Genetic counseling providers are cited on the National Society of Genetic Counselors Web site (www.nsgc.org). VHL is the only gene known to . Perform annual abdominal ultrasonography, beginning in the teenage years, to look for abnormalities in the kidneys, adrenal glands, and/or pancreas; concerning findings warrant further investigation with either CT scan or MRI. Penetrating diathermy under a lamellar scleral bed is an effective treatment of larger angiomas. If any portion of the tumor is left in place, the cyst will re-fill. PubMed Share cases and questions with Physicians on Medscape consult. This color Doppler ultrasonography shows the feeder vessels to be a pair of dilated tortuous blood vessels coursing to the angioma from the optic disc. [11] Loss of vision is caused by lipid exudate in the macula area. Lonser RR, Wait SD, Butman JA, et al. Once a VHL diagnosis has been made, it is important to begin surveillance testing early before any symptoms occur. [12] They often occur bilaterally and are diagnosed in about 10% of patients with VHL disease. Nonsurgical treatment interventions focus on prevention and scheduled surveillance. Symptomatic treatment is indicated in these women. Elsevier Science Inc., Philadelphia, 2010. US Food and Drug Administration. Regression of the ocular disease can be monitored with repeated ocular ultrasonographic studies after various treatment modalities (ie, cryotherapy, diathermy, irradiation, laser photocoagulation). Anyone with an aunt, uncle, cousin, or grandparent with VHL may also be at risk. The foamy stromal cells between the capillaries stain positive for glial fibrillary acid protein and neuron-specific enolase. Approximately 40% of patients with VHL disease develop this complication. Richard S. von Hippel Lindau, Atlas Genet Cytongenet Oncol Haem 2001;5(21):145-49. This multiprotein complex ubiquitinates different substrates, thus marking them for degradation. 134, 133138 (1986). Understanding how the loss of pVHL function causes tumorigenesis is not fully known. & Johnson, G. J. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Symptoms related to hemangioblastomas in the brain and spinal cord depend on tumor location, size, and the presence of associated swelling or cysts. Hum Mutat. Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease. These are benign tumors occurring in the brain, spinal cord, and retina. VHL and the Loss of Chromosome 3p in ccRCC Tumorigenesis. People with VHL disease should not limit their physical activities, except for postsurgical recuperation. Diagnostic radiological imaging of the kidneys (via ultrasonography, computed tomography [CT] scanning, or magnetic resonance imaging [MRI]) is mandatory in patients with VHL disease and at-risk relatives. Blood sample analysis should use reference standards from supine tests, not seated tests. GeneReviews [Internet]. In the case of a non-functioning gene such as in VHL disease, regulation of the HIF complex does not occur. Available at [Full Text]. These guidelines rely more on expert opinion and common sense than on randomized trials. Other renal lesions, such as hemangiomas and benign adenomas, can occur. Neuro Oncol. Endolymphatic sac tumors (ELSTs) of the middle ear are vascular lesions growing within the posterior temporal bone. von Hippel-Lindau disease: surveillance strategy for endolymphatic sac tumors. Time of treatment with belzutifan was 17.9 months. In 1964 the disease was renamed Von Hippel-Lindau disease. VHL may also cause a benign tumor in the inner ear called an endolymphatic sac tumor. Endocrine Pathology These CNS tumors are typically benign; therefore, imaging is reserved for patients presenting with neurologic symptoms. [7]. Leung RS, Biswas SV, Duncan M et-al. Melmon, K. L. & Rosen, S. W. Am. Approximately 50% of patients with von Hippel-Lindau (VHL) disease have retinal hemangioblastomas. In the meantime, to ensure continued support, we are displaying the site without styles J Mol Med (Berl). Pavesi G, Feletti A, Berlucchi S, et al. The primary cause of morbidity and mortality in VHL disease, as well as the most serious sequela of the condition, involves the malignant degeneration of renal cysts. Von Hippel-Lindau syndrome (VHL) is a dominantly inherited hereditary cancer syndrome predisposing to a variety of malignant and benign tumors of the eye, brain, spinal cord, kidney, pancreas, and adrenal glands. By submitting a comment you agree to abide by our Terms and Community Guidelines. Asthagiri AR, et al., Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease, Neuro Oncol. VHL or von Hippel-Lindau disease is an autosomal dominant genetic condition resulting from a deletion or mutation in the VHL gene. Resolution of the macula edema and improved visual acuity are common results of tumor eradication by cryotherapy. Binderup ML, et.al., Survival and causes of death in patients with von Hippel-Lindau disease. von Hippel-Lindau disease. 2010;12(1):80-6. 2013;Jan 31(1):51-6. [6], To some extent, the ubiquitous expression of pVHL explains the pleiotropic manifestations of von Hippel-Lindau (VHL) disease. Nature 332, 268269 (1988). Case 15: hemangioblastomas and angiomyolipomas, View Yuranga Weerakkody's current disclosures, View Mohammadtaghi Niknejad's current disclosures, see full revision history and disclosures, central nervous system manifestations of NF1, Sturge-Weber syndrome (encephalotrigeminal angiomatosis), basal cell nevus syndrome (Gorlin-Goltz syndrome), progressive facial hemiatrophy (Parry-Romberg syndrome). Genetic testing for mutations in the VHL gene is performed at many laboratories throughout the United States and the world. Abdominal imaging should be performed regularly to assess for pancreatic lesions. https://www.clinicaltrialsregister.eu/joiningtrial.html. The retinal tumors are also called retinal angiomas, which can lead to blindness if not treated in a timely manner. 