von Hippel-Lindau Disease 

Von Hippel-Lindau disease, or von Hippel-Lindau syndrome, is a rare genetic disorder characterized by visceral cysts, benign masses, and the potential for malignant transformation in multiple organ systems.

Clinical hallmarks of von Hippel-Lindau disease are the development of retinal and central nervous system (CNS) hemangioblastomas, pheochromocytomas, multiple cysts in the pancreas and kidneys, and an increased risk for malignant transformation of renal cysts into carcinoma. Because of the wide age range and pleiotropic manner in which von Hippel-Lindau disease presents, the diagnosis and the treatment for affected individuals, as well as their at-risk relatives, can be challenging. (See the image below.)

Hemangiomas

Von Hippel-Lindau disease is characterized by benign capillary hamartomas with autosomal dominant inheritance with variable penetrance.^[1] Retinal capillary hemangiomas (von Hippel disease) are seen in 50% of patients. They are composed of endothelial cells and pericytes. The foamy stromal cells between the capillaries stain positive for glial fibrillary acid protein and neuron-specific enolase.^[2]

Similar tumors in the CNS, such as hemangioblastomas in the cerebellum (ie, von Hippel-Lindau disease), and other organs of the body are present in 25% of patients.^[3] Cysts of the pancreas and kidneys may coexist.

Retinal capillary hemangiomas, usually supplied by large, dilated feeder vessels, may occur in any part of the retina. Serum leakage from these vessels and hemangiomas leads to retinal exudates. Organized fibroglial bands with traction retinal detachment and vitreous hemorrhage may occur, with their own secondary sequelae.^[4] (See the image below.)

Diagnostic considerations

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

Because von Hippel-Lindau disease, or von Hippel-Lindau syndrome, is a multiorgan disease that widely varies in clinical presentation, various manifestations may lead to diagnosis. These include the following:

• More than 1 hemangioblastoma in the CNS or retina is acceptable for the diagnosis of von Hippel-Lindau disease.
• 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 1 of the above manifestations
• Elucidation of a deleterious mutation in the von Hippel-Lindau gene

Genetic testing is performed at several laboratories in the United States, including the following:

• Boston University School of Medicine, Center for Human Genetics, Boston, Massachusetts
• Children's Mercy Hospital, Molecular Genetics Laboratory, Kansas City, Missouri
• Johns Hopkins Hospital, DNA Diagnostic Laboratory, Baltimore, Maryland
• University of Pennsylvania School of Medicine, Genetic Diagnostic Laboratory, Philadelphia, Pennsylvania

Epidemiology

Von Hippel-Lindau disease is inherited in an autosomal dominant Mendelian pattern; its frequency in the United States is approximately 1 case per 36,000 newborns. Age at diagnosis varies from infancy to age 60-70 years. The average age of clinical diagnosis in patients is 26 years.

The von Hippel-Lindau gene is located on the short arm of chromosome 3 (3p26-p25) and encodes a ubiquitously expressed 4.7-kilobase (kb) messenger ribonucleic acid (mRNA) that encodes 3 alternately spliced exons. The resultant 2 von Hippel-Lindau proteins (pVHL) shuttle between the nucleus and the cytoplasm, where they form a complex with several proteins. At present, this gene is the only gene known to cause von Hippel-Lindau disease.

The ubiquitous expression of pVHL explains, to some extent, the pleiotropic manifestations of von Hippel-Lindau disease.

Functions of pVHL

Polyubiquitination

Von Hippel-Lindau protein forms a complex with several other proteins (elongins B and C, Cullin2, Rbx1). This multiprotein complex ubiquitinates different substrates, thus marking them for degradation. Ubiquitinated substrates are normally degraded, which means that defective pVHL leads to the accumulation of undegraded products.

Von Hippel-Lindau protein 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 (hypoxia-inducible factor-1a) and HIF2a.

