title: Molecular mechanisms of neonatal hyperinsulinism.
abstract: Congenital hyperinsulinism (CHI), characterized by profound hypoglycaemia related to inappropriate insulin secretion, may be associated histologically with either diffuse insulin hypersecretion or focal adenomatous hyperplasia, which share a similar clinical presentation, but result from different molecular mechanisms. Whereas diffuse CHI is of autosomal recessive, or less frequently of autosomal dominant, inheritance, focal CHI is sporadic. The most common mechanism underlying CHI is dysfunction of the pancreatic ATP-sensitive potassium channel (K(+)(ATP)). The two subunits of the K(+)(ATP) channel are encoded by the sulfonylurea receptor gene (SUR1 or ABCC8) and the inward-rectifying potassium channel gene (KIR6.2 or KCNJ11), both located in the 11p15.1 region. Germ-line, paternally inherited, mutations of the SUR1 or KIR6.2 genes, together with somatic maternal haplo-insufficiency for 11p15.5, were shown to result in focal CHI. Diffuse CHI results from germ-line mutations in the SUR1 or KIR6.2 genes, but also from mutations in several other genes, namely glutamate dehydrogenase (with associated hyperammonaemia), glucokinase, short-chain L-3-hydroxyacyl-CoA dehydrogenase, and insulin receptor gene. Hyperinsulinaemic hypoglycaemia may be observed in several overlapping syndromes, such as Beckwith-Wiedemann syndrome (BWS), Perlman syndrome, and, more rarely, Sotos syndrome. Mosaic genome-wide paternal isodisomy has recently been reported in patients with clinical signs of BWS and CHI. The primary causes of CHI are genetically heterogeneous and have not yet been completely unveiled. However, secondary causes of hyperinsulinism have to be considered such as fatty acid oxidation deficiency, congenital disorders of glycosylation and factitious hypoglycaemia secondary to Munchausen by proxy syndrome.
authors.affiliation: INSERM U654 and Department of Genetics, Hôpital Henri Mondor, Créteil, France. giurgea@im3.inserm.fr
authors.forename: Irina
authors.initials: I
authors.lastname: Giurgea
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: Christine
authors.initials: C
authors.lastname: Sempoux
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Robert
authors.forename: Oliver
authors.initials: O
authors.lastname: Blankenstein
authors.forename: Kahlid
authors.initials: K
authors.lastname: Hussain
authors.forename: Francis
authors.initials: F
authors.lastname: Brunelle
authors.forename: Claire
authors.initials: C
authors.lastname: Nihoul-Fékété
authors.forename: Jacques
authors.initials: J
authors.lastname: Rahier
authors.forename: Francis
authors.initials: F
authors.lastname: Jaubert
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D044903:Congenital Hyperinsulinism / Q000235:genetics* / Q000503:physiopathology; D005799:Genes, Dominant; D005808:Genes, Recessive; D005969:Glutamate Dehydrogenase / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D019656:Loss of Heterozygosity; D015221:Potassium Channels / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D011955:Receptors, Drug / Q000235:genetics; D064233:Sulfonylurea Receptors; D013577:Syndrome; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D005969:Glutamate Dehydrogenase; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human