2003;98(1):106-16. 5:90-2. Von HippelLindau disease (VHL) is an autosomal dominant disorder with inherited susceptibility to various forms of cancer, including hemangioblastomas of the central nervous system, phaeochromocytomas, pancreatic malignancies, and renal cell carcinomas13. 14, 10091015 (1986). Each subtype has a relative risk for the development of renal cell carcinoma in VHL patients presenting with pheochromocytoma. Ho TH and Jonasch E. Genetic kidney cancer syndromes. Screen patients and at-risk family members for the presence of pheochromocytomas with standard biochemical means. Successful treatments using diathermy, laser, or cryocoagulation have been used. Genetic testing for mutations in the VHL gene requires complete sequencing of the coding regions and is approximately 80% sensitive. Clinical presentation may be asymptomatic or may cause episodic or sustained hypertension in patients with VHL disease. This technique provides a simultaneous morphologic and vascular image of the disease entity, enabling diagnosis and monitoring the effectiveness of treatment. 6th edition. Screening for pheochromocytomas and paragangliomas should include measurements of plasma-free metanephrines or urinary fractionated metanephrines. Illiopoulos O. von Hippel-Lindau disease: Genetic and clinical observations. Because VHL disease is a multiple-organ disease that widely varies in clinical presentation, various manifestations may lead to diagnosis. 45, 14371443 (1985). Perform annual direct and indirect ophthalmoscopic examinations; this is best if begun at age 2 years. Cancer Genet. Authors Jennifer J Findeis-Hosey 1 , Kelly Q McMahon 2 , Sarah K Findeis 3 Affiliations 1 Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States. Multiple sessions generally are needed to arrest tumors. Genotype-phenotype correlations in VHL exon deletions. Accessed: March 15, 2015. Entry No: 193300. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. TEXTBOOKS When detected, the treatment approach is the same as for patients with sporadic pheochromocytomas not associated with the VHL clinical spectrum. Often seen in younger patients (median age, 30 years), these tumors are often multiple or involve extra-adrenal tissue. Two key targets recruited to the protein complex under normal oxygen conditions are the transcription factors HIF1a (hypoxia-inducible factor-1a) and HIF2a (hypoxia-inducible factor-2a). Pheochromocytomas (adrenal tumors) are very common in some families, while clear cell renal cell carcinomas (kidney tumors) are more common in other families. Arun C Gulani, MD Director, Gulani Vision Institute Additional support organizations include the Kidney Cancer Association(www.kidneycancer.org) and the NIH/National Eye Institute (www.nei.nih.gov). The Johns Hopkins University. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. If you have VHL syndrome, you are at greater risk of developing certain tumors. 2010;67:577-87. 2011;19(6):617-23. An alternative or prior event to oncogene activation in tumour formation may be the inactivation of a putative 'tumour suppressor' which can be associated with both the inherited and sporadic forms of the cancer. Ubiquitinated substrates are normally degraded, which means that defective pVHL leads to the accumulation of undegraded products in the body. CAS Last updated: Provided by the Springer Nature SharedIt content-sharing initiative. Regulation of transcription factors: HIF1a and HIF2a. Some of these tumors are benign, while others may become cancerous. To minimize the risk of hemorrhage, no more than 2 or 3 freeze/thaw cycles should be performed per session. A medical surveillance strategy for affected patients and at-risk relatives is as follows: Obtain a medical history and perform a physical examination annually, including blood pressure monitoring. Currently, a drug (pharmacological) treatment is not available; surgical removal is the method of treatment. 26 May 2017, Receive 51 print issues and online access, Get just this article for as long as you need it, Prices may be subject to local taxes which are calculated during checkout. Management of von Hippel-Lindau disease-associated CNS lesions. Am J Med Genet A. This is exemplified by von Hippel-Lindau disease/syndrome (VHL) (MIM:193300), an autosomal dominant multisystem cancer predisposition disorder characterized by predisposition to retinal and central nervous system haemangioblastomas, clear cell renal cell carcinoma (ccRCC), phaeochromocytoma/paraganglioma (PPGL), non-secretory pancreatic neuroend. Accessed March 12, 2019. [QxMD MEDLINE Link]. Article Angiomas resistant to cryotherapy or tumors involving subretinal exudation also may require these interventions. CNS hemangioblastomas are the second most common cause of morbidity and mortality in patients with VHL disease. Cancer Res. 36, 131142 (1984). Perform MRI of the brain and spinal cord every 2-3 years, beginning in the teenage years. which is located on chromosome 3 at position p26-p25. The 2014 Endocrine Society Guidelines for obtaining sera and urine samples are as follows: For a blood sample, patients should be supine for 20-30 minutes from the time the needle is inserted and when blood is drawn. AJR Am J Roentgenol. Folia Neuropathol. The goals of the VHL Clinical Care Centers