14 January 2019
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Tumors called hemangioblastomas are characteristic of von Hippel-Lindau syndrome. HIF controls several genes involved in cell division, the formation of new blood vessels, and the production of red blood cells.
These genotype—phenotype correlations suggest that missense mutations of pVHL lead to a '' protein. Seven prototypes were built as part of the development program.
Vis à Vis - If any portion of the tumor is left in place, the cyst will re-fill.
General Discussion Summary Von Hippel-Lindau disease VHL is caused by a gene mutation which frequently induces both nonmalignant tumors and malignant tumors or cancers that can spread to other organs become metastatic. Tumors may develop in up to ten different parts of the body. Many of these tumors involve the abnormal growth of blood vessels in different organs of the body. Most of these tumors are benign, meaning that they stay in the same organ where they began. Introduction Because VHL 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 to remove or disable the tumor before it invades other tissues. Benign tumors may also need treatment or removal if their growth will cause symptoms. VHL has no single primary symptom, does not occur exclusively in one organ of the body, and does not always occur in a particular age group. The condition is hereditary, but the health problems of affected families, and the organs involved are so varied, that the common cause may not be recognized for many years. In addition, the appearance and severity of VHL lesions are so variable that many members of the same family may have only some relatively harmless issue, while others may have a serious illness. If there is a positive DNA diagnosis of VHL, it is important to begin surveillance testing early before any symptoms occur. Most VHL lesions are much easier to treat when they are small. 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. Age at 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. Individuals within a family may differ as to which tumor types they have, although they all share the same VHL gene mutation. The most common symptom of VHL is hemangioblastomas also called angiomas. These are benign tumors occurring in the brain, spinal cord and retina back of the eye in individuals with VHL and appear as knots formed by tiny blood vessels. Although these tumors are benign, in the brain or spinal cord the pressure they exert may cause symptoms. Hemangioblastomas may press on nerve or brain tissue and cause symptoms such as headaches, problems with balance when walking, or weakness of arms and legs. In the eyes, blood or fluid leakage from hemangioblastomas also called retinal capillary hemangioblastomas or retinal angiomas can interfere with vision. Early detection, careful monitoring of the eyes and prompt treatment are very important to maintain healthy vision. Cysts may grow around hemangioblastomas and other VHL tumors. Cysts are fluid-filled sacs which may exert pressure or create blockages that can cause symptoms. 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 behind the inner ear called an endolymphatic sac tumor. If not removed, this tumor can lead to complete loss of hearing in the affected ear as well as balance problems. Less common manifestations of VHL include benign reproductive tract tumors in both men and women, and rare occurrences of hemangioma in the liver, spleen, and lungs. VHL is caused by an alteration in one of the two copies of a gene referred to as the VHL gene. This altered gene may be transmitted to children following an autosomal dominant pattern of inheritance, meaning that it is not limited to one sex, but may occur in both men and women. It also means that only one gene mutation is needed to produce the disease. Each child receives one gene of each pair from each parent. If one parent has an alteration mutation in a dominant gene, each child has a fifty-fifty chance of inheriting that gene and subsequently developing manifestations of the mutated gene. Although some people with VHL have few tumors and virtually no symptoms, VHL does not skip generations. Unless there is a de novo mutation, every child with VHL must have a parent with VHL. There are certain people, approximately 20%, who are the first in their family to have an alteration in the VHL gene. Neither parent is affected, but these people have VHL. This alteration in the VHL gene can now be passed on to future children of this affected person. It necessitates medical screening of these children as well. VHL is the leading hereditary cause of kidney cancer. Even in cases of sporadic kidney cancer in the general population, damage that may occur to the VHL gene is implicated in the advance of kidney and other cancers. While it is estimated that only 1 person in 36,000 in the US has VHL, it is estimated that 60,000 people will develop kidney cancer each year, of which 75% are clear cell renal cell carcinoma, 90% of whom will have changes in the VHL gene in their tumors without having VHL disease. VHL is also one of