Regulation of HIF1a and HIF2a

Cells lacking pVHL fail to degrade HIF in the presence of oxygen, thus permitting accumulation of high levels of stable protein and activating the transcription of a large cohort of hypoxia-responsive genes constitutively. Although many tumors have high levels of HIF genes in hypoxic regions of the tumor, tumors resulting from von Hippel-Lindau 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 those for 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 von Hippel-Lindau disease 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

Von-Hippel-Lindau protein 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.

Tumorigenesis

The mechanism by which the loss of pVHL function causes tumorigenesis is not yet fully understood. The von Hippel-Lindau gene may act as a classic tumor suppressor gene, as originally described by Knudson in his 2-hit theory of carcinogenesis.^[5] When an individual inherits a germline mutation that renders one von Hippel-Lindau allele inactive, an acquired "second hit" in the other von Hippel-Lindau allele in a somatic cell leaves that cell without tumor suppressor activity. Application of Knudson's theory leads to a selective growth advantage and an increased risk of malignant progression.

Due largely to the high incidence of renal cell carcinoma (approximately 40% of affected individuals will develop this complication), the average life expectancy of individuals with von Hippel-Lindau disease is 49 years. However, diligent surveillance may increase life expectancy. The morbidity of von Hippel-Lindau disease varies, depending on the particular organ system involved.

Renal lesions

The primary cause of morbidity and mortality in von Hippel-Lindau disease, as well as the most serious sequela of the condition, involves the malignant degeneration of renal cysts. Renal cysts are seldom clinically significant; however, in von Hippel-Lindau disease they have an appreciable rate of malignant transformation.

Consequently, renal cell carcinoma is the leading cause of death in patients with von Hippel-Lindau disease, with a prevalence of as high as 75% reported in one autopsy series.

The average age at which patients with von Hippel-Lindau disease develop renal cell carcinoma is 44 years, about 20 years before the age at which sporadic renal cell carcinoma typically occurs in the general population. Moreover, although renal cell carcinoma is the presenting feature in approximately 10% of patients with von Hippel-Lindau disease, the risk of developing renal cell carcinoma by age 60 years is approximately 70% for patients with this disorder. These facts reinforce the importance of obtaining renal imaging studies on a regular basis.

In addition to simple cysts and renal cell carcinoma, numerous other renal lesions are seen, such as hemangiomas and benign adenomas.

Periodic imaging of the kidneys (via ultrasonography, computed tomography [CT] scanning, magnetic resonance imaging [MRI]) is mandatory in patients and at-risk relatives. The type of renal imaging used should be determined by local expertise in various imaging modalities.

A nephron-sparing approach for treatment of patients with renal cell carcinoma, such as tumor excision or partial nephrectomy, is often used in an attempt to preserve renal function. However, because of the high incidence of subsequent tumors, many patients ultimately progress to bilateral nephrectomy, necessitating dialysis or transplantation.

CNS hemangioblastomas

CNS hemangioblastomas are the second most common cause of morbidity and mortality in patients with von Hippel-Lindau disease. Approximately 70% of affected individuals develop these tumors, with the mean age of diagnosis being 25 years. The lesions typically occur below the tentorium, with 80% of them in the cerebellum and 20% of them in the spine. Although hemangioblastomas are usually benign, enlargement of these tumors within the confines of the CNS can cause neurologic compromise and death. (See the image below.)

CNS hemangioblastomas are best detected using gadolinium-enhanced magnetic resonance imaging (MRI) and are often surgically resected.

Retinal hemangioblastomas

Retinal hemangioblastomas are diagnosed at an average age of 29 years. Although patients with retinal hemangioblastomas are usually asymptomatic, these benign ocular tumors can lead to considerable morbidity through retinal detachment or vision loss from an enlarging lesion. (Among patients with retinal angiomas, 25% have associated cerebellar hemangioblastomas.^[6] ) Visual complications of retinal angiomas include the following:

• Macular exudation
• Retinal detachment
• Vitreous hemorrhage
• Cataract
• Glaucoma
• Nerve damage
• Iatrogenic complications from argon laser photocoagulation, cryotherapy, or irradiation

Loss of vision usually is caused by lipid exudate in the macula area. If left untreated, this exudation can lead to retinal detachment. Vitreous hemorrhage, secondary iris neovascularization with glaucoma, and cataract formation may follow.

Early detection of retinal hemangioblastomas and treatment with diathermy, laser, or cryocoagulation can prevent significant vision loss.

Endolymphatic sac tumors

Endolymphatic sac tumors (ELSTs) of the middle ear are vascular lesions growing within the posterior temporal bone.^[7] They often occur bilaterally and are diagnosed in about 10% of patients. Presenting clinical signs include hearing loss, tinnitus, vertigo, and facial weakness. Deafness of varying severity is the major complication if appropriate surgical intervention does not occur.

Pheochromocytomas

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 von Hippel-Lindau disease in a specific family. In kindreds with von Hippel-Lindau disease who demonstrate a deletion or protein-truncating mutation of the von Hippel-Lindau gene (type 1 VHL), the risk for pheochromocytoma is less than 10%. However, the risk for developing this tumor increases to approximately 50% in kindreds with a missense mutation (type 2 VHL).

Type 2 von Hippel-Lindau disease can be further divided into types 2A, 2B and 2C, depending on the relative risk for the development of renal cell carcinoma in patients with pheochromocytoma. Patients with type 2A have a low risk of developing renal cell carcinoma, whereas those with 2B have a high risk. Patients with type 2C have a risk for pheochromocytoma but not for renal cell carcinoma.

Pheochromocytomas may be asymptomatic or may cause episodic or sustained hypertension in patients with von Hippel-Lindau disease. Often seen in younger patients (median age 30y), these tumors are often multiple or extra-adrenal. Only about one third of patients have increased catecholamine production.

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.

Pancreatic lesions

Pancreatic involvement is common in patients with von Hippel-Lindau disease. Most pancreatic lesions are simple cysts (70%) and rarely cause symptoms or develop into malignant tumors. Neuroendocrine tumors of the pancreas are less common and have malignant potential, with risk of metastasis to the liver. Occasionally, a malignant islet cell tumor, a functioning islet cell tumor, or a frank pancreatic carcinoma occurs in patients with von Hippel-Lindau disease.

Thus, abdominal imaging should be performed regularly, keeping in mind the potential for pancreatic malignancy.

Epididymal papillary cystadenomas

Epididymal papillary cystadenomas are present in about 50% of patients with von Hippel-Lindau disease. Single papillary cystadenomas occur in the general population; therefore, they do not pose concern if other von Hippel-Lindau disease clinical findings are absent. However, bilateral epididymal cysts are considered pathognomonic for von Hippel-Lindau disease.

These benign cysts are usually asymptomatic and do not require treatment. In women, the equivalent benign lesion is a papillary cystadenoma of the ovarian broad ligament. Symptoms may include pain, dyspareunia, and menorrhagia. Symptomatic treatment is indicated for these patients.

Retinal hemangioblastomas

Approximately one half of individuals with von Hippel-Lindau disease have retinal hemangioblastomas. These lesions are revealed during direct ophthalmoscopic evaluation.^[8] 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. (See the image below.)

Endolymphatic sac tumors

As previously mentioned, presenting clinical signs for ELSTs include hearing loss, tinnitus, vertigo, and facial weakness. Deafness of varying severity is the major complication if appropriate surgical intervention does not occur.

Conditions to consider in the differential diagnosis of von Hippel-Lindau disease include the following:

• Birt-Hogg-Dube (BDH) syndrome
• Multiple endocrine neoplasia
• Multiple paraganglioma syndrome
• Neurofibromatosis
• Pheochromocytoma
• Polycystic kidney disease
• Tuberous sclerosis
• Choroidal mass (tumor/metastasis)
• Retinal telangiectasis
• Retinal macroaneurysms

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

Type 2 multiple endocrine neoplasia

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

Paragangliomas

Multiple paragangliomas are observed in individuals with mutations in the succinate dehydrogenase gene, subunits B, C, and D.^[9] Paragangliomas are endocrinologically active tumors of the sympathetic nervous system that are histologically identical to pheochromocytomas. These paragangliomas occur in the head and neck region, which distinguishes them from the usual locations of pheochromocytomas. Paragangliomas are not part of the spectrum of manifestations seen in von Hippel-Lindau disease.

Autosomal dominant polycystic kidney disease

Multiple renal cysts are found in patients with autosomal dominant polycystic kidney disease (ADPKD), and these cysts are more numerous than in patients with von Hippel-Lindau disease. The architecture of the kidneys is distorted, adversely affecting renal function. Little potential for malignant change is noted in ADPKD.

Although CNS lesions are seen in ADPKD and von Hippel-Lindau disease, the lesions in ADPKD consist of arterial aneurysms and not hemangioblastomas, as is seen in von Hippel-Lindau disease. Hepatic cysts are frequent in ADPKD but rare in von Hippel-Lindau disease, whereas the converse is true for pancreatic cysts.

Renal cell carcinoma

An autosomal dominant predisposition to renal cell carcinoma, as described in Birt-Hogg-Dube syndrome, is occasionally seen. This genetic etiology not caused by von Hippel-Lindau mutations. However, in patients with renal cell carcinoma, ruling out the presence of other manifestations is always important.

Tuberous sclerosis complex

Tuberous sclerosis complex (TSC) should also be considered in the differential diagnosis of multiple renal lesions. Although renal cysts occur in TSC and von Hippel-Lindau disease, the renal tumor typically seen in TSC is the angiomyolipoma, which has a characteristic appearance on abdominal CT and MRI. Unlike von Hippel-Lindau disease, TSC is a neurocutaneous disorder characterized by dermatologic findings, such as hypopigmented macules (ash-leaf spots), shagreen patches, periungual fibromas, and adenoma sebaceum. Seizure disorders and learning disabilities are also seen in TSC.

Manifestations of von Hippel-Lindau disease are pleiotropic. In the early stages, most aspects of the disorder can be detected only with detailed imaging studies, biochemical analyses, or both.

Conduct the following annual laboratory studies in individuals with von Hippel-Lindau disease, in patients in whom the disorder is suspected, and in relatives who are at risk for the disease:

• Complete blood count (CBC) - To look for evidence of polycythemia vera due to erythropoietin expression by renal cysts and cerebellar hemangioblastomas
• Measurement of urinary catecholamine metabolites (inclusive of vanillylmandelic acid [VMA], metanephrines and total catecholamines - To detect pheochromocytomas, even in the absence of hypertension.
• Urinalysis - For hematuria, which can be indicative of a renal abnormality
• Urine cytology - To detect clear cell renal carcinoma

Imaging studies used in the diagnosis of von Hippel-Lindau disease include the following:

• CT scan of the brain with contrast
• MRI of the brain (posterior fossa emphasis)
• Abdominal CT scan - To look for pheochromocytoma
• Ophthalmic ultrasonography

In clinically diagnosed cases of angiomatosis retinae, applied color Doppler sonography is used to delineate the dilated, enlarged, and closely running feeder vessels on the retinal surface. The opposing directions of flow may indicate an artery or a vein. (The angioma is not imaged, because of a low-flow system. ) The above findings may be highly suggestive of angiomatosis retinae. (See the image below.)^{[10, 11]}

A 7.5 MHz linear array transducer (Acuson 128XP) is used to examine the eyes. Real-time, gray-scale images and color Doppler images are obtained. Pulsed Doppler analysis also can be used to evaluate vascular dynamics.

On application of color Doppler sonography, the feeder vessels appear to be a pair of dilated, tortuous blood vessels coursing to the angioma from the optic disc. The color image depicts the flow in these vessels to be in opposite directions. No flow can be appreciated in the angioma. These findings are of value in diagnosing this condition in cases in which the visualization of the fundus is not possible with an ophthalmoscope due to opaque media, which may be a complication of the disease.