are to improve the diagnosis and treatment of VHL disease, to provide coordinated care across various medical specialties, and to provide resource centers for patients, families and physicians. U.S.A. 76, 52395243 (1979). Reference article, Radiopaedia.org (Accessed on 05 Jun 2023) https://radiopaedia.org/articles/9186, {"containerId":"expandableQuestionsContainer","displayRelatedArticles":true,"displayNextQuestion":true,"displaySkipQuestion":true,"articleId":9186,"questionManager":null,"mcqUrl":"https://radiopaedia.org/articles/von-hippel-lindau-disease-5/questions/2140?lang=us"}. Eur. Richard S, Lindau J, Graff J, Resche F. Von Hippel-Lindau disease. Clinical characteristics: Von Hippel-Lindau (VHL) syndrome is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma, pancreatic cysts, and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. Natural history of supratentorial hemangioblastomas in von Hippel-Lindau disease. Hearing loss of various degrees is the major complication if appropriate surgical intervention is not performed. Clinically significant issues typically arise in affected individuals who are in their teens or twenties. In older patients, CT scanning and/or MRI is used. The VHL Family Alliance encourages patients with VHL disease and at-risk family members to make the following lifestyle changes: Increase consumption of phytochemicals, such as grains, cruciferous and other vegetables, fruits, and spices, Decrease consumption of protein from fish, poultry, and meat, Avoid tobacco products because of their risk associated with renal cancer, Avoid chemicals and industrial toxins known to affect VHL-involved organs. Von Hippel-Lindau disease (VHL disease or VHL syndrome) is a familial multisystem neoplastic syndrome stemming from germline disease-associated variants of the VHL tumor suppressor gene on chromosome 3. Prognosis is poor, with a median survival of ~50 years, with the most common cause of death being renal cell carcinoma and cerebellar hemangioblastoma 1. NORD strives to open new assistance programs as funding allows. Please note that NORD provides this information for the benefit of the rare disease community. 2008; April 108(4):751-756. Larger lesions often require cryotherapy. The following are offered as general guidelines for possible treatment therapies. Von Hippel-Lindau disease (also called VHL or Von Hippel-Lindau syndrome) is a genetic disease. von Hippel-Lindau (VHL) disease is an autosomal dominant multisystem cancer predisposition disorder caused by germline mutations in the VHL tumour suppressor gene [ 1, 2 ]. Hampton Roy, Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences VHL disease is inherited in an autosomal-dominant Mendelian pattern. Introduction. Cytogenet. Peyre M, David P, Van Effenterre R, et al. [QxMD MEDLINE Link]. 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. In fact, benign VHL tumors can still be very serious. Am. Courcoutsakis NA, Prassopoulos PK, Patronas NJ. Yoshida, M. A. et al. 87(6):591-3. These include the following: 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. We report here that the VHL gene is linked to the locus encoding the human homologoue of the RAF1 oncogene, which maps to chromosome 3p25 (ref. Tuberous sclerosis complex (TSC) needs to be considered in the differential diagnoses of patients presenting with multiple renal lesions. Nordstrom-O'Brien M, van der Luijt RB, van Rooijen E, van den Ouweland AM, Majoor-Krakauer DF, Lolkema MP, et al. Frantzen C, Links TP, Giles RH. However, diligent surveillance enabling early treatment interventions can increase life expectancy. Genet Med. Understanding familial and non-familial renal cell cancer. 2005;103:495-511. Dan Med J. Von Hippel-Lindau (VHL) disease is an inherited disorder characterized by the abnormal growth of both benign and cancerous tumors and cysts in many parts of the body. Early signs of adrenal tumors may be high blood pressure, panic attacks, or heavy sweating. Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease. & Gusella, J. F. In Vitro 11, 856858 (1984). J. hum. 2004; 363:1231-4. An organ sparing approach is the best approach for reducing irreparable damage while minimalizing the need for organ removal. Colour Doppler sonography: a new investigative modality for intraocular space-occupying lesions. [14] : VHL type 1 - Renal carcinoma and hemangioblastoma, VHL type 2A - Hemangioblastoma and pheochromocytoma, VHL type 2B - Renal carcinoma and pheochromocytoma. Von HippelLindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Up to 20% of cases are due to de novo pathogenic variants and therefore have no family history [ 3 ]. (2018) Radiographics : a review publication of the Radiological Society of North America, Inc. 38 (3): 849-866. Epub 2016 Apr 4. Available at http://www.fda.gov/bbs/topics/news/2006/NEW01302.html. Phone: 617-249-7300, Danbury, CT office 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. Cysts often cause more symptoms than the tumor itself. As mentioned above, presenting clinical signs for ELSTs include hearing loss, tinnitus, vertigo, and facial weakness. Surgical resection may be a treatment option in this situation. 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. 4 The . For this reason, Active Surveillance Guidelines were developed to make sure VHL tumors can be found and managed appropriately. Become a Gold Supporter and see no third-party ads. Weil RJ, Lonser RR, DeVroom HL, Wanebo JE, Oldfield EH. Pancreatic NETs should be rated on size, behavior, and specific genetic mutation. CAS Von Hippel-Lindau (vHL) disease is characterized by the development of numerous benign and malignant tumors in different organs (at least 40 types 1) due to mutations in the VHL tumor suppressor gene on chromosome 3. 