four major genetic causes of pheochromocytomas pheos , accounting for approximately 20—35% of all pheos. Studying VHL and the other genetic causes of pheos is giving researchers a much better understanding of the genetic pathway, or chain of events that can lead to a pheo, as well as clues on how to cure them. The normal VHL gene acts as a tumor-suppressor gene, with the function of suppressing the formation of tumors. In order for a tumor to form, both copies of the VHL gene must become inactivated. In an individual who does not have the inherited alteration in the VHL gene, it is necessary for each of these two normal copies of the VHL gene to undergo some change that inactivates the VHL protein in the same cell and allows a tumor to form. This explains why, when these tumors occur in the general population, they are usually single occurrences in a single organ at an older age. For example, the average age of onset of symptomatic kidney cancer in the general population is age 62. Mutation or inactivation of the VHL gene has been found in 90% of the random clear cell kidney cancers in the general population, studied by the US National Cancer Institute. This demonstrates the importance of this gene and the protein it manufactures in every human being. In the case of people who have inherited one copy of the gene that does not work correctly in the beginning, it is only necessary to deactivate the one remaining copy before a tumor is likely to form. This is a much more probable occurrence meaning that tumors develop more often, at younger ages, and in more organs than in people in the general population. Without preventive action, the most common age at diagnosis for people with VHL ranges from 25—50 years. VHL lesions in the brain and spinal cord may cause symptoms similar to other types of tumors in the same location. VHL lesions in the eyes, if untreated, may lead to partial or complete loss of vision in the affected eye, similar to loss of vision that can occur with diabetes. Detection of affected individuals by DNA analysis of a blood sample is now possible for nearly all VHL families. The accuracy of the testing and its usefulness in most families is increasing rapidly. DNA testing can be used to determine which members of the family need to be followed closely. It can also determine which members may be reassured that they do not carry the VHL gene mutation. If family members do not have the altered VHL gene previously identified in the family, they will not need further testing or annual screening. They also do not have an altered gene to pass to their children. If you are positive for VHL or if genetic testing is not yet available for your suspected VHL mutation, but you have been clinically diagnosed, you will need to continue regular medical screening tests. One normal screening examination does not necessarily mean there is no VHL present, since the first evidence of VHL may occur later in life. Occasionally a person may be so mildly affected that VHL may seem to skip a generation. VHL has been diagnosed for the first time in people as old as 80, often because their children or grandchildren developed VHL tumors. Even if there is no family history of VHL, when any suspected VHL tumor is found, a diagnosis of VHL should be considered, and a full diagnostic evaluation of other areas of the body should be carried out. It is quite possible for someone to be the first in their family to have VHL. It is estimated that no DNA mutation or deletion can be found in approximately 10% of people clinically diagnosed with VHL. These people have VHL, but current DNA testing has not been able to find their specific VHL mutation. Clinical testing and Work-Up The VHL surveillance guidelines were developed to prevent VHL tumors from becoming metastatic. 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 a preventive than a treatment, and long-term results seem to show only marginal benefit. Pancreatic Neuroendocrine Tumors Careful analysis is required to differentiate between serious cystadenomas and pancreatic neuroendocrine tumors pancreatic NETs. Cysts and cystadenomas generally do not require treatment. Pancreatic NETs should be rated on size, behavior, and DNA type. Renal Cell Carcinoma VHL kidney tumors are often found at very small sizes 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. The optimal treatment would be a drug, but to date none has proven successful. Pheochromocytomas Surgical removal is performed after adequate blocking with medication, and laparoscopic partial adrenalectomy is preferred. Even pheos that do not appear to be active or causing symptoms should be removed, 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. Two types of research are needed to ultimately find a cure for VHL: basic science to understand exactly how a VHL mutation causes a tumor to form in a specific organ, and clinical research to learn which medications, surgeries, and lifestyle interventions prevent tumor formation, or slow or even reverse tumor growth. Everyone with VHL can be an important part of the clinical research