VHL Handbook

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.

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.

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.

1. Start the collection in the morning. Empty the bladder and do not save this urine specimen
2. Write this date and time on the jug.*
3. 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.
4. Keep the urine refrigerated at all times. You might keep it in a paper bag in the refrigerator.
5. Write this date and time on the jug when the collection is finished.
6. 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.

Anyone with a first- or second-degree relative with VHL is "at risk" for VHL. First degree relatives are parents, children, sisters, and brothers. Second-degree relatives are cousins, aunts, uncles, grandparents, and grandchildren. The only way to determine for sure whether someone has VHL is through DNA testing. This is a blood test that must be processed at a clinical testing laboratory (lab) that has the necessary equipment and reagents to test for VHL.

If DNA testing finds the altered VHL gene, we say that the results are positive: yes, this person has VHL. If the DNA testing finds that both copies of the VHL gene are unaltered, we say that the test is negative. This person is unlikely to have VHL. There is always some margin for error. When the possibility of error is under 1-2%, it is considered to be as certain as it gets in nature. If the margin for error is 15%, you may wish to have additional testing.

Anyone at risk for VHL who has not received a negative DNA test result should continue to follow a conscientious screening program to ensure early diagnosis of any VHL problems.

To initiate DNA testing in a family, a person in the family with a clinical diagnosis of VHL, working through a geneticist or genetic counselor, should submit a blood sample for testing. The lab will check to see that they can determine the alteration in this person by performing a complete screen of the VHL gene. This test is greater than 99% successful in finding mutations in patients with a germline mutation in the VHL gene. Once a mutation has been found, the exact change in this person's VHL gene will be the same alteration that is passed within this family. Now another person in the same family who does not have a clinical diagnosis of VHL can submit a blood sample, and the lab can go directly to that position and check for that same mutation in this second person's DNA. This first test in the family becomes a road map for the second test.

People who were tested prior to 2000 using a method called "linkage analysis" may wish to be re-tested using DNA sequencing or Southern blot analysis. These improved techniques are significantly more reliable. There have been situations where the results of linkage analysis have proven not to be correct.

For people who are the first in their families to be diagnosed with VHL, or for adoptees or others who do not have known blood relatives to assist in the testing, it can take 4 to 6 weeks or more to get results from a complete screen. For people in this situation, it is important to choose a lab with a high "hit rate" or level of success in finding mutations.

It is important to initiate DNA testing through a geneticist or genetic counselor, to ensure a thorough discussion of the personal impact of the results, whether they are positive or negative, and the possible insurance ramifications. To find a geneticist or genetic counselor, begin with your doctor or with the medical center where you normally go. Ask if they have a department of "cancer genetics." If so, this is the best place to assess your risk for VHL. If not, inquire in the departments of obstetrics, medicine or pediatrics. If they do not have an associated geneticist, they will know where to find one acceptable to your health plan.

If a mother-to-be is having any genetic testing done, she may request a VHL test be part of that scope of tests, especially if there is any VHL in the family at all, or any history of VHL-related tumors in other family members. Prenatal test results are usually part of the mother’s medical record, not the child’s. Ask to be sure.

The list of clinical testing labs offering testing for VHL is maintained on the internet at www.vhl.org As of the date of publication of this booklet, the labs with the highest "hit rates" are those in Philadelphia, Pennsylvania; Padua, Italy; Saõ Paolo, Brazil; Ingelheim, Germany; and Lyon, France.

Catherine Stolle, Ph.D., FACMG
Molecular Genetics Laboratory
The Children’s Hospital of Philadelphia
Abramson Research Center 1106F
34th & Civic Center Boulevard
Philadelphia, PA 19104 USA
Phone: +1 215 590-8736
Fax: +1 215 590-2156
E-Mail: stolle@email.chop.edu

J. C. Casali da Rocha, Oncology
Ludwig Inst for Cancer Research
Rua Prof. A. Prudente 109-4 andar
São Paulo - SP 01509-000 BRAZIL
W: +55-11-2704922
Fax: +55-11-270-7001
E-mail: jccrocha@ludwig.org.br

Dr. Hans-Jochen Decker
Bioscientia Institut für Laboruntersuchungen
Konrad Adenauer Str. 17
55218 Ingelheim GERMANY
Phone: +49 6132 781133
Fax: +49 6132 781262
E-Mail: decker.jochen@bioscientia.de

Dr. Sophie Giraud, Laboratoire de Génétique
Hôpital Edouard Herrior
69437 Lyon Cedex 3, FRANCE
Phone: +33 4 72 11 73 83
Fax: +33 4 72 11 73 81
E-mail: sophie.giraud@chu-lyon.fr

Dr. Alessandra Murgia
Department of Pediatrics
University of Padua
Padova ITALY
Phone: +39 49 821-3512
Fax: +39 49 821-3502
E-mail: murgia@pediatria.unipd.it

Click here for additional DNA testing labs in your area

ADRENAL GLANDS (ad-REE-nal): a pair of glands on top of the kidneys which normally produce epinephrine (adrenaline) when we are stressed or excited.

ADRENALECTOMY (ad-REE-nal-EK-to-mee): surgical removal of an adrenal gland. May be partial or total.

ALLELE (a-LEEL): One of the two copies of each gene in an individual. In people with VHL, one copy is altered and one has the normal sequence.

