DiagnosisClinical Diagnosis The clinical diagnosis of von Hippel-Lindau (VHL) disease is established in [Lonser et al 2003, Butman et al 2008, Maher et al 2011]:A simplex case (i.e., an individual with no known family history of VHL disease) presenting with two or more characteristic lesions:Two or more hemangioblastomas of the retina, spine, or brain or a single hemangioblastoma in association with a visceral manifestation (e.g., multiple kidney or pancreatic cysts)Renal cell carcinoma Adrenal or extra-adrenal pheochromocytomasLess commonly, endolymphatic sac tumors, papillary cystadenomas of the epididymis or broad ligament, or neuroendocrine tumors of the pancreasAn individual with a positive family history of VHL disease in whom one or more of the following disease manifestations is present: Retinal angiomaSpinal or cerebellar hemangioblastomaAdrenal or extra-adrenal pheochromocytomaRenal cell carcinomaMultiple renal and pancreatic cystsNote: Other lesions characteristic of VHL are endolymphatic sac tumors (ELST) and pancreatic neuroendocrine tumors; however these are not typically used to make a clinical diagnosis of VHL. The following tests are used to establish the diagnosis and determine the extent of clinical manifestations. CNS tumors may be detected with:Fundoscopy: retinal angiomasCT: cerebellar, brain stem, supratentorial and spinal hemangioblastomasMRI: cerebellar, brain stem, supratentorial and spinal hemangioblastomas, and endolymphatic sac tumors (ELST)ELST presents as a mass on the posterior wall of the petrous part of the temporal bone and can be missed on standard MRI. MRI with contrast and high signal intensity with T₁, using thin slices of the internal auditory canal is recommended in symptomatic individuals.Visceral lesions may be detected with:Ultrasound: kidney and pancreatic lesions, as well as cysts of the epididymis and broad ligament CT: kidney, pancreatic, and adrenal gland lesionsMRI: kidney, pancreatic, and adrenal gland lesionsBlood or urinary catecholamine metabolites (VMA, metanephrine, and total catecholamine): pheochromocytomaMolecular Genetic TestingGene. VHL is the only gene in which mutations are known to cause VHL disease. Table 1. Summary of Molecular Genetic Testing Used in VHL DiseaseView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityVHLSequence analysisSequence variants 2~72% 3Clinical Deletion / duplication analysis 4Partial- or whole- gene deletion~28% 3, 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Stolle et al [1998]4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. Hoebeeck et al [2005], Banks et al [2006]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a probandMolecular genetic testing is indicated in all individuals known to have or suspected of having VHL disease [Rasmussen et al 2006]. Testing may also be used to evaluate individuals with a single VHL-associated tumor and a negative family history of the disease.For individuals with manifestations of VHL disease who do not meet strict diagnostic criteria and who do not have a detectable VHL germline mutation, somatic mosaicism for a de novo VHL disease-causing mutation should be considered [Sgambati et al 2000]. In some instances, molecular genetic testing of the offspring of such individuals reveals a VHL mutation. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersVHL-associated polycythemia (familial erythrocytosis type 2 [ECYT2]; previously known as Chuvash type polycythemia (OMIM 263400). VHL-associated polycythemia, which is clinically distinct from VHL disease, is caused by homozygous or compound heterozygous mutation in VHL and is characterized by increased circulating red blood cell mass. Although thrombosis and/or hemorrhage have occurred in many individuals with VHL-associated polycythemia, no individuals with this disorder or their heterozygous relatives thus far described have developed VHL-related tumors [Gordeuk et al 2004].Of note, congenital erythrocytosis is endemic in subpopulations worldwide; mutations in VHL are the most common genetic variant causing congenital erythrocytosis [Pastore et al 2003]. In the Chuvash Republic of the Russian Federation, where this condition is endemic, Ang et al [2002] identified homozygosity for the VHL mutation p.Arg200Trp. Haplotype analysis suggested that the p.Arg200Trp mutation arose independently in at least two populations [Cario et al 2005]. A note on terminology from OMIM: “ ‘Erythrocytosis’ is the preferred term used here in order to distinguish inherited disorders characterized by increased circulating red blood cells from ‘polycythemia vera’ (PV; 263300), which is a clonal myeloproliferative disorder associated with somatic mutations in the JAK2 gene (147796).”Other. Acquired somatic mutations in VHL may give rise to sporadic VHL-type tumors (i.e., clear cell RCC and hemangioblastoma) [Iliopoulos 2001, Kim & Kaelin 2004] without other associated tumors characteristic of the hereditary disease.}

