title: The focal form of persistent hyperinsulinemic hypoglycemia of infancy: morphological and molecular studies show structural and functional differences with insulinoma.
abstract: Paternal mutation of ATP-sensitive K(+) (K(ATP)) channel genes and loss of heterozygosity (LOH) of the 11p15 region including the maternal alleles of ABCC8, IGF2, and CDKN1C characterize the focal form of persistent hyperinsulinemic hypoglycemia of infancy (FoPHHI). We aimed to understand the actual nature of FoPHHI in comparison with insulinoma. In FoPHHI, the lesion consists in clusters of beta-cells surrounded by non-beta-cells. Compared with adjacent islets, proinsulin mRNA is similar and proinsulin production higher (P < or = 0.02), indicating regulation at a translational level, with slightly lower insulin stock and lower ABCC8 peptide labeling (P<0.05). Insulinomas, composed of beta-cell nests or cords, have similar proinsulin mRNA compared with adjacent islets, highly variable proinsulin production, lower insulin stock (P < or = 0.02), and higher ABCC8 peptide labeling (P<0.05). Proinsulin mRNA is lower than in FoPHHI (P<0.001). Islets adjacent to FoPHHI appear to be resting, in contrast to those adjacent to insulinomas, evidencing intrapancreatic regulation of islet beta-cell activity. IGF2 peptide is present inside and outside both lesions, but IGF2 mRNA is restricted to the lesions. The 11p15 LOH and absence of CDKN1C peptide staining are demonstrated in all FoPHHI but also in three of eight insulinomas. Despite some molecular similarities, FoPHHI is thus fundamentally different from insulinoma.
authors.affiliation: Department of Pathology (ANPS 1712), Cliniques Universitaires St-Luc, University Hospital, U.C.L. Avenue Hippocrate 10, B-1200 Brussels, Belgium. christine.sempoux@anps.ucl.ac.be
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.forename: Yves
authors.initials: Y
authors.lastname: Guiot
authors.forename: Karin
authors.initials: K
authors.lastname: Dahan
authors.forename: Pierre
authors.initials: P
authors.lastname: Moulin
authors.forename: Martine
authors.initials: M
authors.lastname: Stevens
authors.forename: Virginie
authors.initials: V
authors.lastname: Lambot
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Fournet
authors.forename: Claudine
authors.initials: C
authors.lastname: Junien
authors.forename: Francis
authors.initials: F
authors.lastname: Jaubert
authors.forename: Claire
authors.initials: C
authors.lastname: Nihoul-Fekete
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saudubray
authors.forename: Jacques
authors.initials: J
authors.lastname: Rahier
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002648:Child; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D050761:Cyclin-Dependent Kinase Inhibitor p57; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications* / Q000235:genetics / Q000473:pathology; D007003:Hypoglycemia / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007223:Infant; D007328:Insulin / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000032:analysis / Q000235:genetics; D007340:Insulinoma / Q000235:genetics / Q000473:pathology; D007515:Islets of Langerhans / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology; D015221:Potassium Channels / Q000032:analysis / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying; D011384:Proinsulin / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011955:Receptors, Drug / Q000032:analysis / Q000235:genetics; D064233:Sulfonylurea Receptors
chemical_list: D018528:ATP-Binding Cassette Transporters; C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D007328:Insulin; D009687:Nuclear Proteins; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D007335:Insulin-Like Growth Factor II; D011384:Proinsulin