ANGIOGRAM (ANN-gee-o-GRAM): A picture or map of the blood vessels in a particular area of the body, usually produced by injecting a special dye into the blood vessels and taking x-ray or magnetic resonance pictures. See also Fluorescein angiogram.

ANGIOMA (ann-gee-O-ma): An unusual growth made up of blood or lymphatic vessels, forming a benign tumor; a hemangioma (blood vessels) or lymphangioma (lymphatic vessels). In VHL, angiomas are made up of blood vessels and so are technically hemangiomas.

ANGIOMATOSIS: Another name for von Hippel-Lindau

ASYMPTOMATIC: The patient is not experiencing discomfort or other symptoms.

AUDIOLOGY (aw-dee-OL-o-gy): The study of hearing. Often refers to a hearing test (audiogram), which determines hearing loss.

AUDIOMETRIC (aw-dee-oh-MET-rik): An audiometric examination is an examination in which the hearing is measured and evaluated.

AUTOSOME: A non sex-determining chromosome. An autosomal dominant trait is one which occurs on one of the chromosomes which do not determine gender, and is dominant because it takes only one altered copy of the gene to cause the trait.

BENIGN TUMOR (bee-NINE): An abnormal growth that is not cancer and does not spread to other parts of the body.

BIOMARKER: Some trace chemical in the blood or urine that we can test for, that will indicate the progress of a disease. For example, the PSA test for prostate cancer indicates whether prostate cancer activity in the body is low or high, so that you know whether you need additional testing and treatment.

BROAD LIGAMENT: The broad ligament is a folded sheet of tissue that drapes over the uterus, fallopian tubes and the ovaries.

CAPILLARIES (CAP-a-lar-reez): The smallest of the blood vessels in the body, carrying nourishment to the cells.

CANCER: A general term for more than 100 diseases in which abnormal cells grow and multiply rapidly. Cancer cells can spread through the blood or lymphatic system to start new cancers in other parts of the body.

CATECHOLAMINES (kat-e-COAL-a-meens): adrenaline by-products found in the urine, where their measurement is used as a test for pheochromocytoma.

CEREBELLUM (ser-a-BELL-um): A large portion of the base of the brain which serves to coordinate voluntary movements, posture, and balance.

CEREBRAL (ser-EE-bral): The upper or main portion of the brain, often used to refer to the entire brain.

CHROMOSOME (KRO-mo-sohm): Sets of linear DNA from which the genes are arranged, carrying all the instructions for a species. Human beings have 23 pairs of chromosomes. In each pair, one chromosome, containing one copy of each gene, is inherited from the mother and one from the father.

CODON (KO-don): a triplet of three bases in a DNA molecule, a code for making a single amino acid of a protein.

COMPUTED TOMOGRAPHY (CT) scan: A diagnostic procedure using a combination of X-ray and computer, and optionally some contrast dye. A series of X-ray pictures are taken of the tissues being studied. The computer is then used to calculate the size and density of any tumors seen on the pictures.

CRYOTHERAPY: A method of stunting the growth of tissues by freezing them. Used most commonly on retinal angiomas.

CYSTS: Fluid-filled sacs that may occur normally in tissues from time to time, or that may grow up around irritations in tissues.

DE NOVO (day-NO-vo): New, for the first time.

DENSITY: a quality of a tissue to be soft or solid. Muscle is less dense than bone; a sac filled with fluid is less dense than a hard tumor.

DIFFERENTIAL DIAGNOSIS: Many of the tumors of VHL occur in the general population, or in other syndromes as well. The doctor has to sort out whether the tumor is sporadic or whether it is part of VHL or another syndrome. To answer this question a number of tests may be required, which may include DNA testing.

DNA: Deoxyribonucleic acid (DEE-ox-ee-RYE-bo-nu-KLAY-ik ASS-id). Four substances which makes up chromosomes and their genes. As coding sequences, they determine the function of a gene — for instance the synthesis of a protein and the amino acid sequence of the protein.

-ECTOMY (EK-to-mee): a suffix which means removal. For example, adrenalectomy means removal of the adrenal gland.

EMBRYOLOGICAL (em-bree-o-LODGE-i-kal): Having to do with the process of development of the baby before birth. The baby starts out as a single cell, from which all organs and tissues develop. As the embryo forms, the cells evolve. The epididymis in men and the broad ligament structures in women develop from the same cells.

ENDOCRINOLOGIST (EN-do-krin-OL-o-gist): A physician specializing in the treatment of the endocrine system, its hormones, and glands, which includes the adrenal glands, pancreas and a number of other organs and glands.

ENDOLYMPHATIC SAC (en-do-lim-FA-tik sack): the bulb-like end of the endolymphatic duct, which connects to the semicircular canals of the inner ear.

ENUCLEATION (ee-NU-klee-A-shun): Referring to kidney or pancreas, removal of a tumor with only a small margin of healthy tissue to ensure that all the unhealthy tissue is out. This is sometimes referred to as a lumpectomy, or removal of the tumor (lump) only. In ophthalmology, enucleation means removal of the eye. If the retina has detached, the blood supply to the eye is reduced and the eye may deteriorate, causing discomfort. If this occurs, enucleation of the eye may be recommended. A good prosthesis (artificial eyeball), can be made to look like a healthy eye.

EPIDIDYMIS (epi-DID-imus): A gland which lies behind the testicle, in the scrotum, on the path to the vas deferens, the vessel that carries the sperm from the testicle to the prostate gland, and is important for sperm maturation, mobility and storage.

FALLOPIAN TUBE (fa-LOPE-i-an): the channel carrying eggs from the ovary to the uterus.

FAMILIAL (fam-EE-lee-al): It occurs in families, whether or not transmitted genetically. Chicken pox is considered familial, but is not genetic.

FLUORESCEIN ANGIOGRAM (FLUR-a-seen AN-gio-gram): An angiogram of the retina of the eye, named for the contrast dye that is used. This procedure produces an image of the blood vessels of the retina, sometimes in full motion video so that the ophthalmologist can see the health of the blood vessels and how the blood moves through them.

GADOLINIUM (gad-o-LIN-ee-um): a contrast medium, injected into the patient’s bloodstream prior to an MRI test to highlight the blood vessels and provide better contrast so the radiologist can see any abnormal structures more clearly.

GENE (jeen): The position on a chromosome where a specific DNA sequence, or allele, resides. Changes in the sequence from one allele to another can be transmitted to the next generation.

GENETIC COUNSELOR: A medical professional (not a physician) specializing in working with patients and families with genetically inherited conditions, like VHL. Genetic counseling may include a discussion and analysis of your family tree and some testing procedures.

GENETICIST: A geneticist is a scientist specializing in the study of genes and the way they influence our health, and in treatment of genetic disorders.

GENOME (JEE-nohm): The entire array of genes of an organism or species.

GENOTYPE (JEE-no-type): The particular pair of alleles (copies of the gene) that an individual possesses at a given gene locus or site (two copies of each gene). One of these alleles (copies) is inherited from the mother, the other from the father.

-GRAM: a suffix that indicates that a message or picture is being created. For example, an angiogram is a picture of the blood vessels (ANGIO-)

HEMANGIOMA (hee-MAN-jee-O-ma): An abnormal growth of blood vessels, forming a benign tumor..

HEMANGIOBLASTOMA (hee-MAN-jee-o-blast-O-ma): An abnormal growth of blood vessels forming a benign tumor; a variety of hemangioma found especially in VHL, in the brain or spinal cord.

HEREDITARY: Occurring because of something in the genes you got from your parents, something you inherited. Not due to infection or an event during your lifetime.

HYPERNEPHROMA (hyper-nef-ROH-ma) : A kidney tumor that contains cancer cells. The more modern term is renal cell carcinoma (RCC).

INVASIVE: Describes medical procedures that require entering or “invading” your body.

KIDNEY: One of a pair of organs in back of the abdominal cavity that filter waste materials out of the blood and pass them out of the body as urine.

LAPAROSCOPY (lap-ar-OSS-ko-pee): A technique for performing a surgical procedure through slits in the skin using special surgical probes, rather than making one large incision. Depending on the position of the tumor and the extensiveness of the procedure, use of this technique may or may not be possible.

LASER TREATMENT: The surgical use of a minutely focused light to deliver a microscopic cauterization, or burn.

LESION: Any localized abnormal structural change, such as an ANGIOMA.

LIVER: A large organ in the upper right side of the abdominal cavity that secretes bile and is active in regulating various parts of the process of digesting food and using it to best advantage in the body.

LOCALIZE: To find. Doctors use this term to mean finding on the scan exactly where a tumor is located. For a pheo, for example, the tumor can occur anywhere from your groin to your earlobe, on either side of the body, so finding a pheo is not an easy quest.

MAGNETIC RESONANCE IMAGING (MRI). An imaging technique where magnetic energy is used to examine tissues in your body, and the information is used by a computer to create an image. There is no radiation exposure. The resulting images look very much like X-rays, but include images of soft tissues (like blood vessels) as well as hard tissues (like bones). Claustrophobia can be an issue, since this procedure requires lying still in a tunnel-like structure for at least half an hour. Calming drugs can be used, or there are new machines that have a more open, cage-like structure, and various attempts are being made to shorten the time required. It is important to use enough magnet strength to get a clear picture.

MALIGNANT (ma-LIG-nant): Cancerous. Cancer cells can spread through the blood or lymphatic system to start new cancers in other parts of the body.

METANEPHRINES (met-a-NEF-rins): a group of adrenaline by-products found in the urine, where its measurement is used as a test for pheochromocytoma.

METASTASIZE (me-TAS-ta-size): to spread from one part of the body to another. When cancer cells metastasize and form secondary tumors, the cells in the metastatic tumor are like those in the original tumor. Thus if kidney cancer cells are found in a tumor in the spine, we know it has metastasized, or spread, from the kidney.

MIBG SCAN: A nuclear medicine procedure using a radioactive isotope or tracer, which is absorbed by pheochromocytoma tissue. Meta-Iodo-Benzyl-Guanidine (MIBG) is injected into the patient before the scan is performed, making the pheo stand out clearly on the diagnostic pictures.

MUTATION: A change in the sequence of DNA coding in a gene.

MYELOGRAM (MY-lo-GRAM): a diagnostic procedure which creates an image of the spinal cord. A dye is injected into the spinal canal, and X-ray pictures are taken of the spinal cord.

NEOPLASIA (NEE-oh-PLAY-zia): literally, new growth, a lesion grown from a single cell, not transplanted from another place.

NEPHRECTOMY (nef-REK-to-mee): Removal of all (total) or some (partial) of one kidney.

NEUROLOGIST: A physician specializing in nonsurgical treatment of the nervous system, the brain, spinal cord and peripheral nerves.

NEUROSURGEON: A physician specializing in the surgical treatment of the nervous system, the brain, spinal cord, and nerves.

NEUROTOLOGIST (new-ro-TOLL-uh-jist): A physician specializing in the structure and function of the internal ear, its neural connections with the brain and the management of skull base diseases. A neurotologist is an ear, nose and throat surgeon (otolaryngologist) who has undergone additional training in this area and typically works in conjunction with a team of specialists including other otolaryngologists, neurologists and neurosurgeons.

NUCLEAR MEDICINE: Medical procedures for diagnosis and treatment which involve some sort of radioactive isotope.

ONCOLOGIST (on-KOL-o-gist): A physician specializing in treatment of various forms of cancer.

OPHTHALMOLOGIST (OFF-thal-MOL-o-gist): A physician specializing in treatment of diseases of the eye.

OPTOMETRIST (op-TOM-e-trist): An optometrist, or doctor of optometry (O.D.) is a health care professional who diagnoses and treats eye health and vision problems. They prescribe glasses, contact lenses, low vision rehabilitation, vision therapy and medications, and perform some surgical procedures not related to VHL.

PANCREAS (PAN-kree-as): A gland near the stomach which secretes digestive enzymes into the intestine and also secretes the hormone insulin into the blood as needed to regulate the level of sugar in the blood.

PANCREATITIS (pan-kree-a-TIE-tis): inflammation of the pancreas.

PAPILLARY (PAP-i-lar-ry): nipple-shaped.

PARAGANGLIOMA (PAR-a-GAN-glee-OH-ma): A pheo outside the adrenal gland, which is also called an extra-adrenal pheochromocytoma (extra meaning outside).

PENETRANCE: The probability that a gene will make any effect of its alteration evident. The VHL gene has almost complete penetrance (if someone has the altered VHL gene, they will almost certainly have some manifestation of VHL disease within their lifetime), but widely variable expression (the severity of those manifestations will vary widely).

PET SCANNING: Positron Emission Tomography, a specialized imaging technique using short-lived radioactive substances to provide information about the body’s chemistry. This technique produces three-dimensional color images showing the activity level of certain tumors.

PHENOTYPE (FEE-no-type): The clinical appearance of a specific genotype, for example the set of VHL symptoms one person may have. The same genotype may be expressed differently from one individual to the next due to differences in other genes, or in the environment.

PHEOCHROMOCYTOMA (FEE-o-KRO-mo-sigh-TOE-mah): or “pheo” for short. A tumor (cytoma) of the adrenal gland which causes the adrenal gland to secrete too much adrenalin, potentially causing harm to the heart and blood vessels. Pheos can also occur outside the adrenal glands, and people can have more than two pheos. Outside the adrenals, they are sometimes called paragangliomas.

PNET: Pancreatic Neuro-endocrine Tumor, a solid tumor of the islet-cell portion of the pancreas which secretes hormones when it is “active”.

RADIO FREQUENCY ABLATION (RFA): A laparoscopic surgical procedure where a heat probe is inserted laparoscopically into the tumor, and the tumor is heated to disable its growth potential. This is one possible way to treat a VHL kidney tumor.

RADIOLOGIST: A physician specializing in diagnostic techniques for viewing internal organs and tissues without surgery. Radiological methods include X-ray, MRI, computed tomography (CT) scan, ultrasound, angiography, and nuclear isotopes.

RESECTION (ree-SEK-shun): A term used to describe the removal of a tumor from an organ such as a kidney, while retaining (sparing) the organ itself.

RETINA: The nerve tissue that lives at the back of the eye, similar to the film in a camera, which takes the image you are looking at and transmits it to the brain through the optic nerve. This area is nourished by a web of very fine blood vessels.

RETINAL SPECIALIST: An ophthalmologist who specializes in treatment of diseases of the retina.

SEROUS MICROCYSTIC ADENOMAS: Grapelike clusters of cysts which may occur in the pancreas. Cysts are composed of epithelium-lined collections of serous fluid that vary in size from several millimeters to over 10 cm. (over three inches).

SIGN: Physical evidence of the existence of something which can be demonstrated by a medical doctor.

SPORADIC: Occurring at random in the general population. Not due to heredity.

SYMPATHETIC NERVOUS SYSTEM: a chain of small structures that transmit signals from the central nervous system to the organs. The adrenal gland is the major gland in this chain, but small ganglia run from the groin to the ear lobe on both sides of the body. A pheochromocytoma can hide anywhere along this system.

SYMPTOM: A feeling or other subjective complaint suggestive of a medical condition.

SYMPTOMATIC: The patient is experiencing symptoms.

SYNDROME: A collection of signs and symptoms associated with a disease.

SYRINX (SEER-inks): A fluid-filled sac, like a cyst, but occurring inside the spinal cord where it has the shape of an elongated tube lying inside the spinal cord and the bony spinal column.

TINNITUS (TIN-ih-tis): A ringing in one or both ears. It may also be a roaring or hissing sound.

TUMOR: An abnormal growth that is solid and may be benign or malignant.

ULTRASOUND: A diagnostic technique that provides pictures of internal organs and structures. It works like the sonar used by submarines, bouncing sound waves off an object and using a computer to interpret the sound returned. The interpretation of an ultrasound is very dependent upon body structure, the amount of body fat, and the skill of the operator.

UROLOGIST: A physician specializing in surgical and non-surgical treatment of the kidney, bladder and male genital organs, including the penis and scrotal structures.

VERTIGO (VER-tih-go): A sensation of dizziness or loss of balance, inability to walk a straight line, or “walking into walls”.

VISCERA (VISS-ser-ah): Any of a number of organs in the abdominal area, including the kidney, liver, pancreas, and adrenal glands.

X-RAY: A diagnostic imaging technique where radiation passes through the body to create images of hard tissues (like bones and solid tumors) onto photographic film.

Recommended Reading

The following articles are recommended to you by our Medical Advisors and Reviewers. If you have time to read only three articles, please read those marked
*** by Lonser (Lancet) and Eisenhofer and Lonser on ELST.

Please note: Information on the Internet is sometimes relocated. If you have difficulty finding one of the internet references, try a search engine to find its current location. PMID indicates an index reference for PubMed, an online resource for medical articles at www.pubmed.com

Al-Sobhi, S., et al., “Laparoscopic Partial Adrenalectomy for recurrent pheochromocytoma after open partial adrenalectomy in von Hippel-Lindau disease,” J Endourol. 2002;16(3):171-4.

American Academy of Ophthalmology, online brochures: “Laser Surgery in Ophthalmology,” and “Cryotherapy,” AAO, P.O. Box 7424, San Francisco, CA 94120-7424. +1 415 561-8500. http://www.aao.org

The National Eye Institute (www.nei.nih.gov) and the National Library of Medicine (www.nlm.nih.gov) are both excellent resources for new terms and treatments.

American Brain Tumor Association, “Dictionary for Brain Tumor Patients” and “A Primer of Brain Tumors,” ABTA, 2720 River Road, Suite 146, Des Plaines, IL 60018. (800) 886-2282 or +1 708 827-9910; Fax: +1 708 827-9918. http://hope.abta.org info@abta.org

The American Society of Human Genetics (ASHG) has information on policy and ethics on their website. See http://genetics.faseb.org/genetics/ashg/ashgmenu.htm

The Office of Biotechnology Activities maintains a website that contains information on the work of the Advisory Committee to the Secretary of Health and Human Services on “Genetic Testing.” http://www4.od.nih.gov/oba/

The Human Genome Institute has a section on Policy and Ethics that deals with the Ethical, Legal, and Social Implications of the Human Genome Project and genetic testing See http://www.genome.gov/PolicyEthics

Béroud, Chistophe, The Worldwide VHL Mutations Database, www.umd.be

Blodi, Christopher, et al., “Direct and Feeder Vessel Photocoagulation of Retinal Angiomas with Dye Yellow Laser,” Ophthalmology, 97 (1990) 791-797, with commentary by L. Fingerman and D. Saggan.

Chauveau, D., et al, “Renal involvement in von Hippel-Lindau disease.” Kidney Int. 1996 50:944-951.

Chew, Emily, et al, Von Hippel-Lindau disease: clinical considerations and the use of fluorescein-potentiated argon laser therapy for treatment of retinal angiomas. Seminars in Ophthalmology. 7(3):182-91, 1992 Sep.

Choo, Daniel I., et al, “Endolymphatic Sac Tumors in von Hippel-Lindau Disease,” J. Neurosurg, 2004; 100:480-487.

Choyke, P.L., et al., “The Natural History of Renal Lesions in von Hippel-Lindau Syndrome.” Am J Roentgen 1992 159:1229-1234.

Choyke, Glenn, et al., “Von Hippel-Lindau Disease: Genetic, Clinical, and Imaging Features.” Radiology, March 1995, pp. 639-641. http://www.cc.nih.gov/ccc/papers/vonhip/toc.html

Collins, Debra, Information for Genetic Professionals http://www.kumc.edu/gec/prof/kugenes.html

Diet, Nutrition, and Cancer Prevention: The Good News, U.S. National Institutes of Health, publication 87-2878, and the Five-a-Day Program. 1-800-4CANCER.

Dollfus, Hélène et al, Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study. Invest Ophthalmol Vis Sci 2002 Sep; 43(9):3067-3074.

Drachenberg DE, Mena OJ, Choyke PL, Linehan WM, Walther MM. Parenchymal sparing surgery for central renal tumors in patients with hereditary renal cancers. J Urol. 2004 Jul;172(1):49-53. PMID: 15201735

Duan, Linehan, Klausner et al., “Characterization of the VHL tumor suppressor gene product.” Proc. Natl. Acad. Sci., USA 1995; 92:6459-6463.

Duffey, B. G., Choyke, P. L., Glenn, G., Grubb, R. L., Venzon, D., Linehan, W. M., and Walther, M. M. The Relationship Between Renal Tumor Size and Metastases in Patients with von Hippel-Lindau Disease. J Urol, 172: 63-65, 2004.

*** Eisenhofer, G., and K. Pacak. Diagnosis of pheochromocytoma. Harrison’s On-line.

Eisenhofer, Graeme, et al. Malignant pheochromocytoma: current status and initiatives for future progress. Endocrine-Related Cancer (2004) 11: 423-436.

El-Sayed, Yasser, Pregnancy and VHL. VHL Family Forum, 2001, www.vhl.org/newsletter/vhl2001/01eapreg.php

Glenn, G.M., et al, “Von Hippel-Lindau Disease: Clinical Review and Molecular Genetics,” Problems in Urology 1990 42:312-330.

Glenn et al, “Screening for von Hippel-Lindau Disease by DNA Polymorphism Analysis.” JAMA 1992 267:1226-1231.

Glenn et al, “Von Hippel-Lindau (VHL) disease: distinct phenotypes suggest more than one mutant allele at the VHL locus.” Hum. Genet. 1991 87:207-210.

Goldfarb, David, H. Neumann, I. Penn, A. Novick, “Results of renal transplantation in patients with renal cell carcinoma and von Hippel-Lindau disease.” Transplantation. 1997 Dec 27; 64(12):1726-9.

Green et al, “Von Hippel-Lindau Disease in a Newfoundland kindred,” Canadian Med. Assn. Journal 1986 134:133-146.

Hammel, Pascal R., et al., Pancreatic Involvement in von Hippel-Lindau disease, Gastroenterology, 2000; 119(4), 1087-1095.

Herring, J. C., Enquist, E. G., Chernoff A.C., Linehan, W. M., Choyke, P. L., and Walther, M. M. Parenchymal Sparing Surgery in Patients with Hereditary Renal Cell Carcinoma - Ten Year Experience. The Journal of Urology, 165: 777-781, 2001.

Hoobyar AR, Ferrucci S, Anderson SF, Townsend JC. Juxtapapillary capillary hemangioblastoma. Optom and Vis Sci 2002 June;79(6): 346-352.

Hwang JJ, Uchio EM, Pavlovich CP, Pautler SE, Libutti SK, Linehan WM, Walther MM. Surgical management of multi-organ visceral tumors in patients with von Hippel-Lindau disease: a single stage approach. J Urol. 2003 Mar;169(3):895-8. PMID: 12576808

James, G. P., Hastening the Road to Diagnosis: the Role of the Broad Ligament Cystadenoma in Early Detection of VHL. VHL Family Forum, 1998, www.vhl.org/newsletter/vhl1998/98ccapmo.php

Kaelin, William G. Jr., “The von Hippel-Lindau gene, kidney cancer, and oxygen sensing.” J Am Soc Nephrol. 2003 Nov: 14(11):2703-2011.

Kahle, W., H. Leonhardt, and W. Platzer, Color Atlas and Textbook of Human Anatomy. Georg Thieme Pub., Stuttgart, 1978.

Lamiell et al, “Von Hippel Lindau Disease Affecting 43 Members of a Single Kindred.” Medicine 1989 68:1-29.

Latif, F., et al., “Identification of the von Hippel-Lindau Disease Tumor Suppressor Gene.” Science 1993 260:1317-1320.

Lenders J.W.M., K. Pacak, M.M. Walther, W.M. Linehan, M. Mannelli, P. Friberg, H.R. Keiser, D.S. Goldstein and G. Eisenhofer. Biochemical diagnosis of pheochromocytoma: Which test is best? Journal of the American Medical Association 287: 1427-1434, 2002.

Lonser, Russell R., et al, “Surgical Management of Spinal Cord Hemangioblastomas in patients with von Hippel-Lindau disease,” J. Neurosurg, 2003; 98(106-116)

*** Lonser, Russell R., et al, “Tumors of the Endolymphatic Sac in von Hippel-Lindau Disease,” N. E. J. Med. 2004; 350:2481-2486. PMID: 15190140

*** Lonser, Russell R., et al., “Von Hippel-Lindau Disease,” Lancet, 2003; 361(9374):2059-2067. PMID: 12814730

Maher, E. R., et al, “Von Hippel-Lindau disease: a genetic study,” J. Med. Genet. 1991 28:443-447.

Maher, E. R. et al., “Phenotypic expression in von Hippel-Lindau disease: Correlations with germline VHL gene mutations. J. Med. Genetics, 1996 33:328-332.

Maranchie, J. K., Walther, M. M., and Linehan, W. M. Early Identification of Patients with von Hippel Lindau Disease at Risk for Pheochromocytoma. Current Urology Reports, 2001.

Maranchie, J. K., Afonso, A., Albert, P., Phillips, J. L., Zhou, S., Peterson, J., Hurley, K., Riss, J., Vasselli, J. R., Ried, T., Zbar, B., Choyke, P., Walther, M. M., Klausner, R. D., and Linehan, W. M. Solid Renal Tumor Severity in von Hippel Lindau Disease is Related to Germline Deletion Length and Location. Human Mutation, 23: 40-46, 2004

Marcos, H.B., Libutti S., et al., “Neuroendocrine tumors of the pancreas in von Hippel-Lindau disease: spectrum of appearances at CT and MR imaging with histopathologic comparison,” Radiology, 2002; 225(3):751-8.

McCue, Kathleen, and Ron Bonn, How to Help Children Through a Parent’s Serious Illness. St. Martin’s Press, 1994.

