Von Hippel-Lindau Disease Von Hippel-Lindau disease (VHL) is a rare hereditary can- cer syndrome. The prevalence is estimated as 1 in 85,000 with an incidence of 1 in 45,500 live births. GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant b. Reduced penetrance (95% penetrance at age 60) c. Positive family history in up to 80% of cases d. Sporadic new mutation in about 20% of cases e. Parental mosaicism described 2. Molecular pathogenesis of VHL disease a. VHL disease i. Caused by deletions or mutations in a tumor sup- pressor gene, the VHL gene ii. Two-hit theory of Knudson in a familial cancer syndrome such as VHL disease a) Prediction of the genotype of each neo- plasm which consists of an allele with an inherited germ-line mutation and loss of the second wild-type allele through allelic deletion b) Loss of heterozygosity at chromosome 3p at the VHL gene region has been demon- strated in different VHL disease-associated tumors. iii. A germline mutation in the VHL gene a) Predisposes carriers to tumors in multiple organs b) Consistently detected in 100% of classic families with more than one affected family member or classic sporadic patients with multiple VHL-related tumors c) Missense mutations leading to an amino acid substitution in VHL gene product pVHL, observed in 40% of the families with an iden- tified VHL gene germline mutation d) Microdeletions, insertions, splice site, and nonsense mutations, all predicted to lead to a truncated protein: observed in 30% of the families e) Large deletions including deletions encom- passing the entire gene: account for the remaining 30% of the VHL gene germline mutations iv. Somatic mutations a) Independent somatic alteration of both alle- les of the VHL tumor suppressor gene lead- ing to tumorigenesis in nonfamilial (VHL- related) tumors b) Somatic VHL gene mutations and allele loss: frequent events in sporadic clear cell renal cell carcinomas and sporadic central nervous system hemangioblastoma; uncom- mon in sporadic (i.e., nontumor syndrome associated) pheochromocytoma b. VHL gene i. Mapped on chromosome 3p25 ii. Involved in blood vessel formation by regula- tion of the activity of hypoxia-inducible factor (HIF)-1α c. Patients with VHL disease i. With a positive family history: have inherited an inactive VHL allele from an affected parent ii. Without a positive family history: have a parent who is mosaic for a VHL mutation, presumably as the result of a de novo mutation during early development d. Angiogenesis of VHL tumors: critical role of inacti- vation of VHL gene i. Overexpression of vascular endothelial growth factor (VEGF) resulting in hypervascularization ii. Negative regulation of hypoxia-inducible mRNAs including VEGF mRNA by VHL protein e. Tumor development in VHL disease i. Linked to inactivation or loss of the remaining wild-type VHL allele in a susceptible cell, lead- ing to loss of the VHL gene product pVHL ii. Inactivation of VHL gene contributing to tumori- genesis of the VHL tumor since VHL protein is required for the down-regulation of transcription activity of certain genes CLINICAL FEATURES 1. Great variation in the clinical presentation with variable age of onset 2. Classification of VHL disease a. VHL type 1 i. Without pheochromocytoma ii. Truncating or null mutations in the VHL gene (deletions or frameshift, nonsense, or splice site mutations) observed in approximately 96–97% of patients with type 1 VHL b. VHL type 2 i. With pheochromocytomas ii. Missense mutations observed in 92–98% of patients with type 2 VHL c. Subtypes of type 2 VHL i. VHL type 2A a) VHL without predisposition to renal cell car- cinoma and pancreatic neuroendocrine tumor b) Specific mutations (Y98H, Y112H, V116F, L188V) in the VHL gene conferring an increased risk for VHL disease 1029
Von Hippel-Lindau Disease
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Von Hippel-Lindau Disease
Von Hippel-Lindau disease (VHL) is a rare hereditary can- cer syndrome. The prevalence is estimated as 1 in 85,000 with an incidence of 1 in 45,500 live births.
GENETICS/BASIC DEFECTS 1. Inheritance
a. Autosomal dominant b. Reduced penetrance (95% penetrance at age 60) c. Positive family history in up to 80% of cases d. Sporadic new mutation in about 20% of cases e. Parental mosaicism described
2. Molecular pathogenesis of VHL disease a. VHL disease
i. Caused by deletions or mutations in a tumor sup- pressor gene, the VHL gene
ii. Two-hit theory of Knudson in a familial cancer syndrome such as VHL disease a) Prediction of the genotype of each neo-
plasm which consists of an allele with an inherited germ-line mutation and loss of the second wild-type allele through allelic deletion
b) Loss of heterozygosity at chromosome 3p at the VHL gene region has been demon- strated in different VHL disease-associated tumors.
iii. A germline mutation in the VHL gene a) Predisposes carriers to tumors in multiple
organs b) Consistently detected in 100% of classic
families with more than one affected family member or classic sporadic patients with multiple VHL-related tumors
c) Missense mutations leading to an amino acid substitution in VHL gene product pVHL, observed in 40% of the families with an iden- tified VHL gene germline mutation
d) Microdeletions, insertions, splice site, and nonsense mutations, all predicted to lead to a truncated protein: observed in 30% of the families
e) Large deletions including deletions encom- passing the entire gene: account for the remaining 30% of the VHL gene germline mutations
iv. Somatic mutations a) Independent somatic alteration of both alle-
les of the VHL tumor suppressor gene lead- ing to tumorigenesis in nonfamilial (VHL- related) tumors
b) Somatic VHL gene mutations and allele loss: frequent events in sporadic clear cell
renal cell carcinomas and sporadic central nervous system hemangioblastoma; uncom- mon in sporadic (i.e., nontumor syndrome associated) pheochromocytoma
b. VHL gene i. Mapped on chromosome 3p25
ii. Involved in blood vessel formation by regula- tion of the activity of hypoxia-inducible factor (HIF)-1α
c. Patients with VHL disease i. With a positive family history: have inherited an
inactive VHL allele from an affected parent ii. Without a positive family history: have a parent
who is mosaic for a VHL mutation, presumably as the result of a de novo mutation during early development
d. Angiogenesis of VHL tumors: critical role of inacti- vation of VHL gene i. Overexpression of vascular endothelial growth
factor (VEGF) resulting in hypervascularization ii. Negative regulation of hypoxia-inducible mRNAs
including VEGF mRNA by VHL protein e. Tumor development in VHL disease
i. Linked to inactivation or loss of the remaining wild-type VHL allele in a susceptible cell, lead- ing to loss of the VHL gene product pVHL
ii. Inactivation of VHL gene contributing to tumori- genesis of the VHL tumor since VHL protein is required for the down-regulation of transcription activity of certain genes
CLINICAL FEATURES 1. Great variation in the clinical presentation with variable
age of onset 2. Classification of VHL disease
a. VHL type 1 i. Without pheochromocytoma
ii. Truncating or null mutations in the VHL gene (deletions or frameshift, nonsense, or splice site mutations) observed in approximately 96–97% of patients with type 1 VHL
b. VHL type 2 i. With pheochromocytomas
ii. Missense mutations observed in 92–98% of patients with type 2 VHL
c. Subtypes of type 2 VHL i. VHL type 2A
a) VHL without predisposition to renal cell car- cinoma and pancreatic neuroendocrine tumor
b) Specific mutations (Y98H, Y112H, V116F, L188V) in the VHL gene conferring an increased risk for VHL disease
1029
1030 VON HIPPEL-LINDAU DISEASE
ii. VHL type 2B a) VHL with predisposition to renal cell car-
cinoma and pancreatic neuroendocrine tumor
b) Specific mutations (R167Q, R167W) in the VHL gene conferring an increased risk for VHL disease
iii. VHL type 2C a) VHL with only pheochromocytoma mani-
festation b) Specific mutations (V155L, R238W) in the
VHL gene conferring an increased risk for VHL disease
3. Tumors/cysts linked to VHL disease, typically develop in the 2nd, 3rd, and 4th decades of life a. Retinal angioma/hemangioblastoma
i. Responsible for the first manifestation of VHL in 50% of the patients
ii. Retinal lesions a) Formerly called retinal angiomas b) Histologically identical to hemangioblastomas c) Identified in about 70% of the patients d) Bilateral in about 50% of the patients e) Multiple in about 66% of the patients
iii. Complications when the condition is unrecog- nized and untreated at early stage a) Majority of retinal angiomas eventually
hemorrhage. b) Resulting in massive exudation and retinal
detachment c) Ultimate development of neovascular glau-
coma and blindness b. Cerebellar hemangioblastomas (80% of CNS heman-
gioblastoma) i. The most common initial manifestation (34.9%)
ii. Cumulative occurrence: 60.2% iii. The most common cause of death (47.7%) iv. Symptoms and signs
a) Headache b) Slurred speech c) Nystagmus d) Positional vertigo e) Labile hypertension (without pheochromo-
cytoma) f) Vomiting g) Wide-based gait h) Dysmetria
c. Spinal hemangioblastoma (20% of CNS heman- gioblastoma) i. More specific for VHL disease
ii. About 80% of cases are caused by VHL. iii. Cumulative occurrence (14.5%) iv. Symptoms and signs
a) Pain b) Sensory and motor loss secondary to cord
compression d. Renal lesions
i. Renal cysts: Precursor lesions to clear cell renal carcinomas (75% of patients with VHL) which is a frequent cause of death
ii. Hemangioblastoma iii. Renal cell adenoma iv. Renal cell carcinoma (20–40%)
e. Pheochromocytomas (tumor of adrenal medulla) i. Type 1 families
a) Absence of pheochromocytomas b) Most type 1 families are affected by dele-
tions or premature termination mutations. ii. Type 2 families (7–20% of families)
a) Presence of pheochromocytomas b) Most type 2 families are affected by mis-
sense mutations. iii. Arg238trp and arg238gln mutations: associated
with a 62% risk for pheochromocytoma iv. Location of tumors
a) Usually located in one or both adrenal glands b) May present anywhere along the sympathet-
ic axis in the abdomen or thorax (paragan- gliomas) or head and neck (chemodectomas)
v. Symptoms and signs a) Sustained or episodic hypertension b) Asymptomatic
f. Pancreatic lesions i. Type of lesions
a) Simple pancreatic cysts b) Serous cystadenomas c) Pancreatic neuroendocrine tumors
ii. Rarely causing endocrine or exocrine insufficiency unless the lesion is extensive
iii. Occasionally causing biliary obstruction second- ary to cysts in the head of the pancreas
g. Liver lesions i. Hemangiomas
ii. Cyst iii. Adenoma iv. Carcinoid of the common bile duct
h. Splenic lesions i. Hemangiomas
ii. Cyst i. Pulmonary lesions
i. Hemangiomas ii. Cyst
j. Bladder hemangioblastoma k. Endolymphatic sac tumors of the inner ears (labyrinth)
i. Tinnitus or vertigo ii. Deafness
l. Papillary cystadenomas of the epididymis in males i. Relatively common in males
ii. Unilateral: rarely causing problem iii. Bilateral: infertility
m. Papillary cystadenomas of the broad ligament in females: much less common
n. Skin lesions i. Nevus
ii. Café au lait spot o. Bone lesions
i. Hemangioma ii. Cyst
4. Diagnosis of VHL disease usually made on clinical grounds
VON HIPPEL-LINDAU DISEASE 1031
a. A positive family history of VHL disease plus one of the following lesion (hemangioblastoma or visceral lesion): i. Retinal hemangioblastoma
ii. Cerebellar hemangioblastoma iii. Pheochromocytoma iv. Renal cell carcinoma v. Multiple pancreatic cysts
b. A negative family history of VHL disease need one of the following: i. Two or more retinal or cerebellar hemangioblas-
tomas ii. One hemangioblastoma plus one visceral tumor
5. Prognosis a. Life expectancy: <50 years b. Most common causes of death
i. Renal cell carcinoma ii. Cerebellar hemangioblastoma
c. Improved prognosis in patients with: i. Earlier diagnosis
ii. Regular monitoring for predictable complications iii. Followed by early interventions
DIAGNOSTIC INVESTIGATIONS 1. Biochemical test: elevated urinary catecholamines (VMA,
metanephrine, and total catecholamine) suggesting pheo- chromocytoma even in the absence of hypertension
2. Eye examinations a. Ophthalmoscopy b. Fluorescein angiography, a valuable tool useful in
detecting subclinical fundus lesions 3. Radiography for rare associated bone cysts and osseous
hemangiomas 4. Ultrasound examinations
a. Evaluation of the epididymus and broad ligament b. Screening of the kidneys
5. CAT scan a. To document the presence of CNS and visceral
tumors i. CNS hemangioblastomas
a) Cystic lesions (75%) b) An enhancing lesion with multiple cystic
areas (15%) c) An enhancing solid mass (10%)
ii. Retinal hemangiomas too small to be depicted on CT scans, the diagnosis mainly dependent on the results of an ophthalmoscopic examination
iii. Papillary endolymphatic sac tumors presenting as a thin peripheral rim of calcification, repre- senting the expanded cortex of petrous bone
b. Low sensitivity in the detection of renal cell carcino- ma associated with VHL i. Not reliable in differentiating cystic renal cell
carcinomas, cancers within a cyst, and atypical cysts
ii. Impossible to differentiate a renal cell adenoma from a renal cell carcinoma
6. MRI to document the presence of CNS and visceral tumors
a. MRI appearances of a CNS hemangioblastoma: a well-demarcated cystic lesion with a highly vascular mural nodule that always abuts on the pia mater
b. Spinal hemangioblastomas: intramedullary tumors in most patients (75%) but may be radicular (20%) or intradural extramedullary (5%)
c. Pheochromocytoma: high signal intensity on T2- wighted MRI, differentiating it from adrenal cortical nodules
d. Endolymphatic sac tumors: high signal intensity with T1 imaging on MRI as a mass on the posterior wall of the petrous part of the temporal bone
7. Radionuclide studies a. To provide an indication of metabolic activity of CNS
tumors by positron emission tomography (PET) with 2-[fluorine 18]-fluoro-2-deoxy-D-glucose (FDG)
b. To detect bone metastases resulting from primary malignant tumor of bone of VHL
c. To assess renal function prior to resection of renal tumors
d. To detect pheochromocytoma using iodine-131 metaiodobenzylguanidine (131I MIBG)
8. Angiography a. Hemangioblastoma: a hypervascular lesion with
intense and prolonged early enhancement of the mural nodule associated with dilated feeding vessels
b. Endolymphatic sac tumors i. Hypervascular on angiography and the blood
supply is derived from the external carotid artery ii. Large tumors with an additional blood supply
from the internal carotid artery and posterior circulation
9. Histologic features of VHL tumors a. High degree of vascularization b. Presence of a clear cell component
10. NIH group recommendation for monitoring VHL patients and family members a. Birth to 2 years
i. Annual physical examination ii. Annual ophthalmologic examination
b. 2–10 years: urinary catecholamines every 1–2 years c. 11–19 years
i. Biannual MRI of the brain and spine ii. Annual ultrasound examination of abdomen
iii. CT scans of abdomen every 6 months if renal cysts or tumor present
d. 20–59 years: annual CT scan of abdomen e. 60 years and above without VHL
i. MRI of the brain and spine every 3–5 years ii. CT scan of the abdomen every other year
f. Not necessary to monitor the family members identified previously with an empiric risk of 50% of being affect- ed but are found not to have inherited the mutation
11. Molecular genetic analysis a. Considered standard for the evaluation of patients and
families with suspected VHL disease b. Identification of VHL gene germline mutations
i. Identification of constitutional VHL gene dele- tions by FISH using probes from the VHL gene critical region in 3p25.3
1032 VON HIPPEL-LINDAU DISEASE
a) Offers a comprehensive way to screen for the presence of germline deletions because it enables visualization of individual cells
b) May identify mosaicism or cryptic translo- cation events that cannot be readily detected by other molecular strategies in patients with submicroscopic germline deletions and a nor- mal karyotype
c) Enable to identify a de novo mosaic for the VHL gene deletion
ii. Molecular diagnosis accomplished in virtually all families with classic VHL disease (families with multiple tumors) and in the majority of iso- lated patients with multiple VHL-associated tumors a) Qualitative and quantitative Southern blot-
ting to detect partial or complete gene dele- tions responsible for 28% of all cases
b) DNA-sequence analysis of the protein- encoding region (all three exons) to detect point mutations in the remainder (72%) of the cases
c. Mosaicism i. A potential cause for failure of molecular diag-
nosis in VHL ii. Individuals with mosaicism:
a) Asymptomatic b) Manifesting as a single-system disease c) Manifesting as a multisystem disease
d. Identification of a mutation in a proband allows the identification of mutation carriers among family members who do not yet exhibit any clinical manifes- tation of VHL
GENETIC COUNSELING 1. Recurrence risk
a. Patient’s sib i. A small risk of having a sib with VHL since
parental mosaicism accounts for some apparent- ly sporadic or new cases of VHL
ii. A 50% risk of having a sib with VHL disease if one of the parent is clinically affected or has a disease-causing VHL gene mutation
b. Patient’s offspring i. A 50% risk of inheriting the VHL disease-causing
mutation ii. An individual mosaic for a disease mutation is at
increased risk for having affected offspring, despite negative testing for the mutation by rou- tine DNA diagnostic tests
2. Prenatal diagnosis available by molecular genetic testing of fetal DNA obtained from amniocentesis or CVS for pregnancies at 50% risk when the disease-causing muta- tion has been identified in the affected parent
3. Management a. Ocular management
i. Laser photocoagulation therapy or cryotherapy of retinal lesions
ii. Several treatment strategies on the horizon that show promise for the ocular management of VHL disease a) Vascular endothelial growth factor (VEGF)
inhibitors b) Use of radiotherapy, such as brachytherapy
or linear-accelerated based radiosurgery b. Surgery: the mainstay of treatment for the tumors
arising in patients with VHL disease i. Renal cell carcinomas
a) Partial nephrectomy or radiofrequency abla- tion to spare renal function if tumor involve- ment is not extensive
b) Total nephrectomy often necessary for extensive tumor involvement
ii. CNS hemangioblastomas: radiation therapy in patients with CNS symptoms
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ic, clinical, and imaging features. Radiology 194:629–642, 1995. Clifford SC, Maher ER: Von Hippel-Lindau disease: clinical and molecular
perspectives. Adv Cancer Res 82:85–105, 2001. Couch V, Lindor NM, Karnes PS, et al.: von Hippel-Lindau disease. Mayo Clin
Proc 75:265–272, 2000. Dannenberg H, De Krijger RR, van der Harst E, et al.: Von Hippel-Lindau gene
alterations in sporadic benign and malignant pheochromocytomas. Int J Cancer 105:190–195, 2003.
Decker HJ, Klauck SM, Lawrence JB, et al.: Cytogenetic and fluorescence in situ hybridization studies on sporadic and hereditary tumors associated with von Hippel-Lindau syndrome (VHL). Cancer Genet Cytogenet 77:1–13, 1994.
Dollfus H, Massin P, Taupin P, et al.: Retinal hemangioblastoma in von Hippel- Lindau disease: a clinical and molecular study. Invest Ophthalmol Vis Sci 43:3067–3074, 2002.
Friedrich CA: Genotype-phenotype correlation in von Hippel-Lindau syn- drome. Hum Mol Genet 10:763–767, 2001.
Glenn GM, Linehan WM, Hosoe S, et al.: Screening for von Hippel-Lindau disease by DNA polymorphism analysis. JAMA 267:1226–1231, 1992.
Hes FJ, Hoppener JW, Lips CJ: Clinical review 155: Pheochromocytoma in Von Hippel-Lindau disease. J Clin Endocrinol Metab 88:969–974, 2003.
Jordan DK, Patil SR, Divelbiss JE, et al.: Cytogenetic abnormalities in tumors of patients with von Hippel-Lindau disease. Cancer Genet Cytogenet 42:227–241, 1989.
Kaelin WG, Jr: The von Hippel-Lindau gene, kidney cancer, and oxygen sens- ing. J Am Soc Nephrol 14:2703–2711, 2003.
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Latif F, Tory K, Gnarra J, et al.: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–1320, 1993.
Lubensky IA, Pack S, Ault D, et al.: Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients. Histopathological and molecular genetic analysis. Am J Pathol 153:223–231, 1998.
Maher ER, Yates JR, Harries R, et al.: Clinical features and natural history of von Hippel-Lindau disease. Q J Med 77:1151–1163, 1990.
Murgia A, Martella M, Vinanzi C, et al.: Somatic mosaicism in von Hippel- Lindau Disease. Hum Mutat 15:114–119, 2000.
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Neumann HP, Berger DP, Sigmund G, et al.: Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 329:1531–1538, 1993.
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Petersen G: Genetic testing. Hematol Oncol Clin North Am 14:939–952, 2000.
VON HIPPEL-LINDAU DISEASE 1033
Richard S: Von Hippel-Lindau disease: recent advances and therapeutic per- spectives. Expert Rev Anticancer Ther 3:215–233, 2003.
Richards FM, Webster AR, McMahon R, et al.: Molecular genetic analysis of von Hippel-Lindau disease. J Intern Med 243:527–533, 1998.
Richard S, David P, Marsot-Dupuch K, et al.: Central nervous system heman- gioblastomas, endolymphatic sac tumors, and von Hippel-Lindau disease. Neurosurg Rev 23:1–22; discussion 23–24, 2000.
Sanfilippo P, Troutbeck R, Vandeleur K: Retinal angioma associated with von Hippel-Lindau disease. Clin Exp Optom 86:187–191, 2003.
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Schimke RN, Collins DL, Stolle CA: Von Hippel-Lindau syndrome. Gene Reviews, 2002. http:// www.genetests.org
Sgambati MT, Stolle C, Choyke PL, et al.: Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in off- spring with mosaic parents. Am J Hum Genet 66:84–91, 2000.
Stolle C, Glenn G, Zbar B, et al.: Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 12:417–423, 1998.
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1034 VON HIPPEL-LINDAU DISEASE
Fig. 1. Retinal malformation secondary to von Hippel-Lindau disease.
Fig. 2. Retinal exudates from vascular leakage in a patient with von Hippel-Lindau disease.
Von Hippel-Lindau disease (VHL) is a rare hereditary can- cer syndrome. The prevalence is estimated as 1 in 85,000 with an incidence of 1 in 45,500 live births.
GENETICS/BASIC DEFECTS 1. Inheritance
a. Autosomal dominant b. Reduced penetrance (95% penetrance at age 60) c. Positive family history in up to 80% of cases d. Sporadic new mutation in about 20% of cases e. Parental mosaicism described
2. Molecular pathogenesis of VHL disease a. VHL disease
i. Caused by deletions or mutations in a tumor sup- pressor gene, the VHL gene
ii. Two-hit theory of Knudson in a familial cancer syndrome such as VHL disease a) Prediction of the genotype of each neo-
plasm which consists of an allele with an inherited germ-line mutation and loss of the second wild-type allele through allelic deletion
b) Loss of heterozygosity at chromosome 3p at the VHL gene region has been demon- strated in different VHL disease-associated tumors.
iii. A germline mutation in the VHL gene a) Predisposes carriers to tumors in multiple
organs b) Consistently detected in 100% of classic
families with more than one affected family member or classic sporadic patients with multiple VHL-related tumors
c) Missense mutations leading to an amino acid substitution in VHL gene product pVHL, observed in 40% of the families with an iden- tified VHL gene germline mutation
d) Microdeletions, insertions, splice site, and nonsense mutations, all predicted to lead to a truncated protein: observed in 30% of the families
e) Large deletions including deletions encom- passing the entire gene: account for the remaining 30% of the VHL gene germline mutations
iv. Somatic mutations a) Independent somatic alteration of both alle-
les of the VHL tumor suppressor gene lead- ing to tumorigenesis in nonfamilial (VHL- related) tumors
b) Somatic VHL gene mutations and allele loss: frequent events in sporadic clear cell
renal cell carcinomas and sporadic central nervous system hemangioblastoma; uncom- mon in sporadic (i.e., nontumor syndrome associated) pheochromocytoma
b. VHL gene i. Mapped on chromosome 3p25
ii. Involved in blood vessel formation by regula- tion of the activity of hypoxia-inducible factor (HIF)-1α
c. Patients with VHL disease i. With a positive family history: have inherited an
inactive VHL allele from an affected parent ii. Without a positive family history: have a parent
who is mosaic for a VHL mutation, presumably as the result of a de novo mutation during early development
d. Angiogenesis of VHL tumors: critical role of inacti- vation of VHL gene i. Overexpression of vascular endothelial growth
factor (VEGF) resulting in hypervascularization ii. Negative regulation of hypoxia-inducible mRNAs
including VEGF mRNA by VHL protein e. Tumor development in VHL disease
i. Linked to inactivation or loss of the remaining wild-type VHL allele in a susceptible cell, lead- ing to loss of the VHL gene product pVHL
ii. Inactivation of VHL gene contributing to tumori- genesis of the VHL tumor since VHL protein is required for the down-regulation of transcription activity of certain genes
CLINICAL FEATURES 1. Great variation in the clinical presentation with variable
age of onset 2. Classification of VHL disease
a. VHL type 1 i. Without pheochromocytoma
ii. Truncating or null mutations in the VHL gene (deletions or frameshift, nonsense, or splice site mutations) observed in approximately 96–97% of patients with type 1 VHL
b. VHL type 2 i. With pheochromocytomas
ii. Missense mutations observed in 92–98% of patients with type 2 VHL
c. Subtypes of type 2 VHL i. VHL type 2A
a) VHL without predisposition to renal cell car- cinoma and pancreatic neuroendocrine tumor
b) Specific mutations (Y98H, Y112H, V116F, L188V) in the VHL gene conferring an increased risk for VHL disease
1029
1030 VON HIPPEL-LINDAU DISEASE
ii. VHL type 2B a) VHL with predisposition to renal cell car-
cinoma and pancreatic neuroendocrine tumor
b) Specific mutations (R167Q, R167W) in the VHL gene conferring an increased risk for VHL disease
iii. VHL type 2C a) VHL with only pheochromocytoma mani-
festation b) Specific mutations (V155L, R238W) in the
VHL gene conferring an increased risk for VHL disease
3. Tumors/cysts linked to VHL disease, typically develop in the 2nd, 3rd, and 4th decades of life a. Retinal angioma/hemangioblastoma
i. Responsible for the first manifestation of VHL in 50% of the patients
ii. Retinal lesions a) Formerly called retinal angiomas b) Histologically identical to hemangioblastomas c) Identified in about 70% of the patients d) Bilateral in about 50% of the patients e) Multiple in about 66% of the patients
iii. Complications when the condition is unrecog- nized and untreated at early stage a) Majority of retinal angiomas eventually
hemorrhage. b) Resulting in massive exudation and retinal
detachment c) Ultimate development of neovascular glau-
coma and blindness b. Cerebellar hemangioblastomas (80% of CNS heman-
gioblastoma) i. The most common initial manifestation (34.9%)
ii. Cumulative occurrence: 60.2% iii. The most common cause of death (47.7%) iv. Symptoms and signs
a) Headache b) Slurred speech c) Nystagmus d) Positional vertigo e) Labile hypertension (without pheochromo-
cytoma) f) Vomiting g) Wide-based gait h) Dysmetria
c. Spinal hemangioblastoma (20% of CNS heman- gioblastoma) i. More specific for VHL disease
ii. About 80% of cases are caused by VHL. iii. Cumulative occurrence (14.5%) iv. Symptoms and signs
a) Pain b) Sensory and motor loss secondary to cord
compression d. Renal lesions
i. Renal cysts: Precursor lesions to clear cell renal carcinomas (75% of patients with VHL) which is a frequent cause of death
