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Von Hippel-Lindau Syndrome

NORD is very grateful to Joyce Graff and medical advisors of the VHL Family Alliance (vhl.org) for assistance in the preparation of this report.

Synonyms of Von Hippel-Lindau Syndrome

  • angiomatosis retinae
  • Lindau disease
  • retinocerebellar angiomatosis
  • VHL
  • VHL syndrome
  • Von Hippel Lindau disease

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Von Hippel-Lindau syndrome (VHL) is an autosomal dominant genetic disorder characterized by the abnormal growth of blood vessels in certain parts of the body (angiomatosis). Very small blood vessels (capillaries) "knot" together to form benign growths known as angiomas or hemangioblastomas. These may develop in the retinas of the eyes (retinal hemangioblastomas) or in the brain or spinal cord, or in the inner ear (endolymphatic sac tumors). Vascular tumors may also occur in the kidneys (renal cell carcinoma), pancreas (cysts, microcystic cystadenomas, or pancreatic neuroendocrine tumors) and/or adrenal glands (pheochromocytoma). The symptoms of VHL vary greatly and depend on the size and location of the growths.

Symptoms

The age of onset and the severity of symptoms of VHL vary greatly. For optimal health management, it is important to screen people at risk prior to the occurrence of symptoms, in order to find tumors at early stages. The most common ages for the occurrence of first symptoms are during adolescence or young adulthood. However, retinal issues and pheochromocytomas are often seen in young children (even infants), and some people never have symptoms until later in life. Waiting for symptoms, though, is dangerous. People diagnosed after age 50 are often found to have metastatic disease. The symptoms also vary greatly based on the location and size of the lesions.

Benign tumors (hemangiomas) and fluid-filled sacs (cysts) that press on nerves and brain tissue may develop, most commonly in the cerebellum, brain stem, and/or spinal cord. Neurological symptoms may include headaches, dizziness (vertigo), vomiting, involuntary rhythmic movements of the eyes (nystagmus), difficulty speaking (dysarthria), and/or impaired ability to coordinate movement (ataxia). Some people with VHL may also experience changes in behavior because of benign growths in certain areas of the brain. Symptoms associated with tumors on or in the spinal cord may include weakness or loss of sensation in the arms and legs accompanied by partial paralysis of the legs (spastic paraparesis).

Retinal hemangioblastomas occur in approximately 70% of individuals with VHL. At early stages they do not cause symptoms, but tend to occur on the equator of the eye. Over time they may enlarge, recruit fluid, and may cause retinal detachment. Control with laser or other therapy is important beginning at early stages. As they progress, eye symptoms may include blurred vision, cataracts, glaucoma, and the progressive loss of sight. People known to have VHL should be seen by a retinal specialist. The probability that they will affect vision increases over time.

Endolymphatic sac tumors (ELST) are found in approximately 10% of individuals with VHL and hearing loss is sometimes the first symptom of the disease. Loss of hearing in at least one ear can vary in severity but is often severe to profound with a sudden onset. Dizziness (vertigo) or ringing in the ears (tinnitus) may be early symptoms. Regular audiology exams are recommended to detect subtle changes in the hearing, which may signal an ELST. Strategies now exist for removal of an ELST with conservation of the hearing. Once hearing is lost, it is extremely difficult, if not impossible, to restore.

Epididymal cystadenomas occur frequently in men with VHL. They usually do not cause problems but may result in infertility. If they are painful, they must be seen immediately by a urologist.

As many as 50% of people with VHL develop pancreatic cysts or benign microcystic adenomas. Fewer (about 15%) develop neuroendocrine tumors of the pancreas. These pancreatic neuroendocrine tumors (PNETs) are cancer and can metastasize. It is important to detect and monitor the growth of PNETs and remove them before they metastasize.

Malignant growths in the kidneys (renal cell carcinoma) develop in approximately 40% of affected individuals and are a leading cause of death from this condition. (For more information, choose "carcinoma, renal cell" as your search term in the Rare Disease Database.) With careful monitoring and appropriate intervention, most people are able to stay on their own kidney power their whole lives. RCC tumors may be monitored until they approach 3 cm. At early stages Radio Frequency Ablation (RFA) and cryotherapy have been used successfully to disable the growth and metastatic potential of these tumors. As they approach the 3 cm level, surgery should be considered.

Approximately 10% of people with VHL develop tumors of the adrenal glands (pheochromocytoma). In VHL, only about 3% of pheochromocytomas metastasize. These are nonetheless quite dangerous and life-threatening tumors, as they cause the cardio-vascular system to go into over-drive. If this goes on for a sustained period of time, it can cause heart disease or stroke. Symptoms are caused by a surge of norepinephrine and adrenaline produced at random by the tumor. Symptoms may include chronic or periodic high blood pressure (hypertension), headaches, cold hands and feet, bladder dysfunction, and/or excessive sweating (hyperhidrosis). The surge may also feel like a panic attack, palpitations, or a rage attack. Blood pressure may return to normal as the patient ages. (For more information, choose "Pheochromocytoma" as your search term in the Rare Disease Database.)