Megerian, CA, “Hearing Preservation Surgery for small Endolymphatic Sac Tumors in patients with von Hippel-Lindau syndrome,” Otol Neurotol, 2002; 23:378-387.

Neumann, H.P.H., et al. “Germline Mutations in Non-Syndromic Pheochromocytoma.” New England Journal of Medicine (2002) 346:1459-1466

Pacak, K. G. Eisenhofer, and I. Ilias. Diagnostic imaging of pheochromocytoma. Frontiers of Hormone Research 31:107-120, 2004. PMID: 14674307

Pacak K. G. Eisenhofer, and H.R. Keiser. Pheochromocytoma. In L.S. DeGroot, J.L. Jameson (eds) Textbook of Endocrinology. 5th edition. Elsevier Science Inc., Philadelphia “in press”.

Price, E. B., “Papillary Cystadenoma of the Epididymis.” Arch. Pathol. 1971 91:456-470.

Privacy Commission of Canada: Genetic Testing and Privacy (1992) Ottawa, Canada, ISBN 0-662-58966-1

Richard, S., et al, Pheochromocytoma as the first manifestation of von Hippel-Lindau disease. Surgery, 1994, 116: 1076-1081.

Richard, S., et al. La maladie de von Hippel-Lindau: une maladie à impact tissulaire multiple. Press Méd., 1998, 27:1112-1120.

Richard, S., et al. Von Hippel-Lindau disease: recent advances and therapeutic perspectives. Expert Rev. Anticancer Ther., 2003, 3:215-233. PMID: 12722881

Richard S, Lindau J, Graff J, Resche F. Von Hippel-Lindau disease. Lancet, 2004, 363: 1231-1234. PMID: 15081659

Sanflippo P, Troutbeck R, Vandeleur K. Retinal angioma associated with von Hippel Lindau disease. Clin Exp Optom 2003 May;86(3): 187-191.

Schmidt, D., and H. Neumann, “Retinal Vascular Hamartoma in von Hippel-Lindau Disease.” Arch. Ophthalmol, 1995 113:1163-1167.

Self-Examination of the Testes, PRR, Inc. 48 South Service Road, Melville, NY 11747 (telephone: 631-777-3800) or e-mail orderinfo@cancernetwork.com or download from http://www.cancernetwork.com/PatientGuides/Testes_Examination.htm

Sgambati, M. T., Stolle, C. A., Choyke, P. L., Walther, M. M., Zbar, B., Linehan, W. M., and Glenn, G. M. Mosaicism in von Hippel-Lindau Disease: Lessons from Kindreds with Germline Mutations Identified in Offspring with Parents Mosaic for VHL. Am J Hum Genet, 66: 84-91, 2000.

Singh AD, Nouri M, Shields CL, Shields JA, Perez N. Treatment of retinal capillary hemangioma. Ophthalmology. 2002 Oct;109(10):1799-806.

Singh AD, Shields CL, Shields JA. von Hippel-Lindau Disease. Surv Ophthalmol 2001 Sept-Oct;46(2):117-142

Steinbach, Novick, et al., “Treatment of Renal Cell Carcinoma in von Hippel-Lindau Disease: A Multi-Center Study.” Journal of Urology, June 1995.

Stolle, C., et al, “Improved Detection of Germline Mutations in the von Hippel-Lindau disease tumor-suppressor gene,” Human Mutat, 1998; 12:417-423

Testicular Cancer Resource Center, http://tcrc.acor.org. See also Self-Examination... above

Von Hippel-Lindau Family Alliance website (information for families, clinicians, researchers) http://www.vhl.org

Walther MM, Reiter R, Keiser HR, Choyke PL, Venzon D, Hurley K, Gnarra JR, Reynolds JC, Glenn GM, Zbar B, Linehan WM. Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. J Urol. 1999 Sep;162(3 Pt 1):659-64. PMID: 10458336

Walther, MM, Herring, J., Choyke, P. L., and Linehan, W. M. Laparoscopic partial adrenalectomy in patients with hereditary forms of pheochromocytoma. J Urol, 164: 14-17, 2000. PMID: 10840414

Walther MM. New therapeutic and surgical approaches for sporadic and hereditary pheochromocytoma. Ann N Y Acad Sci. 2002 Sep;970:41-53. Review. PMID: 12381540

Walther, McC., et al., “Parenchymal Sparing Surgery in patients with hereditary renal cell carcinoma.” J. Urology 1995 153:913-916.

Wanebo, J. E., et al., “The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease,” J. Neurosurg, 2003, 98:82-94.

Welch, R. B., “Von Hippel-Lindau Disease: The Recognition and Treatment of Early Angiomatosis Retinae and the use of Cryosurgery as an Adjunct to Therapy.” Trans. Am. Ophthalmol. Soc. 1970 68:367-424.

Willett, Walter C., Eat, Drink, and Be Healthy, copyright 2001, Simon & Schuster. Pyramid developed by the Harvard School of Public Health, www.hsph.harvard.edu (copyright 2004 President and Fellows of Harvard College).

