Background: Congenital hyperinsulinism (CHI) results from unregulated insulin secretion from pancreatic β-cells, which leads to persistent hypoglycaemia. Mutations in nine different genes are reported and phenotypic variability exists both within and between the genetic subgroups. Variable penetrance has been described in some families with the same mutation; for example HNF4A mutations cause neonatal hypoglycaemia and/or maturity onset diabetes of the young (MODY).
Case: A male born at 35 weeks gestation with a birth weight of 4.3 kg (+3.6 SDS) had recurrent hypoglycaemic episodes from day one of life. Investigations revealed a raised plasma insulin (1357 pmol/l) and C-peptide (3280 pmol/l) with supressed plasma free fatty acids and β-hydroxybutyrate during hypoglycaemia (glucose <0.5 mmol/l). Diazoxide (5 mg/kg per day) was started with a progressive increase to 20 mg/kg per day to maintain euglycaemia. His father was slim, had been diagnosed with diabetes mellitus in his thirties and was on Metformin. The paternal grandmother was also diabetic. There was no family history of hypoglycaemia. Sequence analysis identified a heterozygous HNF4A mutation (p.R245P) and two heterozygous ABCC8 mutations (p.G92S; p.A1185V) in the proband. The p.A1185V ABCC8 mutation had been inherited from his unaffected mother and the p.R245P HNF4A and p.G92S ABCC8 mutations from his father. All three mutations are novel, affect conserved residues, and are predicted to be pathogenic by in silico analysis. It is therefore likely that the CHI in the proband is resulting from a dual aetiology. Identification of a HNF4A mutation in the father is consistent with a diagnosis of MODY. He has subsequently switched treatment to Gliclazide resulting in improved glycaemic control.
Conclusion: HNF4A CHI is often transient and responsive to diazoxide. In contrast recessively inherited ABCC8 mutations usually cause diazoxide-resistant CHI. Interestingly, our patient is responsive to diazoxide despite the dual genetic aetiology. The mechanism(s) underlying the molecular interaction between HNF4A and ABCC8 mutations are unclear.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology