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


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.
Clinical and Translational Research Center, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, 3615 Civic Center Boulevard, Abramson Research Center Room 802A, Philadelphia, Pennsylvania 19104, USA.
Diana E
DE
Stanescu
Nkecha
N
Hughes
Bernard
B
Kaplan
Charles A
CA
Stanley
Diva D
DD
De León
D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D044903:Congenital Hyperinsulinism / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics; D020125:Mutation, Missense; D010641:Phenotype
C496487:HNF1A protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4