Causes

VHL syndrome is an autosomal dominant genetic disorder caused by a mutation in the VHL gene located on chromosome 3 at 3p26-25.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. Approximately 80% of affected individuals have an affected parent and about 20% develop VHL as the result of a new gene mutation. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 3p26-25" refers to band 26-25 on the short arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Affected Populations

VHL syndrome affects males and females in equal numbers. The incidence of this condition is approximately 1 in 36,000 births per year for all ethnic groups, in every country of the world.

Related Disorders

Symptoms of the following disorders can be similar to those of von Hippel-Lindau syndrome. Comparisons may be useful for a differential diagnosis:

VHL brain tumors may look symptomatically like any other brain tumor, causing headaches, and intracranial pressure and therefore a host of symptoms. With MRI, it should be easy to locate the tumor (which in VHL is usually in cerebellum or brain stem, but may occasionally be supratentorial), and its distinctive composition as a mass of capillaries, often with an associated cyst.

Renal cell carcinoma is a form of kidney cancer. At early stages, there are usually no symptoms. Once symptoms appear the tumor has likely already metastasized. Thus, it is critically important to screen patients and find tumors are early stages when they can be successfully treated. When symptoms are present, they may include blood in the urine; urine that is brown or rusty-colored; abdominal pain; weight loss; enlargement of one testicle or varicose veins of the testis (varicocele) in a male patient; fever; a thin, malnourished appearance; vision abnormalities; and elevated blood pressure. The most common feature of the syndrome is the passing of blood in the urine (hematuria). (For more information on this disorder, choose "carcinoma, renal cell" as your search term in the Rare Disease Database.)

Pancreatic-islet cell tumors appear in one of two forms. They may be nonfunctioning or functioning tumors. In VHL they are almost always nonfunctioning. Nonfunctioning tumors and cysts may cause obstruction in the shortest part of the small intestine (duodenum) or in the biliary tract, which connects the liver to the duodenum and includes the gall bladder. These nonfunctioning tumors may erode and bleed into the stomach and/or the intestines, or they may cause an abdominal mass. Cysts may also cause blockages in the delivery of pancreatic enzymes or insulin, causing bloating, digestive issues, anorexia, or diabetes. Functioning tumors (pancreatic neuroendocrine tumors or PNETs) secrete excessive amounts of hormones, which may lead to various syndromes including low blood sugar (hypoglycemia), multiple bleeding ulcers (Zollinger-Ellison syndrome), pancreatic cholera (Verner-Morrison syndrome), carcinoid syndrome or diabetes. Approximately 90% of islet-cell tumors are noncancerous. (For more information on this disorder, choose "pancreatic islet cell tumor" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
VHL syndrome is diagnosed by the presence of physical findings such as hemangioblastomas, kidney cysts, kidney tumors, pheochromocytomas (noncancerous tumors of the adrenal glands that produce norepinephrine, causing higher levels of these hormones in the blood and an increase in blood pressure), and endolymphatic sac tumors (a type of middle ear tumor). An ophthalmologist can detect retinal hemangioblastomas with high-powered magnification of the vascular structure of the eye. Plasma free metanephrine is the most reliable chemical test for a pheochromocytoma. Imaging techniques such as MRI and CT may be necessary to detect other types of tumors. A clinical diagnosis of VHL is based on two or more kinds of VHL-related tumors, or a family history plus one tumor. Molecular genetic testing for the VHL gene is available to confirm the diagnosis.

Clinical Testing and Work-Up
Individuals diagnosed with VHL should receive a thorough evaluation to determine the extent of the disease, with follow-up screening every one to two years. The VHL Handbook includes guidelines for screening based on age. This should include a neurologic exam, ophthalmologic exam, blood pressure determination, measurement of fractionated plasma metanephrines (especially normetanephrine), abdominal ultrasound after 16 years of age, and a baseline MRI of the brain.

Treatment
Surgical removal of central nervous system hemangioblastomas should be considered. Hemangioblastomas (brain and spine) should be completely removed to prevent regrowth and refilling of any associated cyst. Retinal hemangioblastomas can be treated with a variety of techniques. Renal cell tumors should be ablated or surgically removed before 3 cm. Pheochromocytomas should be surgically removed, preferably with laparoscopic partial adrenalectomy to preserve even minimal adrenal function. Endolymphatic sac tumors can be surgically removed with care to preserve the hearing. Epididymal tumors usually do not require surgery unless they are obstructive.

