Von Hippel-Lindau disease (ORPHA:892)
A familial cancer predisposition syndrome associated with a variety of malignant and benign neoplasms, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma (RCC), and pheochromocytoma/paraganglioma.
Epidemiology
Prevalence is estimated at 1/53,000 and annual birth incidence at 1/36,000. Men and women are equally affected. Mean age at diagnosis is 26 years (range: infancy - 7th decade).
Clinical description
Retinal hemangioblastomas are the most common presenting feature (multiple and bilateral in about 50% of cases). They are usually asymptomatic, but they can cause retinal detachment, macular edema, glaucoma, and vision loss. Central nervous system (CNS) hemangioblastomas are the presenting feature in about 40% and occur overall in 60-80% of patients. They are most often located in the cerebellum, but also in the brainstem and spinal cord. They are benign but cause symptoms by compressing adjacent nervous tissue. In the cerebellum they are most often associated with increased intracranial pressure causing headaches, vomiting, and limb or truncal ataxia (difficulty in controlling fine movements of the arms and legs and unsteadiness in walking). Multiple renal cysts are very common and there is an increased lifetime risk of RCC (up to 70%). Some patients have pheochromocytomas that can be asymptomatic, but may cause hypertension. Epididymal cysts and cystadenomas (60% of male patients) may occur, as well as multiple pancreatic cysts (most patients). Non-secretory pancreatic islet cell tumours occur in a minority (10-15%). Endolymphatic sac tumors (ELST) are also been found (up to 10%) and may cause hearing loss. Head and neck paragangliomas are rare (0.5%). The mean age at diagnosis of tumors (e.g. haemangioblastoma, RCC) in VHL disease is considerably younger than in non-inherited sporadic cases. The clinical manifestations of VHL disease van vary between family members.
Etiology
VHL disease is caused by pathogenic variants (mutations) in the VHL gene (3p25.3), a classic tumor suppressor. Most cases are diagnosed via a germline mutation. In addition to VHL disease, pathogenic variants in the VHL gene can also cause, albeit more rarely, predisposition to isolated phaeochromocytoma/paraganglioma and familial erythrocytosis (polycythemia).
Diagnostic methods
Diagnosis can be made in the presence of a single typical tumor (e.g. retinal or CNS hemangioblastomas or RCC) and a positive family history of VHL. If there is no family history (about 20% of cases occur de novo), multiple tumors (e.g. two hemangioblastomas or a hemangioblastoma and an RCC) are required for diagnosis. A complete blood count, measurement of urinary or plasma catecholamine metabolites and urinalysis may be indicative of polycythemia, pheochromocytoma/paraganglioma, and RCC bit regular ophthalmology review and MRI scans are the mainstay of surveillance. Imaging studies can be used to detect CNS tumors, pheochromocytoma/paraganglioma, endolymphatic sac tumors, renal tumors, and renal and pancreatic cysts.
Differential diagnosis
Differential diagnoses include multiple endocrine neoplasia, neurofibromatosis type 1, polycystic kidney disease, tuberous sclerosis, Birt-Hogg-Dube syndrome, and hereditary pheochromocytoma-paraganglioma syndromes associated with succinate dehydrogenase subunit mutations (SDHB, SDHC and SDHD).
Antenatal diagnosis
Prenatal diagnosis is possible when a pathogenic variant has been detected in an affected family member.
Genetic counseling
Inheritance is autosomal dominant with age-dependent penetrance. Most cases are familial and at risk relatives should be identified and offered surveillance and, when available, cascade testing (relatives who test negative can be discharged from follow-up). Surveillance is commenced in early childhood and genetic testing of children can be offered to avoid unnecessary surveillance.
Management and treatment
Surveillance to enable early detection of VHL-related tumors is the mainstay of management. Surveillance (ophthalmologic, MRI brain and abdominal scans, laboratory testing) is lifelong and reduces morbidity and mortality. Tumors detected by surveillance may not require immediate intervention and there are agreed consensus protocols to keep some tumors under surveillance until certain size thresholds are reached (e.g. 3 cm diameter for RCC). When treatment of VHL tumors is indicated surgery has been the most frequently used intervention for abdominal and CNS lesions but recently medical therapy with HIF-2 antagonist (e.g. belzutifan) has become an option in some countries.
Prognosis
Regular surveillance and early detection and management of tumors has reduced the morbidity and mortality of VHL disease and recently average life expectancy has been estimated to be ~64 years.

                            Last update: 
                            July 2023


                            - Expert reviewer(s): 
                            Pr Eamonn MAHER | ERN GENTURIS*


                                * European Reference Network