Familial liver adenomatosis associated with hepatocyte nuclear factor 1alpha inactivation.
OBJECTIVE
Germline mutations in hepatocyte nuclear factor 1alpha (TCF1/HNF-1alpha) are associated with maturity-onset diabetes of the young type 3 (MODY3), and somatic biallelic inactivations of the gene are found in hepatocellular adenomas and liver adenomatosis. This study investigated cosegregation of HNF-1alpha germline mutations with diabetes and liver adenomatosis in 2 families.


METHODS
Two unrelated patients with liver adenomatosis and harboring HNF-1alpha germline and somatic mutations were studied. Subsequently, we screened 9 relatives in the 2 independent families for diabetes, hepatocellular adenomas, and HNF-1alpha germline mutations.


RESULTS
In family A, a father and his son presented with an intraperitoneal hemorrhagic rupture of a liver adenomatosis without diabetes. A heterozygous R229X germline mutation was identified in HNF-1alpha in the father and his son and also in his second 27-year-old son without hepatocellular adenomas. In family B, a diagnosis of liver adenomatosis was made fortuitously in a 14-year-old girl. A heterozygous G55fsX57 germline mutation in HNF-1alpha was identified in this patient, her diabetic father, and her 2 sisters. Systematic exploration showed liver adenomatosis in the 2 sisters. Somatic inactivation of the second HNF-1alpha allele was found in liver tumors in both families.


CONCLUSIONS
This study describes familial liver adenomatosis and shows the association with germline HNF-1alpha mutations in adults and children. It also highlights the importance of screening for hepatocellular adenomas, diabetes, and HNF-1alpha germline mutations in relatives of patients with liver adenomatosis. Finally, prevalence of liver adenomatosis remains to be evaluated in MODY3 subjects.
Department of Hepatogastroenterology, Centre Hospitalier de Tours, Hôpital Trousseau, 37044 Tours Cedex, France. bacq@med.univ-tours.fr
Yannick
Y
Bacq
Emmanuel
E
Jacquemin
Charles
C
Balabaud
Emmanuelle
E
Jeannot
Beatrice
B
Scotto
Sophie
S
Branchereau
Christophe
C
Laurent
Pascal
P
Bourlier
Daniele
D
Pariente
Anne
A
de Muret
Monique
M
Fabre
Paulette
P
Bioulac-Sage
Jessica
J
Zucman-Rossi
D000236:Adenoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D004268:DNA-Binding Proteins; D005260:Female; D020868:Gene Silencing; D018095:Germ-Line Mutation; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006579:Heterozygote; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta