AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Background

von Hippel-Lindau (VHL) disease is a rare inherited disorder manifested by visceral cysts, benign masses, and the potential for malignant transformation in multiple organ systems. Clinical hallmarks of VHL are development of retinal and central nervous system (CNS) hemangioblastomas, pheochromocytomas, multiple cysts of the pancreas and kidneys, and a high potential for malignant transformation of renal cysts into carcinoma. Given the wide age range and pleiotropic manner in which VHL disease manifests, diagnosis of VHL and treatment of patients and their at-risk relatives are challenging.

Pathophysiology

The VHL gene resides on the short arm of chromosome 3 and encodes a ubiquitously expressed 4.7-kilobase (kb) messenger RNA (mRNA) that encodes 3 alternately spliced exons. The resultant 2 VHL proteins (pVHL) shuttle between the nucleus and the cytoplasm, where they form a complex with several proteins.

Functions of pVHL are as follows:

• Polyubiquitination: pVHL forms a complex with several proteins (elongins B and C, Cullin2, Rbx1). This multiprotein complex ubiquitinates different substrates, thus marking them for degradation. Ubiquitinated substrates are normally degraded, thus defective pVHL leads to the accumulation of undegraded products. pVHL gives the complex its target specificity, recruiting specific proteins to the complex for degradation. Two of the key targets that are recruited to the complex under normal oxygen conditions are the transcription factors HIF1a and HIF2a.
• Regulation of hypoxia-inducible factors (HIF1a, HIF2a): Cells lacking pVHL fail to degrade HIF in the presence of oxygen, thus permitting accumulation of high levels of stable protein and activating transcription of a large cohort of hypoxia responsive genes constitutively. While many tumors have high levels of HIF genes in hypoxic regions of the tumor, tumors resulting from VHL inactivation express high levels of HIF genes in all of the tumor cells.
• Regulation of other hypoxia-inducible genes: Cells without pVHL activity overproduce other hypoxia-induced mRNAs such as erythropoietin (EPO), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and enzymes involved in glycolysis through HIF-mediated transcription. Tumors associated with VHL are often highly vascular, possibly because of overproduction of these mRNAs. Paraneoplastic polycythemia is frequently observed as a result of erythropoietin production.
• Interaction with the extracellular matrix: pVHL also binds to microtubules and to fibronectin, a glycoprotein that interacts with structural proteins of the cell. Cells with defective pVHL have increased proliferation and decreased differentiation.
• Cell cycle control: This is likely a multifactorial activity; pVHL can interact with cyclin D1 and affects the exit from the cell cycle.

The mechanism by which loss of VHL function causes tumorigenesis is not yet fully understood. The VHL gene may act as a classic tumor suppressor gene, as originally described by Knudson in his 2-hit theory of carcinogenesis. When an individual inherits a germline mutation that renders one VHL allele inactive, an acquired "second hit" in the other VHL allele in a somatic cell leaves that cell without tumor suppressor activity, leading to a selective growth advantage and an increased risk of malignant progression. The ubiquitous expression of the VHL protein explains, to some extent, the pleiotropic manifestations of this disorder.

Frequency

United States

VHL disease is transmitted in an autosomal dominant fashion with a frequency of approximately 1 case per 36,000 population.

Mortality/Morbidity

Due largely to the high incidence of renal carcinoma (approximately 40% of people with VHL eventually develop this complication), the average life expectancy of individuals with VHL is 49 years. However, diligent surveillance may increase life expectancy. The current surveillance strategies outlined in Further Outpatient Care will hopefully improve this statistic.

The morbidity of VHL varies, depending on the particular organ system involved.

• The most serious sequela of VHL involves malignant degeneration of renal cysts. Renal cysts are seldom clinically significant; however, they have an appreciable rate of malignant transformation, and renal cell carcinoma (RCC) is the leading cause of death in patients with VHL disease (35-75% prevalence in one autopsy series). The average age at which patients with VHL develop RCC is 44 years. These facts reinforce the importance of obtaining renal imaging studies on a regular basis.
• The second most common cause of morbidity and mortality in patients with VHL is CNS hemangioblastomas. Approximately 70% of affected individuals develop such tumors at some point, and they typically occur below the tentorium (80% of the time in the cerebellum, 20% of the time in the spine). The mean age at diagnosis is 25 years. While the lesions are rarely malignant, enlargement of the tumors within the confines of the CNS can result in neurologic compromise and death if they are not resected. Retinal hemangioblastomas, while also not malignant, can result in considerable morbidity through retinal detachment or visual loss from an enlarging lesion.
• Via secreted catecholamines, development of pheochromocytomas can result in hypertension and its numerous deleterious sequelae. Pancreatic lesions are simple cysts and rarely cause symptoms or develop into malignant tumors. Endolymphatic sac tumors are seen in approximately 10% of patients and can cause deafness of varying severity. Epididymal tumors are present in approximately 50% of patients with VHL. They are papillary cystadenomas and rarely cause problems. When they occur bilaterally, these cystadenomas may result in infertility. For women, the equivalent lesion is a papillary cystadenoma of the ovarian broad ligament.

Race

VHL disease affects all races and ethnic groups without apparent differences in incidence.

Sex

No sex predilection exists.

Age

Age at diagnosis varies from infancy to the seventh decade of life. Average age at diagnosis due to clinical manifestations is 26 years.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

History

The unexpected finding of a retinal or CNS hemangioblastoma or the diagnosis of a pheochromocytoma should prompt a search for other VHL-associated stigmata, since many of these individuals meet the criteria for diagnosis. Identification is important, given the increased risk of serious complications (eg, renal cancer) that are readily treated with early intervention.

Since VHL disease is a multiorgan disease with great variability in clinical presentation, a variety of manifestations may lead to diagnosis. Acceptable criteria for diagnosis are as follows:

• More than one hemangioblastoma in the CNS or retina
• • A single hemangioblastoma of the CNS or retina plus a visceral manifestation (multiple renal, pancreatic, or hepatic cysts; pheochromocytoma; renal cancer)
  • Definite family history plus any one of the above manifestations
  • Elucidation of a deleterious mutation in the VHL gene
• Since VHL is a genetic disorder, diagnosis is important in family members. Since the interpretation of pedigree information and the results of mutational analysis can be complicated, the assistance of a geneticist is highly recommended.
• Even if VHL manifestations are not discovered upon first evaluating an at-risk relative, these individuals should have periodic surveillance for VHL-associated lesions through age 60-70 years.
• Genetic testing is indicated for identifying individuals in a family who have inherited a VHL mutation. Those who test positive for a mutation require life-long surveillance, while at-risk family members who test negative for a known familial mutation do not need further diagnostic examination or surveillance.
• Since VHL is inherited in an autosomal dominant fashion, children of affected patients have a 50% risk of inheriting the disorder. Siblings, parents, and relatives who are more distant are at risk for VHL disease as well. Thus, the diagnosis in an individual mandates a careful family history and diagnostic studies of appropriate relatives to detect serious complications while they are still in the early, hopefully treatable, stages. Regular surveillance is strongly suggested for these at-risk individuals as outlined above, at least until age 60 years or until genetic testing excludes the presence of the familial mutant allele in an individual. New mutations (ie, no mutation identified in either parent) occur in approximately 25% of patients.

Physical

Manifestations are pleiotropic. In the early stages, most aspects of VHL can be detected only with detailed imaging studies, biochemical analyses, or both.

• Retinal hemangioblastomas
• • Approximately one half of individuals with VHL have retinal hemangioblastomas. These lesions are revealed during direct ophthalmoscopic evaluation. They appear as a dilated artery leading from the disc to a peripheral tumor with an engorged vein. Patients usually present with retinal hemangioblastomas in the third decade of life. While patients with retinal hemangioblastomas are usually asymptomatic, enlargement or a central location can result in significant visual loss. Moreover, the presence of retinal hemangioblastomas can predispose patients to retinal detachment, macular edema, and glaucoma. Early detection followed by laser coagulation or cryotherapy can prevent significant visual loss.
• CNS hemangioblastomas
• • CNS hemangioblastomas are histologically identical to retinal hemangioblastomas and are almost exclusively subtentorial. The mean age at diagnosis is 25 years. Most often, CNS hemangioblastomas are located in the cerebellum, but they also can be found in the brainstem and spinal cord.
  • Although CNS hemangioblastomas are histologically benign, they may result in diverse neurologic symptoms, which are dictated by the precise location. Hemorrhage into the lesions appears to be relatively unusual. CNS hemangioblastomas are best detected using gadolinium-enhanced MRI, and they often are resected surgically.
• Renal involvement
• • As many as 76% of VHL patients demonstrate multiple renal cysts. While the lesions themselves are not problematic, they do have a significant predilection to degenerate to clear cell RCC, which is the major cause of excess mortality. RCC is the presenting feature in only 10% of patients, but the risk of developing RCC by age 60 years is approximately 70%. RCC develops in patients at an average age of 44 years, which is significantly younger than the average age of 62 years, when sporadic RCC develops in the general population. In addition to simple cysts and RCC, a number of other renal lesions are seen, such as hemangiomas and benign adenomas.
  • Periodic imaging of the kidneys (via ultrasound, CT, MRI) is mandatory in patients and at-risk relatives. Type of renal imaging should be dictated by local expertise in various imaging modalities.
  • Usually, a nephron-sparing approach to treatment of patients with RCC, such as tumor excision or partial nephrectomy, is used in an attempt to preserve renal function. However, given the high incidence of subsequent tumors, it is not unusual for a patient to ultimately progress to bilateral nephrectomy, necessitating transplant or dialysis.
• Pheochromocytoma
• • Patients are at increased risk for developing pheochromocytomas. The risk of developing such tumors (which are usually histologically benign) appears to hinge on the precise nature of the mutation responsible for VHL disease in a specific family. In kindreds with VHL who demonstrate a deletion or protein-truncating mutation of the VHL gene (type 1 VHL), the risk for pheochromocytoma is less than 10%. However, the risk is approximately 50% for pheochromocytoma development in kindreds with a missense mutation (type 2 VHL).
  • Screen patients and at-risk family members for the presence of pheochromocytomas with standard biochemical means. When detected, treatment is identical to that in patients with sporadic pheochromocytomas.
• Other lesions
• • Various other lesions are observed, including epididymal cysts, epididymal cystadenomas, and multiple pancreatic cysts. Most pancreatic lesions are asymptomatic and benign, but, occasionally, a malignant islet cell tumor, a functioning islet cell tumor, or a frank pancreatic carcinoma arises in patients with VHL. Thus, abdominal imaging should be performed regularly, keeping in mind the potential for pancreatic malignancy.
  • Endolymphatic sac tumors have been described as part of the VHL spectrum. Searching for these tumors in at-risk individuals who present with otologic symptoms such as deafness and tinnitus is important.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Retinal hemangioblastomas and CNS hemangioblastomas are pathognomonic for VHL disease, and their presence is a critical clue to diagnosis. These lesions also clearly differentiate VHL disease from similar entities that can confuse the practitioner.

While a diagnosis of pheochromocytoma should prompt consideration of both VHL disease and multiple endocrine neoplasia type 2, the latter is easily differentiated from VHL disease by the frequent presence of parathyroid tumors and medullary thyroid carcinoma.

Multiple paragangliomas are observed in individuals with mutations in the succinate dehydrogenase gene, subunits B, C, and D. Paragangliomas are endocrinologically active tumors of the sympathetic nervous system that are histologically identical to pheochromocytomas. However, they occur in the head and neck region, distinguishing them from pheochromocytomas. They are not part of the spectrum of manifestations seen in VHL.

Multiple renal cysts are found in autosomal dominant polycystic kidney disease (ADPKD), and these cysts are much more numerous than in patients with VHL disease. The architecture of the kidneys is distorted, adversely affecting renal function. Little potential exists for malignant degeneration in ADPKD. While CNS lesions are seen in both disorders, the lesions in ADPKD consist of arterial aneurysms and not hemangioblastomas, as in VHL. Hepatic cysts are frequent in ADPKD but rare in VHL disease, while the converse is true for pancreatic cysts.

An autosomal dominant predisposition to renal cell carcinoma is occasionally observed but is not related to VHL mutations if none of the other manifestations of VHL are observed.

Consider tuberous sclerosis complex (TSC) in the differential diagnosis of multiple renal lesions. While renal cysts occur in both TSC and VHL, the renal tumor that typically is seen in TSC is the angiomyolipoma, which has a rather characteristic appearance on CT scans and MRI. TSC is also characterized by a number of dermatologic manifestations, such as facial or periungual fibroma and ash-leaf spots, as well as a high risk for mental retardation and epilepsy.

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Lab Studies

• Conduct the following annual laboratory studies in individuals with VHL disease, in patients in whom VHL disease is suspected, and in relatives who are at risk for VHL:
• • CBC count to look for evidence of polycythemia vera due to erythropoietin expression by renal cysts and cerebellar hemangioblastomas
  • Urine study for vanillylmandelic acid (VMA) and metanephrines
  • Urinalysis for hematuria, which can be present in renal cell carcinoma
  • Urine cytology to detect the presence of clear cell renal carcinoma

Imaging Studies

• Annual abdominal imaging studies are suggested in individuals diagnosed with VHL disease, in individuals in whom VHL disease is suspected, and in at-risk relatives of a patient with VHL disease.
• • Pay specific attention to the kidneys because of the high risk of renal carcinoma.
  • CT scan of the abdomen with and without contrast usually is the most accepted form of surveillance; however, MRI may be of equal or greater efficacy, depending on expertise of the personnel performing and interpreting MRIs.
• CNS imaging: Periodic imaging to detect hemangioblastomas of the brain and spinal cord is usually not required. These tumors are typically benign; therefore, imaging is needed only if symptoms or signs manifest during neurologic examination.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical Care

