title: Congenital hyperinsulinism: clinical and molecular characterisation of compound heterozygous ABCC8 mutation responsive to Diazoxide therapy.
abstract: BACKGROUND
  Mutations in ABCC8 and KCNJ11 are the most common cause of congenital hyperinsulinism (CHI). Recessive as well as dominant acting ABCC8/KCNJ11 mutations have been described. Diazoxide, which is the first line medication for CHI, is usually ineffective in recessive ABCC8 mutations. We describe the clinical and molecular characterisation of a recessive ABCC8 mutation in a CHI patient that is diazoxide response.
  
  
  METHODS
  A term macrosomic female infant presented with symptomatic persistent hypoglycaemia confirmed to be secondary to CHI. She exhibited an excellent response to moderate doses of diazoxide (10 mg/kg/day). Molecular genetic analysis of the proband confirmed a biallelic ABCC8 mutation - missense R526C inherited from an unaffected mother and a frameshift c.1879delC mutation (H627Mfs*20) inherited from an unaffected father. Follow-up highlighted persistent requirement for diazoxide to control CHI. Functional analysis of mutants confirmed them to result in diazoxide-responsive CHI, consistent with the clinical phenotype.
  
  
  CONCLUSIONS
  Biallelic ABCC8 mutations may result in diazoxide-responsive CHI. Irrespective of the molecular genetic analysis results, accurate assessment of the response to diazoxide should be undertaken before classifying a patient as diazoxide-responsive or unresponsive CHI.
authors.affiliation: London centre for Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH and The Institute of Child Health, University College London, London, WC1N 1EH UK.
authors.forename: Ved Bhushan
authors.initials: VB
authors.lastname: Arya
authors.affiliation: The Heart Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, UK.
authors.forename: Qadeer
authors.initials: Q
authors.lastname: Aziz
authors.affiliation: The Institute of Child Health, University College London, London, WC1N 1EH UK.
authors.forename: Azizun
authors.initials: A
authors.lastname: Nessa
authors.affiliation: The Heart Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tinker
authors.affiliation: London centre for Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH and The Institute of Child Health, University College London, London, WC1N 1EH UK.|Developmental Endocrinology Research Group, Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH UK.
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
keywords: ABCC8; Congenital hyperinsulinism; Diazoxide; Hypoglycaemia