ii. Hemangioblastoma iii. Renal cell adenoma iv. Renal cell carcinoma (20–40%)
e. Pheochromocytomas (tumor of adrenal medulla) i. Type 1 families
a) Absence of pheochromocytomas b) Most type 1 families are affected by dele-
tions or premature termination mutations. ii. Type 2 families (7–20% of families)
a) Presence of pheochromocytomas b) Most type 2 families are affected by mis-
sense mutations. iii. Arg238trp and arg238gln mutations: associated
with a 62% risk for pheochromocytoma iv. Location of tumors
a) Usually located in one or both adrenal glands b) May present anywhere along the sympathet-
ic axis in the abdomen or thorax (paragan- gliomas) or head and neck (chemodectomas)
v. Symptoms and signs a) Sustained or episodic hypertension b) Asymptomatic
f. Pancreatic lesions i. Type of lesions
a) Simple pancreatic cysts b) Serous cystadenomas c) Pancreatic neuroendocrine tumors
ii. Rarely causing endocrine or exocrine insufficiency unless the lesion is extensive
iii. Occasionally causing biliary obstruction second- ary to cysts in the head of the pancreas
g. Liver lesions i. Hemangiomas
ii. Cyst iii. Adenoma iv. Carcinoid of the common bile duct
h. Splenic lesions i. Hemangiomas
ii. Cyst i. Pulmonary lesions
i. Hemangiomas ii. Cyst
j. Bladder hemangioblastoma k. Endolymphatic sac tumors of the inner ears (labyrinth)
i. Tinnitus or vertigo ii. Deafness
l. Papillary cystadenomas of the epididymis in males i. Relatively common in males
ii. Unilateral: rarely causing problem iii. Bilateral: infertility
m. Papillary cystadenomas of the broad ligament in females: much less common
n. Skin lesions i. Nevus
ii. Café au lait spot o. Bone lesions
i. Hemangioma ii. Cyst
4. Diagnosis of VHL disease usually made on clinical grounds
VON HIPPEL-LINDAU DISEASE 1031
a. A positive family history of VHL disease plus one of the following lesion (hemangioblastoma or visceral lesion): i. Retinal hemangioblastoma
ii. Cerebellar hemangioblastoma iii. Pheochromocytoma iv. Renal cell carcinoma v. Multiple pancreatic cysts
b. A negative family history of VHL disease need one of the following: i. Two or more retinal or cerebellar hemangioblas-
tomas ii. One hemangioblastoma plus one visceral tumor
5. Prognosis a. Life expectancy: <50 years b. Most common causes of death
i. Renal cell carcinoma ii. Cerebellar hemangioblastoma
c. Improved prognosis in patients with: i. Earlier diagnosis
ii. Regular monitoring for predictable complications iii. Followed by early interventions
DIAGNOSTIC INVESTIGATIONS 1. Biochemical test: elevated urinary catecholamines (VMA,
metanephrine, and total catecholamine) suggesting pheo- chromocytoma even in the absence of hypertension
2. Eye examinations a. Ophthalmoscopy b. Fluorescein angiography, a valuable tool useful in
detecting subclinical fundus lesions 3. Radiography for rare associated bone cysts and osseous
hemangiomas 4. Ultrasound examinations
a. Evaluation of the epididymus and broad ligament b. Screening of the kidneys
5. CAT scan a. To document the presence of CNS and visceral
tumors i. CNS hemangioblastomas
a) Cystic lesions (75%) b) An enhancing lesion with multiple cystic
areas (15%) c) An enhancing solid mass (10%)
ii. Retinal hemangiomas too small to be depicted on CT scans, the diagnosis mainly dependent on the results of an ophthalmoscopic examination
iii. Papillary endolymphatic sac tumors presenting as a thin peripheral rim of calcification, repre- senting the expanded cortex of petrous bone
b. Low sensitivity in the detection of renal cell carcino- ma associated with VHL i. Not reliable in differentiating cystic renal cell
carcinomas, cancers within a cyst, and atypical cysts
ii. Impossible to differentiate a renal cell adenoma from a renal cell carcinoma
6. MRI to document the presence of CNS and visceral tumors
a. MRI appearances of a CNS hemangioblastoma: a well-demarcated cystic lesion with a highly vascular mural nodule that always abuts on the pia mater
b. Spinal hemangioblastomas: intramedullary tumors in most patients (75%) but may be radicular (20%) or intradural extramedullary (5%)
c. Pheochromocytoma: high signal intensity on T2- wighted MRI, differentiating it from adrenal cortical nodules
d. Endolymphatic sac tumors: high signal intensity with T1 imaging on MRI as a mass on the posterior wall of the petrous part of the temporal bone
7. Radionuclide studies a. To provide an indication of metabolic activity of CNS
tumors by positron emission tomography (PET) with 2-[fluorine 18]-fluoro-2-deoxy-D-glucose (FDG)
b. To detect bone metastases resulting from primary malignant tumor of bone of VHL
c. To assess renal function prior to resection of renal tumors
