The Knudson's two-hit model and timing of somatic mutation may account for the phenotypic diversity of focal congenital hyperinsulinism

J Clin Endocrinol Metab. 2006 Oct;91(10):4118-23. doi: 10.1210/jc.2006-0397. Epub 2006 Aug 1.

Abstract

Background: Congenital hyperinsulinism (CHI) is associated with focal hyperplasia of endocrine tissue in 40-65% of patients. Focal CHI is sporadic and is caused by a germline, paternally inherited, mutation of the SUR1 (ABCC8) or KIR6.2 (KCNJ11) genes (encoding subunits of the pancreatic ATP-dependent potassium channel) together with somatic maternal haploinsufficiency for 11p15.5. Plurifocal or large forms of focal CHI are a cause of apparent failure of surgery, and their underlying mechanism has not been thoroughly investigated.

Patients: We here report two patients with bifocal CHI as evidenced by relapsing hypoglycemia after removal of the first focal lesion and the detection of a second, distinct, focal adenomatous hyperplasia during later surgery (patients 1 and 2) and a patient with a giant focal lesion involving the major part of the pancreas (patient 3).

Results: In the three patients, a germline, paternally inherited, mutation of SUR1 was found. In patients 1 and 2, haploinsufficiency for the maternal 11p15.5 region resulted from a somatic deletion specific for each of the focal lesions, as shown by the diversity of deletion break points. In patient 3, an identical somatic maternal 11p15 deletion demonstrated by similar break points was shown in two independent lesion samples, suggesting a very early event during pancreas embryogenesis.

Conclusion: Individual patients with focal hyperinsulinism may have more than one focal pancreatic lesion due to separate somatic maternal deletion of the 11p15 region. These patients and those with solitary focal lesions may follow the two-hit model described by Knudson. The stage of embryogenesis at which the somatic event occurs may account for the observed histological diversity (early event giant lesion, later event small lesion).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics*
  • Congenital Hyperinsulinism / genetics*
  • Congenital Hyperinsulinism / pathology
  • Duodenum / pathology
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Loss of Heterozygosity
  • Models, Biological
  • Mutation*
  • Pancreas / pathology
  • Phenotype
  • Potassium Channels / genetics*
  • Potassium Channels, Inwardly Rectifying / genetics*
  • Receptors, Drug / genetics*
  • Sulfonylurea Receptors
  • Time Factors

Substances

  • ABCC8 protein, human
  • ATP-Binding Cassette Transporters
  • Insulin
  • Potassium Channels
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Sulfonylurea Receptors