• An annual physical examination, with specific attention to possible neurologic manifestations of CNS hemangioblastoma, is suggested in individuals with VHL disease, in individuals with suspected VHL disease, or in at-risk relatives.
• Focal neurologic signs should prompt imaging of the brain, spinal cord, or both. MRI is the preferred modality because of the preponderance of subtentorial and posterior fossa tumors.
• Medical care for patients with VHL is dictated entirely by the specific complications that present. Most therapies for complications of VHL are surgical (eg, excision of tumors of the CNS, adrenal glands). Thus, the most crucial aspect of medical care in these patients is close surveillance and prompt evaluation with appropriate imaging.
• A substantial minority of patients eventually require renal dialysis, as the presence of tumors necessitates nephrectomy.
• The increasing knowledge about the molecular role of pVHL has led to clinical trials of several antiangiogenic drugs designed to reduce or prevent tumorigenesis in VHL. Those remain under investigation and are not available outside of a research protocol.
• Annual ophthalmologic examination is recommended because of the risk for retinal hemangioblastomas.

Surgical Care

Surgery is the mainstay of treatment for tumors that arise in patients with VHL. The standard of care is organ-sparing surgery.

• The most significant life-threatening tumor that tends to occur in individuals with VHL is renal cell carcinoma. Partial nephrectomy or radiofrequency ablation is preferred to spare renal function if tumor involvement is not extensive. However, total nephrectomy is often necessary because of extensive tumor involvement.
• Since multiple primary tumors are common in VHL, bilateral nephrectomies may ultimately be required. Bilateral nephrectomies necessitate renal dialysis or transplantation.
• CNS hemangioblastomas are typically not malignant; thus, they can be monitored if their size is stable and they are not producing neurologic symptoms or signs. However, if these tumors cause neurologic symptoms, neurosurgical excision is required.
• Retinal hemangioblastomas should be monitored by an ophthalmologist. Treatment typically consists of laser treatment or cryotherapy to preserve vision.

Consultations

Consult a geneticist or genetic counselor when dealing with an individual or family in which VHL has been diagnosed. Genetic counseling is critical because this diagnosis may impact family members who are at risk and because the interpretation of genetic testing is often complex.

As a result of the multiorgan nature of this disease, the following specialists should be involved in the patient's care:

• Consult an ophthalmologist because of the risk of retinal hemangioblastoma.
• Obtain consultations with surgeons as needed, depending on the results of surveillance studies as detailed elsewhere in this article. Typically, a urologist is consulted with regard to the discovery of renal masses, and neurosurgeons are consulted with concerns about CNS masses.
• An endocrinologist may be helpful in interpreting the results of laboratory tests used for pheochromocytoma surveillance.

Diet

The VHL Family Alliance offers some diet guidelines that rely more on expert opinion and common sense than on randomized trials. They encourage patients with VHL and at-risk family members to do the following:

• Limit alcohol intake.
• Increase consumption of phytochemicals, such as grains, cruciferous and other vegetables, fruits, and spices.
• Decrease consumption of protein from fish, poultry, and meat.

Activity

No evidence exists to indicate that people with VHL should limit their physical activities, except for short periods of recuperation after surgeries. Moderate exercise is likely beneficial to most.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• As a result of the pleiotropic clinical manifestations of VHL disease and the potential for malignancy, a lifelong strategy of surveillance (particularly in the eyes, CNS, and kidneys) is necessary for early detection and treatment of complications. A reasonable annual surveillance strategy for affected patients and at-risk relatives is as follows:
• • Obtain laboratory studies annually, commencing at age 5 years. Testing consists of urinalysis, urine cytologic examination, 24-hour urinary metanephrine, VMA analysis, and CBC counts.
  • Perform annual direct and indirect ophthalmoscopic examinations, beginning in children aged 5 years.
  • Perform audiologic examination at the first sign of hearing problems, vertigo, or tinnitus.
  • Some experts recommend that MRI of the brain and posterior fossa be performed every 2-3 years, beginning at age 10-15 years. This is controversial; typically, space-occupying lesions in the CNS cause symptoms, and, if asymptomatic, they usually would not be resected.
  • Obtain annual abdominal MRI or CT scans (depending on local availability) beginning at approximately age 16 years because of the high risk for renal cancer.
• Screening may be discontinued in at-risk relatives at approximately age 60 years if no abnormalities have been found.
• Genetic testing
• • Once diagnosed, a search for the causative mutation (in the originally identified patient or "proband") can benefit family members. If the proband's causative mutation can be identified, then its presence or absence in at-risk family members can reliably and unequivocally define their status. Individuals who have not inherited the mutant VHL allele can dispense with the burdensome and expensive task of unnecessary annual screening, while individuals with the mutant allele can be monitored closely for early manifestations of VHL disease.
  • Genetic testing for mutations in the VHL gene requires complete sequencing of the coding regions and is approximately 80% sensitive. The addition of Southern blot analysis detects virtually all mutations. In the rare event that no causative mutation is identified in the proband, all at-risk relatives must continue to undergo annual screening at least until age 60 years, as outlined above.

