title: The Knudson's two-hit model and timing of somatic mutation may account for the phenotypic diversity of focal congenital hyperinsulinism.
abstract: BACKGROUND
  Congenital hyperinsulinism (CHI) is associated with focal hyperplasia of endocrine tissue in 40-65% of patients. Focal CHI is sporadic and is caused by a germline, paternally inherited, mutation of the SUR1 (ABCC8) or KIR6.2 (KCNJ11) genes (encoding subunits of the pancreatic ATP-dependent potassium channel) together with somatic maternal haploinsufficiency for 11p15.5. Plurifocal or large forms of focal CHI are a cause of apparent failure of surgery, and their underlying mechanism has not been thoroughly investigated.
  
  
  METHODS
  We here report two patients with bifocal CHI as evidenced by relapsing hypoglycemia after removal of the first focal lesion and the detection of a second, distinct, focal adenomatous hyperplasia during later surgery (patients 1 and 2) and a patient with a giant focal lesion involving the major part of the pancreas (patient 3).
  
  
  RESULTS
  In the three patients, a germline, paternally inherited, mutation of SUR1 was found. In patients 1 and 2, haploinsufficiency for the maternal 11p15.5 region resulted from a somatic deletion specific for each of the focal lesions, as shown by the diversity of deletion break points. In patient 3, an identical somatic maternal 11p15 deletion demonstrated by similar break points was shown in two independent lesion samples, suggesting a very early event during pancreas embryogenesis.
  
  
  CONCLUSIONS
  Individual patients with focal hyperinsulinism may have more than one focal pancreatic lesion due to separate somatic maternal deletion of the 11p15 region. These patients and those with solitary focal lesions may follow the two-hit model described by Knudson. The stage of embryogenesis at which the somatic event occurs may account for the observed histological diversity (early event giant lesion, later event small lesion).
authors.affiliation: INSERM U654, and Department of Genetics, Hôpital Henri Mondor, 51 Avenue du Marechal de Lattre de Tassigny, 94010 Creteil Cedex, France. irina.giurgea@im3.inserm.fr
authors.forename: Irina
authors.initials: I
authors.lastname: Giurgea
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: Maria
authors.initials: M
authors.lastname: Ribeiro
authors.forename: Laurence
authors.initials: L
authors.lastname: Hubert
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saudubray
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Robert
authors.forename: Francis
authors.initials: F
authors.lastname: Brunelle
authors.forename: Jacques
authors.initials: J
authors.lastname: Rahier
authors.forename: Francis
authors.initials: F
authors.lastname: Jaubert
authors.forename: Claire
authors.initials: C
authors.lastname: Nihoul-Fékété
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D044903:Congenital Hyperinsulinism / Q000235:genetics* / Q000473:pathology; D004386:Duodenum / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D019656:Loss of Heterozygosity; D008954:Models, Biological; D009154:Mutation; D010179:Pancreas / Q000473:pathology; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors; D013997:Time Factors
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors