Congenital hyperinsulinism, or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is a glucose metabolism disorder characterized by unregulated secretion of insulin and profound hypoglycemia. From a morphological standpoint, there are two types of histopathological lesions, a focal adenomatous hyperplasia of islet cells of the pancreas in approximately 30% of operated sporadic cases, and a diffuse form. In sporadic focal forms, specific losses of maternal alleles (LOH) of the imprinted chromosomal region 11p15, restricted to the hyperplastic area of the pancreas, were observed. Similar mechanisms are observed in embryonal tumors and in the Beckwith-Wiedemann syndrome (BWS), also associated with neonatal but transient hyperinsulinism. However, this region also contains the sulfonylurea receptor (SUR1) gene and the inward rectifying potassium channel subunit (KIR6.2) gene, involved in recessive familial forms of PHHI, but not known to be imprinted. Although the parental bias in loss of maternal alleles did not argue in favor of their direct involvement, the LOH may also unmask a recessive mutation leading to persistent hyperinsulinism. We now report somatic reduction to hemizygosity or homozygosity of a paternal SUR1 constitutional heterozygous mutation in four patients with a focal form of PHHI. Thus, this somatic event which leads both to beta cell proliferation and to hyperinsulinism can be considered as the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation leading to a somatic recessive disorder.
V Verkarre, J C Fournet, P de Lonlay, M S Gross-Morand, M Devillers, J Rahier, F Brunelle, J J Robert, C Nihoul-Fékété, J M Saudubray, C Junien
Title and authors | Publication | Year |
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Advances in the diagnosis and management of hyperinsulinemic hypoglycemia
RR Kapoor, C James, K Hussain |
Nature clinical practice. Endocrinology & metabolism | 2009 |
Persistent hypoglycemia in a child with a gastrocolic fistula—an unexpected presentation of leucine-sensitive hypoglycemia
DD Lee, EF Hollinger, AW Kim, MJ Holterman |
Journal of Pediatric Surgery | 2009 |
Update of mutations in the genes encoding the pancreatic beta-cell KATPchannel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism
SE Flanagan, S Clauin, C Bellann��-Chantelot, P Lonlay, LW Harries, AL Gloyn, S Ellard |
Human Mutation | 2009 |
The spectrum ofABCC8mutations in Norwegian patients with congenital hyperinsulinism of infancy
T Sandal, LB Laborie, K Brusgaard, SÅ Eide, HB Christesen, O Søvik, PR Njølstad, A Molven |
Clinical Genetics | 2009 |
Hyperinsulinismus bei Säuglingen und Kindern: wenn ein Insulinspiegel nicht immer ausreicht / Hyperinsulinism in infancy and childhood: when an insulin level is not always enough1)
AA Palladino, MJ Bennett, CA Stanley |
LaboratoriumsMedizin | 2009 |