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.
Bacq
Yannick
Y
Department of Hepatogastroenterology, Centre Hospitalier de Tours, Hôpital Trousseau, 37044 Tours Cedex, France. bacq@med.univ-tours.fr
Jacquemin
Emmanuel
E
Balabaud
Charles
C
Jeannot
Emmanuelle
E
Scotto
Beatrice
B
Branchereau
Sophie
S
Laurent
Christophe
C
Bourlier
Pascal
P
Pariente
Daniele
D
de Muret
Anne
A
Fabre
Monique
M
Bioulac-Sage
Paulette
P
Zucman-Rossi
Jessica
J
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