Mini Review

Molecular Mechanisms of Neonatal Hyperinsulinism
Irina Giurgea^a, Christine Bellanné-Chantelot^b, Maria Ribeiro^c, Laurence Hubert^d, Christine Sempoux^e, Jean-Jacques Robert^d, Oliver Blankenstein^f, Kahlid Hussain^g, Francis Brunelle^d, Claire Nihoul-Fékété^d, Jacques Rahier^e, Francis Jaubert^d, Pascale de Lonlay<sup>d

a</sup>INSERM U654 and Department of Genetics, Hôpital Henri Mondor, Créteil;
^bDepartment of Biology, Hôpital Saint-Antoine, Paris;
^cERM 0205 INSERM-CEA, Service Hospitalier Frédéric Joliot, DSV, DRM, Orsay;
^dDepartments of Pediatrics, Radiology, Surgery and Pathology, Hôpital Necker-Enfants Malades, Paris, France;
^eDepartment of Pathology, Cliniques universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium;
^fDepartments of Pediatrics, Humboldt-Universität zu Berlin, and Charité CVK OHC Kinderklinik, Berlin, Germany; and
^gDepartments of Pediatrics, Great Ormond Street Children's Hospital NHS Trust and Institute of Child Health, London, UK

Address of Corresponding Author

Horm Res 2006;66:289-296 (DOI: 10.1159/000095938)

  Key Words

• Neonatal hyperinsulinism, molecular mechanisms
• Hypoglycaemia
• Diffuse insulin hypersecretion
• Focal adenomatous hyperplasia

  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.

Copyright © 2006 S. Karger AG, Basel

  Author Contacts

Dr. Irina Giurgea
INSERM U654 and Department of Genetics, Hôpital Henri Mondor
51, avenue du mal de Lattre de Tassigny
FR-94010 Créteil Cedex (France)
Tel. +33 1 4981 6871, Fax +33 1 4981 2842, E-Mail giurgea@im3.inserm.fr

  Article Information

Published online: September 26, 2006
Number of Print Pages : 8
Number of Figures : 2, Number of Tables : 1, Number of References : 55