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Front Genet. 2019 Apr 24;10:358. doi: 10.3389/fgene.2019.00358. eCollection 2019.

Intra-Familial Phenotypic Heterogeneity and Telomere Abnormality in von Hippel- Lindau Disease: Implications for Personalized Surveillance Plan and Pathogenesis of VHL-Associated Tumors.

Wang J1,2,3,4,5, Peng X1,2,3,6, Chen C7, Ning X1,2,3,8, Peng S1,2,3,9, Li T1,2,3,10, Liu S1,2,3,11, Hong B1,2,3, Zhou J1,2,3, Ma K1,2,3, Cai L1,2,3, Gong K1,2,3.

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Department of Urology, Peking University First Hospital, Beijing, China.
Institute of Urology, Peking University, Beijing, China.
National Urological Cancer Center, Beijing, China.
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
School of Statistics, Renmin University, Beijing, China.
Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
Department of Urology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Department of Urology, Beijing Hospital, Beijing, China.


von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The current recommendations have proposed uniform surveillance strategies for all patients, neglecting the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical methods were used to compare the onset age of patients among different generations and different birth orders. The results showed that the average onset age was 18.9 years earlier in children than in their parents, which was statistically significant in all of the four statistical methods. Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in VHL families, while it failed to explain the birth order effect. Moreover, no significant difference was observed for overall survival between parents and children (p = 0.834) and between first-born patients and the other siblings (p = 0.390). This study provides definitive evidence and possible mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines.


birth order effect; genetic anticipation; phenotypic heterogeneity; telomere length; von Hippel-Lindau disease

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