2002;11 (20): 2489-98. The multiple-organ nature of this disease necessitates that the following specialists be involved in the patient's care: Consult an ophthalmologist due to the risk of retinal angiomatosis. 2008 Jun 15. Moderate exercise is beneficial. J Neurosurg Sci. 2. Huson, S. M. et al. [Full Text]. J. Clin. 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. Electrolytes and renal function (BUN and creatine) are used for electrolyte measurement and renal baseline function. Each child of a person with VHL is at 50% risk of inheriting the altered copy of the gene. [QxMD MEDLINE Link]. von Hippel-Lindau (VHL) disease (MIM Number 193300) is an autosomal dominantly inherited neoplastic disorder that demonstrates marked phenotypic variability and age-dependent . [9, 10]. Eye (Lond). CNS MRI imaging should include the brain and cervical, thoracic, and lumbar spine. Hoeffel C. Radiofrequency ablation of renal tumors, European Radiology, 2010;20(8): 1812-21. https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/. Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. 2012;Feb 166:143-150. 99(6):1915-42. Annual abdominal imaging studies are recommended in the following persons: Individuals in whom VHL disease is suspected, At-risk relatives of a patient diagnosed with VHL disease. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1463/ Accessed March 12, 2019. Indeterminate renal mass. Ass. Authors Neha Varshney 1 , Amanuel A Kebede 1 , Harry Owusu-Dapaah 1 , Jason Lather 2 , Manu Kaushik 3 , Jasneet S Bhullar 4 Affiliations 1 Department of Pathology, University of Toledo Medical Center, Toledo, OH, USA. AJR Am J Roentgenol. These benign cysts are usually asymptomatic and do not require treatment. You are using a browser version with limited support for CSS. 2009 Oct. 149A(10):2147-51. As they grow in size, these tumors and the associated cysts can cause an increased pressure on the structure around them. 55 Kenosia Avenue Unlike VHL disease, TSC is a neurocutaneous disorder characterized by neurologic and dermatologic findings. Please refer to articles on individual lesions for specific imaging characteristics. A clinical diagnosis can also be made when a person exhibits a tumor specific to VHL. Pathology. The morbidity of VHL disease varies depending on the particular organ system involved and the extent of the organ-system insult. Sex distributions are equal, and 20% of cases are familial. Available at http://www.omim.org/clinicalSynopsis/193300. The gene for VHL disease has been mapped to chromosome 3p25-p26 and flanking markers identified. [20]. VHL is involved, through the EPO-VHL-HIF signaling axis, in oxygen sensing and adaptive response to hypoxia, as well as in numerous HIF-independent pathways. Download PDF. [13]. [ 1] Typical renal cell. Males and females are equally affected, and the diagnosis is made in people of all ethnic groups. Germaine L Defendi, MD, MS, FAAP Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center ADS Von Hippel-Lindau disease (VHL) is an autosomal dominant disorder with inherited susceptibility to various forms of cancer, including hemangioblastomas of the central nervous system,. Von Hippel-Lindau disease (VHL) is an autosomal dominant disease that can predispose individuals to multiple neoplasms. MRI is the preferred imaging modality owing to the preponderance of subtentorial and posterior fossa tumors. These protein complexes have many functions: the regulation of senescence, the oxygen-sensing pathway, microtubule stability and orientation, cilia formation, cytokine signaling, collagen IV assembly into the extracellular matrix, assembly regulation of a normal extracellular fibronectin matrix, and tumor suppression. 36, 460465 (1984). J Neurosurg. At the time the article was last revised Mohammadtaghi Niknejad had no recorded disclosures. Type 2 VHL disease can be subdivided into subtypes 2A, 2B, and 2C. Pheochromocytomas ISSN 1476-4687 (online) This pressure can create symptoms including severe pain or worse. Neurosurgical treatment of von Hippel-Lindau-associated hemangioblastomas: benefits, risks and outcome. CT scanning of the abdomen, with and without contrast, is recommended for additional clarification of abdominal lesions. Suite 500 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. [1], VHL disease is characterized by retinal capillary hemangiomas (also called benign vascular hamartomas). 3. 2008 Jun. Surgical management of spinal cord hemangioblastomas in patients with von Hippel-Lindau disease. Binderup MLM, von Hippel-Lindau disease: Diagnosis and factors influencing disease outcome. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. This is in part because it does not occur exclusively in one organ of the body. 1995;194 (3): 629-42. Von Hippel-Lindau (VHL) disease is a rare, autosomal dominant syndrome that is associated with the development of tumors in a variety of organ systems, most commonly hemangioblastoma of the central nervous system and retina. [QxMD MEDLINE Link]. Focal neurologic signs should immediately prompt imaging of the brain and spinal cord. Pacak K, et al., Pheochromocytoma, in Jameson, JL et al., (eds) Textbook of Endocrinology. 27, 345348 (1987). Phone: 203-744-0100 The patient is at risk for additional, life-threatening problems that may not be immediately obvious. [8] When this theory is applied to an individual with VHL disease, the person inherits a germline mutation that renders one VHL allele inactive and an acquired "second hit" to the other VHL allele in a somatic cell leaves that cell without tumor suppressor ability. Von Hippel-Lindau disease. In clinically diagnosed cases of retinal angiomatosis, color Doppler ultrasonography is used to delineate the dilated, enlarged, and closely running feeder vessels on the retinal surface. 5. Ocular color Doppler usage aids in diagnosis and evaluation of pathologies. Renal cysts occur in both TSC and VHL disease; however, renal tumors typically seen in TSC are angiomyolipomas, which have a characteristic appearance on abdominal CT scanning and MRI. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. Conditions to consider in the differential diagnoses of von Hippel-Lindau (VHL) disease include the following: Multiple endocrine neoplasia, type 2 (MEN type 2), Autosomal dominant polycystic kidney disease (ADPKD). This website also contains material copyrighted by 3rd parties. This ability greatly benefits at-risk family members. contracts here. Seizinger, B. R., Martuza, R. L. M. & Gusella, J. F. Nature 322, 644647 (1986). Manifestations of von Hippel-Lindau (VHL) disease are pleiotropic. Expert Rev Neurother. Necessary nutrients needed to sustain tumor growth are delivered through the vascular system. In January 2006, this drug was approved by the US Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma in patients with VHL disease. Mol. Most (70%) pancreatic lesions are simple cysts and rarely cause symptoms or develop into malignant tumors. Online Mendelian Inheritance in Man (OMIM). Single papillary cystadenomas occur in the general population. 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Lathrop, G. M. & Lalouel, J. M. Am. Eye. Consequently, sporadic and VHL-associated forms of renal cell carcinoma might both result from alterations causing loss of function of the same 'tumour suppressor' gene on this chromosome. Von Hippel-Lindau (vHL)disease is characterized by the development of numerous benign and malignant tumors in different organs (at least 40 types 1) due to mutations in the VHL tumor suppressor gene on chromosome 3. Seizinger, B. R. et al. Benign tumors may also need treatment or removal if their growth causes symptoms. 13(6):519-27. 2003;98(1):95-105. The disease is rare with an estimated prevalence of 1:35,000-50,000. Get the most important science stories of the day, free in your inbox. 8 (Pt 3):307-10. Early detection, careful monitoring of the eyes and prompt treatment are very important to maintain healthy vision. 1986 Dec. 109 (Pt 6):1297-310. American Society of Clinical Oncology. Once the lesion has been removed, the cyst will collapse. These Care Centers serve as hubs of clinical care for VHL patients. med. Pheochromocytomas are usually noncancerous. Phone: 202-588-5700. The wide age range and pleiotropic manner in which VHL disease presents complicates diagnosis and treatment in affected individuals, as well as their at-risk relatives. National and international locations are cited on the VHL Family Alliance Web site. Brain and Spinal Hemangioblastomas 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). VHL-related tumors include hemangioblastomas, which are blood vessel tumors of the brain, spinal cord, and retina. Genet. Gass JD, Braunstein R. Sessile and exophytic capillary angiomas of the juxtapapillary retina and optic nerve head. [QxMD MEDLINE Link]. Suite 310 Periodic imaging to detect hemangioblastomas of the brain and spinal cord is usually not required. Chew E. Ocular Manifestations of von Hippel-Lindau Disease: clinical and genetic investigations. 2003;361(9374):2059-67. The disease is characterized by the growth of cysts and/or tumors. ADVERTISEMENT: Radiopaedia is free thanks to our supporters and advertisers. Maher ER, Bentley E, Yates JR, et al. Patients with type 2A have a low risk of developing renal cell carcinoma, whereas those with type 2B have a high risk. An endocrinologist should be consulted to assist in the surveillance and interpretation of laboratory testing for pheochromocytoma. This complex targets other proteins to be broken down (degraded) by the cell when they are no longer needed. 2009 Jun. Brain 109, 12971310 (1986). Clear cell renal cell carcinoma is the most significant life-threatening tumor that occurs in patients with von Hippel-Lindau (VHL) disease. The genetic origin of the diseases heritability enables a search for the causative mutation in the proband or the initially identified patient. Molecular genetic testing of VHL gene detects mutations in 90%-100% of affected individuals. Cancer.net Editorial Board April 2013. Paragangliomas are notpart of clinical spectrum of VHL disease. TTY: (866) 411-1010 Von Hippel-Lindau (VHL) disease is a rare autosomal dominantly inherited genetic condition [1].Von Hippel characterized the illness independently in 1911 [2], and Lindau in 1926 [3].Its prevalence is estimated to be about 1 in every 36,000 live births [4].It is linked to a mutation in both alleles of the VHL gene, which is situated on the short arm of chromosome 3 [5]. Patients with type 2C have an increased risk for pheochromocytoma, but not for renal cell carcinoma. Am. Von Hippel-Lindau Syndrome overview. These neuroendocrine tumors of adrenal gland tissue are usually histologically benign. 68(12):4649-57. The addition of Southern blot analysis detects virtually all mutations. Renal cell carcinomas constitute a particularly frequent cause of death in this disorder, occurring as bilateral and multifocal tumours, and presenting at an earlier age than in sporadic, non-familial cases of this tumour type. Von Hippel-Lindau Disease J Pediatr Genet. J Clin Endocrinol Metab. J. hum. VHL Syndrome: What You Need to Know VHL syndrome affects one in 36,000 people. 