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Persistent Hyperinsulinemic Hypoglycemia and Maturity-Onset Diabetes of the Young Due to Heterozygous HNF4A Mutations

¹ 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, U.K
² Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K
³ Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, U.K
⁴ Department of Paediatric Endocrinology, Sheffield Children's Hospital, Sheffield, U.K
⁵ Royal Women's Hospital, Carlton, Victoria, Australia

Corresonding author: Dr. K. Hussain, Developmental Endocrinology Research Group, Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford St., London WC1N 1EH. E-mail: k.hussain{at}ich.ucl.ac.uk

Abbreviations: ¹⁸F-DOPA-PET, ¹⁸fluoro-L-Dopa positron emission tomography; HNF, hepatocyte nuclear factor; MODY, maturity-onset diabetes of the young; PPAR, peroxisome proliferator–activated receptor

OBJECTIVE—Mutations in the human HNF4A gene encoding the hepatocyte nuclear factor (HNF)-4 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 β-cells. HNF-4 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.

RESEARCH DESIGN AND 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.

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