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Last updated: 10/25/2023
Years published: 1986, 1988, 1989, 1990, 1991, 1993, 1994, 1995, 1996, 1997, 1998, 1999, 2007, 2012, 2016, 2019, 2023
NORD gratefully acknowledges the VHL Alliance and their Clinical Advisory Council for assistance in the preparation of this report.
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VHL or von Hippel-Lindau disease is a rare genetic disorder associated with an increased risk of developing certain tumors. VHL disease is caused by a deletion or disease-causing variant (mutation) in the VHL gene. People who have VHL disease may experience tumors and/or cysts in up to ten parts of the body, including the brain, spine, eyes, kidneys, pancreas, adrenal glands, inner ears, reproductive tract, liver and lung. The mean age of onset is 26 years and 97% of people with a VHL gene variant have symptoms by the age of 65.
Most VHL tumors are benign (not cancerous), but benign VHL tumors can still be very serious. As they grow, these tumors and the associated cysts can cause increased pressure on the structure around them. This pressure can create symptoms including severe pain or other problems.
VHL disease is different in every patient, even within the same family. Since it is impossible to predict how and when the disease will present for each person, it is important to check regularly for possible VHL manifestations throughout a person’s lifetime.
VHL disease does not have a single primary symptom. This is in part because it does not occur exclusively in one organ of the body. It also does not always occur in a particular age group. The condition is hereditary, but the presentation of the disease can be very different between individuals, even if they have the same VHL gene variant. The appearance and severity of VHL lesions are so different between people that some members of the same family may have only relatively harmless issues, while others have a serious illness.
The most common symptom of VHL is hemangioblastomas. These are benign tumors occurring in the brain, spinal cord and retina. In the brain or spinal cord, hemangioblastoma may, in some cases, be contained within a cyst or fluid-filled sac. The hemangioblastomas or surrounding cysts may press on nerve or brain tissue and cause symptoms such as headaches, balance problems when walking or weakness of arms and legs. In the eyes, blood or fluid leakage from hemangioblastomas can be associated with floaters and retinal detachment and interfere with vision. Early detection, careful monitoring of the eyes and prompt treatment are very important to maintain healthy vision.
Early signs of adrenal tumors may be high blood pressure, panic attacks or heavy sweating. Early signs of pancreatic cysts and tumors may include digestive complaints like bloating or disturbance of bowel and bladder function. Some of these tumors are benign, while others may become cancerous.
Kidney tumors and cysts (clear cell renal cell carcinoma) may lead to reduced kidney function, but there are usually no symptoms in the early stages. Kidney tumors will spread (metastasize), if not removed, when they reach approximately 3 cm in diameter.
VHL may also cause a benign tumor in the inner ear called an endolymphatic sac tumor. If not removed, this tumor can lead to hearing loss in the affected ear as well as ringing in the ear (tinnitus) and balance problems (vertigo).
Pheochromocytomas (adrenal tumors) are common in some families with VHL disease. Symptoms can include high blood pressure, panic attacks or post-operative adrenal insufficiency.
Clear cell renal cell carcinomas (kidney tumors) are common in some families with VHL disease. Symptoms can include lower back pain, blood in urine (hematuria) and fatigue.
Less common manifestations of VHL include benign reproductive tract tumors in both males and females, including cystadenomas. These tumors can lead to problems with infertility.
Tumors in the liver and lungs do not usually cause health problems.
VHL is caused by a deletion or disease-causing variant (mutation) in the VHL gene. The function of the VHL gene is to act as a tumor suppressor and prevent the formation of tumors. The VHL gene is responsible for the production of the VHL protein. This protein is the key regulator of cellular hypoxia signaling through the HIF (hypoxia-inducible factor) complex and is indirectly responsible for enhanced levels of growth factors including vascular endothelial factor, platelet derived growth factor and transforming growth factor alpha.
People with VHL disease have a nonfunctioning VHL gene, so regulation of the HIF complex does not occur. The result is increased levels of the various growth factors allowing for increased blood vessel growth (angiogenesis) and the formation of tumors.
VHL disease is an autosomal dominant genetic disorder. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. About 20% of people with VHL are first-in-family or de novo cases. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
VHL disease affects 1 in 36,000 people (10,000 cases in the U.S and 200,000 cases worldwide). VHL disease affects males and females and all ethnic groups equally and occurs in all parts of the world.
VHL disease is diagnosed with molecular genetic testing for disease-causing variants in the VHL gene. A clinical diagnosis can be made when a person exhibits a tumor specific to VHL.
Once a VHL disease diagnosis has been made, it is important to begin surveillance testing early before any symptoms occur. Most VHL lesions are much easier to treat when they are small. Several possible complications of VHL do not result in symptoms until the problem has developed to a critical level.
Universal treatment recommendations for VHL disease do not exist. Treatment options are determined by careful evaluation of the patient’s symptoms, test results, imaging studies and general physical condition. General guidelines for possible treatments are as follows:
Brain and Spinal Hemangioblastomas
Symptoms related to hemangioblastomas in the brain and spinal cord depend on tumor location, size and the presence of associated swelling or cysts. Symptomatic lesions grow more rapidly than asymptomatic lesions. Cysts often cause more symptoms than the tumor itself. Once the lesion has been removed, the cyst will collapse. If any portion of the tumor is left in place, the cyst will re-fill. Small hemangioblastomas, which are not symptomatic and are not associated with a cyst, have sometimes been treated with stereotactic radiosurgery, but this is more preventative than a treatment, and long-term results seem to show only marginal benefit. In addition, during the recovery period symptoms may not be reduced.
Pancreatic Neuroendocrine Tumors
Careful analysis is required to differentiate between serous cystadenomas and pancreatic neuroendocrine tumors (pancreatic NETs). Cysts and cystadenomas generally do not require treatment. Pancreatic NETs should be rated on size, behavior and the patient’s VHL gene variant.
Renal Cell Carcinoma
VHL kidney tumors are often found when they are very small in size and at very early stages of development. A strategy for ensuring that an individual will have a sufficient functioning kidney throughout their lifetime begins with careful monitoring and choosing to operate only when tumor size (approximately 3 cm) or rapid growth rate suggest the tumor may begin to spread (metastasize). The technique of kidney-sparing surgery is widely used in this setting. Radio frequency ablation (RFA) or cryosurgery (cryotherapy) may be considered, especially for smaller tumors at earlier stages. Care must be taken not to injure adjacent structures and to limit scarring which may complicate subsequent surgeries.
Retinal Hemangioblastomas
Small peripheral lesions can be successfully treated with little to no loss of vision using laser. Larger lesions often require cryotherapy. If the hemangioblastoma is on the optic disc, there are few treatment options that will successfully preserve vision.
Pheochromocytomas
Surgical removal is performed after adequate blocking with medication, and laparoscopic partial adrenalectomy is preferred. Even pheochromocytomas that do not appear to be active or causing symptoms should be considered for removal, ideally prior to pregnancy or non-emergency surgery.
Endolymphatic Sac Tumors (ELSTs)
Patients who have a tumor or hemorrhage visible on MRI but who can still hear require surgery to prevent a worsening of their condition. Deaf patients with evidence on imaging of a tumor should undergo surgery if other neurological symptoms are present to prevent worsening of balance problems. Not all ELSTs are visible with imaging; some are only found during surgery.
In 2021, the U.S. Food and Drug Administration (FDA) approved belzutifan (Welireg) as the first systemic therapy for VHL, specifically for VHL-related renal cell carcinoma, central nervous system hemangioblastomas or pancreatic neuroendocrine tumors not requiring immediate surgery. Despite this, surgical removal remains the primary method of treatment for most people with VHL. An organ sparing approach is the best approach for reducing irreparable damage while minimizing the need for organ removal. For this reason, Active Surveillance Guidelines were developed to make sure VHL tumors can be found and managed appropriately. With careful monitoring, early detection and appropriate treatment, the most harmful consequences of this disease can be greatly reduced, or in some people, completely prevented.