The regression of the disease (angioma) can be followed and monitored by repeated studies after treatment with various modalities (ie, cryotherapy, diathermy, irradiation, laser photocoagulation). It is common to see new angiomas appearing or growing in the region of treated angiomas.

Color Doppler sonography provides a simultaneous morphologic and vascular image of the disease entity, enabling diagnosis and monitoring the effectiveness of treatment.

Ocular color Doppler sonography is a safe, noninvasive, relatively inexpensive investigative modality in diagnostic ophthalmology.

Optical coherence tomography (OCT), higher definition imaging systems with angiography, and neuroimaging advances have made von Hippel-Lindau disease more visible, thus allowing early interventions and effective outcomes.^[12]

Abdominal imaging

Annual abdominal imaging studies are suggested for individuals diagnosed with von Hippel-Lindau disease, for individuals in whom von Hippel-Lindau disease is suspected, and for at-risk relatives of a patient with von Hippel-Lindau disease.

Abdominal ultrasonography can be used to identify lesions in the kidneys, adrenal glands and/or pancreas.

CT scanning of the abdomen, with and without contrast, is recommended for additional clarification of abdominal lesions. However, MRI may be of equal or greater efficacy, depending on the expertise of the personnel performing and interpreting the imaging studies.

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 concerning neurologic symptoms or signs are present upon examination. However, 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.

Renal imaging

The American College of Radiology has established guidelines for the assessment of indeterminate renal masses.^[13]

Because von Hippel-Lindau disease is inherited in an autosomal dominant fashion, children of affected patients have a 50% risk of inheriting the disorder. However, the degree of clinical severity cannot be predicted. Siblings, parents, and relatives who are more distant are also at risk for von Hippel-Lindau disease.

Because of the disease’s heritability, 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 annual screening, and individuals with the mutant allele can be closely monitored for early manifestations of the 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.

Interpreting pedigree information and understanding the results of mutational analysis is complicated. The assistance of personnel trained in medical genetics (geneticists, genetic counselors) is needed to give guidance to patients and their family members.

New or de novo mutations (ie, no mutation identified in either parent) occur in approximately 20% of patients.

Medical care for patients with von Hippel-Lindau disease is dictated entirely by the specific complications that are present. Most therapies for complications of von Hippel-Lindau disease are surgical (eg, excision of tumors of the CNS or adrenal glands).

However, if a patient presents with one manifestation of von Hippel-Lindau 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. Thus, the most crucial aspect of medical care in these patients is close surveillance and prompt evaluation with appropriate imaging.

A substantial number of patients eventually require renal dialysis because the presence of tumors necessitates nephrectomy.

The increasing knowledge about the molecular role of von Hippel-Lindau proteins (pVHLs) has led to clinical trials of several antiangiogenic drugs designed to reduce or prevent tumorigenesis in von Hippel-Lindau disease. These drugs remain under investigation and are not available outside of a research protocol.

Annual ophthalmologic examination is recommended because of the risk for retinal hemangioblastomas. Early detection and treatment of retinal lesions can help to reduce limitation of vision.

Diet

Dietary guidelines for patients with von Hippel-Lindau disease have been recommended by the VHL Family Alliance. These guidelines rely more on expert opinion and common sense than on randomized trials. The VHL Family Alliance encourages patients with von Hippel-Lindau disease 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 suggests that people with von Hippel-Lindau syndrome should limit their physical activities, except for short periods of recuperation after surgeries. Moderate exercise is likely beneficial to most.

Von Hippel-Lindau disease is usually a progressive disorder, and ophthalmic therapy should begin as soon as the diagnosis is made. Surgical treatment may consist of the following:

• Argon laser photocoagulation
• Cryotherapy
• Fluid drainage
• Scleral buckling
• Penetrating diathermy
• Vitreous surgery
• Endodiathermy

Argon laser photocoagulation

Argon laser photocoagulation is effective in treating angiomatosis retinae. Treatment involves the use of a large spot size, with low-intensity, long-duration burns being directed at the angioma. Repeated laser treatment is required, except for small tumors. Obliteration of the tumor is confirmed by clinical observation and fluorescein angiography. If the tumor turns yellowish, photocoagulation becomes difficult because of the poor penetration of laser light.

