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.

Fig. 1.

Liver biopsy specimen in case 3 with HNF4A mutation. Periodic acid-Schiff stain (A) showing intense cytoplasmic positivity within hepatocytes was abolished with diastase (B) and consistent with abundant cytoplasmic glycogen (×10 magnification).

Fig. 2.

Proposed relationship between HNF4α, HNF1α, and their targets. HNF4α and HNF1α can bind and activate each other's promoter; both can also regulate the expression of GLUT2. Although there is evidence for only HNF4α regulating the expression of K_ATP subunit Kir6.2, it is possible HNF1α might also have the same function.