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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 3 1476-1480
Copyright © 2004 by The Endocrine Society

COMMENT

Hepatocyte Nuclear Factor-1{alpha} Gene Inactivation: Cosegregation between Liver Adenomatosis and Diabetes Phenotypes in Two Maturity-Onset Diabetes of the Young (MODY)3 Families

Yves Reznik, Thong Dao, Regis Coutant, Laurence Chiche, Emmanuelle Jeannot, Severine Clauin, Pierre Rousselot, Monique Fabre, Frederic Oberti, Armelle Fatome, Jessica Zucman-Rossi and Christine Bellanne-Chantelot

Department of Endocrinology (Y.R.), Department of Hepatology (T.D, A.F.), Department of Hepatic Surgery and Transplantation (L.C.), and Laboratory of Pathology (P.R.), Centre Hospitalier Universitaire (CHU) of Caen, 14033 Caen; Department of Pediatrics (R.C.) and Department of Gastroenterology (F.O.), CHU of Angers, 49033 Angers; Institut National de la Santé et de la Recherche Médicale U434 (E.J., J.Z.-R), CEPH-Fondation Jean Dausset, 75010 Paris; Laboratory of Anatomy, Cytology, and Pathology, Bicêtre Hospital, Le Kremlin Bicêtre 94275 (M.F.); and Laboratories of Molecular Biology (S.C., C.B.-C.) and Embryology and Cytogenetics (C.B.-C.), Saint-Antoine Hospital, 75012 Paris, France

Address all correspondence and requests for reprints to: Yves Reznik, M.D., Département d’Endocrinologie, Centre Hospitalier Universitaire Côte de Nacre, 14033 Caen, France. E-mail: reznik-y{at}chu-caen.fr.

Heterozygous germline mutations of the hepatocyte nuclear factor (HNF)-1{alpha} are associated with maturity-onset diabetes of the young (MODY)3. Recently, the biallelic inactivation of the HNF-1{alpha} gene was reported in liver adenomas. We show the occurrence of liver adenomatosis in six MODY3-affected patients from two unrelated and large families. Liver adenomatosis was characterized by the presence of numerous adenomas within a normal hepatic parenchyma. The HNF-1{alpha} hot-spot germline mutation P291fs was identified in the two probands and in 16 relatives from the two families. The six patients affected by liver adenomatosis and diabetes exhibited the mutation. The analysis of liver-cell tumors from two affected patients evidenced the biallelic inactivation of HNF-1{alpha}. The familial screening confirmed the clinical heterogeneity of the liver phenotype, from silent liver adenomatosis to fatal hemorrhage. These observations warrant the systematic screening for liver adenomatosis in MODY3 families to prevent its potentially deadly complications. Moreover, such screening may help to determine if a particular mutational spectrum of HNF-1{alpha} is associated with liver adenomatosis and to establish its prevalence in this frequent form of diabetes in the young adult.

Abbreviations: MODY, Maturity-onset diabetes of the young; MRI, magnetic resonance imaging.




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