Von Hippel-Lindau disease (VHL) is associated with increased risk of developing multiple tumours in different anatomical districts caused by pathogenic variants in VHL. The aim of the study was to investigate the association between pathogenic variants and clinical phenotype in a cohort of VHL patients enrolled into a prospective observational surveillance study.
33 VHL patients enrolled in our prospective surveillance study since January 2021 were included. All patients received a comprehensive clinical evaluation. The primary outcome of the study was the rate of different anatomical sites involved, defined by at least one VHL- related primary diagnosed before enrolment or during surveillance; the secondary outcome of the study was the total number of VHL-related primaries before enrolment or during surveillance. First, we investigated the risk of any anatomical site involvement according to pathogenic variants defined as partial or complete deletion [DEL] or missense [MISS] and study outcomes. Second, multivariable logistic and linear regression models were used to test the association between pathogenic variants.
Complete data about pathogenic variants were available in 26 patients. 35% of the cases (n=9) had a DEL and 65% (n=17) had MISS. At a median age of 46 (95% CI 32 – 55), the rate of different anatomical sites involved was 0, 1, 2, 3 and 4 in 10% (n=3), 18% (n=6), 21% (n=7), 24% (n=8), and 27% (n=9). No difference was recorded between patients with DEL relative to MISS with respect to age, gender, and renal function at enrolment. Fig. 1 depicts the rate of men with MISS and DEL mutations in each anatomical site. At multivariable Poisson’s regression reanalysis accounting for age and gender, patients with MISS had higher risk of having more anatomical sites affected (estimate: 0.85; p=0.03) relative to DEL. Conversely, pathogenic variant was not associated with the total number of lesions (p=0.5).
For the first time, our study elucidates the relationship between pathogenic variants and clinical phenotype in VHL patients. Patients with MISS had a more aggressive disease with more anatomical sites affected. This information can be used to improve and individualize surveillance and treatment strategies in VHL patients.