Natural HistoryVon Hippel-Lindau (VHL) disease is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and renal cell carcinoma; pheochromocytoma; pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. Some clustering of tumors occurs, resulting in the designation of specific VHL disease phenotypes. The manifestations and severity are highly variable both within and between families, even among those with the same mutation.Hemangioblastoma. CNS hemangioblastoma is the prototypic lesion of VHL disease [Catapano et al 2005, Glasker 2005]. Roughly 80% develop in the brain and 20% in the spinal cord. Some hemangioblastomas are not symptomatic and are discovered only on imaging. Within the brain the vast majority are infratentorial, mainly in the cerebellar hemispheres. The pituitary stalk is the most common site for the development of supratentorial hemangioblastomas in individuals with VHL disease [Lonser et al 2009]. Multiple CNS tumors, occurring either synchronously or metachronously, are common. Spinal hemangioblastomas are generally intradural, most commonly occur in the cervical or thoracic regions, and occasionally may involve the entire cord. Rarely, peripheral nerve hemangiomas may develop [Giannini et al 1998]. Hemangioblastomas are often accompanied by cysts. Cysts in the spinal cord are referred to as syrinx, which contribute to rapid growth and development of symptoms. Symptom management relies on complete removal of the hemangioblastoma causing syrinx growth.Clinical symptoms depend on the site of the tumor. With infratentorial tumors, headache, vomiting, and gait disturbances or ataxia predominate. With tumors above the tentorium, symptoms depend on the location of the lesion. Hemangioblastomas oscillate between periods of growth and stability [Wanebo et al 2003] and are generally slow growing, but on occasion include rapidly enlarging cysts that produce hydrocephaly with papilledema. Spinal hemangioblastomas usually present with pain; sensory and motor loss may develop with cord compression. Most symptom-producing spinal hemangioblastomas are associated with syringomyelia/syrinx [Wanebo et al 2003].Retinal hemangioblastoma. These retinal lesions, sometimes called retinal angiomas, are histologically identical to CNS hemangioblastomas. They may be the initial manifestations of VHL disease and may occur in childhood. About 70% of affected individuals are identified as having retinal angiomas [Webster et al 1999, Kreusel 2005] with mean age of about 25 years [Dollfus et al 2002]. The tumors are most often located in the temporal periphery of the retina with feeder and draining vessels going to and from the optic disc. However, they may develop in the posterior pole (1%) and optic disc (8%). They may be asymptomatic and may be detected on routine ophthalmoscopy. Others present with a visual field defect or a loss of visual activity resulting from retinal detachment, exudation, or hemorrhage. Tests of retinal function may be abnormal even in the presence of quiescent retinal angiomas [Kreusel et al 2006]. While the number of retinal angiomas does not appear to increase with age, the probability of vision loss increases with age [Kreusel et al 2006].Renal lesions. Multiple renal cysts are common in VHL disease [Lonser et al 2003].Renal cell carcinoma (RCC), specifically of the clear cell subtype, developing either within a cyst or in the surrounding parenchyma, occurs in about 70% of affected individuals by age 60 years, and is a leading cause of mortality in VHL disease [Maher et al 1990, Maher et al 1991]. Mutations in VHL are the most common cause of both inheritable and sporadic RCC. Pheochromocytoma may present with sustained or episodic hypertension or be totally asymptomatic, being detected incidentally by an abdominal imaging procedure. Pheochromocytomas are usually located in one or both adrenal glands. They are usually benign, but malignant behavior has been reported [Chen et al 2001, Jimenez et al 2009]. Similar in etiology, paragangliomas can develop along the sympathetic axis in the abdomen or thorax [Schimke et al 1998]; these tumors are mostly nonfunctional. Pancreatic lesions. Most pancreatic lesions are simple cysts; however, while they can be numerous in individuals with VHL, they rarely cause endocrine or exocrine insufficiency. Occasionally, cysts in the head of the pancreas cause biliary obstruction. Five to seventeen percent of individuals with VHL develop neuroendocrine tumors of the pancreas [Lonser et al 2003, Maher et al 2011]. They are not usually hormonally active and are slow growing, but malignant behavior has been observed, particularly in tumors greater than 3 cm [Marcos et al 2002, Corcos et al 2008]. Endolymphatic sac tumors. The endolymphatic sac and duct are ectodermal extensions of the membranous labyrinth. Tumors of the sac cause deafness of varying severity, often severe to profound and of sudden onset [Choo et al 2004, Kim et al 2005]. Less commonly, vertigo or tinnitus is the presenting complaint. Large tumors can involve other cranial nerves. Endolymphatic sac tumors are seen in approximately 10% of individuals with VHL disease, and in some instances the associated uni- or bilateral hearing loss is the initial feature of the disease [Kim et al 2005]. In rare cases, the tumors may be malignant [Muzumdar et al 2006]. Endolymphatic sac tumors in VHL are often misdiagnosed as Menière disease.Epididymal tumors. Epididymal or papillary cystadenomas are relatively common in males with VHL disease. They rarely cause problems, unless bilateral, in which case they may result in infertility. The equivalent, much less common, lesion in women is a papillary cystadenoma of the broad ligament.

