OVERVIEW: What every practitioner needs to know

Von Hippel-Lindau (VHL) disease is a hereditary disease characterized by neoplasms affecting multiple organ systems, resulting from inactivating mutations of the VHL tumor suppressor gene. The various cancers of VHL typically appear in adulthood, although the initial manifestations can occur in adolescence.

Are you sure your patient has Von Hippel-Lindau disease? What are the typical findings for this disease?

The primary findings of VHL are listed below. In parentheses are rough estimates of the incidence of each:

Hemangioblastomas of the brain or spinal cord (40%-70%)

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Clear cell renal cell carcinoma (70%)

Retinal angiomas (also known as retinal hemangioblastomas) (60%)

Serous cystadenomas (70%) or neuroendocrine tumors of the pancreas (15%)

Papillary cystadenomas of the epididymis (40%) or broad ligament (rare)

Endolymphatic sac tumors of the ear (15%)

Pheochromocytomas (10%)

What other disease/condition shares some of these symptoms?

Any of the key findings described above should raise the suspicion of VHL, but each may also appear in isolation. Pheochromocytomas can be seen in familial pheochromocytoma, in non-familial bilateral pheochromocytoma, or in patients with multiple endocrine neoplasia syndromes.

What caused this disease to develop at this time?

VHL is an autosomal dominant genetic disorder, but can also arise sporadically in 20% of affected patients. It is not known what influences the timing of the various manifestations.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

If VHL is suspected due to the clinical findings, or if a patient is at risk due to an affected parent, molecular testing for the VHL gene should be obtained, along with referral to a geneticist or genetic counselor. The sensitivity and specificity of VHL testing is almost 100%.

Would imaging studies be helpful? If so, which ones?

Imaging with CT or MRI is usually obtained to evaluate for or confirm the findings which are associated with VHL, as indicated by the particular neoplasm of interest. See the screening guidelines below.

Confirming the diagnosis

If there is no family history of VHL, then a diagnosis is established with either:

a) two or more hemangioblastomas of the central nervous system, or

b) one retinal or brain hemangioblastoma together with any one of the following: pheochromocytoma, renal cell carcinoma, serous cystadenoma or neuroendocrine tumor of the pancreas, papillary cystadenoma of the epididymis and broad ligament.

With a positive family history of VHL, a diagnosis is made with any one of the following: renal cell carcinoma (before age 60), central nervous system hemangioblastoma, retinal angioma, multiple renal or pancreatic cysts, cystadenomas of the epididymis or broad ligament. However, when there is concern for VHL due to an affected family member, the diagnosis can be made with molecular genetic testing for VHL.

General screening guidelines for asymptomatic individuals with VHL include:

Annually: Physical exam, urine screen with cytology for renal cell carcinoma, direct and indirect ophthalmoscopy, renal ultrasound, fluorescein angiography of the eye, 24-hour urine collection for vanillylmandelic acid levels, abdominal ultrasound (beginning in adolescence).

Any hearing complaints should be evaluated with audiology.

Every 3 years: MRI of the brain and spine (to age 50; every 5 years after age 50), abdominal CT. Some experts question the utility of screening MRIs in asymptomatic individuals.

These guidelines fall in the category of expert opinion, and their validity has not been formally assessed.

If you are able to confirm that the patient has Von Hippel-Landau disease, what treatment should be initiated?

Currently, any treatments for VHL are directed at the specific clinical problem which is present. The treatment is generally not affected by the overall diagnosis (i.e., treat the pheochromocytoma as if one would an isolated case). There is no overall pharmacologic or other global treatment available for VHL.

What are the adverse effects associated with each treatment option?

The adverse effects of the treatment for any of the features seen in VHL are similar to those which could occur in treating those conditions in the absence of VHL. There are no specific risks or concerns which a diagnosis of VHL confers on the various treatments.

What are the possible outcomes of Von Hippel-Lindau disease?

Outcomes in VHL vary widely from person to person, and depend on the specific pathology which arises. The leading cause of death is renal cell carcinoma. CNS hemangioblastomas can cause significant neurologic impairment, depending on the location, even with treatment. Retinal lesions may lead to blindness, and endolymphatic sac tumors can result in deafness.

What causes this disease and how frequent is it?

VHL is an autosomal dominant disorder and is thought to occur in 1 of 36,000 live births. It has a high penetrance, such that nearly all people with VHL mutations will have one of the key features of VHL during their lifetime.

How do these pathogens/genes/exposures cause the disease?

The VHL gene on chromosome 3p25 encodes for the VHL tumor suppressor protein. This protein is constitutively translated in most cells, and is involved in suppressing hypoxia-inducible factor (HIF). In the setting of hypoxia, HIF is the transcription factor that is involved in the regulation of multiple cellular cascades and homeostatic mechanisms.

It is not currently clear why VHL gene mutations lead to the specific set of abnormalities seen in VHL. A thorough discussion of the mechanism of pathology of VHL is beyond the scope of this text, but see the article by Kaelin (2007) for a detailed review.

Other clinical manifestations that might help with diagnosis and management


What complications might you expect from the disease or treatment of the disease?

Complications are related to the surgical, medical, or radiation therapy undertaken to address the specific malignancy involved.

Are additional laboratory studies available; even some that are not widely available?

Commercial testing for VHL is available, which has nearly 100% sensitivity and specificity.

How can Von Hippel-Lindau disease be prevented?

As an autosomal dominant disorder, VHL cannot be prevented once an individual has the mutation. Genetic counseling of patients with VHL who wish to have children should be provided. Testing for a VHL mutation in a fetus is possible with amniocentesis or chorionic villus sampling. Preimplantation genetic diagnosis is also available.

What is the evidence?

Diagnostic algorithms and treatment protocols for VHL are largely based on expert opinion. There are no large scale trials which have assessed how a particular screening method or frequency affects outcomes. The evidence for treatment depends on the particular feature of VHL being treated and will not be discussed here.

Kaelin, WG. “Von Hippel-Lindau disease”. Annu Rev Pathol. vol. 2. 2007. pp. 145-73. A detailed review of the molecular basis of pathology seen in VHL.

Kim, JJ, Rini, BI, Hansel, DE. “Von Hippel Lindau syndrome”. Adv Exp Med Biol. vol. 685. 2010. pp. 228-49. A review of VHL syndrome, including a section devoted to the diagnosis and treatment of each of the primary clinical manifestations of VHL.