ongoing glucometer finger-prick monitoring. Initial genetic testing excluded possible pathogenic mutations in KCNJ11, ABCC8 and INS genes but subsequent methylation-specific analysis of chromosome 6 detected paternal uniparental disomy (UPD) of 6q24 locus. The phenotypic variations of TNDM due to 6q24 mutations is being broadened, with the novel clinical observation of hypoglycaemia following remission of 6q24 TNDM was first described in 2013 by Flanagan et al. The mechanism for hypoglycaemic in 6q24 methylation defects is not understood, however a more severe hypoglycaemic-phenotype appears to occur in the paternal UPD cohort compared to parternal duplication defects. Our patient was readmitted at 6 and 7 weeks of age for symptomatic hypoglycaemia. He continues to experience symptomatic hypoglycaemic episodes presenting as irritability, floppiness, and mood changes at 22months of age. These are unrelated to intercurrent illness or protein-rich meals, which have both been described. Hypoglycaemia has been managed orally. Our case further describes the phenotypic variation of TNDM due to 6q24 methylation defects and management difficulty this cohort presents.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology