Abstract
Von Hippel-Lindau (VHL) disease is an autosomal, dominant inherited tumour syndrome. The disease is named after the German ophthalmologist Eugen
von Hippel, who described retinal haemangioblastoma in 1904, and the Swedish pathologist Arvid Lindau who associated
retinal and CNS haemangioblastoma with cysts of the kidneys, pancreas
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and epididymis in 1926. The estimated prevalence of
the disease varies between 1:31,000 and 1:53,000 persons. Objectives The main objective of this thesis is to identify patients
and families with VHL disease by molecular genetic analysis. Presymptomatic DNA analysis and identification of carriers of
VHL germline mutations in families then permits tumour development to be followed from a relative early age, and optimises the
time at which treatment is carried out. In addition, we collected clinical and genetic data to identify possible
genotype-phenotype correlations and aimed to formulate national guidelines for diagnosis and periodic monitoring of VHL
patients. Results and conclusions In order to prevent both patient and doctor delay in the diagnosis of VHL disease, persons at
risk for the disease as well as doctors should be provided with clear oral and written information about the clinical and genetic
aspects of the disease. In addition, an intercentre co-operation should be established between the medical specialists involved
to prevent unnecessary morbidity and mortality in VHL patients. Multidisciplinary teams following national and international
guidelines should guarantee the best results in the management of VHL patients. We demonstrate genotype-phenotype
correlations for some tumours In VHL disease, but there appears to be no simple relationship between a germline mutation in
the VHL gene and the manifestation of VHL-related tumours. For example, there is intrafamilial variability in the age of onset and
the manifestation of different types of VHL-related tumours. Furthermore, we provide evidence non-penetrance of certain VHL
germline mutations. We estimate that the prevalence of VHL disease in the Netherlands is 1:64,000 and will almost certainly
prove to be higher. We demonstrate that 12% to 21% of the VHL germline mutations occur de novo. In addition, we illustrate
that VHL germline mutations can be identified in sporadic patients with VHL-related tumours who do not meet the current
diagnostic criteria. These findings emphasise the importance of screening sporadic patients with one or more typical
VHL-related tumours for germline mutations in the VHL gene. A principal finding of this study is that the early detection of VHL
families and patients using molecular genetic analysis is effective, assuming that annual monitoring and timely treatment leads
to a better prognosis for VHL patients. However, regarding the early detection of VHL patients, we observe that: (1) there is
insufficient evidence of an improved quality of life or a longer life span; (2) there is no reliable analysis of the
cost-effectiveness; and (3) the psychological consequences have not been studied sufficiently. These three observations
should provide a basis for further clinical investigations. More extensive genetic research is indicated for clinical situations
suggesting the presence of VHL disease, but without a VHL germline mutation.
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