Bacq Yannick, Jacquemin Emmanuel, Balabaud Charles, Jeannot Emmanuelle, Scotto Beatrice, Branchereau Sophie, Laurent Christophe, Bourlier Pascal, Pariente Daniele, de Muret Anne, Fabre Monique, Bioulac-Sage Paulette, Zucman-Rossi Jessica
Department of Hepatogastroenterology, Centre Hospitalier de Tours, Hôpital Trousseau, 37044 Tours Cedex, France.
Gastroenterology. 2003 Nov;125(5):1470-5. doi: 10.1016/j.gastro.2003.07.012.
BACKGROUND & AIMS: 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.
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.
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.
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.
肝细胞核因子1α（TCF1/HNF-1α）的种系突变与青年型3型成年发病型糖尿病（MODY3）相关，并且在肝细胞腺瘤和肝腺瘤病中发现该基因的体细胞双等位基因失活。本研究调查了2个家系中HNF-1α种系突变与糖尿病和肝腺瘤病的共分离情况。
研究了2例患有肝腺瘤病且携带HNF-1α种系和体细胞突变的无关患者。随后，我们在这2个独立家系中筛查了9名亲属是否患有糖尿病、肝细胞腺瘤以及HNF-1α种系突变。
在A家系中，一名父亲及其儿子出现了肝腺瘤病的腹腔内出血破裂，但无糖尿病。在父亲及其儿子以及其27岁未患肝细胞腺瘤的次子中，均鉴定出HNF-1α的杂合R229X种系突变。在B家系中，一名14岁女孩偶然被诊断为肝腺瘤病。在该患者、其患糖尿病的父亲及其2个姐妹中，均鉴定出HNF-1α的杂合G55fsX57种系突变。系统检查发现这2个姐妹患有肝腺瘤病。在两个家系的肝肿瘤中均发现了第二个HNF-1α等位基因的体细胞失活。
本研究描述了家族性肝腺瘤病，并显示了其与成人和儿童HNF-1α种系突变的关联。它还强调了对肝腺瘤病患者亲属进行肝细胞腺瘤、糖尿病和HNF-1α种系突变筛查的重要性。最后，MODY3患者中肝腺瘤病的患病率仍有待评估。