Genotype-Phenotype CorrelationsFour general VHL disease phenotypes have been suggested based on the likelihood of pheochromocytoma or renal cell carcinoma. Many lines of research support the conclusion that the molecular etiology of pheochromocytomas appears to be distinct from other VHL lesions. Therefore, the most relevant genotype-phenotype correlations rely mostly on scoring the presence/absence of pheochromocytomas associated with a given allele. The following discussion summarizes the genotype-phenotype studies published to date, with the cautionary note that further investigation is needed. In conclusion, the patterns are not clear-cut, and genotype-phenotype correlations have no current diagnostic or therapeutic value and are used for academic purposes only. VHL type 1. Retinal angioma, CNS hemangioblastoma, renal cell carcinoma, pancreatic cysts and neuroendocrine tumors. VHL type 1 is characterized by a low risk for pheochromocytoma. Truncating mutations or missense mutations that are predicted to grossly disrupt the folding of the VHL protein [Stebbins et al 1999] are associated with VHL type 1. VHL type 2. Pheochromocytoma, retinal angiomas and CNS hemangioblastoma. VHL type 2 is characterized by a high risk for pheochromocytoma. Individuals with VHL type 2 commonly have a missense mutation. Some missense mutations seem to correlate with a specific type 2 VHL phenotype [Weirich et al 2002, Sanso et al 2004, Abbott et al 2006, Knauth et al 2006]. (See also Molecular Genetics). Missense mutations that lead to pheochromocytoma with a low (or no) risk for RCC (types 2A and 2C) may encode a VHL protein that retains the ability to ubiquinate (and thereby downregulate) HIF1α in the presence of molecular oxygen to a greater degree than mutations that result in VHL disease with pheochromocytoma and RCC (type 2B). Furthermore, mutant pVHL may predispose to pheochromocytoma by altering the balance among a group of proteins in a molecular pathway that controls apoptosis of sympatho-adrenal precursor cells during development. Such cells may be at increased risk of developing into pheochromocytomas at a later stage [Lee et al 2005, Kaelin 2007].VHL type 2 is further subdivided:Type 2A. Pheochromocytoma, retinal angiomas and CNS hemangioblastoma; low risk for renal cell carcinoma. Type 2B. Pheochromocytoma, retinal angioma, CNS hemangioblastomas, pancreatic cysts and neuroendocrine tumor with a high risk for renal carcinomaType 2C. Risk for pheochromocytoma only Several groups report a reduced risk for renal cell carcinoma in individuals with a deletion of VHL [Cybulski et al 2002, Maranchie et al 2004, McNeill et al 2009]. In particular, individuals with a complete or partial deletion that extends 5’ of VHL to include C3orf10 have a significantly reduced risk of renal cell carcinoma [Maranchie et al 2004, McNeill et al 2009]. This genotype may constitute a distinct phenotype, VHL type 1B, characterized by a reduced risk for both renal cell carcinoma and pheochromocytoma. Some individuals within families with apparent type 2C disease have developed hemangioblastomas [Neumann & Eng 2009].

