title: Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations.
abstract: OBJECTIVE
  Mutations in the human HNF4A gene encoding the hepatocyte nuclear factor (HNF)-4alpha 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 beta-cells. HNF-4alpha 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 hyperinsulinemic hypoglycemia associated with macrosomia.
  
  
  METHODS
  Three infants presented with macrosomia and severe hypoglycemia with a positive family history of MODY. The hypoglycemia was confirmed to be due to hyperinsulinism, and all three patients required diazoxide therapy to maintain normoglycemia. Two of the three infants are still requiring diazoxide therapy at 8 and 18 months, whereas one of them had resolution of hyperinsulinemic hypoglycemia 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 hyperinsulinemic hypoglycemia associated with macrosomia. We recommend that macrosomic infants with transient or persistent hyperinsulinemic hypoglycemia should be screened for HNF4A mutations if there is a family history of youth-onset diabetes.
authors.affiliation: London Centre for Paediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children NHS Trust, and The Institute of Child Health, University College London, London, UK.
authors.forename: Ritika R
authors.initials: RR
authors.lastname: Kapoor
authors.forename: Jonathan
authors.initials: J
authors.lastname: Locke
authors.forename: Kevin
authors.initials: K
authors.lastname: Colclough
authors.forename: Jerry
authors.initials: J
authors.lastname: Wales
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Conn
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
mesh_terms: D017668:Age of Onset; D001724:Birth Weight; D004251:DNA Transposable Elements; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005320:Fetal Macrosomia / Q000235:genetics; D016368:Frameshift Mutation; D006580:Genetic Carrier Screening; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics*; D007003:Hypoglycemia / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010375:Pedigree; D017384:Sequence Deletion
chemical_list: D004251:DNA Transposable Elements; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4