What is von Hippel-Lindau (VHL) disease?

Related conditions:

Renal cysts; clear cell form of renal cell carcinoma; hemangioblastomas of the brain, spinal cord, and retina; pheochromocytoma; endolymphatic sac tumors

Definition:
A hereditary cancer syndrome, von Hippel-Lindau (VHL) disease is associated with renal cell carcinoma (kidney cancer); pheochromocytoma (an adrenal gland tumor that releases stress hormones); catecholamine-secreting paraganglioma (a tumor that releases stress hormones like a pheochromocytoma but is located outside the adrenal gland); hemangioblastomas (blood vessel tumors) of the brain, spinal cord, and retina; neuroendocrine tumors (nerve-cell tumors that may produce hormones) of the pancreas; and endolymphatic sac tumors (inner ear tumors). For individuals with VHL, the lifetime risk of developing renal cell carcinoma—the leading cause of VHL-associated death—is approximately 70 percent, as E. R. Maher, H. P. H. Neumann, and S. Richard reported in their 2011 European Journal of Human Genetics review. Several distinct clinical presentations of VHL have been described based on the risk for pheochromocytoma and renal cell carcinoma. The types of tumors and the severity of the disease vary within and between families.

Risk factors: Because von Hippel-Lindau disease is hereditary, the main risk factor is having a family history of this syndrome. Each child of a person with von Hippel-Lindau disease has a 50 percent chance of inheriting the disease.

Etiology and the disease process: The underlying genetic cause of von Hippel-Lindau disease is a mutation, or a genetic change, in the VHL gene. Normally, the protein made by the VHL gene acts as a tumor suppressor, which means that it helps stop uncontrolled cell growth and proliferation. Mutations in the VHL gene either prevent the protein from being made or cause the protein to be made incorrectly, which leads to the multistep process of tumorigenesis (formation or production of tumors).

Usually, each person has two normal copies of the VHL gene. A mutation in one copy of the gene is sufficient to cause von Hippel-Lindau disease, which is why this condition is referred to as autosomal dominant (autosomal means the VHL gene is located on one of the twenty-two pairs of autosomes, which are the non-sex chromosomes). A person with von Hippel-Lindau disease has a VHL gene mutation from the time of conception in the womb; however, symptoms of the disease may not manifest until later in life. Symptoms can occur before the age of five, and nearly all people with a VHL gene mutation have symptoms of the disease by the age of sixty-five, as reported by endocrinologists C. Frantzen and T. P. Links and nephrologist R. H. Giles in GeneReviews (2012).

Different types of mutations in the VHL gene lead to different clinical presentations. Therefore, a person with von Hippel-Lindau disease may be more likely to have pheochromocytoma, renal cell carcinoma, or both.

Incidence: According to the US National Library of Medicine's Genetic Home Reference (2012), approximately 1 in 36,000 people has von Hippel-Lindau disease. Some 80 percent of people with von Hippel-Lindau disease inherit the disease from a parent, but 20 percent of people with the disease have a new gene mutation, meaning the mutation occurs for the first time in that individual.

Symptoms: Symptoms depend on where the tumors are located. Hemangioblastomas of the brain or spinal cord can cause headaches, vomiting, coordination problems, and walking difficulties. Retinal (eye) hemangioblastomas can lead to vision problems. Pheochromocytomas and catecholamine-secreting paragangliomas release catecholamines (stress hormones) that can cause dangerously high blood-pressure levels. Neuroendocrine tumors of the pancreas usually do not produce hormones and may have no associated symptoms. Tumors of the endolymphatic sac can result in deafness, which may occur suddenly and be severe to profound.

Screening and diagnosis: Von Hippel-Lindau disease is clinically diagnosed in a person who has two or more tumors associated with this condition. However, if a person has a family history of the disease, just one of the characteristic findings is needed to make a diagnosis. Tools used to check for disease include computed tomography (CT) or magnetic resonance imaging (MRI) to look for pheochromocytomas, endolymphatic sac tumors, or tumors of the brain and spinal cord. Ultrasound or CT may be used to examine the kidneys and pancreas, and urine testing may be done to check for catecholamines and metanephrines released by pheochromocytomas or paragangliomas. Ophthalmologic examination (an eye exam) is performed to check for retinal hemangioblastomas.

Because von Hippel-Lindau disease is caused by mutations in the VHL gene, genetic testing is a valuable tool to confirm a suspected diagnosis or to test a family member who is at risk for the disease but has no symptoms. Genetic testing detects 90 to 100 percent of VHL gene mutations, according to Frantzen, Links, and Giles.

Treatment and therapy: The main focus of treatment for von Hippel-Lindau disease is surgery to remove tumors. Early surgery offers the best outcome for most of the tumors associated with von Hippel-Lindau disease, including renal cell carcinoma. Renal cell carcinoma may also be treated with chemotherapy, radiation therapy, ablation therapy (using probes to destroy the tumor with heat or cold), biological therapy (using the patient’s immune system to fight the cancer), and targeted therapy (using drugs that attack cancer cells without damaging normal cells).

Prognosis, prevention, and outcomes: Because von Hippel-Lindau disease is a genetic condition, its manifestations cannot be prevented. However, monitoring of individuals who are at risk for the disease based on their family history or who are known to have a VHL gene mutation can detect problems early and lead to more effective treatment and better outcomes. Such monitoring includes yearly ophthalmologic screening, yearly blood pressure checks, yearly urine testing for catecholamines and metanephrines, yearly abdominal ultrasounds, periodic MRI of the brain and spinal cord, and hearing evaluation if symptoms of hearing loss are present. The medical team caring for patients decides the age at which monitoring should start.

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