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The Knudson’s Two-Hit Model and Timing of Somatic Mutation May Account for the Phenotypic Diversity of Focal Congenital Hyperinsulinism

Institut National de la Santé et de la Recherche Médicale U654 and Department of Genetics (I.G.), Hôpital Henri Mondor, 94010 Creteil, France; Department of Pathology (C.S., J.R.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, B-1348 Brussels, Belgium; Department of Biology (C.B.-C.), Hôpital Saint-Antoine, 75012 Paris, France; Service Hospitalier Frédéric Joliot (M.R.), Commissariat a l’Energie Atomique, Direction des Sciences du Vivant, Departement de Recherche Médicale, 75270 Orsay, France; and Departments of Pediatrics, Radiology, and Surgery (L.H., N.B., J.-M.S., J.-J.R., F.B., F.J., C.N.-F., P.d.L.), Hôpital Necker-Enfants Malades, 75270 Paris, France

Address all correspondence and requests for reprints to: Dr. Irina Giurgea, Department of Genetics, Hôpital Henri Mondor, Créteil, 51, Avenue du Mal de Lattre de Tassigny, 94010 Creteil Cedex, France. E-mail: irina.giurgea{at}im3.inserm.fr.

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).

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