Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations
Open Access
- 1 May 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Acta Endocrinologica
- Vol. 162 (5), 987-992
- https://doi.org/10.1530/eje-09-0861
Abstract
Objective The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH). Subjects and methods We sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype. Results A genetic diagnosis was possible for 59/220 (27%) patients. KATP channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years. Conclusions In this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once KATP channel mutations have been excluded.Keywords
This publication has 20 references indexed in Scilit:
- Hyperinsulinism–hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype–phenotype correlationsActa Endocrinologica, 2009
- Extremes of Clinical and Enzymatic Phenotypes in Children With Hyperinsulinism Caused by Glucokinase Activating MutationsDiabetes, 2009
- Persistent Hyperinsulinemic Hypoglycemia and Maturity-Onset Diabetes of the Young Due to Heterozygous HNF4A MutationsDiabetes, 2008
- Macrosomia and Hyperinsulinaemic Hypoglycaemia in Patients with Heterozygous Mutations in the HNF4A GenePLoS Medicine, 2007
- Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the youngHuman Mutation, 2006
- Identification of a Familial Hyperinsulinism-causing Mutation in the Sulfonylurea Receptor 1 That Prevents Normal Trafficking and Function of KATP ChannelsPublished by Elsevier BV ,2002
- Familial Hyperinsulinism Caused by an Activating Glucokinase MutationThe New England Journal of Medicine, 1998
- Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancyHuman Molecular Genetics, 1996
- Cross sectional stature and weight reference curves for the UK, 1990.Archives of Disease in Childhood, 1995
- Mutations in the Sulfonylurea Receptor Gene in Familial Persistent Hyperinsulinemic Hypoglycemia of InfancyScience, 1995