Genotype-phenotype associations in Von-Hippel Lindau Syndrome: implications for screening

Abstract Background Von Hippel-Lindau (VHL) is an autosomal dominant genetic disease with an estimated incidence of 1:36,000. The type of germline VHLI alteration has been shown to impact downstream VHL expression and clinical phenotype. However, current screening practices do not differ based on VHL genomic subtype. We aim to assess genotype-phenotype association among an institutional cohort of VHL patients. Methods We conducted a retrospective cohort study of 69 patients (27 families) at the University of Utah and Huntsman Cancer Institute from 1998- December 2023. 41 patients had documented germline testing in our system to define VHL type. VHL Type 1 was defined as those with nonsense mutations, deletions, and duplications and Type 2 as those with missense and splice mutations. Mean follow-up was 86- and 59-months for VHL type 1 and 2 respectively. We then evaluated the association of VHL type with risk of pheochromocytoma (Pheo), renal cancer (RCC), and hemangioblastoma (HB). Results We identified 24 unique VHL alterations among 41 patients. 83% (29/41) patients had missense mutations, 7.5% (3/41) had nonsense mutations, 17% (6/41) had splice mutations, and 3% (3/41) had a deletion. The median age at VHL diagnosis was 43 years old for type 1 (range 19-76) and 38 for VHL type 2 (range 4-67). VHL Type 2 was more common, 85% (35/41). All VHL Type 1 patients (6/6) developed RCC and HB. No patients with VHL Type 1 developed PheoPara. Of the 35 patients diagnosed with VHL Type 2, 20% (7/35) were diagnosed with PheoPara, 9% (3/35) with RCC, 31% (n = 11) with HB, and 37% (n = 13) were asymptomatic. No VHL Type 1 patients were asymptomatic. Conclusions VHL type 2 comprised the majority of VHL diagnoses in our cohort. Individuals diagnosed with VHL type 2 have the highest penetrance for: hemangioblastoma (hb), Pheo-Para, and renal cell carcinoma (RCC). In our study, 37% of VHL type 2 participants did not demonstrate any VHL manifestation. VHL type 1 had a high prevalence for RCC and HB, with a notable absence of PheoPara manifestation. However, majority of these patients (75%) were below the age of 20, and thus likely did not develop a manifestation yet. This cohort add to evidence supporting utilizing genetic VHL Types to personalize surveillance guidelines. Validation in larger cohorts with longer follow-up suggest that VHL type 1 patients could forgo pheo/para screening.