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. 2018 Aug;19(5):910-916.
doi: 10.1111/pedi.12655. Epub 2018 Mar 1.

Clinical heterogeneity of hyperinsulinism due to HNF1A and HNF4A mutations

Joanna Yuet-Ling Tung  1 , Kara Boodhansingh  1 , Charles A Stanley  1   2 , Diva D De León  1   3
Affiliations

Clinical heterogeneity of hyperinsulinism due to HNF1A and HNF4A mutations

Joanna Yuet-Ling Tung et al. Pediatr Diabetes. 2018 Aug.

Abstract

Background: Dominant inactivating mutations in HNF1A and HNF4A have been described to cause hyperinsulinism (HI) before evolving to diabetes. However, information available in the literature regarding the clinical phenotype is limited.

Objective: To report the prevalence of HNF1A and HNF4A mutations in a large cohort of children with HI, and to describe their genotypes and phenotypes.

Design: Retrospective descriptive study.

Methods: Medical records were reviewed to extract clinical information. Mutation analysis was carried out for 8 genes associated with HI (ABCC8, KCNJ11, GLUD1, GCK, HADH, HNF4A, HNF1A, and UCP2).

Results: HNF1A and HNF4A mutations were identified in 5.9% (12 out of 204; HNF1A = 7, HNF4A = 5) of diazoxide-responsive HI probands. The clinical phenotypes were extremely variable. Two children showed evidence of ketone production during hypoglycemia, a biochemical profile atypical for hyperinsulinism. At the time of analysis, diazoxide was discontinued in 5 children at a median age of 6.8 years. None had developed diabetes mellitus at a median age of 7.0 years.

Conclusions: Given the heterogeneous clinical phenotypes of HNF1A- and HNF4A-HI, all children with transient, diazoxide-responsive HI without clear history of perinatal stress, should be screened for HNF1A and HNF4A mutations as it predicts the clinical course and affects the subsequent management plan.

Keywords: HNF1A; HNF4A; MODY; beta-cell; hypoglycemia; insulin.

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Figures

FIGURE 1
FIGURE 1
Mutations of the HNF1A and HNF4A genes. A total of 10 unique mutations in HNF1A (panel A) and HNF4A (panel B) were identified in 12 children with HI. Novel mutations not reported previously are bolded
See this image and copyright information in PMC

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