Von Hippel-Lindau disease

Definition

Von Hippel-Lindau disease (VHL) is a rare familial cancer syndrome. A person with VHL can develop both benign and malignant tumors and cysts in many different organs in the body. Tumors and cysts most commonly develop in the brain and spine, eyes, kidneys, adrenal glands, pancreas, and inner ear.

Description

VHL does not have a predictable set of symptoms. VHL affects approximately 1 in 35,000 people, and affects men and women equally. Some families may have different symptoms than other families. Even within a family, there may be people with very mild signs of VHL, and others with more severe medical problems. The age when symptoms develop can range from infancy to late adulthood, although most people with VHL will have some clinical symptoms by age 65. It is important for a person with VHL to have regular physical examinations to check for signs of VHL in all areas of the body that may be affected.

Tumors in the brain and spine, or central nervous system, are called hemangioblastomas. Hemangioblastomas are benign growths (not cancerous), but they may cause symptoms, such as headaches and balance problems, if they are growing in tight spaces and pressing on surrounding tissues or nerves. The eye tumors in VHL are called retinal angiomas or retinal hemangioblastomas, and may cause vision problems and blindness if they are not treated. Kidney cysts rarely cause problems, but the kidney tumors can be malignant, and are called renal cell carcinoma. Tumors in the adrenal glands are called pheochromocytomas. Pheochromocytomas are usually not malignant, but they can cause serious medical problems if untreated. This is because pheochromocytomas secrete hormones that can raise blood pressure to dangerous levels, causing heart attacks or strokes. Benign cysts can be found in the pancreas, and pancreatic islet cell tumors can also occur. These tumors grow very slowly and are rarely malignant. Tumors that grow in the ear are called endolymphatic sac tumors, which can result in hearing loss if untreated. Occasionally men and women with VHL will have infertility problems if cysts are present in certain places in the reproductive organs, such as the epididymis (a duct in the testes)in men or the fallopian tubes in women.

Diagnosis

A clinical diagnosis of VHL can be made in a person with a family history of VHL if he or she has a single retinal angioma, central nervous system hemangioblastoma, or pheochromocytoma, or if he or she has renal cell carcinoma. If there is no known family history of VHL, two or more retinal or central nervous system hemangioblastomas must be present, or one retinal or central nervous system hemangioblastoma and one other feature of VHL. Melmon and Rosen published these criteria in 1964, when they first described VHL as a disease with a specific set of features. Because not all people with VHL will meet these diagnostic criteria, VHL may be an under-diagnosed disease. Genetic testing can confirm a diagnosis of VHL in a person with clinical symptoms, who may or may not meet the above diagnostic criteria.

Causes

VHL is a genetic disease caused by a mutation of the VHL tumor suppressor gene on chromosome three. It is inherited as an autosomal dominant condition, which means that a person with VHL has a 50% chance of passing it on to each of his or her children. Usually a person with VHL will have a family history of VHL (a parent or sibling who also has VHL), but occasionally he or she is the first person in the family to have VHL. Screening and/or genetic testing of family members can help establish who is at risk for developing VHL. Identification of a person with VHL in a family may result in other family members with more mild symptoms being diagnosed, and subsequently receiving appropriate screening and medical care.

Risks

The United States National Institutes of Health (NIH) has determined risk ranges for a person with VHL to develop certain tumors. Persons with VHL have a 21-72% chance of developing hemangioblastomas of the brain or spinal cord, a 43-60% chance of developing retinal angiomas, a 24-45% chance of developing cysts and tumors of the kidney, an 8-37% chance of developing pancreatic cysts, and an 8-17% chance of developing pancreatic islet cell tumors. It has been proposed that VHL be divided into subtypes depending on the types of tumors present in a family. It is likely that in the future, specific risk figures will be available for the different types of tumors depending on the specific genetic mutation in a family.

Genetic testing

Almost 100% of people with VHL will have an identifiable mutation in the VHL gene. There have been many different mutations found in the VHL gene, but all persons with VHL in the same family will have the same mutation. If a mutation is known in a family, genetic testing can be done on family members who have not had any symptoms of VHL. A person who tests positive for the family mutation is at risk for developing symptoms of VHL and can pass the mutation on to his or her children. A person who tests negative for the family mutation is not at risk for developing symptoms of VHL, and his or her children are not at risk for developing VHL. Screening is needed for people who test positive for a VHL mutation, and people who are found not to have the family mutation can be spared from lifelong screening procedures. Genetic testing can also be used to determine if a pregnant woman is carrying a fetus affected with VHL. Other techniques may become available which allow selection of an unaffected fetus prior to conception. Families work with a physician, geneticist, or genetic counselor familiar with the most up-to-date information on VHL when having genetic testing, in order to understand the risks, benefits, and current technological limitations prior to testing.

Screening and Treatment

Regular screening and monitoring of tumors in people with VHL allows early detection and treatment, before serious complications can occur. A physician familiar with all aspects of VHL can coordinate screening with a variety of specialists, such as an ophthalmologist for eye examinations. Ultrasounds, computed tomography scans (CT), and magnetic resonance imaging (MRI) may be used to screen and detect tumors and cysts. Whether or not treatment is necessary depends on the size of the tumor, where it is growing, what the symptoms are, and if the tumor is benign or malignant. Treatment for benign tumors may include surgery or laser treatments. Cancer in people with VHL is treated just as it would be in someone in the general population with that type of cancer. People with VHL who develop cancer have a better prognosis if the cancer is detected at an earlier stage before it has spread. Urine tests, ultrasound, CT and/or MRI screen for pheochromocytomas. It is especially important to screen for pheochromocytomas prior to surgery, because an undiagnosed pheochromocytoma can cause complications during surgery. Prior to becoming pregnant, a woman should have a full physical examination looking for all signs of VHL, but most importantly pheochromocytomas. It is best for a woman to avoid VHL-related surgery while she is pregnant unless medically necessary. Pregnancy itself does not seem to make VHL worse or make the tumors grow faster, but any tumors that are present should be evaluated, and a plan for surgical removal or monitoring should be in place.

KEY TERMS

Benign

Not cancerous, not able to spread to new places in the body.

Cyst

A fluid filled sac that can be normal or abnormal.

Hemangioblastoma

A benign tumor caused by the abnormal growth of blood vessels.

Malignant

Cancerous, able to spread to new places in the body.

Mutation

A change in the DNA code.

Tumor

An abnormal growth caused by the uncontrolled growth of cells.