Molecular Mechanisms and Clinical Pathophysiologies of Focal ATP-Sensitive Potassium Channel Hyperinsulinism and Beckwith-Wiedemann Syndrome [chapter]

Jean-Baptiste Arnoux, Virginie Verkarre, Sylvie Rossignol, Yves Aigrain, Pascale de Lonlay
2012 Monogenic Hyperinsulinemic Hypoglycemia Disorders  
One of the major advances in the care of patients with congenital hyperinsulinism was the discovery of focal adenomatous hyperplasia since patients can be definitively cured after a limited pancreatectomy. The histological features include hyperplasia and an increased beta-cell mass within the focal lesion. These findings were already reported in the pancreas of patients with Beckwith-Wiedemann syndrome (BWS), a condition which is known to be associated with hyperinsulinism. However, the
more » ... However, the pathophysiology of focal hyperinsulinism (FoHI) is more complex and includes a 'two hits' mechanism: (1) a paternally inherited mutation of an ATP-sensitive potassium (K ATP ) channel gene located on the 11p15 chromosome; and (2) in a pancreatic endocrine progenitor, a deletion of the maternally inherited 11p15 chromosomal region, compensated by a paternal uniparental disomy as observed in some cases of BWS. The loss of heterozygosity in the imprinted 11p15.5 region bearing genes involved in tumor suppression and cell proliferation explains the histopathological findings of FoHI, while the paternally inherited K ATP channel mutation reduced to homozygosity within the beta-cells of the focal lesion causes hyperinsulinemic hypoglycemia unresponsive to diazoxide.
doi:10.1159/000334492 fatcat:6j3ahnddm5dzbpizmsl6xhkbva