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J Pediatr Endocrinol Metab. 2019 Mar 26;32(3):301-304. doi: 10.1515/jpem-2018-0389.

A rare case of congenital hyperinsulinism (CHI) due to dual genetic aetiology involving HNF4A and ABCC8.

Author information

1
Department of Paediatric Endocrinology, Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom.
2
Department of Paediatric Endocrinology, Bristol Royal Hospital for Children, Bristol, United Kingdom.
3
Department of Molecular Genetics, The Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.
4
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom.

Abstract

Background Congenital hyperinsulinism (CHI) occurs due to an unregulated insulin secretion from the pancreatic β-cells resulting in hypoglycaemia. Causative mutations in multiple genes have been reported. Phenotypic variability exists both within and between different genetic subgroups. Case presentation A male infant born at 35+6 weeks' gestation with a birth weight of 4.3 kg [+3.6 standard deviation score (SDS)] had recurrent hypoglycaemic episodes from birth. Biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and the dose was progressively increased to maintain euglycaemia. His father was slim and had been diagnosed with type 2 diabetes in his 30s. Sequence analysis identified a heterozygous hepatocyte nuclear factor 4 alpha (HNF4A) mutation (p.Arg245Pro, c.734G>C) and compound heterozygous ABCC8 mutations (p.Gly92Ser, c.274G>A and p.Ala1185Val, c.3554C>T) in the patient. The p.Ala1185Val ABCC8 mutation was inherited from his unaffected mother and the p.Arg245Pro HNF4A and p.Gly92Ser ABCC8 mutations from his father. All three mutations were predicted to be pathogenic. Identification of the HNF4A mutation in the father established a diagnosis of maturity-onset diabetes of the young (MODY), which enabled medication change resulting in improved glycaemic control. Conclusions We report a rare patient with CHI due to dual genetic aetiology. Although he is currently responsive to the maximum dose of diazoxide, the long-term prognosis remains unclear.

KEYWORDS:

ABCC8; HNF4A; congenital hyperinsulinism; dual genetic aetiology

PMID:
30730840
DOI:
10.1515/jpem-2018-0389

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