Relatives at risk for VHL or individuals who have a VHL gene mutation but are asymptomatic should be monitored regularly including an annual eye exam beginning before three years of age, annual blood pressure monitoring and measurement of fractionated serum metanephrines beginning at five years of age, and annual abdominal ultrasound examination beginning at 16 years of age. The American Society of Clinical Oncologists identifies VHL as a hereditary syndrome for which genetic testing is considered part of standard management for at-risk family members.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site. All trials available to people with VHL, with or without government funding, are posted at www.vhl.org/trials.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Von Hippel-Lindau Syndrome Resources

NORD offers an online community for this rare disease. RareConnect was created by EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders) to provide a safe space where individuals and families affected by rare diseases can connect with each other, share vital experiences, and find helpful information and resources. You can view these international, rare disease communities at www.rareconnect.org.

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

TEXTBOOKS
Michels VV and Couch V. Von Hippel Lindau Disease. In: The NORD Guide to Rare Disorders, Philadelphia, PA: Lippincott, Williams and Wilkins, 2003:265-266.

Illiopoulos O. von Hippel-Lindau disease: Genetic and clinical observations. In: Dahlia
PLM and Eng C (eds). Genetic Disorders of Endocrine Neoplasia. Front Horm Res
Basel, vol 28, Karger Publishers. 2001:131-66.

JOURNAL ARTICLES
Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19(6):617-23.

Wind JJ, Lonser RR. Management of von Hippel-Lindau disease-associated CNS
lesions. Expert Rev Neurother. 2011;11(10):1433-41.

Kim M, Kim J, Kim SH, et al. Hemorrhage in the endolymphatic sac: a cause of
hearing fluctuation in enlarged vestibular aqueduct. Int J Pediatr
Otorhinolaryngol. 2011;75(12):1538-44.

Abadie C, Coupier I, Bringuier-Branchereau S, Mercier G, Deveaux S, Richard S.
The role of pregnancy on hemangioblastomas in von Hippel-Lindau disease: a
retrospective French study. 9th International Symposium on VHL; October 2010;
Rio de Janeiro, Brazil.

Peyre M, David P, Van Effenterre R, et al. Natural history of supratentorial
hemangioblastomas in von Hippel-Lindau disease. Neurosurgery. 2010;67:577-
87.

Zach L, et al. Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease. Neuro Oncol. 2010;12(1):80-6.

Wong WT, Chew EY. Ocular von Hippel-Lindau disease: clinical update and
emerging treatments. Curr Opin Ophthalmol. 2008;19(3):213-7.

Jagannathan J, Lonser RR, Smith R, DeVroom HL, Oldfield EH. Surgical management
of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease. J
Neurosurg. 2008;108(2):210-22.

Chew E. Ocular Manifestations of von Hippel-Lindau Disease: clinical and genetic
investigations. Trans Am Ophthalmol Soc. 2005;103:495-511.

Kim HJ, Butman JA, Brewer C. Tumors of the endolymphatic sac in patients with von
Hippel-Lindau disease: implications for their natural history, diagnosis, and treatment. J
Neurosurg. 2005;102(3):503-12.

Richard S, Lindau J, Graff J, Resche F. Von Hippel-Lindau disease. Lancet. 2004; 363:1231-4.

Lonser RR, Glenn GM, Chew EY, Libutti SK, Linehan WM, Oldfield EH. von Hippel-Lindau disease. Lancet. 2003;361(9374):2059-67.

Lonser RR, Weil RJ, Wanebo JE, DeVroom HL, Oldfield EH. Surgical management of
spinal cord hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg.
2003;98(1):106-16.

Weil RJ, Lonser RR, DeVroom HL, Wanebo JE, Oldfield EH. Surgical management of
brainstem hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg.
2003;98(1):95-105.

Lonser RR, Wait SD, Butman JA, et al. Surgical management of lumbosacral nerve root
hemangioblastomas in von Hippel-Lindau syndrome. J Neurosurg. 2003;99(1 Suppl):64-
9.

Couch V, Lindor NM and Karnes PS, et al. von Hippel-Lindau disease. Mayo Clin Proc.
2000;75:265-272.

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

INTERNET
Graff, Joyce, ed. The VHL Handbook, What You Need to Know About VHL (in English,
French, Spanish, Chinese, Japanese, and Arabic). www.vhl.org/handbook. January 2012.
Accessed April 11, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Von
Hippel-Lindau Syndrome; VHL. Entry No: 193300. Last Edited June 13, 2011. Available
at: http://www.ncbi.nlm.nih.gov/omim/. Accessed April 11, 2012.

Schimke RN, Collins DL and Stolle CA. (Updated December 22, 2009). Von-Hippel Lindau Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at http://www.genetests.org. Accessed April 11, 2012.

Pacak K, Brouwers FM, Ohta S, et al. Diagnosis, Localization, Pathophysiology, and Molecular Biology of Pheochromocytoma. Harrison's Textbook online.. http://2004annualreport.nichd.nih.gov/preb/ucn.htm. 2004. Accessed April 11, 2012.

El-Sayed YY. Pregnancy and VHL. VHL Family Alliance.http://www.vhl.org/newsletter/vhl2001/01eapreg.php.June 2001. Accessed April 11, 2012.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2012/04/17 00:00:00 GMT+0

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