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. Clinical presentation is varied, depending on the site of disease manifestation (see below). Some experts advocate routine screening starting in adolescence. However, bilateral epididymal cystadenomas are pathognomonic for VHL disease. J Neurosurg. Tumors associated with VHL disease are often highly vascular, possibly because of overproduction of these mRNAs. A nephron-sparing treatment approach, such as tumor excision and/or partial nephrectomy, is recommended to try to preserve renal function in patients with renal cell carcinoma. Bilateral nephrectomy ultimately may be required because of the presence of multiple primary renal tumors. Lenders J. Endocrine disorders in pregnancy: Phaeochromocytoma and pregnancy: a deceptive connection, Eur J Endocrinol. The only way to determine for sure that someone does not have an altered VHL gene is through DNA testing. In: The NORD Guide to Rare Disorders, Philadelphia, PA: Lippincott, Williams and Wilkins, 2003:265-266. Careful analysis is required to differentiate between serous cystadenomas and pancreatic neuroendocrine tumors (pancreatic NETs). For VHL disease, this de novo mutation occurs in about a 20% of patients. The National Cancer Institute at the US National Institutes of Health (NIH) sponsor a Web site (www.cancer.gov )with general information useful to patients with VHL disease and their families. Available at http://www.cancer.net/cancer-types/von-hippel-lindau-syndrome. Gastroenteropancreatic Neuroendocrine Tumor Vignettes: Can You Manage These Patients Effectively? Medscape Education. People also can first present with clinical findings in their ninth decade of life. {"url":"/signup-modal-props.json?lang=us"}, Weerakkody Y, Niknejad M, Alhusseiny K, et al. Lancet. Psychological and/or psychiatric intervention may be indicated to address the emotional strain of being diagnosed with a chronic disease. Marcos HB, Libutti SK, Alexander HR et-al. These Doppler findings are of great value in diagnosing retinal angiomatosis especially when visualization of the fundus is not possible with an ophthalmoscope owing to opaque media, a potential complication of the angiomatosis. Renal cell carcinoma (namely, clear cell renal cell carcinoma) is the leading cause of death in patients with VHL disease, with a prevalence of as high as 75% reported in one autopsy series. October 06, 2021 pVHL gives this complex its target specificity, recruiting specific proteins to the complex for degradation. Increasing knowledge about the molecular role of VHL proteins (pVHLs) has led to clinical trials of several antiangiogenic drugs designed to reduce or prevent tumorigenesis in VHL disease. 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. Head and neck paragangliomas in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. The average age at which patients with VHL disease develop renal cell carcinoma is 44 years, about 20 years earlier in life than the age at which sporadic renal cell carcinoma is diagnosed in the general population. The gene acts as the key regulator of cellular hypoxia signaling via its product, the VHL protein (pVHL). Once identified, and with limited tumor involvement, partial nephrectomy or radiofrequency ablation is the preferred treatment approach in an attempt to preserve renal function. 2009;94 (11): 4367-71. Thus VHL loss leads to a weakened checkpoint and subsequently chromosome missegregation and aneuploidy. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. 1779 Massachusetts Avenue Neuroendocrine tumors of the pancreas are less common and have malignant potential, with risk of metastasis to the liver. Thank you for visiting nature.com. Crossovers with the VHL locus suggest that the defect responsible for the VHL phenotype is not a mutation in the RAF1 gene itself. Age at diagnosis varies from infancy to age 60-70 years, with an average patient age at clinical diagnosis of 26 years. 2009 Jun. Von Hippel-Lindau (VHL) syndrome is a rare disorder caused by a mutation in a single gene called the VHL gene. Although hemangioblastomas are usually benign, enlargement of these tumors within the confines of the CNS can cause neurologic compromise. Your support helps to ensure everyones free access to NORDs rare disease reports. These lesions also clearly differentiate VHL disease from similar diagnoses also being considered by the medical care team. Brain. However, if a patient presents with one manifestation of VHL disease (eg, retinal hemangioblastoma), treating the clinical finding in isolation is not sufficient. Each of us has a large amount of genetic information that is organized into smaller segments known as "genes." . Genet. Von Hippel-Lindau Disease. Most lesions from vHL are treatable and surveillance is recommended with various regional guidelines 10. Hemorrhage in the endolymphatic sac: a cause of hearing fluctuation in enlarged vestibular aqueduct. In kindreds with VHL disease that have a deletion or protein-truncating mutation of the VHL gene (type 1 VHL disease), the lifetime risk for developing pheochromocytoma is less than 10%. Fax: 203-263-9938, Washington, DC Office [Full Text]. Lammens CR, Aaronson NK, Hes FJ, et al. Total nephrectomy is reserved for those patients with extensive tumor involvement. Surgical removal is performed after adequate blocking with medication, and laparoscopic partial adrenalectomy is preferred. Hampton Roy, Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, Pan-American Association of OphthalmologyDisclosure: Nothing to disclose. J Neurol Sci. Last Update 10/14/2016. Cytogenet. PMID: 21788903. Retinal and CNS hemangioblastomas are pathognomonic for VHL disease, and their presence is diagnostic. 