MyVHL: The Patient Natural History Study is an important, online, secure and confidential longitudinal research study open to everyone diagnosed with VHL or with symptoms of VHL. The study was designed to complement existing clinician-driven natural history studies and to find out how to manage this disease more effectively and how lifestyle might be correlated with the manifestations of VHL. More importantly, the data from MyVHL is an important piece of the approval process for potential treatment options.
Information on current clinical trials for treating VHL is posted online at vhl.org/trials and www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com.
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/joiningtrial.html
TEXTBOOKS
Pacak K, et al., Pheochromocytoma, in Jameson, JL et al., (eds) Textbook of Endocrinology. 6th edition. Elsevier Science Inc., Philadelphia, 2010.
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
Binderup MLM, von Hippel-Lindau disease: Diagnosis and factors influencing disease outcome. Dan Med J. 2018 Mar;65(3)
Nielsen SM, et al., Von Hippel-Lindau Disease: Genetics and Role of Genetic Counseling in a Multiple Neoplasia Syndrome, J Clin Oncol. 2016 Jun 20;34(18):2172-81.
Binderup ML, et.al., Survival and causes of death in patients with von Hippel-Lindau disease. J Med Genet. 2017 Jan;54(1):11-18.
Ho TH and Jonasch E. Genetic kidney cancer syndromes. J Natl Compr Canc Netw, 2014 Sep;12(9):1347-55.
Chew E. Ocular Manifestations of von Hippel-Lindau Disease: clinical and genetic investigations. Trans Am Ophthalmol Soc. 2005;103:495-511.
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.
Gupta GN, et al., Robot-assisted laparoscopic partial nephrectomy for tumors greater than 4 cm and high nephrotomy score: feasibility, renal function, and oncological outcomes with minimum 1 year follow-up, Urol Oncol. 2013;Jan 31(1):51-6
Lenders J. Endocrine disorders in pregnancy: Phaeochromocytoma and pregnancy: a deceptive connection, Eur J Endocrinol. 2012;Feb 166:143-150.
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.
Shuch B, et al., Repeat partial nephrectomy: surgical, functional, and oncological outcomes, Curr Opin Urol. 2011;Sep 21(5):368-75. doi: 10.1097/MOU.0b013e32834964ea. PMID: 21788903
Asher KP, et al., Robot-assisted laparoscopic partial adrenalectomy for pheochromocy-tomas: the National Cancer Institute technique, Eur Urol, 2011;Jul 60(1):118-24.
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.
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.
Asthagiri AR, et al., Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease, Neuro Oncol. 2010;Jan 12(1):80-6. Epub 2009 Dec 23. PMID: 20150370
Zach L, et al. Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease. Neuro Oncol. 2010;12(1):80-6.
Hoeffel C. Radiofrequency ablation of renal tumors, European Radiology, 2010;20(8): 1812-21
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.
Lonser RR, et al., The vestibular aqueduct: site of origin of endolymphatic sac tumors, J Neurosurgery. 2008; April 108(4):751-756.
Matin SF, et al., Patterns of intervention for renal lesions in von Hippel-Lindau disease, BJU International 2008;Oct 102 (8):940-45.
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, 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.
Richard S. von Hippel Lindau, Atlas Genet Cytongenet Oncol Haem 2001;5(21):145-49.
INTERNET
The VHL Handbook: What You Need to Know About VHL www.vhl.org/handbook.
van Leeuwaarde RS, Ahmad S, van Nesselrooij B, et al. Von Hippel-Lindau Syndrome. 2000 May 17 [Updated 2023 Sep 21]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1463/ Accessed Oct 24, 2023.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. VonHippel-Lindau Syndrome; VHL. Entry No: 193300. Last Update 06/04/2020. Available at: https://omim.org/entry/193300 Accessed Oct 24, 2023.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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