Oldfield Leslie E, Grzybowski Jessica, Grenier Sylvie, Chao Elizabeth, Downs Gregory S, Farncombe Kirsten M, Stockley Tracy L, Mete Ozgur, Kim Raymond H
Princess Margaret Cancer Centre, Toronto, ON, Canada.
Ambry Genetics, Aliso Viejo, CA, USA.
NPJ Genom Med. 2022 Mar 18;7(1):21. doi: 10.1038/s41525-022-00291-3.
Von Hippel-Lindau disease (VHL) is an autosomal dominant, inherited syndrome with variants in the VHL gene causing predisposition to multi-organ benign and malignant neoplasms. A germline VHL variant is identified in 95-100% of individuals with a clinical diagnosis of VHL. Here, we present the case of an individual with a clinical diagnosis of VHL disease where peripheral blood DNA analysis did not detect a VHL variant. Sequencing of four tumor tissues (ccRCC, pheochromocytoma, lung via sputum, liver) revealed a VHL c.593 T > C (p.Leu198Pro) variant at varying allele fractions (range: 10-55%) in all tissues. Re-examination of the peripheral blood sequencing data identified this variant at 6% allele fraction. Tumor analysis revealed characteristic cytomorphological, immunohistochemical reactivity for alpha-inhibin, and CAIX, and reduced pVHL reactivity supported VHL-related pseudohypoxia. This report of a rare case of VHL mosaicism highlights the value of tissue testing in VHL variant negative cases.
冯·希佩尔-林道病（VHL）是一种常染色体显性遗传性综合征，VHL基因的变异会导致多器官发生良性和恶性肿瘤的易感性。在临床诊断为VHL的患者中，95%-100%可检测到种系VHL变异。在此，我们报告一例临床诊断为VHL病的患者，其外周血DNA分析未检测到VHL变异。对四个肿瘤组织（肾透明细胞癌、嗜铬细胞瘤、痰液来源的肺组织、肝脏）进行测序，结果显示所有组织中均存在VHL基因c.593 T > C（p.Leu198Pro）变异，等位基因比例各不相同（范围：10%-55%）。重新检查外周血测序数据时，发现该变异的等位基因比例为6%。肿瘤分析显示出特征性的细胞形态学、α-抑制素和碳酸酐酶IX（CAIX）的免疫组化反应性，以及降低的磷酸化VHL反应性，支持VHL相关的假性缺氧。本报告介绍了一例罕见的VHL嵌合体病例，突出了在VHL变异阴性病例中进行组织检测的价值。
