title: Clinical characteristics and phenotype-genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations.
abstract: OBJECTIVE
  Congenital hyperinsulinism (CHI) is the commonest cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous. The aim of this study was to describe the clinical characteristics, analyse the genotype-phenotype correlations and describe the treatment outcome of Turkish CHI patients.
  
  
  METHODS
  A total of 35 patients with CHI were retrospectively recruited from four large paediatric endocrine centres in Turkey. Detailed clinical, biochemical and genotype information was collected.
  
  
  RESULTS
  Diazoxide unresponsiveness was observed in nearly half of the patients (n=17; 48.5%). Among diazoxide-unresponsive patients, mutations in ABCC8/KCNJ11 were identified in 16 (94%) patients. Among diazoxide-responsive patients (n=18), mutations were identified in two patients (11%). Genotype-phenotype correlation revealed that mutations in ABCC8/KCNJ11 were associated with an increased birth weight and early age of presentation. Five patients had p.L1171fs (c.3512del) ABCC8 mutations, suggestive of a founder effect. The rate of detection of a pathogenic mutation was higher in consanguineous families compared with non-consanguineous families (87.5 vs 21%; P<0.0001).Among the diazoxide-unresponsive group, ten patients were medically managed with octreotide therapy and carbohydrate-rich feeds and six patients underwent subtotal pancreatectomy. There was a high incidence of developmental delay and cerebral palsy among diazoxide-unresponsive patients.
  
  
  CONCLUSIONS
  This is the largest study to report genotype-phenotype correlations among Turkish patients with CHI. Mutations in ABCC8 and KCNJ11 are the commonest causes of CHI in Turkish patients (48.6%). There is a higher likelihood of genetic diagnosis in patients with early age of presentation, higher birth weight and from consanguineous pedigrees.
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, TurkeyDepartments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, TurkeyDepartments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Trainin
authors.forename: Huseyin
authors.initials: H
authors.lastname: Demirbilek
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, TurkeyDepartments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey.
authors.forename: Ved Bhushan
authors.initials: VB
authors.lastname: Arya
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey.
authors.forename: Mehmet Nuri
authors.initials: MN
authors.lastname: Ozbek
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey.
authors.forename: Aysehan
authors.initials: A
authors.lastname: Akinci
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey.
authors.forename: Murat
authors.initials: M
authors.lastname: Dogan
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey.
authors.forename: Fatma
authors.initials: F
authors.lastname: Demirel
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey.
authors.forename: Jayne
authors.initials: J
authors.lastname: Houghton
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey.
authors.forename: Sultan
authors.initials: S
authors.lastname: Kaba
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey.
authors.forename: Fatma
authors.initials: F
authors.lastname: Guzel
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey.
authors.forename: Riza Taner
authors.initials: RT
authors.lastname: Baran
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey.
authors.forename: Sevim
authors.initials: S
authors.lastname: Unal
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey.
authors.forename: Selahattin
authors.initials: S
authors.lastname: Tekkes
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, TurkeyDepartments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey Khalid.Hussain@ucl.ac.uk.
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
mesh_terms: D044903:Congenital Hyperinsulinism / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005808:Genes, Recessive; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D054086:KATP Channels / Q000235:genetics*; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D012189:Retrospective Studies; D064233:Sulfonylurea Receptors / Q000235:genetics*; D014421:Turkey / Q000453:epidemiology; D000099161:Kcnj11 Channel
chemical_list: D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human