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

Abstract

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.

• Authors: Diana E Stanescu, Nkecha Hughes, Bernard Kaplan, Charles A Stanley, Diva D De León
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 97 Issue 10 Pg. E2026-30 (Oct 2012) ISSN: 1945-7197 [Electronic] United States
• PMID: 22802087 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

• 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