Hepatocyte nuclear factor 4 alpha and its role in hyperinsulinaemic hypoglycaemia

Hepatocyte nuclear factor 4 alpha (HNF4A) mutations are the third most common genetic cause of hyperinsulinaemic hypoglycaemia after KCNJ11 and ABCC8 mutations. Transient or chronic neonatal hypoglycaemia results from inactivating HNF4A mutations, which affect insulin control in pancreatic β-cells. Mutations in the inactivating HNF4A gene impact insulin regulation in the pancreatic β-cells, causing either temporary or persistent hypoglycaemia in newborns. Less than 20 pathogenic variations of heterozygous mutations in the transcription factor HNF4A have been identified to date, making them a rare cause of maturity-onset diabetes of the young (MODY). We describe a 19-month-old boy who needs a glucose infusion to maintain normoglycaemia due to persistent hyperinsulinaemic hypoglycaemia. He was prescribed diazoxide, which was titrated to 2.5 mg/kg/ day, after he began experiencing frequent hypoglycaemic seizures. This medication successfully stabilised his blood glucose levels. A heterozygous HNF4A mutation was found by genetic testing (c.148T>C; p.Tyr 50His, exon 2). After starting diazoxide, there were no more hypoglycaemic episodes or seizures. The significance of taking into account HNF4A mutations in patients who need diazoxide due to persistent hypoglycaemia, even in the absence of macrosomia or a family history of diabetes, is demonstrated by this case. Given that some HNF4A carriers develop MODY later in life, early genetic diagnosis can direct long-term metabolic surveillance.