Differential DiagnosisThe level of mutation detection obtained by molecular genetic testing of VHL makes it possible to effectively rule out von Hippel-Lindau (VHL) disease with a high degree of certainty in individuals with (1) isolated hemangioblastoma, retinal angioma, or clear cell renal cell carcinoma and (2) no detectable VHL disease-causing germline mutation. Somatic mosaicism for VHL mutation could still be considered in such individuals. A younger individual, especially one with multiple lesions, is more likely to have a germline VHL mutation than an older individual with a single lesion [Neumann et al 2002]. Since pheochromocytoma is part of the VHL disease spectrum and may occur as the exclusive manifestation of VHL disease (type 2C), individuals with a family history of these tumors, or those in whom the disease is bilateral or multifocal, should be offered molecular genetic testing for VHL germline mutations. Germline VHL mutations are rare in simplex cases of unilateral pheochromocytoma (i.e., an affected individual with no family history of VHL disease), unless the individual is younger than age 20 years. Exceptions are those individuals with a family history that is more consistent with familial paragangliomas of the head and neck, which are caused by mutations in various subunits of the gene encoding succinic dehydrogenase (SDH) [Maher & Eng 2002, Bryant et al 2003] (see Hereditary Paraganglioma-Pheochromocytoma Syndromes), or those individuals who have features of other heritable diseases associated with pheochromocytoma including multiple endocrine neoplasia type 2A or 2B or neurofibromatosis type 1 [Neumann et al 2002]. Individuals with familial RCC should be examined for hereditary leiomyomatosis and renal cell cancer (HLRCC) and Birt-Hogg-Dubé (BHD) syndrome.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with von Hippel-Lindau (VHL) disease, the following evaluations are recommended:Neurologic history and physical examination for evidence of CNS or peripheral nerve hemangioblastomatosis. A baseline brain and spine MRI is considered standard procedure. Ophthalmologic evaluation for retinal hemangioblastomas Audiologic evaluation for hearing loss associated with endolymphatic sac tumors Blood pressure determination, supplemented by measurement of urinary catecholamine metabolites after age five years to evaluate for pheochromocytoma Abdominal ultrasound examination after age 16 years. Suspicious lesions in the kidney, adrenal gland, or pancreas should be evaluated by more sophisticated techniques, such as CT scan or MRI. Genetics consultation Treatment of ManifestationsNo guidelines exist for the management VHL lesions.Nervous system hemangioblastoma Some advocate early surgical removal of both symptomatic and asymptomatic CNS lesions, while others follow asymptomatic lesions with yearly imaging studies. Surgical intervention of syrinx in the spinal cord is recommended.Preoperative arterial embolization may be indicated, especially for extensive spinal tumors. Gamma knife surgery may be useful with small tumors or those in inoperable sites [Asthagiri et al 2010, Simone et al 2011]. While this technique may reduce the size of the solid tumor, it does not appear to prevent cyst formation. Overall operative mortality is roughly 10%, with higher figures for brain stem tumors [Lonser et al 2003].Retinal hemangioblastoma Most ophthalmologists favor prospective treatment of retinal (but not optic nerve) angiomas to avoid blindness, although spontaneous regression has occurred. Therapeutic modalities used to treat retinal hemangioblastomas include diathermy, xenon, laser, and cryocoagulation, with variable degrees of success depending on the location, size, and number of lesions. Recurrent tumors have been noted, even after many years, but some may be new tumors in the same general area rather than recurrent disease. External beam radiotherapy has been shown to be useful when standard therapy has not prevented progression [Raja et al 2004]. Renal cell carcinoma Early surgery is the best option for renal cell carcinoma, although close monitoring only is recommended for lesions smaller than 3 cm. Depending on the size and location of the tumor, nephron-sparing or partial nephrectomy may be possible without compromising survival [Grubb et al 2005]. Nephrectomy should leave the adrenal gland in situ, as is done in individuals with RCC who do not have a confirmed diagnosis of VHL. If contralateral pheochromocytoma occurs, the remaining adrenal gland will prevent or delay steroid replacement therapy. Cryoablation is being increasingly used for small lesions or in individuals who are likely to require multiple surgical procedures [Shingleton & Sewell 2002]. Radio frequency ablation therapy is often applied to smaller tumors. However, smaller