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This syndrome is characterized by multiple clear cell neoplasms in various organs including the retina, central nervous system (CNS) hemangioblastomas (most frequently cerebellar and spinal), renal cell carcinomas, pheochromocytomas, pancreatic endocrine tumors, and cysts.

Neumann and Wiesler have classified this entity into two different types based on the presence or absence of a pheochromocytoma. Type I (without pheochromocytoma) and type II (with pheochromocytoma). In 1995, Brauch et al. subdivided type II into IIA (with pheochromocytoma) and type IIB (with pheochromocytoma and renal cell carcinoma). Recently, a type IIC was described when patients affected with von Hippel Lindau had an isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma

The estimated birth incidence in East Anglia, Norfolk, UK, is believed to be 1:36,000 live births and an estimated prevalence of heterozygotes to be 1 in 53,000. Direct and indirect estimates of the mutation rate were 4.4 per million gametes per generation and 2.32 per million gametes per generation, respectively. There are no significant associations between parental age or birth order and new mutations. In the Freiburg district of Germany, the prevalence has been calculated for this disorder to be 1 in 38,951. In the northwest of England, 83 affected persons were reported in 1996 and the calculated prevalence for this disease was estimated (heterozygotes) in the region to be 1 in 85,000 persons, with an estimated birth incidence of 1 in 45,500 live births. The incidence of the most common lesions are as follows: retinal angiomatosis (57%), cerebellar (55%), medullary (6%), and spinal (14%) hemangioblastomas; pheochromocytoma (19%), renal cysts (14%), renal cell carcinoma (24%), epididymal cystadenoma (17%), pancreatic cysts (14%), pancreatic malignancy (4%).

The gene is a putative tumor suppressor gene responsible for von Hippel Lindau, an autosomal dominant multitumor syndrome. It is also implicated in the development of sporadic tumors including clear cell renal carcinoma and CNS hemangioblastoma. The gene has recently been isolated by positional cloning and the cDNA encodes 852 nucleotides in 3 exons. The von Hippel Lindau (VHL) gene seems to be unrelated to any known gene families.

Interfamilial differences in predisposition to pheochromocytoma in VHL reflect allelic heterogeneity such that there is a strong association between missense mutations and risk of pheochromocytoma.

The presence of visceral cysts of the kidney, pancreas, and epididymis occurs not only as features of VHL but also in the general population; however, the association of those cysts with retinal, CNS hemangioblastoma may represent a more significant association for the disease. The use of markers as presymptomatic diagnosis of VHL in patients with epididymal cysts has been demonstrated to be not suitable as a diagnostic criterion. Similarly, the genetic studies suggested that VHL with or without pheochromocytomas is caused by defects within the same gene may be misleading. Renal cell carcinoma occurs as part of VHL; a second more proximal region of chromosome 3, 3p14.2, is responsible for “pure familial renal cell carcinoma.” It ...

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