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Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations

Flanagan, S. E.; Kapoor, R. R.; Mali, G.; Cody, D.; Murphy, N.; Schwahn, B.; Siahanidou, T.; ... Ellard, S.; + view all (2010) Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. European Journal of Endocrinology , 162 (5) pp. 987-992. 10.1530/EJE-09-0861. Green open access

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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.

Type: Article
Title: Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations
Open access status: An open access version is available from UCL Discovery
DOI: 10.1530/EJE-09-0861
Publisher version: http://dx.doi.org/10.1530/EJE-09-0861
Language: English
Additional information: © 2010 European Society of Endocrinology. This is an Open Access article distributed under the terms of the European Journal of Endocrinology’s Re-use Licence which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
UCL classification:
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
URI: https://discovery.ucl.ac.uk/id/eprint/20039
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