title: Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: Ved Bhushan
authors.initials: VB
authors.lastname: Arya
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Guemes
authors.affiliation: 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.
authors.forename: Azizun
authors.initials: A
authors.lastname: Nessa
authors.affiliation: 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.
authors.forename: Syeda
authors.initials: S
authors.lastname: Alam
authors.affiliation: 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.
authors.forename: Pratik
authors.initials: P
authors.lastname: Shah
authors.affiliation: 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.
authors.forename: Clare
authors.initials: C
authors.lastname: Gilbert
authors.affiliation: 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.
authors.forename: Senthil
authors.initials: S
authors.lastname: Senniappan
authors.affiliation: 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.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.affiliation: 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.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: 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.
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
mesh_terms: D015331:Cohort Studies; D044903:Congenital Hyperinsulinism / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D005260:Female; D018740:Genetic Heterogeneity; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D064233:Sulfonylurea Receptors / Q000235:genetics*; D000099161:Kcnj11 Channel
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human