VHL Handbook

Section 5: Suggested Screening Guidelines

Screening is the testing of individuals at risk for von Hippel-Lindau disease (VHL) who do not yet have symptoms, or who are known to have VHL but do not yet have symptoms in a particular area. The unaffected organs should still be screened.

Modifications of screening schedules may sometimes be done by physicians familiar with individual patients and with their family history. Once a person has a known manifestation of VHL, or develops a symptom, the follow-up plan should be determined with the medical team. More frequent testing may be needed to track the growth of known lesions.

People who have had a DNA test and do not carry the altered VHL gene may be excused from testing. Even with the VHL gene, once an individual has reached the age of sixty and still has no evidence of VHL on these screening tests of VHL and has no known children with VHL, imaging tests may be every two years for CT and every three years for MRI.

Baseline audiometric tests have been added to the screening protocol, and imaging of the internal auditory canal (IAC) is indicated at the first sign or symptom of hearing loss, tinnitus (ringing in the ears), and/or vertigo (dizziness, loss of balance). Radiologist review of head MRI may comment on IAC region.

Any Age	Families are informed that, if they choose, they and their geneticist may contact one of the clinical DNA testing laboratories familiar with VHL for DNA testing. If the family marker is detectable, DNA testing can identify those family members who are not at risk and may discontinue screening. Testing may also be useful in calculating risks for family members who do carry the altered gene and require periodic screening tests. Risk factors are not definitive indicators of what will happen, but only highlight areas at higher or lower risk probability. Early detection and appropriate treatment are our best defenses.
From Conception	Inform obstetrician of family history of VHL. If the mother has VHL, see also the discussion of pregnancy in this booklet and in the screening protocol. A mother-to-be who is having any genetic testing done may request a VHL test be part of that scope of tests. Prenatal test results are usually part of the mother’s medical record, not the child’s. Ask to be sure.
From Birth	Inform pediatrician of family history of VHL. Pediatrician to look for signs of neurological disturbance, nystagmus, strabismus, white pupil, and other signs which might indicate a referral to a retinal specialist. Routine newborn hearing screening
Age 1	Annually: - Eye/retinal examination with indirect ophthalmoscope by ophthalmologist skilled in diagnosis & management of retinal disease, especially for children known to carry the VHL mutation.
Ages 2-10	Annually: - Physical examination and neurological assessment by Pediatrician informed about VHL, with particular attention to blood pressure, lying and standing, neurological disturbance, nystagmus, strabismus, white pupil, and other signs which might indicate a referral to a retinal specialist. - Eye/retinal examination with indirect ophthalmoscope by ophthalmologist informed about VHL, using a dilated exam. - Test for elevated catecholamines and metanephrines in 24-hour urine or blood sample. Abdominal ultrasonography annually from 8 years or earlier if indicated. Abdominal MRI or MIBG scan only if biochemical abnormalities found. Every 2-3 years: - Complete audiology assessment by an audiologist. Annually if any hearing loss, tinnitus, or vertigo is found.
Ages 11-19	Every six months: - Eye/retinal examination with indirect ophthalmoscope by ophthalmologist informed about VHL. Annually: - Physical examination and neurological assessment by physician informed about VHL. (Physicals include scrotal examination in males.) - Test for elevated catecholamines and metanephrines in 24 hour urine collection. Abdominal MRI or MIBG scan only if biochemical abnormalities found - Ultrasound of abdomen (kidneys, pancreas, and adrenals). If abnormal, MRI or CT of abdomen, except in pregnancy. Every 1-2 years and if symptoms: - MRI with gadolinium of brain and spine. Annually at onset of puberty or before and after pregnancy (not during pregnancy except in medical emergencies.) - Audiology assessment by an audiologist.
Age 20 and beyond	Annually: - Eye/retinal examination with indirect ophthalmoscope by ophthalmologist informed about VHL, using a dilated exam. - Quality ultrasound, and at least every other year CT scan of abdomen with and without contrast to assess kidneys, pancreas, adrenals but not during pregnancy. Ultrasound is especially suggested for women during their reproductive years. - Physical examination by physician informed about VHL. - Test for elevated catecholamines and metanephrines in 24 hour urine collection or blood. Abdominal MRI or MIBG scan if biochemical abnormalities found Every two years: - MRI with gadolinium of brain and spine (annually before and after but not during pregnancy) - Audiology assessment by an audiologist. If there is hearing loss, tinnitus, and/or vertigo, add: - MRI of internal auditory canal (IAC) to look for possible endolymphatic sac tumor.

Commonly Occurring VHL Manifestations

Age at onset varies from family to family and from individual to individual. The figures shown in Figure 18 include age at symptomatic diagnosis, particularly in the early literature, and age at presymptomatic diagnosis because of a screening protocol. With better diagnostic techniques, diagnoses are being made earlier. This does not mean that action needs to be taken when early lesions are found, but care must be taken to watch the progression of these lesions and act at the appropriate moment.

Pheochromocytoma is very common in some families, while renal cell carcinoma is more common in other families. Individuals in a family may differ as to which of the family tumor types they express.

Rare manifestations include cerebral (upper brain) hemangioblastoma, and rare occurrences of hemangioma in liver, spleen and lung.

Figure 18: Occurrence and age of onset in VHL. Compiled from a survey of papers from 1976 through 2004, and including data from the VHL Family Alliance. * Frequency of pheochromocytoma varies widely depending on genotype. Refer to Figure 14.
	Ages at Diagnosis	Most common ages at dx	Frequency in patients
CNS Retinal hemangioblastomas	0-68 yrs	12-25 yrs	25-60%
Endolymphatic sac tumors	1-50 yrs	16-28 yrs	11-16%
Cerebellar hemangioblastomas	9-78 yrs	18-25 yrs	44-72%
Brainstem hemangioblastomas	12-46 yrs	24-35 yrs	10-25%
Spinal cord hemangioblastomas	12-66 yrs	24-35 yrs	13-50%
Viscera Renal cell carcinoma or cysts	16-67 yrs	25-50 yrs	25-60%
Pheochromocytomas	4-58 yrs	12-25 yrs	10-20%*
Pancreatic tumor or cyst	5-70 yrs	24-35 yrs	35-70%
Epididymal cystadenomas	17-43 yrs	14-40 yrs	25-60% of males
APMO or broad ligament cystadenoma	16-46 yrs	16-46 yrs	estimated 10% of females

Common Treatment Recommendations

There are no universal treatment recommendations; treatment options can only be determined by careful evaluation of the patient’s total situation: symptoms, test results, imaging studies, and general physical condition. The following are offered as general guidelines for possible treatment therapies. Doctors are asked to read Lonser et al (Lancet 2003; 361:2059-67) for a more detailed explanation.

Retinal angiomas: In the periphery, Consider treatment of small lesions with laser and larger lesions with cryotherapy. If the angioma is on the optic disc, follow the growth pattern. There are few treatment options for tumors of the optic disc. The optimal treatment would be a drug, and as of this publication date, drugs are only just now going into clinical trials. Check with one of the expert centers for the latest treatment options for angiomas on the optic nerve. The optimal treatment would be chemoprevention, and as of the publication date, drugs are only just now going into clinical trials.

Brain and spinal hemangioblastomas: Symptoms related to hemangioblastomas in the brain and spinal cord depend on tumor location and size, and the presence of associated swelling or cysts. Symptomatic lesions grow more rapidly than asymptomatic lesions. Cysts often cause more symptoms than the tumor itself. Once the lesion has been removed, the cyst will collapse. If any portion of the tumor is left in place, the cyst will re-fill. Small hemangioblastomas (under 3 cm) which are not associated with a cyst have sometimes been treated with stereotactic radiosurgery, but more follow-up studies are needed to establish the long-term effects of this treatment. (Lonser et al, Lancet)

Endolymphatic sac tumors: Patients who have a tumor or hemorrhage visible on MRI but who can still hear require surgery to prevent a worsening of their condition. Deaf patients with evidence on imaging of a tumor should undergo surgery if other neurological symptoms are present, to prevent worsening of their balance problems. Further study is needed to determine whether patients with clinical symptoms of ELST, but without evidence of a tumor or hemorrhage on imaging, should undergo surgery to prevent hearing loss or to alleviate symptoms. (Lonser et al, N.E.J. Med)

Pheochromocytoma: Surgery after adequate blocking with medication. Laparoscopic partial adrenalectomy is preferred. Special caution is warranted during surgical procedures of any type, and during pregnancy and delivery. There is a debate over the wisdom of leaving in place pheos which do not appear to be active. US NIH generally monitors small pheos until urinary catecholamines are at least two times the upper limit of normal (even if plasma catecholamines are elevated).

Renal Cell Carcinoma: With improved imaging techniques, kidney tumors are often found at very small sizes, and at very early stages of development. A strategy for insuring that an individual will have sufficient functioning kidney throughout his or her lifetime begins with careful monitoring and choosing to operate only when tumor size or rapid growth rate suggest the tumor may gain metastatic potential (approximately 3 cm). The technique of kidney sparing surgery is widely used in this setting. Radio Frequency Ablation (RFA) or cryotherapy may be considered.

Pancreatic Neuroendocrine Tumors: Careful analysis is required to differentiate between serous cystadenomas and pancreatic neuroendocrine tumors (PNET). Cysts and Cystadenomas generally do not require treatment. PNET greater than 3 cm in the body or tail, or greater than 2 cm in the head of the pancreas should be considered for resection. (Lonser et al, Lancet)

Preparing for Pheo Testing

It is most important to test for pheochromocytomas before undergoing surgery for any reason, and before going through the childbirthing process. Undergoing either of these stressful experiences with an unknown pheo can be extremely dangerous. If the doctors are aware that the pheo is there, they can take preventive action that will ensure the safety of the patient, and any unborn child.

Testing of blood and urine are the best tests to determine whether an active pheo is present, and whether additional scanning is needed to localize or find the tumor. The urine and blood tests for pheo are most reliable when care is taken in two areas — diet prior to the testing and preservation of the urine sample from the start of the test until the lab processing is complete.

To get the best information from a 24-hour urine test, it is critically important that the patient — that’s you! — follows carefully the pheo test instructions that go with the test. Not all hospitals provide these instructions to the patient, and not all patients follow them conscientiously. Differences in instructions may reflect different methods of analysis.

If your own hospital lab staff has provided instructions, that’s great! If not, ask them if the following instructions would be good to follow to ensure that the sample is fresh and that the chemical levels for which they are testing are not artificially influenced by things in your diet. It is also very important that the urine be carefully refrigerated and preserved throughout the 24-hour urine collection period and delivered fresh to the lab for immediate processing. Some people carry the jug in an insulated bag or backpack, with one or more plastic cold packs alongside the jug.

Preparation for Blood Testing

Do not take any medications, including aspirin and acetaminophen, without the knowledge and agreement of the doctor ordering the test. In particular, be sure to discuss theophylline, anti-hypertensives (blood pressure medicines), methyldopa, L-dopa, or any diuretic, birth control pills, patches for birth control, smoking cessation etc., or any anti-depressants. Theophylline is found in tea and some other herbal supplements as well as medication.

Refrain from eating or drinking anything except water from 10 P.M. the evening prior to your blood test and do not take any medications the morning of the test unless specifically approved by the doctor ordering the test. If you are instructed not to take your morning medications, please take them with you to the test so that you can take them right after the completion of the test.

If you smoke, you should not smoke on the day of the test. If you have questions regarding your diet, please contact your physician.

The procedure usually takes about 45 minutes. It is important that you be quiet and calm for 20-30 minutes prior to the blood draw to ensure accurate results. Bring a book to read or your tape recorder with some favorite music, something you will find relaxing. You may be asked to lie quietly on a table for 20 minutes before the test begins.

Preparation for 24-hour Urine Testing.

Vanillyl Mandelic Acid testing (VMA): This test is no longer used as it does not measure fractionated metanephrines.

For Catecholamines, Metanephrines, Epinephrine, Norepinephrine: Avoid smoking, medications, chocolate, fruits (especially bananas), and caffeine on the day of the test. Be sure to tell your doctor and the technician what medications you are taking, including any anti-depressants.

Collection instructions: Do not begin collection on Friday or Saturday. This ensures that your sample will be delivered to the lab on a working day and can be processed promptly.

Start the collection in the morning. Empty the bladder and do not save this urine specimen
Write this date and time on the jug.*
Save all the urine passed for the next 24 hours in the jug provided, include the final specimen passed exactly 24 hours after beginning the collection.
Keep the urine refrigerated at all times. You might keep it in a paper bag in the refrigerator.
Write this date and time on the jug when the collection is finished.
Bring the collection and the paper work to the lab as soon as possible after collection. (Drop it off on the way to school or work. Labs are usually open early in the morning or have a place where you can arrange to drop it off early).

* If there is a preservative added to the jug, be careful not to get it on the skin. If this happens, wash the area immediately with water.

Section 5: Suggested Screening Guidelines

Commonly Occurring VHL Manifestations

Common Treatment Recommendations

Preparing for Pheo Testing

Preparation for Blood Testing

Preparation for 24-hour Urine Testing.

Section 6: Obtaining DNA Testing

Section 7: Medical Terms

Section 8: References

Section 9: Prepared by...

Section 10: Tissue Bank for VHL