Persistent Hyperinsulinaemic Hypoglycaemia and Maturity Onset Diabetes of the Young (MODY) due to Heterozygous HNF4A Mutations

Objective: Mutations in the human HNF4A gene encoding the hepatocyte nuclear factor 4 alpha (HNF-4α) are known to cause maturity-onset diabetes of the young (MODY), which is characterized by autosomal dominant inheritance and impaired glucose-stimulated insulin secretion from pancreatic ß-cells. HNF-4α has a key role in regulating the multiple transcriptional factor networks in the islet. Recently heterozygous mutations in the HNF4A gene were reported to cause transient hyperinsulinaemic hypoglycaemia associated with macrosomia. Research Design and Methods: Three infants presented with macrosomia and severe hypoglycaemia with a positive family history of MODY. The hypoglycaemia was confirmed to be due to hyperinsulinism and all three patients required diazoxide therapy to maintain normoglycaemia. Two of the three infants are still requiring diazoxide therapy at 8 and 18 months while one of them had resolution of hyperinsulinaemic hypoglycaemia at 32 months of age. Results: Sequencing of the HNF4A gene identified heterozygous mutations in all three families. In family 1 a frameshift mutation L330fsdel17ins9 (c.987_1003del17ins9; p.Leu330fs) was present in the proband, a mutation affecting the conserved A nucleotide of the intron 2 branch site (c.264-21A>G) was identified in the proband of family 2 and finally a nonsense mutation, Y16X (c.48C>G, p.Tyr16X), was found in the proband of family 3. Conclusions: Heterozygous HNF4A mutations can therefore cause both transient and persistent hyperinsulinaemic hypoglycaemia associated with macrosomia. We recommend that macrosomic infants with transient or persistent hyperinsulinaemic hypoglycaemia should be screened for HNF4A mutations if there is a family history of young-onset diabetes.