Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A

J Clin Endocrinol Metab. 2012 Oct;97(10):E2026-30. doi: 10.1210/jc.2012-1356. Epub 2012 Jul 16.


Context: Inactivating mutations in HNF1A and HNF4A cause the maturity-onset diabetes of youth (MODY)-3 and MODY1 forms of monogenic diabetes, respectively. Children carrying HNF4A (MODY1) mutations can present in early infancy with macrosomia and diazoxide-responsive hyperinsulinism.

Objective: Our objective was to describe three novel cases of hyperinsulinism associated with MODY1 and MODY3 mutations.

Research design and methods: Clinical data were obtained from chart review. Gene sequencing was performed on genomic DNA.

Results: Case 1 was diagnosed at 20 months with persistent hyperinsulinemic hypoglycemia and was found to have a novel MODY3 HNF1A mutation, carried by her father who had diabetes. Case 2 was diagnosed with diazoxide-responsive hyperinsulinism at 3 months of age and had complete resolution of hyperinsulinism by 4 yr. She was found to have a novel MODY3 HNF1A missense mutation, also carried by her father. Case 3 presented as a newborn with diazoxide-responsive hyperinsulinism and later developed renal Fanconi syndrome, hypophosphatemic rickets, and hepatic glycogenosis. Although the latter's features suggested Fanconi-Bickel syndrome, sequencing of the SLC2A2 gene was normal. The patient was found to have a known MODY1 mutation in HNF4A. In all cases, the hyperinsulinism improved with age.

Conclusions: The first two cases demonstrate that mutations in HNF1A (MODY3) can cause hyperinsulinism early in life and diabetes later, similar to the phenotype recently reported for HNF4A (MODY1) mutations. Case 3 indicates that the effects of HNF4A mutations in infancy may extend beyond pancreatic β-cells to produce a disorder similar to glucose transporter 2 deficiency involving both liver glycogen metabolism and renal tubular transport.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Age of Onset
  • Child
  • Child, Preschool
  • Congenital Hyperinsulinism / genetics*
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Hepatocyte Nuclear Factor 1-alpha / genetics*
  • Hepatocyte Nuclear Factor 4 / genetics*
  • Humans
  • Hypoglycemia / genetics
  • Mutation, Missense
  • Phenotype


  • HNF1A protein, human
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 4

Supplementary concepts

  • Maturity-Onset Diabetes of the Young, Type 1
  • Maturity-Onset Diabetes of the Young, Type 3