lesions treated with radio frequency need frequent intervention [Joly et al 2011] and concerns about related necrosis have not yet been adequately addressed. Renal transplantation has been successful in individuals in whom bilateral nephrectomy has been necessary. It is imperative to evaluate any living related potential donor for VHL disease and to exclude those found to have VHL disease. Pheochromocytomas Pheochromocytomas should be surgically removed. Laparoscopic approaches have been shown to be effective. Preoperative treatment with alpha-adrenergic blockade, and optional additional beta-adrenergic blockade for seven to ten days is appropriate even in individuals with no known hypertension. Partial adrenalectomy could be considered. One long-term follow-up study (9.25 years) of 36 affected individuals showed no metastatic disease; ipsilateral recurrence after partial adrenalectomy was seen in three individuals (11%) [Benhammou et al 2010].Pancreatic neuroendocrine tumor and cysts Pancreatic cysts are common, but rarely influence endocrine function and generally do not require surgical removal. Pancreatic neuroendocrine tumors need to be differentiated from cysts and serous cystadenomas. Pancreatic tumors are usually slow growing and are not hormonally active, although they can cause metastatic disease. Surgery should be considered when the risk of metastases is high. Prognostic criteria [Blansfield et al 2007]: A tumor of ≥3 cm; A mutation in exon 3; or A tumor with a doubling rate <500 days Endolymphatic sac tumors. Consideration of surgical removal of these slow-growing tumors must include discussion of the possible complication of total deafness. Early intervention with small tumors has been shown to preserve both hearing and vestibular function [Kim et al 2005].Epididymal or broad ligament papillary cyst adenomas. These generally do not require surgery, unless they are symptomatic or are threatening fertility. Prevention of Secondary ManifestationsEarly detection through surveillance and removal of tumors may prevent or minimize deficits such as hearing loss, vision loss, neurologic symptoms, and the need for renal replacement therapy.SurveillanceIndividuals with known VHL disease, individuals without clinical manifestations but identified as having a VHL mutation, and first-degree relatives who have not undergone DNA-based testing need regular clinical monitoring by a physician or medical team familiar with the spectrum of VHL disease. Physician/pediatricianAnnual evaluation starting at age one year for neurologic symptoms, vision problems or hearing disturbance Annual examination starting at age one year for signs of nystagmus, strabismus, or white pupilsAnnual blood pressure monitoring starting at age one yearMonitoring for the following complications includes:Retinal angiomas. Annual ophthalmology evaluation with indirect ophthalmoscope starting at age one yearPheochromocytoma. Annual blood or urinary fractionated metanephrines starting at age five yearsEndolymphatic sac tumors (ELST)Audiology assessment every two to three years (annually if hearing loss, tinnitus or vertigo) starting at age five yearsIf repeated ear infections are present, MRI with contrast of the internal auditory canal using thin slicesVisceral lesions. Annual abdominal ultrasound, and every other year MRI scan of the abdomen (kidney, pancreas and adrenal glands), starting at age 16 yearsCNS lesions. MRI of the brain and total spin every two years starting at age 16 years. Attention should be given to the inner ear/petrous temporal bone (for ELST) and the posterior fossa.While current medical surveillance guidelines do not address structured psychological support for individuals with VHL, their partners, and their family members, research suggests a distinct need for psychosocial support [Lammens et al 2010, Lammens et al 2011b].Note: The surveillance guidelines established for VHL are not evidence based and rely on experiential reporting, largely from North America. Guidelines may vary somewhat depending on the local standard of care. In the United States, the VHL Family Alliance has worked extensively with healthcare professionals to assemble guidelines which are generally accepted throughout the world [VHL Handbook]. Other guidelines originate from Denmark and the Netherlands. For example, Dutch guidelines recommend screening for ELST only upon indication. In addition, examination by a primary care physician and assessment of metanephrine levels start at age ten years, while ophthalmologic examination begins at age five years. Improved surveillance guidelines have increased the life expectancy of individuals with VHL by over 16 years since 1990 [Wilding et al 2012]. Two studies evaluated the implementation of national surveillance guidelines in Denmark