Cryotherapy

Cryotherapy, a repetitive freeze/thaw technique, may be used to treat anterior angiomas and larger posterior angiomas. To minimize the risk of hemorrhage, no more than 2 or 3 freeze/thaw cycles should be used per session. Multiple sessions generally are needed to arrest tumors. Resolution of the macula edema and improved visual acuity are common results of tumor eradication by cryotherapy.

Scleral buckling and fluid drainage

Scleral buckling and fluid drainage methods may be needed to treat larger tumors, tumors associated with retinal detachment, angiomas resistant to cryotherapy, or tumors involving subretinal exudation. Large tumors may develop surface membranes and vitreous traction, leading to vitreous hemorrhage or rhegmatogenous retinal detachment. Such complications may require treatment by vitreous surgery, endodiathermy, or scleral buckling techniques.

Penetrating diathermy and endodiathermy

Penetrating diathermy under a lamellar scleral bed is an effective treatment of larger angiomas. Endodiathermy may be used instead of vitreous surgical techniques or scleral buckling procedures, to treat vitreous hemorrhage or retinal detachment.

Radiation

Radiation, applied in various forms, is another field among future directions in the care for this incessant pathology.

The most significant life-threatening tumor that occurs in individuals with von Hippel-Lindau disease 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 von Hippel-Lindau disease, 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.

Consult a geneticist or genetic counselor when von Hippel-Lindau disease has been diagnosed in an individual or family. 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 nephrologist and/or urologist are consulted with regard to the discovery of renal masses, and neurosurgeons are consulted concerning CNS masses
• An endocrinologist should be consulted to assist in the surveillance and interpretation of laboratory testing for pheochromocytoma

Because of the pleiotropic clinical manifestations of von Hippel-Lindau disease and the potential for malignancy, a lifelong strategy of surveillance (particularly for the brain, eyes, and kidneys) is necessary for early detection and treatment of complications. A plan for periodic surveillance should be made and a copy provided to the primary care physician and to the patient (or to the parents of pediatric patients).

Compliance with these screening tests at proper intervals has been shown to correlate strongly to the recommendations made by the physician.^[14] A case manager or a nurse practitioner can be assigned to ensure proper surveillance.

A reasonable annual surveillance strategy for affected patients and at-risk relatives is as follows:

• Obtain medical history and perform physical examination annually
• Obtain laboratory studies annually, starting at age 5 years; testing consists of urinalysis, urine cytologic examination, urinary catecholamine metabolites, CBC, and plasma catecholamines
• Perform annual direct and indirect ophthalmoscopic examinations; this is best if started before age 5 years.
• Perform audiologic examination at the first sign of hearing problems, vertigo, or tinnitus; in one study of VHL gene mutation carriers, more than 90% of radiologically diagnosed endolymphatic sac tumors were associated with abnormal audiometric findings^[15] (when abnormalities are found, a T1-weighted MRI of the temporal bone should be performed)
• Perform annual abdominal ultrasonography, beginning at age 16 years, to look for abnormalities in the kidneys, adrenal glands and/or pancreas; concerning findings warrant further investigation with either CT scanning or MRI.

Screening may be discontinued for at-risk relatives at approximately age 60 years if no abnormalities have been found.

Some experts recommend that MRI of the brain to properly assess the posterior fossa should be performed every 2-3 years, beginning at age 10-15 years. This recommendation is controversial. Typically, space-occupying lesions in the CNS cause neurological symptoms, but if lesions are present and the patient is asymptomatic, they are usually not resected.

Patients and families can benefit from contacting the VHL Family Alliance at 800-767-4845 (800-767-4VHL) or by email at info@vhl.org.

The National Cancer Institute ,through the US National Institutes of Health (NIH), sponsors a Web site with general information that may be useful to patients with VHL syndrome and their families.

Additional support organizations include the following:

• Kidney Cancer Association
• NIH/National Eye Institute at 301-496-5248