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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.
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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
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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%).
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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.
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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.
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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 ...