title: Paternally inherited ABCC8 mutation causing diffuse congenital hyperinsulinism.
abstract: BACKGROUND
  Congenital hyperinsulinism (CHI) is a rare genetic disorder characterised by inappropriate insulin secretion in the face of severe hypoglycaemia. There are two histological subtypes of CHI namely diffuse and focal. Diffuse CHI is most common due to recessive mutations in ABCC8/KCNJ11 (which encode the SUR/KIR6.2 components of the pancreatic β-cell KATP channel) whereas focal CHI is due to a paternally inherited ABCC8/KCNJ11 mutation and somatic loss of heterozygosity for the 11p allele inside the focal lesion. Fluorine-18-l-dihydroxyphenylalanine positron emission tomography/computed tomography ((18)F-DOPA-PET/CT) is used in the pre-operative localisation of focal lesions prior to surgery. Diffuse CHI if medically unresponsive will require a near total pancreatectomy whereas focal CHI will only require a limited lesionectomy, thus curing the patient from the hypoglycaemia.
  
  
  OBJECTIVE
  To report the first case of genetically confirmed CHI in Singapore from a heterozygous paternally inherited ABCC8 mutation.
  
  
  RESULTS
  A term male infant presented with severe hyperinsulinaemic hypoglycaemia (HH) after birth and failed medical treatment with diazoxide and octreotide. Genetic testing (paternally inherited mutation in ABCC8/p.D1472N) suggested focal disease, but due to the unavailability of (18)F-DOPA-PET/CT to confirm focal disease, a partial pancreatectomy was performed. Interestingly, histology of the resected pancreatic tissue showed changes typical of diffuse disease.
  
  
  CONCLUSIONS
  Heterozygous paternally inherited ABCC8/KCNJ11 mutations can lead to diffuse or focal CHI.
  
  
  CONCLUSIONS
  HH is a cause of severe hypoglycaemia in the newborn period.Paternal mutations in ABCC8/KCNJ11 can lead to diffuse or focal disease.(18)F-DOPA-PET/CT scan is the current imaging of choice for localising focal lesions.Gallium-68 tetra-aza-cyclododecane-N N'N″N-‴-tetra-acetate octreotate PET scan is not a useful imaging tool for localising focal lesions.The molecular mechanism by which a heterozygous ABCC8 mutation leads to diffuse disease is currently unclear.Focal lesions are curable by lesionectomy and so genetic studies in patients with HH must be followed by imaging using (18)F-DOPA-PET/CT scan.
authors.affiliation: Department of Neonatology KK Women's and Children's Hospital 100 Bukit Timah Road, Singapore, 229899 Singapore.
authors.forename: Suresh
authors.initials: S
authors.lastname: Chandran
authors.affiliation: Department of Paediatric Endocrinology KK Women's and Children's Hospital 100 Bukit Timah Road, Singapore, 229899 Singapore.
authors.forename: Fabian Yap Kok
authors.initials: FY
authors.lastname: Peng
authors.affiliation: Department of Neonatology KK Women's and Children's Hospital 100 Bukit Timah Road, Singapore, 229899 Singapore.
authors.forename: Victor Samuel
authors.initials: VS
authors.lastname: Rajadurai
authors.affiliation: Department of Paediatric Surgery KK Women's and Children's Hospital 100 Bukit Timah Road, Singapore, 229899 Singapore.
authors.forename: Yap Te
authors.initials: YT
authors.lastname: Lu
authors.affiliation: Department of Children's Pathology KK Women's and Children's Hospital 100 Bukit Timah Road, Singapore, 229899 Singapore.
authors.forename: Kenneth T E
authors.initials: KT
authors.lastname: Chang
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School Exeter, EX2 5DW UK.
authors.forename: S E
authors.initials: SE
authors.lastname: Flanagan
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School Exeter, EX2 5DW UK.
authors.forename: S
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Department of Paediatric Endocrinology Great Ormond Street Hospital for Children NHS Trust London, WC1N 3JH UK.
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain