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2478
American Cancer Society Second National Conference on
Cancer Genetics
Supplement to Cancer
Von Hippel-Lindau Syndrome
A Pleomorphic Condition
Christopher A. Friedrich,
M.D., Ph.D.
Von Hippel-Lindau (VHL) syndrome (OMIM 193300) is an autosomal dominant
disorder caused by deletions or mutations in a tumor suppressor gene mapped to
Division of Medical Genetics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
human chromosome 3p25. It is characterized clinically by vascular tumors, including retinal and central nervous system hemangioblastomas (cerebellar, spinal, and
brain stem). Hemangioblastomas are benign and do not metastasize. Other features include cysts of the kidneys, liver, and pancreas. Clear cell renal cell carcinoma occurs in up to 70% of patients with VHL and is a frequent cause of death.
Pheochromocytomas occur in association with specific alleles of the VHL gene;
therefore, a family history of pheochromocytoma in association with VHL is an
indication for thorough surveillance for pheochromocytoma in affected family
members. Recently, it has been appreciated that patients with VHL may develop
endolymphatic sac tumors, which can cause tinnitus or deafness.
The diagnosis of VHL may be made in a patient with a family history of VHL
based on a single retinal or cerebellar hemangioblastoma, renal cell carcinoma or
pheochromocytoma, and, possibly, multiple pancreatic cysts. Renal and epididymal cysts are not sufficient to make the diagnosis of VHL. In the absence of a family
history of VHL the presence of two or more retinal or cerebellar hemangioblastomas, or one hemangioblastoma with one visceral tumor, is required for diagnosis.
Studies of the natural history of VHL showed a life expectancy less than 50
years before surveillance protocols were developed. Annual assessments (physical
and ophthalmologic examinations) should begin in infancy. Imaging of abdominal
organs and the brain and spine should be added in teenagers and adults. Renal
cysts and tumors should be monitored by computed tomography every 6 months.
Mutation analysis has allowed presymptomatic identification of affected family
members; those found not to have inherited the gene do not need to be monitored.
The VHL gene coding sequence contains three exons, and two isoforms of
mRNA exist, reflecting the presence or absence of exon 2. Tumors arise after the
loss or inactivation of the wild type allele in a cell. About 20% of patients have large
germline mutations detectable by Southern blot analysis, 27% have missense
mutations, and 27% have nonsense or frameshift mutations. In about 20% of VHL
families no deletion or mutation can be detected. Families may be characterized by
the presence (type 2; 7% to 20% of families) or absence (type 1) of pheochromocytomas. Most type 2 families have missense mutations, whereas most type 1
Presented at the American Cancer Society Second
National Conference on Cancer Genetics, San
Francisco, CA, June 26 –28, 1998.
families are affected by deletions or premature termination mutations. Prognostic
counseling regarding the lifetime risk of pheochromocytoma can be aided by
determination of the underlying mutation in patients without family histories of
VHL. Cancer 1999;86:2478 – 82. © 1999 American Cancer Society.
Address for reprints: Christopher A. Friedrich,
M.D., Ph.D., Division of Medical Genetics, Maloney
1, Hospital of the University of Pennsylvania, 3400
Spruce Street, Philadelphia, PA 19104-4283.
Received May 25, 1999; accepted June 3, 1999.
© 1999 American Cancer Society
KEYWORDS: von Hippel-Lindau syndrome, cancer genetics, presymptomatic diagnosis, molecular diagnosis, genetic counseling, medical oncology, medical
genetics.
Von Hippel-Lindau Syndrome/Friedrich
TABLE 1
Age of Onset of Characteristic Tumors
Retinal lesions
Cerebellar lesions
Renal cell carcinoma
Mean age (yrs)
(range)
Percentage of patients
25
30
37
(1–67)
(11–78)
(16–67)
45%–59%
44%–72%
40%–70%
2479
Freiburg.4 The northwest England VHL registry found
the prevalence to be 1 in 85,000 and the incidence to
be 1 in 45,500.10
The life expectancy of affected individuals has
been less than 50 years. The prognosis may be improved because of earlier diagnosis and the recent
development of surveillance protocols emphasizing
regular monitoring for predictable complications and
early interventions.
BACKGROUND
The von Hippel-Lindau (VHL) syndrome is a rare autosomal dominant condition characterized by the development of specific tumors, both benign and malignant.
It is caused by deletions or point mutations in a tumor
suppressor gene. Those who inherit a mutated gene are
at greatly increased risk for retinal hemangioblastoma;
cerebellar hemangioblastoma; pheochromocytoma;
pancreatic and renal cysts; spinal hemangioblastoma;
renal cell carcinoma (RCC); hemangiomas of the adrenals, liver, and lungs; endolymphatic sac tumors; and
papillary cystadenoma of the epididymis or broad ligament.1–3 Up to 50% of patients in VHL families show
only one manifestation of the syndrome.4,5 Expressivity
is variable among families; however, some clinical features are similar within families. Clear cell RCC has been
found to occur in up to 70% of patients.5 In early studies
the most common causes of death were complications
of cerebellar hemangioblastoma (53%) and metastatic
RCC (32%).5– 8 The retinal lesions may cause retinal detachment or hemorrhage, leading to blindness, but they
usually respond to treatment with laser therapy or cryotherapy if detected early.
The ages of onset of typical findings are listed in
Table 1.5,9 If pheochromocytoma is present in the
family it may be the initial presentation. A registry
started in northwest England in 1990 has registered 83
patients.10 In that population the mean age of onset of
the first sign or symptom was 26.25 years, with a mean
age at diagnosis of 30.87 years. The most common
initial manifestation was cerebellar hemangioblastoma (34.9%). The mean age at death was 40.9 years,
and the most common cause of death was complications of cerebellar hemangioblastoma (47.7%). In this
population the cumulative occurrence of cerebellar
hemangioblastoma was 60.2%, that of retinal hemangioblastoma was 41%, that of RCC was 25.3%, that of
spinal hemangioblastoma was 14.5%, and that of
pheochromocytoma was 14.5%.
Family studies have shown reduced penetrance of
the expression of the gene. Three lesion-free obligate
carriers were found in the northwest England registry.10 The prevalence of VHL disease has been estimated at 1 in 53,000 in East Anglia, with an incidence
of 1 in 36,000;1 the prevalence was 1 in 38,951 in
CLINICAL DIAGNOSIS
The diagnosis of VHL may be made on clinical
grounds. In a patient with a positive family history of
VHL, the finding of a single retinal or cerebellar hemangioblastoma, pheochromocytoma, or RCC is sufficient to make the diagnosis.11 Some have argued that
the presence of multiple pancreatic cysts is also sufficient. Renal or epididymal cysts alone are not sufficient because they occur frequently in the general
population.12
If no known family history of VHL exists, two or
more retinal or cerebellar hemangioblastomas or one
hemangioblastoma plus one visceral tumor must be
present to justify the diagnosis. New mutations are
thought to account for 1% to 3% of VHL cases.13,14
Symptoms of cerebellar hemangioblastoma may
include headache, vomiting, wide-based gait, slurred
speech, nystagmus, labile hypertension (without
pheochromocytoma), positional vertigo, and dysmetria.15 Erythrocytosis occurs in 5% to 20% of patients.16
Up to 30% of patients with cerebellar hemangioblastoma have VHL disease.5,17 Spinal hemangioblastomas
are more specific for VHL disease, and about 80% are
caused by VHL disease. They occur in 13% to 59% of
VHL patients.5,7,18
Renal cell carcinomas may occur in renal cysts.
The tumors tend to grow slowly, less than 2 cm per
year, and it has been recommended they by followed
with computed tomography scans every 6 months.19
When they reach 3 cm nephron-sparing surgery may
preserve renal function and postpone the need for
dialysis.20,21
GENE IDENTIFICATION
Based on family linkage studies, the gene responsible
for VHL disease was mapped to chromosome 3p25.22
Pulsed-field gel electrophoresis revealed nested constitutional deletions in three unrelated patients.23 The
gene was identified by positional cloning using overlapping yeast artificial chromosomes and cosmidphage contigs.13
The gene coding sequence involves three exons
containing 712 nucleotides, including 70 base pairs
of 59 untranslated sequence in exon 1.3 Two mRNA
2480
CANCER Supplement December 1, 1999 / Volume 86 / Number 11
TABLE 2
Recommendations for Monitoring Patients with von Hippel-Lindau Syndrome and Family Members
Age (yrs)
Recommendation
Infancy (birth–23 mos)
2
11
Annual examinations (physical examinations including ophthalmologic examination)
Urinary catecholamines every 1–2 years
Biannual MRI of brain and spine; annual ultrasound examination of abdomen; if renal cysts or tumor
present, CT scans every 6 months
Change annual abdominal ultrasound examination to annual CT scan
If no evidence of von Hippel-Lindau syndrome, change MRI of brain and spine to every 3 to 5 years;
change CT scan of abdomen to every other year
20
60
CT: computed tomography; MRI: magnetic resonance imaging. Table adapted from Choyke et al.16
isoforms exist, differing based on the presence or
absence of exon 2.24 Tumors may arise after inactivation, e.g., deletion or hypermethylation, of the
remaining wild-type allele in a cell (i.e., loss of heterozygosity).25–27
Although it was predicted originally that the VHL
gene product (pVHL) would contain 284 amino acids,13 it was later shown that the resulting protein
contained 213 amino acid residues, and the numbering scheme was updated.28,29 The apparent molecular
weight of pVHL is 28 to 30 kD.28,29 The VHL gene
product binds to two transcription factors, elongin B
and elongin C, and its binding site is mutated frequently in VHL disease.30 –32 The normal function of
this protein seems to involve inhibition of transcription elongation.30,31 Introduction of wild-type, but not
mutant, VHL protein into clear cell RCC cell lines
lacking functioning VHL genes suppressed their ability
to form tumors in nude mouse xenograft assays, confirming that the VHL gene product functions as a
tumor suppressor.29,33
CLINICAL APPLICATION OF MOLECULAR
CHARACTERISTICS
Mutation analysis has revealed the proportions of specific molecular changes. About 15% to 20% of patients
have large germline deletions, 27% have missense mutations, 27% have nonsense or frameshift mutations,
and the remainder have no deletion or mutation detected.3 The identification of a mutation in an index
patient allows the identification of other mutation carriers among family members who may not yet exhibit
any manifestation of disease.34 Surveillance protocols
for monitoring these high-risk patients have been developed by several groups, and the recommendations
of the National Institutes of Health (NIH) group are
listed in Table 2.16 Those family members who did not
inherit the mutation and previously had an empiric
risk of 50% for being affected do not need regular
monitoring. Prenatal diagnosis is possible.
Genotype-phenotype correlation studies have
been useful in prognostic counseling, especially as
regards the risk of pheochromocytoma. Mutation
analysis studies of 55 unrelated VHL kindreds showed
the presence of an arg238gln mutation in five of the
kindreds and that of an arg238trp mutation in four of
them. Large deletions or premature truncation mutations were identified in 36 of 53 families without a
history of pheochromocytoma but in only 2 of 12
families with pheochromocytoma. In 10 of 12 families
with pheochromocytoma missense mutations were
identified, whereas only 13 of 53 families without
pheochromocytomas had missense mutations. The
arg238trp and arg238gln mutations were associated
with a 62% risk of pheochromocytoma.35
This was confirmed in subsequent studies. Families
without a history of pheochromocytomas are labeled
type 1, and families with a history of pheochromocytoma (7% to 20% of families) are designated type 2.5,36 In
type 2 families renal and pancreatic cysts are rarely
present. Deletions or premature termination mutations
affect 56% of type 1 families, whereas 96% of type 2
families are affected by missense mutations, 43% at nucleotide 238.37 Prognostic counseling regarding pheochromocytoma may be possible based on molecular results even if the family history is negative for VHL
disease.
Similar results were found in a large study of 469
families from North America, Europe, and Japan.38
The authors of the study also examined additional
phenotypes: families with RCC but not pheochromocytoma, those with RCC and hemangioblastoma plus
pheochromocytoma, and those with pheochromocytoma alone. They identified mutations in 63% of families and found a total of 137 mutations, most occurring in one or two families.
It is essential patients or family members receive
genetic counseling before and after undergoing molecular testing. The physician or genetic counselor
must ensure that those considering being tested are
Von Hippel-Lindau Syndrome/Friedrich
aware of the potential benefits and disadvantages of
learning that they have a gene mutation that places
them at high risk for developing tumors. This includes
preparing them for common reactions that other patients and families have experienced after receiving a
diagnosis, including isolation, guilt, anxiety, denial,
and overprotectiveness.39 Some may be concerned
about the potential effect of carrying such a gene on
their ability to obtain insurance or employment.
9.
10.
11.
12.
CONCLUSIONS
The protein encoded by the VHL gene is unique and
inhibits transcription elongation. Loss of this function
allows the unregulated growth of vascular tumors in
multiple tissues. Patients with tumors characteristic of
VHL, e.g., retinal or cerebellar hemangioblastomas,
should be evaluated formally for the possibility of VHL
disease. This includes a detailed family history focused
on tumors in relatives. In most patients with VHL, a
deletion or significant mutation can be identified, allowing confirmation of the diagnosis. Prognosis for
individual patients can be affected by mutation analysis results. Families may benefit from presymptomatic detection of affected gene carriers or the exclusion
of at-risk family members by negative test results.
Those who are found to carry the gene may suffer
psychological and financial difficulties (e.g., insurability, employability) because of the likelihood they will
develop clinical disease in the future. All patients and
family members being tested for VHL gene mutations
should receive genetic counseling before testing and
after test results return, and they should give informed
consent before being tested.
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