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Chromosome 11p15 Paternal Isodisomy in Focal Forms of Neonatal Hyperinsulinism

Department of Pathology (L.D., V.V., C.W., F.J.), Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris, Service d’Anatomie Pathologique and Tumorotheque, Departments of Genetics (M.l.L., S.P.R.) and Surgery (C.N.-F., Y.A.), Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris, and Centre de Référence des Maladies Métaboliques (L.H., Y.d.K., P.d.L.), Institut National de la Santé et de la Recherche Médicale U-781, Hôpital Necker-Enfants Malades, 75015 Paris, France (Assistance Publique-Hôpitaux de Paris, Université Paris 5 René Descartes); Department of Genetics (C.B.-C.), Groupe hospitalier Pitié-Salpétrière, 75651 Paris, France; and Department of Pediatrics (L.D.), Rennes Teaching Hospital, 35043 Rennes, France

Address all correspondence and requests for reprints to: Professor F. Jaubert, Department of Pathology, Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris, Service d’Anatomie Pathologique and Tumorotheque, 149 rue de Sèvres, 75015 Paris, France. E-mail: francis.jaubert{at}nck.aphp.fr.

Context: Focal forms of congenital hyperinsulinism are due to a constitutional heterozygous mutation of paternal origin in the ABCC8 gene, more often than the KCNJ11 gene, located in the 11p15.1 region. This mutation is associated with the loss of the maternally inherited 11p15.1 to 11p15.5 region in the lesion. We investigated the possible occurrence of a compensatory duplication of the paternal 11p15.1-11p15.5 region.

Materials and Methods: A combined immunohistochemistry and fluorescent in situ hybridization study on β-cell interphase nuclei with probes covering two genes located in this region (ABCC8 and CDKN1C genes) was performed in four cases of focal forms of hyperinsulinism.

Results: β-Cells in the lesions of four cases of focal congenital hyperinsulinism were diploid for chromosomes 11 and 13. The 11p15.1 to 11p15.2 and 11p15.4 to 11p15.5 regions containing ABCC8 and CDKN1C genes, respectively, were present with two copies. Loss of the maternal allele was confirmed in these focal lesions with microsatellite markers flanking the ABCC8 and CDKN1C genes, whereas a heterozygous mutation in the ABCC8 gene was inherited from the father.

Conclusions: There is a duplication of the paternal allele on chromosome 11 in the focal forms of hyperinsulinism lesion. The paternal isodisomy observed rendered the β-cells homozygous for ABCC8 mutation and harbored a K-channel defect in the lesion similar to that observed in diffuse forms of congenital hyperinsulinism.

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