Mikhaylenko Dmitry S, Kuryakova Natalya B, Efremova Anna V, Volodin Ilya V, Kutsev Sergey I, Zaletaev Dmitry V, Strelnikov Vladimir V
Research Centre for Medical Genetics, 115522 Moscow, Russia.
Department of Translational Medicine and Biotechnology, Sechenov University, 119991 Moscow, Russia.
Int J Mol Sci. 2025 Mar 19;26(6):2751. doi: 10.3390/ijms26062751.
von Hippel-Lindau syndrome (VHLS) is a hereditary cancer syndrome with CNS hemangioblastomas, clear cell renal carcinoma, pheochromocytoma, retinal angiomas, and a number of other manifestations. VHLS is caused by a mutation in the gene and is inherited in an autosomal dominant manner. However, some cases of VHLS develop de novo, and among them, there are rare patients with a mosaic form of the disease. Genetic testing in mosaic patients is prone to false-negative results due to the low copy number of a mutant allele in DNA isolated from the blood. We describe a case of molecular genetic diagnostics of VHLS in a 39-year-old patient using various methods, including mutation analysis in asynchronous primary tumors and repeated DNA analysis from blood using NGS with high coverage for the mutant position. As a result, the patient was diagnosed with a mosaic form of VHLS caused by the variant c.481C>T (p.Arg161Ter), the proportion of which in the blood DNA was 2%. We also summarized the literature data on the mosaic form of VHLS: the severity of clinical manifestations, the features of differential diagnostics of VHLS with a negative result of routine molecular genetic testing, and specific options of active surveillance and treatment for mutation carriers.
冯·希佩尔-林道综合征（VHLS）是一种遗传性癌症综合征，伴有中枢神经系统血管母细胞瘤、透明细胞肾细胞癌、嗜铬细胞瘤、视网膜血管瘤以及许多其他表现。VHLS由该基因的突变引起，以常染色体显性方式遗传。然而，一些VHLS病例是新发的，其中有罕见的疾病镶嵌型患者。由于从血液中分离的DNA中突变等位基因的拷贝数较低，镶嵌型患者的基因检测容易出现假阴性结果。我们描述了一例39岁患者VHLS的分子遗传学诊断病例，使用了多种方法，包括异步原发性肿瘤的突变分析以及使用对突变位点具有高覆盖度的二代测序（NGS）对血液进行重复DNA分析。结果，该患者被诊断为因c.481C>T（p.Arg161Ter）变异导致的镶嵌型VHLS，其在血液DNA中的比例为2%。我们还总结了关于VHLS镶嵌型的文献数据：临床表现的严重程度、常规分子遗传学检测结果为阴性时VHLS的鉴别诊断特征，以及突变携带者主动监测和治疗的具体方案。