and the Netherlands. One study showed that more than 90% of the 84 affected individuals included reported that they were familiar with their national VHL surveillance guidelines. However, daily practice showed that 64% of those individuals had received information that was only partially consistent with the Dutch guidelines [Lammens et al 2011a]. In a Danish study, compliance and frequency of follow-up was surprisingly low with regard to the national VHL guidelines for individuals with VHL and subjects at risk [Bertelsen & Kosteljanetz 2011]. These studies collectively suggest that correct implementation of surveillance guidelines through a doctor- and patient-oriented information campaign could have an immediate positive impact for individuals with VHL.Agents/Circumstances to Avoid Tobacco products should be avoided since they are considered a risk factor for kidney cancer.Chemicals and industrial toxins known to affect VHL involved organs should be avoided. Contact sports should be avoided if adrenal or pancreatic lesions are present. Evaluation of Relatives at RiskUse of molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces the need for screening procedures in those at-risk family members who have not inherited the disease-causing mutation [Priesemann et al 2006]. The American Society of Clinical Oncologists (ASCO) identifies VHL disease as a Group 1 disorder, i.e., a hereditary disease for which genetic testing is considered part of the standard management for at-risk family members [American Society of Clinical Oncology 2003]. However, at-risk individuals may decline genetic testing for religious or financial reasons, in which case continued screening for VHL lesions is warranted. Additionally, current DNA tests do not detect VHL mutations in all at-risk individuals. Therefore, surveillance guidelines are recommended for all individuals in whom VHL is suspected, as well as in first-degree relatives of these individuals.Early recognition of manifestations of VHL disease may allow for timely intervention and improved outcome; thus, clinical surveillance of asymptomatic at-risk individuals (including children) for early manifestations of VHL disease is appropriate.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Medical surveillance for pregnant women with VHL is typically stricter than in non-pregnant women. Research by the French VHL Study Group showed a significantly higher complication rate of hemangioblastomas in individuals with VHL who had had at least one pregnancy [Abadie et al 2010]. Another study concluded that pregnancy has a significant influence on cerebellar hemangioblastoma growth and causes an overall high complication rate (17%) [Frantzen et al, in press]. Intensified surveillance is recommended in a specialized medical center during preconception care and pregnancy. Special attention should be paid to pheochromocytoma and cerebellar hemangioblastoma. The VHL Handbook recommends MRI of the cerebellum without contrast at four months’ gestation.Therapies Under Investigation Certain VHL mutations fail to downregulate HIFα, leading to overexpression of vascular endothelial growth factor (VEGF). An intravitreal VEGF receptor inhibitor, ranibizumab, has been used with some success in individuals with retinal hemangioblastomas who have either failed local therapy or whose lesions are not amenable to local therapy [Wong et al 2008]. Stabilization of some, but not all, CNS hemangioblastomas has also been demonstrated [Madhusudan et al 2004]. A tyrosine kinase inhibitor, sunitinab, has had some utility in the rare unresectable malignant pheochromocytomas, but simple surgical excision is clearly preferable for these usually benign tumors [Jimenez et al 2009].Sardi et al [2009] reported three-year stabilization of previously progressive multifocal spinal hemangioblastomas with thalidomide.Gene replacement therapy and other curative treatment approaches are still in the early developmental phases. The medical and research communities are largely focused on ameliorating disease progression and on improvement of early detection methodology. Surgical techniques are rapidly improving and therapeutic options are broadening every year. Premature termination codon 124 (PTC124), also known as ataluren, may benefit a subset of affected individuals in whom nonsense mutations give rise to premature stop codons in the messenger RNA (mRNA) [Auld et al 2010]. There are three stop codons: UAA, UAG, and UGA. PTC124 promotes read-through of all three stop codons with different efficiencies. The highest read-through efficiency takes place at UGA, followed by UAG and then UAA. PTC124 has been successfully proven to promote read-through of nonsense mutations in Duchenne muscular dystrophy (DMD), cystic fibrosis (CF), and Usher syndrome type 1C. Phase 1 and 2 clinical trials have shown no serious side-effects with PTC124 treatment, even after long-term use [Wilschanski et al 2011]. Preclinical investigation of PTC124 effects on VHL is ongoing. Aminoglycosides such as gentamicin promote read-through of premature stop codons when they are supplied in high concentrations, but they have serious side effects.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Von Hippel-Lindau Disease: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDVHL3p25​.3Von Hippel-Lindau disease tumor suppressorCatalogue of Somatic Mutations in Cancer (COSMIC)
