Von Hippel-Lindau syndrome
Von Hippel-Lindau (VHL) syndrome is a rare genetic disorder characterized by abnormal blood vessel growth that can lead to tumors and cysts in various organs, particularly those rich in blood vessels. Affecting approximately 1 in 36,000 people, VHL is primarily inherited in an autosomal dominant manner, meaning that a single copy of the mutated gene is sufficient to express the syndrome. The VHL gene, located on chromosome 3, plays a crucial role in regulating processes like cell division and blood vessel formation through the degradation of hypoxia-inducible factor (HIF). When mutations occur in the VHL gene, it can result in uncontrolled cell growth, leading to the characteristic lesions associated with the syndrome.
Common symptoms of VHL include vision problems, headaches, and issues with balance or coordination, while more severe manifestations can involve tumors in the adrenal glands, kidneys, brain, and other areas. Diagnosis typically involves a combination of genetic testing and regular screenings, starting in childhood, to monitor for complications. While there is currently no cure, treatment strategies may include surgical intervention for problematic tumors and ongoing management to monitor growth and mitigate symptoms. Genetic counseling is advised for families affected by VHL, emphasizing the importance of early detection and proactive health measures to manage risks associated with this syndrome.
Von Hippel-Lindau syndrome
ALSO KNOWN AS: Von Hippel-Lindau disease; VHL
DEFINITION Von Hippel-Lindau (VHL) syndrome is a rare genetic disorder (affecting approximately 1 in 36,000 people according to 2024 statistics) in which some blood vessels grow in an abnormal way and cause tumors in parts of the body that are rich in blood vessels.
Risk Factors
The only known risk factor for VHL is having family members with this syndrome.
Etiology and Genetics
A single gene, VHL, located on the short arm of chromosome 3 at position 3p25.3, is known to be associated with Von Hippel-Lindau syndrome. There are actually two different proteins specified by this gene, depending on how the coding portions of the messenger are spliced together. These proteins normally move back and forth in cells between the nucleus and the cytoplasm, and they form complexes with several other proteins in a pathway that targets yet other proteins to be degraded when they are no longer needed. One such protein that is often targeted for degradation is the hypoxia-inducible factor (HIF), which acts to control cell division and the formation of new blood vessels. When mutations in the VHL gene result in missing or altered VHL proteins, an excess of HIF may develop. This can lead to uncontrolled cell division with superfluous blood vessels, resulting in the characteristic tumors and cysts seen in patients with VHL.
The inheritance of VHL follows a classic autosomal dominant pattern, meaning that a single copy of the mutation is sufficient to cause full expression of the syndrome. An affected individual has a 50 percent chance of transmitting the mutation to each of his or her children. In about 20 percent of cases, however, the disease results from a spontaneous new mutation, so in these instances affected individuals will have unaffected parents. Curiously, it has been shown that at the molecular level within cells, both copies of the VHL gene must be mutated in order to initiate the formation of tumors and cysts. One of these mutations is the inherited one that is present in all cells, while the second occurs randomly during normal cell growth in tissues, such as the kidney, brain, or retina. It is this acquired second mutation that triggers tumor or cyst formation in the affected tissue.
Symptoms
There is wide variation in the age at which VHL begins, the organs where problems occur, and the types and severity of symptoms. These differences occur even among members of the same family.
Although there is no consistent set of symptoms, the most common ones are vision problems (retinal angiomatosis), headaches, signs of elevated intracranial pressure, and trouble walking (cerebellar hemangioblastoma). Less common findings include pheochromocytoma, a tumor of the adrenal gland that leads to many problems, including very high or spiking blood pressure; and tumors and/or cysts in the spinal cord, lungs, liver, pancreas, and epididymis (part of the scrotum). Renal cell carcinoma is the most common cause of death.
Few people with VHL have all these problems. Full-blown symptoms usually occur in adulthood, but they can begin in childhood.
Screening and Diagnosis
The doctor will ask about a patient’s symptoms and medical history and will perform a physical exam. A blood test that analyzes DNA may be done to determine if the patient has the VHL gene. Not all families with VHL have an identifiable VHL mutation. If members of the patient’s family are positive for the gene and the patient is not, the patient does not need any further testing.
However, if other family members have been diagnosed with VHL despite a negative genetic test, or if the patient tests positive for the VHL gene, the patient needs to have regular medical exams and tests to uncover early signs. Even in the absence of symptoms, screening should begin in childhood and continue periodically throughout life.
Screening for VHL complications includes a physical exam with special attention to the patient’s eyes and nervous system. Tests may include a magnetic resonance imaging (MRI) scan, a test that uses powerful magnets and radio waves to generate images of the inside of the body; a computed tomography (CT) scan, a type of X ray that uses a computer to generate images of the inside of the body; ultrasound, a test that uses high-pitched sound waves to examine the inside of the body; angiography, X rays taken after a dye is injected into the arteries allowing their interior to be seen; and a twenty-four-hour urine test for elevated levels of hormones. Depending on the test results, the doctor will tell the patient what symptoms to watch for and if the patient needs treatment.
If the patient has any VHL symptoms, he or she should consider being tested for the gene. This is advised even if the patient has no known family history of the disease. The patient could be the first person in his or her family to have VHL, or he or she could be the first one to have it properly diagnosed since many people are not aware they have it.
Treatment and Therapy
There is no known cure for VHL. Treatment depends on a patient’s specific symptoms, test results, and general health. Retinal angiomas may be treated with photocoagulation or cryocoagulation. When treatment is needed (for example, for cerebellar lesions), it usually involves surgery to remove tumors. However, tumors are usually removed only if they are cancerous or causing other problems, such as preventing an organ from working properly. If tumors are not removed, they must be watched carefully for further growth.
Prevention and Outcomes
There is no known way to prevent the VHL gene from causing its many manifestations. Therefore, genetic counseling is advised for families with known VHL or who test positive for the gene.
Individuals who have a family history of the disease or know they have the gene can reduce their risks of serious health problems by having regular screening tests to detect VHL complications early, watching carefully for any suspicious symptoms, and getting treatment as soon as symptoms occur. Individuals can also take steps to reduce their risk of the cancers associated with VHL, such as eating a diet high in fruits and vegetables, not smoking, and limiting their consumption of alcohol.
Bibliography
Choyke, P. L., et al. “Von Hippel-Lindau Disease: Genetic, Clinical, and Imaging Features.” Radiology 194.3 (March, 1995): 629–42. Print.
Kleigman, Robert M., et al., eds. Nelson Textbook of Pediatrics. 18th ed. Philadelphia: Elsevier, 2007. Print.
Mahon, Suzanne M., and Laura Waldman. "Von Hippel-Lindau Syndrome: Implications for Nursing Care." Oncology Nursing Forum 39.6 (2012): 533–36. Print.
Murray, Michael F., et al. Clinical Genomics: Practical Applications in Adult Patient Care. New York: McGraw-Hill Education/Medical, 2014. Print.
O'Brien, F. J., et al. "Manifestations of Von Hippel-Lindau Syndrome: A Retrospective National Review." QJM: An Intl. Journ. of Medicine 107.4 (2014): 291–96. Print.
Schmike, R. Neil, and Debra L. Collins. “Von Hippel-Lindau Syndrome.” Management of Genetic Syndromes. Ed. Suzanne B. Cassidy and Judith E. Allanson. Hoboken: Wiley-Liss, 2005. Print.
Van Leeuwaarde, Rachel S., et al. “Von Hippel-Lindau Syndrome." Gene Reviews, 29 Feb. 2024, www.ncbi.nlm.nih.gov/books/NBK1463/. Accessed 9 Sept. 2024.
"Von Hippel-Lindau Syndrome." Medline Plus, 1 Oct. 2018, medlineplus.gov/genetics/condition/von-hippel-lindau-syndrome/. Accessed 9 Sept. 2024.