title: Clinical and genetic characterization of congenital hyperinsulinism in Spain.
abstract: BACKGROUND
  Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous disease characterized by severe hypoglycemia caused by inappropriate insulin secretion by pancreatic β-cells.
  
  
  OBJECTIVE
  To characterize clinically and genetically CHI patients in Spain.
  
  
  METHODS
  We included 50 patients with CHI from Spain. Clinical information was provided by the referring clinicians. Mutational analysis was carried out for KCNJ11, ABCC8, and GCK genes. The GLUD1, HNF4A, HNF1A, UCP2, and HADH genes were sequenced depending on the clinical phenotype.
  
  
  RESULTS
  We identified the genetic etiology in 28 of the 50 CHI patients tested: 21 had a mutation in KATP channel genes (42%), three in GLUD1 (6%), and four in GCK (8%). Most mutations were found in ABCC8 (20/50). Half of these patients (10/20) were homozygous or compound heterozygous, with nine being unresponsive to diazoxide treatment. The other half had heterozygous mutations in ABCC8, six of them being unresponsive to diazoxide treatment and four being responsive to diazoxide treatment. We identified 22 different mutations in the KATP channel genes, of which ten were novel. Notably, patients with ABCC8 mutations were diagnosed earlier, with lower blood glucose levels and required higher doses of diazoxide than those without a genetic diagnosis.
  
  
  CONCLUSIONS
  Genetic analysis revealed mutations in 56% of the CHI patients. ABCC8 mutations are the most frequent cause of CHI in Spain. We found ten novel mutations in the KATP channel genes. The genetic diagnosis is more likely to be achieved in patients with onset within the first week of life and in those who fail to respond to diazoxide treatment.
authors.affiliation: Endocrinology and Diabetes Research GroupBioCruces Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Martínez
authors.affiliation: Pediatric Endocrinology SectionBasurto University Hospital, BioCruces Health Research Institute, UPV/EHU, Bilbao, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Fernández-Ramos
authors.affiliation: Pediatric Endocrinology SectionCruces University Hospital, BioCruces Health Research Institute, CIBERDEM, CIBERER, UPV/EHU, Barakaldo, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Vela
authors.affiliation: Endocrinology and Diabetes Research GroupBioCruces Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Velayos
authors.affiliation: Endocrinology and Diabetes Research GroupBioCruces Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Aguayo
authors.affiliation: Endocrinology and Diabetes Research GroupBioCruces Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Urrutia
authors.affiliation: Pediatric Endocrinology SectionCruces University Hospital, BioCruces Health Research Institute, CIBERDEM, CIBERER, UPV/EHU, Barakaldo, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Rica
authors.affiliation: Endocrinology and Diabetes Research GroupBioCruces Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain lcastano@osakidetza.net.
authors.forename: L
authors.initials: L
authors.lastname: Castaño
mesh_terms: D002675:Child, Preschool; D044903:Congenital Hyperinsulinism / Q000175:diagnosis* / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D000081410:Germinal Center Kinases; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013030:Spain; D064233:Sulfonylurea Receptors / Q000235:genetics*; D000099161:Kcnj11 Channel
chemical_list: D000081410:Germinal Center Kinases; D024661:Potassium Channels, Inwardly Rectifying; D017346:Protein Serine-Threonine Kinases; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human