VHL @ LOVDVHLData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Von Hippel-Lindau Disease (View All in OMIM) View in own window 193300VON HIPPEL-LINDAU SYNDROME; VHL 608537VHL GENE; VHLNormal allelic variants. VHL, which comprises three exons spanning about 10 kb of genomic DNA, is highly conserved among worms, flies, rodents, and humans [Kaelin 2002]. An mRNA about 4.5 kb in size is almost ubiquitously expressed and encodes proteins of 213 and 159 amino acid residues. The latter isoform is the major product in most tissues and results from initiation of translation from an internal methionine codon at position 54. Both protein isoforms appear to be functional. Pathologic allelic variants. More than 300 germline mutations have been identified in families with von Hippel-Lindau (VHL) disease (see Table A) [Beroud et al 1998]. They consist of partial- and whole-gene deletions and frameshift, nonsense, missense, and splice site mutations. Point mutations have been identified in all three exons. Codon 167 is considered a mutational "hot spot." Nordstrom-O'Brien describes detailed phenotype and gene mutation information for 945 families with VHL. The spectrum of mutations found: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice mutations. In families whose described phenotype includes pheochromocytoma, 83.5% had a missense mutation. Families without pheochromocytoma had 6.6% more truncating mutations than missense mutations [Nordstrom-O'Brien et al 2010].Normal gene product. Von Hippel-Lindau disease tumor suppressor (pVHL) has been implicated in a variety of functions including transcriptional regulation, post-transcriptional gene expression, apoptosis, extracellular matrix formation, and ubiquitinylation [Kaelin 2007, Roberts & Ohh 2008]. The role of pVHL in the regulation of hypoxia-inducible genes through the targeted ubiquitinylation and degradation of HIF1α has been described, leading to a model of how disruption of VHL results in renal cell carcinoma, hemangioblastoma, and the production of other highly vascularized tumors. Normal pVHL binds to elongin C, which forms a complex with elongin B and cullin-2 (encoded by TCEB2 and CUL2, respectively), and Rbx1 (see Figure 1). This complex resembles the SCF ubiquitin ligase or E3 complex in yeast that catalyzes the polyubiquitinylation of specific proteins and targets them for degradation by proteosomes. Under normoxic conditions, HIF1α is hydroxylated at one of two specific proline residues, catalyzed by a member of the EglN family of prolyl hydroxylase enzymes.FigureFigure 1. Schematic view of pVHL and HIF
A. Normoxia in a normal cell; HIF binds to pVHL.
B. Hypoxia in a normal cell; HIF does not bind to pVHL.
C. Cell with VHL mutation; HIF cannot bind to pVHL, therefore the cell (more...)The VHL protein then binds to hydroxylated HIF1α and targets it for degradation. Under hypoxic conditions, HIF1α is not hydroxylated, pVHL does not bind, and HIF1α subunits accumulate. HIF1α forms heterodimers with HIF1β and activates transcription of a variety of hypoxia-inducible genes (i.e., VEGF, EPO, TGFα, PDGFβ). Likewise, when pVHL is absent or mutated, HIF1α subunits accumulate, resulting in cell proliferation and the neovascularization of tumors characteristic of VHL disease [Kaelin 2002].Abnormal gene product. Mutations in VHL either prevent its expression (i.e., deletions, frameshifts, nonsense mutations, and splice site mutations) or lead to the expression of an abnormal protein (i.e., missense mutations). The type of VHL that results from a missense mutation depends on its effect on the three-dimensional structure of the protein [Stebbins et al 1999]. Mutations in VHL cause misfolding and subsequent chaperonin-mediated breakdown [Feldman et al 2003]. Missense mutations that destabilize packing of the alpha-helical domains, decrease the stability of the alpha-beta domain interface, interfere with binding of elongin C and HIF1α, or disrupt hydrophobic core residues result in loss of HIF regulation and are more likely to result in VHL type 1. Missense mutations that result in pVHL that is normal with respect to HIF regulation are more likely to be associated with VHL type 2 (see Genotype-Phenotype Correlations).