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Summary
VHL or von Hippel-Lindau disease is an autosomal dominant genetic condition resulting from a deletion or mutation in the VHL gene. VHL disease effects 1 in 36,000 people (10,000 cases in the U.S and 200,000 cases worldwide) and 20% of patients are first-in-family or de novo cases. The mean age of onset of 26 years and 97% of people with a VHL gene mutation have symptoms by the age of 65. VHL disease affects males and females and all ethnic groups equally, and occurs in all parts of the world.
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:
Most of these VHL tumors are benign, but that does not mean they are problem-free. In fact, benign VHL tumors can still be very serious. As they grow in size, these tumors and the associated cysts can cause an increased pressure on the structure around them. This pressure can create symptoms including severe pain or worse.
VHL disease is different in every patient, even within the same family. Since it is impossible to predict exactly how and when the disease will present for each person, it is very important to check regularly for possible VHL manifestations throughout a person’s lifetime.
Currently, a drug (pharmacological) treatment is not available; surgical removal is the method of treatment. An organ sparing approach is the best approach for reducing irreparable damage while minimalizing 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 gene mutation can be greatly reduced, or in some people, completely prevented.
Introduction
Because VHL disease can cause malignant tumors, it is considered one of a group of familial cancer risk factors, which are transmitted genetically. The objective is to find tumors early, watch for signs that a tumor is growing, and remove or disable the tumor before it invades other tissues. Benign tumors may also need treatment or removal if their growth causes symptoms.
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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, despite the same genetic mutation. In addition, the appearance and severity of VHL lesions are so different between people that many members of the same family may have only some relatively harmless issue, while others may have a serious illness.
Age of onset varies from family to family and from individual to individual. Pheochromocytomas (adrenal tumors) are very common in some families, while clear cell renal cell carcinomas (kidney tumors) are more common in other families.
The most common symptom of VHL is hemangioblastomas. These are benign tumors occurring in the brain, spinal cord, and retina. Hemangioblastomas are benign. In the brain or spinal cord, the 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 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 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 balance problems. Less common manifestations of VHL include benign reproductive tract tumors in both men and women. These tumors, however, can lead to impregnation problems or becoming pregnant
Tumors in the liver and lungs are considered non-problematic.
VHL disease is an autosomal dominant disorder resulting from a deletion or mutation in the VHL gene located on the short arm of chromosome 3. Each child of a person with VHL is at 50% risk of inheriting the altered copy of the gene.
The normal VHL gene acts as a tumor-suppressor gene, with the function of preventing the formation of tumors. The gene acts as the key regulator of cellular hypoxia signaling via its product, the VHL protein (pVHL). pVHL through the HIF (hypoxia-inducible factor) complex, is indirectly responsible for enhanced levels of growth factors including vascular endothelial factor, platelet derived growth factor, and transforming growth factor alpha.
In the case of a non-functioning gene such as in VHL disease, 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. This is the same process involved in other more common cancers, such as kidney, breast, pancreas, adrenal cancers.
Researchers believe that intervening in growth factor and/or HIF activity will prove to be an effective treatment for VHL and other forms of cancer.
VHL is a familial genetic condition, however, 20% of all patients are first-in-family or de novo cases. The incidence is 1 in 36,000 births, affecting males and females and all ethnic groups equally, and occurring in all parts of the world.
Anyone with a parent with VHL and most people with a brother or sister with VHL are at a 50% chance of having VHL disease. Anyone with an aunt, uncle, cousin, or grandparent with VHL may also be at risk. The only way to determine for sure that someone does not have an altered VHL gene is through DNA testing. A clinical diagnosis can also be made when a person exhibits a tumor specific to VHL.
Once a VHL 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. A number of possible complications of VHL do not present with symptoms until the problem has developed to a critical level. Treatment may only be able to stop symptoms that have occurred; it is not always possible to reverse the changes and go back to normal.
A universal treatment recommendation does not exist. Treatment options can only be determined by careful evaluation of the individual patient’s total situation—symptoms, test results, imaging studies, and general physical condition. The following are offered as general guidelines for possible treatment therapies.
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 specific genetic mutation.
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 his or her lifetime begins with careful monitoring and choosing to operate only when tumor size or rapid growth rate suggest the tumor may gain metastatic potential (at approximately 3 cm). 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. Vital signs are carefully monitored for at least a week following surgery while the body readjusts to its “new normal.” Special caution is warranted during surgical procedures of any type and during pregnancy and delivery. 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 in order to prevent worsening of balance problems. Not all ELSTs are visible with imaging; some are only found during surgery.
In 2021, belzutifan (Welireg) was approved for adult patients with von Hippel-Lindau disease who require therapy for associated renal cell carcinoma, central nervous system hemangioblastomas or pancreatic neuroendocrine tumors not requiring immediate surgery.
MyVHL: The Patient Natural History Study (www.vhl.org/MyVHL) 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/for-patients-and-families/information-resources/news-patient-recruitment/
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, Links TP, et al. Von Hippel-Lindau Syndrome. 2000 May 17 [Updated 2018 Sep 6]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1463/ Accessed March 12, 2019.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. VonHippel-Lindau Syndrome; VHL. Entry No: 193300. Last Update 10/14/2016. Available at: http://omim.org/entry/193300. Accessed March 12, 2019.
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