Molecular mechanisms of neonatal hyperinsulinism.
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.
Giurgea
Irina
I
INSERM U654 and Department of Genetics, Hôpital Henri Mondor, Créteil, France. giurgea@im3.inserm.fr
Bellanné-Chantelot
Christine
C
Ribeiro
Maria
M
Hubert
Laurence
L
Sempoux
Christine
C
Robert
Jean-Jacques
JJ
Blankenstein
Oliver
O
Hussain
Kahlid
K
Brunelle
Francis
F
Nihoul-Fékété
Claire
C
Rahier
Jacques
J
Jaubert
Francis
F
de Lonlay
Pascale
P
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
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