Von Hippel-Lindau (VHL) disease is an autosomal dominant rare tumor syndrome characterized by high penetrance. VHL mutation carriers develop numerous manifestations in multiple organs during life. The natural course of development of new and growth of existing VHL-related manifestations is still unclear. In this study we aimed to gain insight into the development of subsequent manifestations in VHL disease. We retrospectively scored each new VHL-related manifestation as detected by standard follow-up (retina, central nervous system, kidneys and pancreas, excluding adrenal and endolymfatic sac manifestations) in 75 VHL mutation carriers. The Kaplan–Meier method was used to plot the cumulative proportions of all consecutive manifestations in each organ against age. The cumulative average number of manifestations in all organs during life was calculated by summating these cumulative proportions. Poisson model parameters were used to calculate average time to the detection of consecutive VHL manifestations in each organ. Consecutive VHL-related kidney and retina manifestations during life occur linearly according to Poisson distribution model. The total number of VHL manifestations rises linearly, with an average of seven VHL-related lesions at age 60 years. The incidence of consecutive VHL-related manifestations is constant during life in VHL mutation carriers. Our data is consistent with the notion that somatic inactivation of the remaining allele (Knudson’s “two-hit” hypothesis) is the determining factor in developing new VHL-related manifestations.

中文翻译：

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Von Hippel-Lindau疾病连续表现的发生率。

冯·希佩尔·林道（VHL）疾病是一种常染色体显性遗传性罕见肿瘤综合征，其特征是高外显率。VHL突变携带者在一生中会在多个器官中形成多种表现。新型和现有VHL相关表现的自然发展过程仍不清楚。在这项研究中，我们旨在深入了解VHL疾病后续表现的发展。我们回顾性地对75例VHL中通过标准随访（视网膜，中枢神经系统，肾脏和胰腺，不包括肾上腺和淋巴结囊肿表现）检测到的每个新的VHL相关表现评分。突变携带者。Kaplan-Meier方法用于绘制每个器官中所有连续表现的累积比例与年龄的关系。通过累加这些累积比例来计算生命中所有器官的累积平均表现数。泊松模型参数用于计算检测每个器官中连续VHL表现的平均时间。根据Poisson分布模型，生命中连续的VHL相关的肾脏和视网膜表现线性发生。VHL表现的总数呈线性增加，在60岁时平均有7个VHL相关病变。连续性VHL相关表现的发生率在VHL的一生中是恒定的突变携带者。我们的数据与剩余等位基因的体细胞失活（努德森的“两次打击”假设）是发展新的VHL相关表现的决定性因素的观点相一致。