OBJECTIVE: In this study, our aim was to search for new genotype-phenotype correlations in patients with Von Hippel-Lindau (VHL) disease. SUBJECTS AND METHODS: We retrospectively studied 53 consecutive patients with VHL disease and confirmed genetic diagnoses from 32 relatives. RESULTS: Most VHL pathogenic or likely pathogenic variants were missense (18 out of 32
56.25%). The median size of the large carcinoma (RCC) was 3.6 cm (interquartile range, 2.8 to 6.5 cm). Interestingly, the size of the large RCC in patients harboring VHL pathogenic variants (n = 9) was significantly greater than that in patients with VHL likely pathogenic (n = 7) variants (5.4 cm [3.65 to 6.6] vs. 2.9 cm [2.45 to 3.35]
p = 0.008). Moreover, adrenal paraganglioma (PGL) (82.35% vs. 17.65%
p = 0.0001) and pancreatic neuroendocrine tumor (PNET) (81.81% vs. 18.18%
p = 0.007) were associated with missense VHL pathogenic or likely pathogenic variants compared with non-missense defects. In contrast, central nervous system (CNS) hemangioblastomas (HBs) (90.47% vs. 53.12%
p = 0.004), pancreatic cysts (76.19% vs. 28.12%
p = 0.001) and RCCs (57.14% vs. 12.5
p = 0.001) were more common in patients with non-missense VHL variants. CONCLUSION: VHL pathogenic variants were associated with larger RCCs than were VHL likely pathogenic variants.