Loss of imprinted genes and paternal SUR1 mutations lead to hyperinsulinism in focal adenomatous hyperplasia.

Two types of histopathological lesions, a focal adenomatous hyperplasia of islet cells of the pancreas in about 30% of operated sporadic cases, and a diffuse form can be observed in congenital hyperinsulinism, or Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI). 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 which is 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. We now report somatic reduction to hemizygosity or homozygosity of a paternal SUR1 constitutional heterozygous mutation, in five patients with a focal form of PHHI. Thus this somatic event (LOH) which leads both to b 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.