PATERNAL MUTATION OF THE SULFONYLUREA RECEPTOR (SUR1) GENE AND MATERNAL LOSS OF 11P15 IMPRINTED GENES LEAD TO PERSISTENT HYPERINSULINISM INFOCAL ADENOMATOUS HYPERPLASIA

Congenital hyperinsulinism, or persistent hyperinsulinemic hypoglycemi a of infancy (PHHI), is a glucose metabolism disorder characterized by unregulated secretion of insulin and profound hypoglycemia. From a mo rphological standpoint, there are two types of histopathological lesio ns, a focal adenomatous hyperplasia of islet cells of the pancreas in similar to 30% of operated sporadic cases, and a diffuse form. In spor adic focal forms, specific losses of maternal alleles (LOH) of the imp rinted chromosomal region 11p15, restricted to the hyperplastic area o f the pancreas, were observed, Similar mechanisms are observed in embr yonal tumors and in the Beckwith-Wiedemann syndrome (BWS), also associ ated with neonatal but transient hyperinsulinism. However, this region also contains the sulfonylurea receptor (SUR1) gene and the inward re ctifying potassium channel subunit (KIR6.2) gene, involved in recessiv e 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 th eir direct involvement, the LOH may also unmask a recessive mutation l eading to persistent hyperinsulinism. We now report somatic reduction to hemizygosity or homozygosity of a paternal SUR1 constitutional hete rozygous mutation in four patients with a focal form of PHHI. Thus, th is somatic event which leads both to beta cell proliferation and to hy perinsulinism can be considered as the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy as sociated with unmasking of a heterozygous parental mutation leading to a somatic recessive disorder.