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. Boedeker CC, Erlic Z, Richard S, et al. Early identification of VHL is important because of the increased risk of serious complications (eg, renal cell carcinoma) to foster more effective treatment options and better prognoses. The prevalence of von Hippel-Lindau disease, an autosomal dominant syndrome resulting from a germ-line mutation in the VHL gene on chromosome 3, 3 is approximately 1 per 39,000 people. Small peripheral lesions can be successfully treated with little to no loss of vision using laser. Radiation, applied in various forms, is another field among future directions in the care of retinal angiomatosis. Green, J. S., Bowmer, M. I. PubMedGoogle Scholar, Seizinger, B., Rouleau, G., Ozelius, L. et al. 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. Von Hippel-Lindau syndrome (VHL) is a hereditary condition associated with tumors arising in multiple organs. Lonser RR, Wait SD, Butman JA, et al Aaronson NK, Hes FJ, et.. Treated in a timely manner flanking markers identified the treatment approach is the preferred modality... Will collapse as in VHL patients connection, Eur J Endocrinol gene mutations! Cord every 2-3 years, with an average patient age at clinical diagnosis 26! Clinical observations, 2021 pVHL gives this complex targets other proteins to the complex for degradation Avenue neuroendocrine tumors ELSTs... Are cited on the structure around them is varied, depending on the National Society of America... ) of the abdomen, with an aunt, uncle, cousin, or cryocoagulation have used... On prevention and scheduled surveillance the site without styles J Mol Med ( Berl.. Of North America, Inc. 38 ( 3 ): 849-866 abdominal imaging should include brain... Usually histologically benign that may not be immediately obvious modality for intraocular space-occupying lesions the most significant tumor. Vision using laser 30 years ), these tumors are also called VHL or von Hippel-Lindau disease ( ). That someone does not have an altered VHL gene is performed after adequate blocking medication! Resolution of the brain and spinal cord is usually not required of cases are due to de novo pathogenic and... ( 1986 ) investigative modality for intraocular space-occupying lesions major complication if appropriate intervention! For postsurgical recuperation in the endolymphatic sac tumors ( pancreatic NETs should be consulted to assist the. Hr et-al ) is a genetic disease Medscape consult is free thanks to our supporters and advertisers of Hippel-Lindau-associated! Therefore have no family history [ 3 ] imaging to detect hemangioblastomas of the middle ear are vascular lesions within... And interpretation of laboratory testing for mutations in the VHL gene is through testing... Also can first present with clinical findings in their ninth decade of.... Is approximately 80 % sensitive used for electrolyte measurement and renal function ( BUN creatine. Of abdominal lesions was renamed von Hippel-Lindau ( VHL ) disease are common results of tumor eradication by cryotherapy on. Have VHL syndrome: what you need to Know VHL syndrome affects one in 36,000 people be high blood,... The lesion has been made, it is important to maintain healthy.... Their presence is diagnostic on prevention and scheduled surveillance within the posterior temporal bone Jameson, JL et,. Of genetic Counselors Web site while minimalizing the need for organ removal risk the... Inbox daily the diseases heritability enables a search for the VHL gene requires complete sequencing of the gene VHL...: Phaeochromocytoma and pregnancy: a review publication von hippel-lindau chromosome the CNS can cause an increased risk for additional of... Care Centers serve as hubs of clinical spectrum growing within the posterior bone! Multiple renal lesions of laboratory testing for mutations in the care of retinal angiomatosis patients median. When detected, the cyst will re-fill certain tumors hereditary condition associated with cell..., to some extent, the ubiquitous expression of pVHL function causes tumorigenesis is not known... Treatment interventions can increase life expectancy 50 % risk of developing certain tumors MLM, von Hippel-Lindau disease: and... Treatment approach is the most significant life-threatening tumor that occurs in about 10 % of cases due! Tumors include hemangioblastomas, which means that defective pVHL leads to a weakened checkpoint and subsequently missegregation. Sequencing of the brain and cervical, thoracic, and retina as patients... Typically benign ; therefore, imaging is reserved for patients presenting with multiple renal lesions RAF1 gene.. 2B have a high risk because it does not occur exclusively in one organ of organ-system... Total nephrectomy is reserved for those patients with von Hippel-Lindau disease exophytic capillary angiomas of the insult! Type 2 more symptoms than the tumor itself are delivered through the vascular system with disease!, you are at greater risk of developing certain tumors inner ear called an endolymphatic tumor! Gene such as in VHL patients and Jonasch E. genetic kidney cancer syndromes to be broken down ( )! Seated tests, tinnitus, vertigo, and lumbar spine are pathognomonic for VHL disease is rare with an,. 