d. To detect pheochromocytoma using iodine-131 metaiodobenzylguanidine (131I MIBG)
8. Angiography a. Hemangioblastoma: a hypervascular lesion with
intense and prolonged early enhancement of the mural nodule associated with dilated feeding vessels
b. Endolymphatic sac tumors i. Hypervascular on angiography and the blood
supply is derived from the external carotid artery ii. Large tumors with an additional blood supply
from the internal carotid artery and posterior circulation
9. Histologic features of VHL tumors a. High degree of vascularization b. Presence of a clear cell component
10. NIH group recommendation for monitoring VHL patients and family members a. Birth to 2 years
i. Annual physical examination ii. Annual ophthalmologic examination
b. 2–10 years: urinary catecholamines every 1–2 years c. 11–19 years
i. Biannual MRI of the brain and spine ii. Annual ultrasound examination of abdomen
iii. CT scans of abdomen every 6 months if renal cysts or tumor present
d. 20–59 years: annual CT scan of abdomen e. 60 years and above without VHL
i. MRI of the brain and spine every 3–5 years ii. CT scan of the abdomen every other year
f. Not necessary to monitor the family members identified previously with an empiric risk of 50% of being affect- ed but are found not to have inherited the mutation
11. Molecular genetic analysis a. Considered standard for the evaluation of patients and
families with suspected VHL disease b. Identification of VHL gene germline mutations
i. Identification of constitutional VHL gene dele- tions by FISH using probes from the VHL gene critical region in 3p25.3
1032 VON HIPPEL-LINDAU DISEASE
a) Offers a comprehensive way to screen for the presence of germline deletions because it enables visualization of individual cells
b) May identify mosaicism or cryptic translo- cation events that cannot be readily detected by other molecular strategies in patients with submicroscopic germline deletions and a nor- mal karyotype
c) Enable to identify a de novo mosaic for the VHL gene deletion
ii. Molecular diagnosis accomplished in virtually all families with classic VHL disease (families with multiple tumors) and in the majority of iso- lated patients with multiple VHL-associated tumors a) Qualitative and quantitative Southern blot-
ting to detect partial or complete gene dele- tions responsible for 28% of all cases
b) DNA-sequence analysis of the protein- encoding region (all three exons) to detect point mutations in the remainder (72%) of the cases
c. Mosaicism i. A potential cause for failure of molecular diag-
nosis in VHL ii. Individuals with mosaicism:
a) Asymptomatic b) Manifesting as a single-system disease c) Manifesting as a multisystem disease
d. Identification of a mutation in a proband allows the identification of mutation carriers among family members who do not yet exhibit any clinical manifes- tation of VHL
GENETIC COUNSELING 1. Recurrence risk
a. Patient’s sib i. A small risk of having a sib with VHL since
parental mosaicism accounts for some apparent- ly sporadic or new cases of VHL
ii. A 50% risk of having a sib with VHL disease if one of the parent is clinically affected or has a disease-causing VHL gene mutation
b. Patient’s offspring i. A 50% risk of inheriting the VHL disease-causing
mutation ii. An individual mosaic for a disease mutation is at
increased risk for having affected offspring, despite negative testing for the mutation by rou- tine DNA diagnostic tests
2. Prenatal diagnosis available by molecular genetic testing of fetal DNA obtained from amniocentesis or CVS for pregnancies at 50% risk when the disease-causing muta- tion has been identified in the affected parent
3. Management a. Ocular management
i. Laser photocoagulation therapy or cryotherapy of retinal lesions
ii. Several treatment strategies on the horizon that show promise for the ocular management of VHL disease a) Vascular endothelial growth factor (VEGF)
inhibitors b) Use of radiotherapy, such as brachytherapy
or linear-accelerated based radiosurgery b. Surgery: the mainstay of treatment for the tumors
arising in patients with VHL disease i. Renal cell carcinomas
a) Partial nephrectomy or radiofrequency abla- tion to spare renal function if tumor involve- ment is not extensive
b) Total nephrectomy often necessary for extensive tumor involvement
ii. CNS hemangioblastomas: radiation therapy in patients with CNS symptoms
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1034 VON HIPPEL-LINDAU DISEASE
Fig. 1. Retinal malformation secondary to von Hippel-Lindau disease.
Fig. 2. Retinal exudates from vascular leakage in a patient with von Hippel-Lindau disease.
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