Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

Ved Bhushan Arya; Maria Guemes; Azizun Nessa; Syeda Alam; Pratik Shah; Clare Gilbert; Senthil Senniappan; Sarah E Flanagan; Sian Ellard; Khalid Hussain

doi:10.1530/EJE-14-0353

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

Eur J Endocrinol. 2014 Dec;171(6):685-95. doi: 10.1530/EJE-14-0353. Epub 2014 Sep 8.

Authors

Affiliations

¹ Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK.
² Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK.
³ Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK Khalid.Hussain@ucl.ac.uk.

PMID: 25201519
DOI: 10.1530/EJE-14-0353

Abstract

Context: Congenital hyperinsulinism (CHI) has two main histological types: diffuse and focal. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to either phenotype. However, the relative proportion of these two phenotypes in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations has not been reported.

Objective: The purpose of this study is to highlight the variable clinical phenotype and to characterise the distribution of diffuse and focal disease in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations.

Design: A retrospective chart review of the CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted.

Results: Paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 CHI patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. Fluorine-18 l-3, 4-dihydroxyphenylalanine positron emission tomography computerised tomography 18F DOPA-PET CT) scanning in 3/18 children showed diffuse disease. The remaining 35 (66%) diazoxide-unresponsive children either had pancreatic venous sampling (n=8) or 18F DOPA-PET CT (n=27). Diffuse, indeterminate and focal disease was identified in 13, 1 and 21 patients respectively. Two patients with suspected diffuse disease were identified to have focal disease on histology.

Conclusions: Paternally inherited heterozygous ABCC8/KCNJ11 mutations can manifest as a wide spectrum of CHI with variable 18F DOPA-PET CT/histological findings and clinical outcomes. Focal disease was histologically confirmed in 24/53 (45%) of CHI patients with paternally inherited heterozygous ABCC8/KCNJ11 mutations.

MeSH terms

Cohort Studies
Congenital Hyperinsulinism / epidemiology
Congenital Hyperinsulinism / genetics*
Congenital Hyperinsulinism / pathology*
Female
Genetic Heterogeneity
Heterozygote
Humans
Infant
Infant, Newborn
Inheritance Patterns / genetics
Male
Mutation
Polymorphism, Single Nucleotide
Potassium Channels, Inwardly Rectifying / genetics*
Sulfonylurea Receptors / genetics*

Substances

ABCC8 protein, human
Kir6.2 channel
Potassium Channels, Inwardly Rectifying
Sulfonylurea Receptors

Abstract

MeSH terms

Substances

Grants and funding