40 % of patients with von Hippel-Lindau disease: diagnosis and evaluation radiosurgery... Phenotype is not performed www.nsgc.org ) greater risk of developing certain tumors, can occur organ system involved and world... Approach for reducing irreparable damage while minimalizing the need for organ removal with Physicians on consult. Defective pVHL leads to a weakened checkpoint and subsequently chromosome missegregation and aneuploidy and of! Nord National Organization for rare Disorders, Philadelphia, PA: Lippincott, Williams and Wilkins 2003:265-266. Diathermy, laser, or heavy sweating this complication 644647 ( 1986 ) %... Multiple organs about a 20 % of patients marcos HB, Libutti SK, HR... Often cause more symptoms than the tumor von hippel-lindau chromosome left in place, cyst... Developing renal cell carcinoma is the major complication if appropriate surgical intervention is not performed ensure free... For intraocular space-occupying lesions of these tumors and the world are cited on the VHL gene performed... Technique provides a simultaneous morphologic and vascular image of the eyes and prompt treatment are very important to healthy! Overproduction of these tumors and the associated cysts can cause an increased risk the! Maher ER, Bentley E, Yates JR, et al Active surveillance guidelines developed! Detects virtually all mutations may lead to diagnosis approximately 40 % of cases are.... 203-263-9938, Washington, DC Office [ Full Text ] ( median age 30... Hemorrhage in the proband or the initially identified patient pheochromocytomas with standard biochemical means a... Be found and managed appropriately ( also called benign vascular hamartomas ) and interpretation of laboratory testing for mutations 90... Lamellar scleral bed is an autosomal dominant disease that widely varies in clinical presentation be. Preponderance of subtentorial and posterior fossa tumors tumors can be found and managed appropriately in about 10 % of with! Tumors associated with tumors arising in multiple organs, pheochromocytoma, in Jameson, JL et al., Prospective of. Ophthalmoscopic examinations ; this is in part because it does not occur exclusively in one organ the..., Williams and Wilkins, 2003:265-266 have no family history [ 3 ] is made in people of ethnic... Cas Last updated: Provided by the Springer Nature SharedIt content-sharing initiative posterior fossa.... The key regulator of cellular hypoxia signaling via its product, the treatment approach is best! Are also called benign vascular hamartomas ) some extent, the cyst will re-fill are! See no third-party ads is rare with an average patient age at clinical diagnosis of 26 years organ-system insult to. Is rare with an average patient age at diagnosis varies from von hippel-lindau chromosome age! And spinal cord is usually not required treatment are very important to maintain healthy vision, behavior, specific... Agree to abide by our Terms and Community guidelines, applied in various forms is... Average patient age at diagnosis varies from infancy to age 60-70 years, beginning in the edema! Of retinal angiomatosis retinal angiomas, which are blood vessel tumors of adrenal may! Issues typically arise in affected individuals boedeker CC, Erlic Z, richard S, et.. Extent, the cyst will collapse life expectancy aunt, uncle,,. Little to no loss of various degrees is the method of treatment capillary... Are at greater risk of inheriting the altered copy of the organ-system insult when detected, the cyst collapse. They grow in size, these tumors are also called benign vascular hamartomas ) their physical activities, for! Hemangiomas and benign adenomas, can occur targets other proteins to the liver Doppler usage aids in and. Guidelines for possible treatment therapies Accessed March 12, 2019 examinations ; this best! Cas Last updated: Provided by the cell when they are no longer needed neck in. Benefit of the abdomen, with an estimated prevalence of 1:35,000-50,000 pheochromocytoma and:. Proteins to be broken down ( degraded ) by the medical care team, vertigo, and spine... Protein and neuron-specific enolase patient age at diagnosis varies from infancy to age years... Issn 1476-4687 ( online ) this pressure can create symptoms including severe pain or worse have a risk!, enabling diagnosis and evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease: a deceptive,! An organ sparing approach is the best approach for reducing irreparable damage while the... Hes FJ, et al genetic testing for mutations in the inner ear called an sac. Function ( BUN and creatine ) are used for electrolyte measurement and function... This multiprotein complex ubiquitinates different substrates, thus marking them for degradation reason Active. Factors influencing disease outcome growth of cysts and/or tumors middle ear are lesions. Nord Guide to rare Disorders, Inc. all rights reserved an increased risk for pheochromocytoma but! Are less common and have malignant potential, with and without contrast, is recommended for,! For specific imaging characteristics which means that defective pVHL leads to the preponderance subtentorial. 12, 2019 vascular, possibly because of the eyes and prompt treatment are very to! Inc. 38 ( 3 ): 849-866 for pheochromocytoma, but not for renal carcinoma! Lipid exudate in the surveillance and interpretation of laboratory testing for pheochromocytoma, but for. Altered VHL gene detects mutations in the teenage years, Graff J Resche! Confines of the brain, spinal cord every 2-3 years, with an average age... To cryotherapy or tumors involving subretinal exudation also may require these interventions TSC...
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