Yang H, Kaelin WG Jr., et al., “Analysis of von Hippel-Lindau hereditary cancer syndrome: Implications of oxygen sensing.” Methods Enzymol. 2004; 381:320-335

Zbar, Berton, Chief, Frederick Cancer Research Facility, Role of the National Cancer Institute in kidney cancer research http://web.ncifcrf.gov/research/kidney/bassci.html

Members of the VHL Family Alliance -- Edited by Joyce Wilcox Graff
with the kind assistance of

Lloyd M. Aiello, M.D., Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts

Lloyd P. Aiello, M.D., Ph.D., Beetham Eye Institute, Joslin Diabetes Center, Boston, Mass.

Lewis S. Blevins, Jr., M.D., Endocrinology, Vanderbilt University, Nashville, Tennessee

Michael Brown, O.D., Veterans Administration, Huntsville, Alabama

Jerry D. Cavallerano, Ph.D., Optometry, Joslin Diabetes Center, Boston, Massachusetts

Emily Y. Chew, M.D., Ophthalmology, National Eye Institute, Bethesda, Maryland

Daniel Choo, M.D., Otolaryngology, Children’s Hospital Medical Center, Cincinnati, Ohio

Debra L. Collins, M.S., Department of Genetics, University of Kansas Medical Center, Kansas City

Graeme Eisenhofer, Ph.D., Endocrinology, U.S. National Institutes of Health, Bethesda, Maryland

Yasser El-Sayed, M.D., Obstetrics, Stanford University Medical Center, Palo Alto, California

Joal Fischer, M.D. and Tina B. Farney, SupportWorks, Charlotte, North Carolina

Vincent Giovannucci, O.D., medical cartoonist, Auburn, Massachusetts

Gladys M. Glenn, M.D., Ph.D., Cancer Epidemiology and Genetics, National Institutes of Health, Bethesda, Maryland

Michael B. Gorin, M.D., Ophthalmology, University of Pittsburgh, Pennsylvania

Jane Green, M.S., Ph.D., Community Medicine, Health Sciences Center, St. John’s, Newfoundland, Canada

David Gross, M.D., Endocrinology, Hadassah Hospital, Jerusalem, Israel

Pascal Hammel, M.D., Gastroenterology, Hôpital Beaujon, Clichy, France

Yujen Edward Hsia, M.D., Medical Genetics, Retired, Honolulu, Hawaii

Howard Hughes Medical Institute, Chevy Chase, Maryland

G. P. James, M.S., Medical writer, and Frank James, Illustrator, Springfield, Ohio

William G. Kaelin, Jr., Genetics, Dana-Farber Cancer Institute, Boston, Massachusetts

Jeffrey Kim, M.D., Neurotology, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland

James M. Lamiell, M.D., Clinical Investigation Regulatory Office, AMEDDC&S, Fort Sam Houston, Texas

Jacques W. M. Lenders, M.D., Internal Medicine, St. Radboud University Hospital, Nymegen, the Netherlands

Richard Alan Lewis, M.D., M.S., Ophthalmology, Pediatrics and Genetics, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas

John Libertino, M.D., Urology, Lahey Clinic, Burlington, Massachusetts

Steven K. Libutti, M.D., Endocrinology, National Cancer Institute, Bethesda, Maryland

W. Marston Linehan, Chief, Urologic Oncology, National Cancer Institute, Bethesda, Maryland

Cornelius J. M. Lips, M.D., Department of Internal Medicine, University Hospital, Utrecht, the Netherlands.

Joseph A. Locala, M.D., Psychiatry and Psychology, Cleveland Clinic Foundation, Cleveland, Ohio

Russell R. Lonser, M.D., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland

Eamonn R. Maher, M.D., Medical Genetics, University of Birmingham, Birmingham, England, U.K.

Virginia V. Michels, M.D., Chair, Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota

Haring J.W. Nauta, M.D., Ph.D., Neurosurgery, University of Texas, Galveston, Texas

Hartmut P. H. Neumann, M.D., Department of Nephrology, Albert-Ludwigs University, Freiburg, Germany, and the VHL Study Group in Germany

Andrew Novick, M.D., Urology, Cleveland Clinic Foundation, Cleveland, Ohio

Edward H. Oldfield, M.D., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland

The Illustration Studios of Stansbury, Ronsaville, Wood

Stéphane Richard, M.D., Ph.D., Oncogenetics, Faculté de Médecine, Paris-Sud and Bicêtre Hospital, Le Kremlin-Bicêtre, France, and the International French-Speaking VHL Study Group

Armand Rodriguez, M.D., Internal Medicine, Fort Lauderdale, Florida

R. Neil Schimke, M.D., Ph.D., Endocrinology and Genetics, University of Kansas Medical Center, Kansas City, Kansas

Taro Shuin, M.D., Urology, Kochi Medical School, Kochi, Japan

McClellan M. Walther, M.D., Urologic Oncology, National Cancer Institute, Bethesda, Maryland

Robert B. Welch, M.D., Emeritus Professor of Ophthalmology, Johns Hopkins University School of Medicine and Greater Baltimore Medical Center, Baltimore, Maryland

Gary L. Wood, Psy.D., Psychology, Wood and Associates, Tampa, Florida

Berton Zbar, M.D., Chief, Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland

VHL Family Alliance
2001 Beacon St, Suite 208, Boston, MA 02135-7787 USA
Tel: +1 800 767-4845 or +1 617 277-5667; Fax: +1 858-712-8712
http://www.vhl.org; E-mail: info@vhl.org