von Hippel-Lindau disease: Diagnosis and factors influencing disease outcome.

von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition caused by mutations in the VHL tumor suppressor gene. VHL mutation-carriers are at life-long risk of multi-organ tumor development. The mainstay of vHL management is close surveillance and surgical tumor removal. The disease has been reported to be fully penetrant at 60 years of age, and has a highly variable phenotype, which complicates vHL management and causes distress and uncertainty for affected families. vHL survival has historically been poorer than the survival of the general population, with a median life expectancy for vHL patients of only 49 years. vHL life expectancy is expected to be improved by better surveillance, tumor diagnosis, and treatment approaches, although this has not
yet been directly demonstrated. The prevalence of vHL is between 1 in 39,000 and 1 in 91,000 individuals, and the birth incidence is between 1 in 36,000 and 1 in 45,500 live births in different populations. Based on these estimates, vHL is underdiagnosed in Denmark, and many undiagnosed families are not offered genetic counseling or prophylactic surveillance.
We aimed to assess 1) how the rate of new manifestation development is influenced by age, sex, genotype, tumor location, and pregnancy, 2) how vHL survival has developed over time, and is affected by sex, genotype, and surveillance attendance, 3) to determine the prevalence and incidence of vHL, and 4) to calculate vHL penetrance based on an unselected national cohort. 
We included almost all diagnosed vHL patients in Denmark in a retrospective cohort study. We further used the national health registers to find individuals who had a missed vHL diagnosis despite fulfilling the clinical diagnostic criteria.
We found that the risk of new vHL manifestations varies with age, genotype, and tumor location. The risk of new retinal tumors is highest in the patients' teenage years, while cerebellar tumors developed at the highest rates in patients' thirties. Patients with truncating mutations had higher rates of new manifestation diagnosis than patients with missense mutations. Men tend to have higher manifestation rates in adulthood compared to women, and pregnancy was associated with a lower frequency of new manifestations. vHL survival has improved over time, and is getting closer to that of their siblings without vHL and the general population. Survival is significantly influenced by a patient's birth year, sex, and genotype. We estimate the mean life expectancy of VHL mutation-carriers born in 2000 to be 67 years for men and 60 years for women. We estimate the vHL prevalence to be about 1 in 46,900 individuals and the birth incidence to be about 1 in 27,300 live births. We found a penetrance at age 60 of 87%, and only 80% among pa-tients who have not attended surveillance prior to diagnosis, which is considerably lower than previous estimates. 
Our findings form the basis of a more targeted vHL surveillance and counseling. The lower age-related penetrance greatly influences risk assessment in a clinical genetic setting. Even though the prevalence has increased over recent years, vHL is still underdiagnosed, and there is a need for increased awareness about the disease.