Summary
Von Hippel Lindau disease (VHL) is 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 (see these terms). Prevalence is estimated at 1/53,000 and birth incidence at 1/36,000. Men and women are equally affected. Mean age at diagnosis is 26 years, but the disease can be detected from infancy to the seventh decade of life. Retinal hemangioblastomas may be the initial manifestation. They are usually asymptomatic, but they can cause retinal detachment, macular edema, glaucoma, and vision loss. Central nervous system (CNS) hemangioblastomas, when present, are often located in the cerebellum, but they also can affect the brainstem and spinal cord. They may be associated with headache, vomiting, and gait disturbances or ataxia. Multiple renal cysts can be present and the lifetime risk of RCC is very high in many cases. In some cases, patients present pheochromocytomas that can be asymptomatic, but may cause hypertension. Epididymal cysts, epididymal cystadenomas, and multiple pancreatic cysts may also appear. Endolymphatic sac tumors have sometimes been reported (up to 10% of cases) and may cause hearing loss. VHL is caused by mutations in the VHL gene (3p25.3), a classic tumor suppressor gene. Mutations of VHL are highly penetrant. Transmission is autosomal dominant. Most cases are diagnosed by the identification of a germline VHL mutation. A clinical diagnosis can be made in the presence of a single typical tumour (e.g. retinal or CNS hemangioblastomas or RCC) and a positive family history of VHL disease. If there is no family history (~20% of cases arise de novo) multiple tumours (e.g. two haemangioblastomas or a haemangioblastoma and a RCC) are required. Complete blood count, measurement of urinary catecholamine metabolites, urinalysis, and urine cytology may suggest polycythemia, pheochromocytoma, renal abnormality, and RCC. Imaging studies (MRI, CT, ultrasonography) can also detect CNS tumor, pheochromocytoma, endolymphatic sac tumor, and renal tumor, renal and pancreatic cysts. Differential diagnoses include multiple endocrine neoplasia, neurofibromatosis, polycystic kidney disease, tuberous sclerosis, Birt-Hogg-Dube syndrome (see these terms) and succinate dehydrogenase subunit mutations (SDHB, SDHC, SDHD). Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villus cells if a disease-causing mutation has been identified in an affected family member. A genetic counseling should be offered to the patients and their families. Surgery is the mainstay of treatment for tumors developing in VHL. Management also includes a lifelong surveillance. Prognosis depends on the occurrence of multiple tumors as CNS tumors, pheochromocytoma and RCC. RCC is the first cause of death in patients with VHLS, CNS hemangioblastomas the second one. The average life expectancy was previously estimated at 49 years, however, regular surveillance and early management of tumours reduces morbidity and mortality. *Author: Prof. E.R. Maher (October 2009)*.
