Familial liver adenomatosis associated with hepatocyte nuclear factor 1α inactivation
Familial liver adenomatosis associated with hepatocyte nuclear factor 1α inactivation
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DOI：
10.1016/j.gastro.2003.07.012
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发表时间：
2003-11-01
期刊：
影响因子：
29.4
通讯作者：
Zucman-Rossi, J
中科院分区：
文献类型：
--
作者：
Bacq, Y;Jacquemin, E;Zucman-Rossi, J
背景和目标：肝细胞核因子1 α（TCF 1/HNF-1 α）的种系突变与青年3型成熟型糖尿病（MODY 3）相关，该基因的体细胞双等位基因失活见于肝细胞腺瘤和肝腺瘤病。本研究调查了2个家族中HNF-1 α生殖系突变与糖尿病和肝腺瘤病的共分离。方法：两个无关的肝腺瘤病和窝藏HNF-1 α胚系和体细胞突变的患者进行了研究。随后，我们对2个独立家族的9名亲属进行了糖尿病、肝细胞腺瘤和HNF-1 α种系突变的筛查。结果：在家庭A，父亲和他的儿子提出了腹腔出血破裂的肝腺瘤病没有糖尿病。在父亲和他的儿子以及他的第二个27岁的没有肝细胞腺瘤的儿子的HNF-1 α中鉴定出杂合R229 X种系突变。在家庭B中，一个14岁的女孩偶然被诊断为肝腺瘤病。HNF-1 α基因的G55 fsX 57杂合子突变在这位患者、她的糖尿病父亲和她的两个姐妹篇中被发现。系统探查显示2姐妹篇均为肝腺瘤病。第二个HNF-1 α等位基因的体细胞失活在两个家族的肝肿瘤中被发现。结论：本研究描述了家族性肝腺瘤病，并显示了成人和儿童的生殖系HNF-1 α突变。它还强调了在肝腺瘤病患者亲属中筛查肝细胞腺瘤、糖尿病和HNF-1 α种系突变的重要性。最后，MODY 3受试者中肝腺瘤病的患病率仍有待评估。
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. 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 germ line 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.