uestion: What are the common signs and symptoms of paragangliomas or pheochromocytomas associated with VHL gene mutations?

nswer: These tumors, which can develop in various parts of the body, often produce excess hormones. Symptoms can include high blood pressure, headaches, sweating, palpitations (a sensation of a racing heart), tremors, and anxiety. The specific symptoms depend on the tumor's location and the hormones it produces.

uestion: How frequently should individuals with a known VHL gene mutation be screened for tumors, and what types of tests are typically performed?

nswer: Individuals with a VHL gene mutation require lifelong, regular surveillance due to the increased risk of developing various tumors. Screening protocols are individualized but often include annual physical exams, blood and urine tests for hormone levels (e.g., catecholamines), MRI scans of the brain, spine, and abdomen, and ophthalmologic exams. The

VHL gene

The VHL gene provides instructions for making a protein that acts as a tumor suppressor, regulating cell growth and oxygen-sensing pathways.

Normal Function

The VHL gene provides instructions for making a protein that functions as part of a complex called the VCB-CUL2 complex. This complex targets other proteins to be broken down (degraded) by the cell when they are no longer needed, a process that helps maintain normal cellular function.

One of the primary targets of the VCB-CUL2 complex is hypoxia-inducible factor 2-alpha (HIF-2α). This protein is part of a larger complex, HIF, which allows the body to adapt to changing oxygen levels. HIF regulates genes involved in cell division, the formation of new blood vessels, and the production of red blood cells. When adequate oxygen is available, the VCB-CUL2 complex prevents HIF from building up inappropriately.

The VHL protein is classified as a tumor suppressor, meaning it prevents cells from growing and dividing too rapidly or in an uncontrolled way. It also plays a role in regulating other genes and forming the extracellular matrix, which provides structural support to tissues.

Health Conditions Related to Genetic Changes

Nonsyndromic paraganglioma

Mutations in the VHL gene increase the risk of developing paragangliomas or pheochromocytomas. These can occur as part of von Hippel-Lindau syndrome or nonsyndromically (without other signs of the syndrome).

Inheritance and Spontaneous Mutations: Mutations can be inherited or occur spontaneously. De novo mutations occur in reproductive cells or just after fertilization and are present in every cell. Somatic mutations are acquired during a person's lifetime and are present only in tumor cells.
Mechanism: These mutations disrupt VHL protein function, preventing the breakdown of HIF-2α. The resulting excess HIF stimulates abnormal cell division and unnecessary blood vessel production.

Familial erythrocytosis

At least 10 inherited mutations in the VHL gene cause familial erythrocytosis (often designated ECYT2), characterized by an increased number of red blood cells and a higher risk of blood clots.

Mechanism: Mutations, such as the Arg200Trp (R200W) mutation, disrupt the VHL protein's ability to target HIF-2α for degradation. This leads to an accumulation of HIF, which triggers the production of red blood cells even when they are not needed.

Von Hippel-Lindau syndrome

More than 370 inherited mutations in the VHL gene are associated with von Hippel-Lindau syndrome, a disorder characterized by the formation of tumors and fluid-filled sacs (cysts) throughout the body.

Mechanism: These mutations either prevent the production of the VHL protein or create an abnormal version. The resulting buildup of HIF leads to uncontrolled cell division and abnormal blood vessel formation, causing cysts and tumors.

Other disorders

Somatic mutations in the VHL gene are associated with hemangioblastomas—tumors made of newly formed blood vessels that develop in the brain and spinal cord. While these are a feature of von Hippel-Lindau syndrome, they can also occur sporadically in individuals without the syndrome.

Cancers

Somatic mutations in the VHL gene are associated with clear cell renal cell carcinoma. These mutations occur only in certain kidney cells, preventing the production of functional VHL protein and allowing cells to grow and divide abnormally.

Other Names for This Gene

pVHL
VHL1
VHL_HUMAN