Patient Education

• Genetic testing is performed at several laboratories in the United States, including the following:
• • Boston University School of Medicine, Center for Human Genetics, Boston, Mass
  • Children's Mercy Hospital, Molecular Genetics Laboratory, Kansas City, Mo
  • Johns Hopkins Hospital, DNA Diagnostic Laboratory, Baltimore, Md
  • University of Pennsylvania School of Medicine, Genetic Diagnostic Laboratory, Philadelphia, Pa
• Patients and families may benefit from contacting the VHL Family Alliance at 800-767-4845 or e-mail info@vhl.org.
• The National Cancer Institute sponsors a Web site with general information that may be useful to patients with VHL disease and their families.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize VHL disease results in risk to the patient because further appropriate screening modalities will not be performed.
• If a patient presents with one manifestation of VHL disease (eg, retinal hemangioblastoma), treating the manifestation in isolation is not sufficient. The patient is at risk for additional life-threatening problems that may not be immediately obvious. If screening is not initiated for occult manifestations, the physician may be liable when the patient presents with other manifestations (eg, advanced RCC). Surveillance for VHL-associated conditions is considered the standard of care, and failure to implement such measures may result in liability.
• Consider VHL disease in a patient in whom retinal or cerebellar hemangioblastoma, multiple renal cysts, or a pheochromocytoma is diagnosed.
• Since VHL disease is inherited, potential liability exists in another major area. If VHL disease is diagnosed in a patient, it is imperative that an extensive family history be obtained and that appropriate family members are screened for VHL disease. If family members are not notified of the risk and are unaware of the need to undergo regular examinations, substantial morbidity and mortality may result, with obvious legal ramifications.
• For the above reasons, it is strongly recommended that a geneticist or genetic counselor be consulted when a patient is thought to have VHL disease.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

• Decker HJ, Weidt EJ, Brieger J. The von Hippel-Lindau tumor suppressor gene. A rare and intriguing disease opening new insight into basic mechanisms of carcinogenesis. Cancer Genet Cytogenet. Jan 1997;93(1):74-83. [Medline].
• Huson SM, Rosser EM. Von Hippel-Lindau disease. In: Rimoin DL, Connor JM, Pyeritz RE, Emery AE, eds. Emery and Rimoin's Principles and Practice of Medical Genetics. 3rd ed. Churchill Livingston;1996:2290-5.
• Johns Hopkins University. #193300. OMIM: Online Mendelian Inheritance in Man. Accessed June 3, 2002. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=193300. [Full Text].
• Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. Dec 15 2004;22(24):4991-5004. [Medline].
• Lindor NM, Greene MH. The concise handbook of family cancer syndromes. Mayo Familial Cancer Program. J Natl Cancer Inst. Jul 15 1998;90(14):1039-71. [Medline].
• Maher ER, Kaelin WG Jr. von Hippel-Lindau disease. Medicine (Baltimore). Nov 1997;76(6):381-91. [Medline].
• Richards FM, Webster AR, McMahon R, et al. Molecular genetic analysis of von Hippel-Lindau disease. J Intern Med. Jun 1998;243(6):527-33. [Medline].
• Schimke RN, Collins DL, Stolle CA. von Hippel-Lindau Syndrome. GeneTests GeneClinics web site. 1 December 2004. Available at http://www.geneclinics.org. Accessed June 13, 2002.
• Schoenfeld AR, Davidowitz EJ, Burk RD. Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products. PNAS. 2000;97:8507-8512.
• Sun X, Kanwar JR, Leung E. Regression of Solid Tumors by Engineered Normal Expressin of VHL Tumor Supressor Protein and Anti-Sense Hypoxia-Inducible Factor-1 Alpha. Gene Therapy. 2003;25:2081-2089.

Article Last Updated: May 23, 2006