Abstract
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.
Highlights
Heterogeneity and Telomere Abnormality in von Hippel- Lindau Disease: Implications for Personalized Surveillance Plan and Pathogenesis of von Hippel-Lindau (VHL)-Associated Tumors
PVHL has been found to act as a component of the ataxia telangiectasia mutated (ATM) dependent DNA-damage response (DDR) network, inactivation of which contributes to the genomic instability associated with sporadic renal cell carcinoma (RCC) (Metcalf et al, 2014)
Studies on the average onset ages of VHL-related tumors have helped the VHL Alliance to propose the VHL tumor surveillance regimen for the last decades, according to which routine imaging screening should start at 1 year old for retinal hemangioblastomas (RA), 8 for PHEO, 16 for central nervous system hemangioblastomas (CHB), and 8 for RCC and pancreatic cyst and neuroendocrine tumors (PCT) (VHL Alliance, 2015)
Summary
Heterogeneity and Telomere Abnormality in von Hippel- Lindau Disease: Implications for Personalized Surveillance Plan and Pathogenesis of VHL-Associated Tumors. Von Hippel-Lindau (VHL) disease (MIM 193300) is a rare autosomal dominant cancer syndrome caused by germline mutations in the VHL tumor suppressor gene (Latif et al, 1993; Lonser et al, 2003). Patients with consanguinity may develop tumors at different age even in the same family with the same genotype, implying that intra-familial phenotypic heterogeneity may be an important part in the complexity of VHL disease. Genetic anticipation (GA) is one of the most common intra-familial phenotypic varieties for hereditary diseases, in which case the generations are affected at an earlier age or manifest more serious presentations than their parents. Further study on intra-familial phenotypic heterogeneity and the underlying mechanism is needed for better understanding of the disease
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