effort. Participation is needed in all types of clinical research in order to have enough people tested to draw scientific conclusions. In-person clinical trials are listed here: The Cancer in our Genes International Patient Databank is an online clinical research study open to everyone diagnosed with VHL or with symptoms of VHL. In 2014, the VHL Alliance, in partnership with NORD, launched a first of its kind patient databank. The Databank is an innovative and comprehensive clinical research study designed through the work of an International Task Force made up of some of the leading VHL researchers and clinicians in the world. The information from the Databank is helping researchers to: 1. Better understand the natural history of VHL 2. Determine the relationship between lifestyle and VHL progression 3. Identify best practices for VHL treatment and diagnosis 4. Identify patients to participate in future clinical trials—as a means of accelerating a cure. The Databank also includes conditions similar to VHL including hereditary leiomyomatosis and renal cell cancer HLRCC , Birt-Hogg-Dubé BHD , and succinate dehydrogenase complex SDH. This will allow researchers to learn from the similarities and the differences of these related genetic cancer conditions. For more information visit: Information on current clinical trials is posted on the Internet at www. All studies receiving U. 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: prpl cc. 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. In: Dahlia PLM and Eng C eds. Genetic Disorders of Endocrine Neoplasia. Basel, vol 28, Karger Publishers. JOURNAL ARTICLES Gupta GN, et al. Endocrine disorders in pregnancy: Phaeochromocytoma and pregnancy: a deceptive connection, Eur J Endocrinol. Maher ER, Neumann HP, Richard S. Eur J Hum Genet. Wind JJ, Lonser RR. Management of von Hippel-Lindau disease-associated CNS lesions. Shuch B, et al. PMID: 21788903 Asher KP, et al. 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. Abadie C, Coupier I, Bringuier-Branchereau S, Mercier G, Deveaux S, Richard S. The role of pregnancy on hemangioblastomas in von Hippel-Lindau disease: a retrospective French study. Rio de Janeiro, Brazil. Peyre M, David P, Van Effenterre R, et al. Natural history of supratentorial hemangioblastomas in von Hippel-Lindau disease. Asthagiri AR, et al. Epub 2009 Dec 23. PMID: 20150370 Zach L, et al. Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease. 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. Jagannathan J, Lonser RR, Smith R, DeVroom HL, Oldfield EH. Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease. Lonser RR, et al. Matin SF, et al. Ocular Manifestations of von Hippel-Lindau Disease: clinical and genetic investigations. Trans Am Ophthalmol Soc. 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. Richard S, Lindau J, Graff J, Resche F. Lonser RR, Glenn GM, Chew EY, Libutti SK, Linehan WM, Oldfield EH. Lonser RR, Weil RJ, Wanebo JE, DeVroom HL, Oldfield EH. Surgical management of spinal cord hemangioblastomas in patients with von Hippel-Lindau disease. Weil RJ, Lonser RR, DeVroom HL, Wanebo JE, Oldfield EH. Surgical management of brainstem hemangioblastomas in patients with von Hippel-Lindau disease. Lonser RR, Wait SD, Butman JA, et al. Surgical management of lumbosacral nerve root hemangioblastomas in von Hippel-Lindau syndrome. INTERNET Frantzen C, Klasson TD, Links TP, et al. In: Pagon RA, Adam MP, Ardinger HH, et al. Seattle WA : University of Washington, Seattle; 1993-2016. Accessed August 8, 2016. Online Mendelian Inheritance in Man OMIM. The Johns Hopkins University. Accessed August 8, 2016. The content of the website and databases of the National Organization for Rare Disorders NORD is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. National Organization for Rare Disorders NORD 55 Kenosia Ave. This is not a comprehensive database since there are nearly 7,000 diseases considered rare in the U. We add new topics as we are able to do so, with the help of rare disease medical experts. If you are seeking information about a rare disease that is not in this database, we would suggest contacting the at the National Institutes of Health. NIH has the most complete database of rare diseases in the U. Representatives of patient organizations whose medical advisors are interested in assisting NORD in creating a report on a disease not currently covered in this database may write to. Copyright ©2018 NORD - National Organization for Rare Disorders, Inc. NORD is a registered 501 c 3 charity organization. Please note that NORD provides this information for the benefit of the rare disease community. NORD is not a medical provider or health care facility and thus can neither diagnose any disease or disorder nor endorse or recommend any specific medical treatments. Patients must rely on the personal and individualized medical advice of their qualified health care professionals before seeking any information related to their particular diagnosis, cure or treatment of a condition or disorder.
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