NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Von Hippel-Lindau Syndrome

Synonyms: VHL Syndrome, Von Hippel-Lindau Disease

, MD, , BSc, , MD, PhD, and , PhD.

Author Information
, MD
Department of Clinical Genetics
University Medical Center Groningen
Groningen, The Netherlands
, BSc
Department of Nephrology and Hypertension
University Medical Center Utrecht
Utrecht, The Netherlands
, MD, PhD
Department of Endocrinology
University Medical Center Groningen
Groningen, The Netherlands
, PhD
Department of Nephrology and Hypertension
University Medical Center Utrecht
Utrecht, The Netherlands

Initial Posting: ; Last Update: August 6, 2015.

Summary

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. Cerebellar hemangioblastomas may be associated with headache, vomiting, gait disturbances, or ataxia. Spinal hemangioblastomas and related syrinx usually present with pain. Sensory and motor loss may develop with cord compression. Retinal hemangioblastomas may be the initial manifestation of VHL syndrome and can cause vision loss. Renal cell carcinoma occurs in about 70% of individuals with VHL and is the leading cause of mortality. Pheochromocytomas can be asymptomatic but may cause sustained or episodic hypertension. Pancreatic lesions often remain asymptomatic and rarely cause endocrine or exocrine insufficiency. Endolymphatic sac tumors can cause hearing loss of varying severity, which can be a presenting symptom. Cystadenomas of the epididymis are relatively common. They rarely cause problems, unless bilateral, in which case they may result in infertility.

Diagnosis/testing.

The diagnosis of VHL is established in a proband who fulfills existing diagnostic clinical criteria. Identification of a heterozygous germline VHL pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Intervention for most CNS lesions (remove brain and spinal lesions completely when large and/or symptomatic); treat retinal (but not optic nerve) angiomas prospectively; early surgery (nephron-sparing or partial nephrectomy when possible) for renal cell carcinoma; renal transplantation following bilateral nephrectomy; remove pheochromocytomas (partial adrenalectomy when possible); monitor pancreatic cysts and neuroendocrine tumors and consider removal of neuroendocrine tumors; consider surgical removal of endolymphatic sac tumors (particularly small tumors in order to preserve hearing and vestibular function); cystadenomas of the epididymis or broad ligament need treatment when symptomatic or threatening fertility.

Prevention of secondary complications: Early detection and removal of tumors to prevent/minimize secondary deficits such as hearing loss, vision loss, neurologic symptoms, and the need for renal replacement therapy.

Surveillance: For individuals with VHL syndrome, those with a VHL pathogenic variant, and at-risk relatives of unknown genetic status:

  • Starting at age one year: Annual evaluation for neurologic symptoms, vision problems, and hearing disturbance; annual blood pressure monitoring; annual ophthalmology evaluation.
  • Starting at age five years: Annual blood or urinary fractionated metanephrines; audiology assessment every two to three years; thin-slice MRI with contrast of the internal auditory canal in those with repeated ear infections.
  • Starting at age 16 years: Annual abdominal ultrasound; MRI scan of the abdomen and MRI of the brain and total spine every two years.

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 risk: If the pathogenic variant in a family is known, molecular genetic testing can be used to clarify the genetic status of at-risk family members to eliminate the need for surveillance of family members who have not inherited the pathogenic variant.

Pregnancy management: Intensified surveillance for cerebellar hemangioblastoma and pheochromocytoma during preconception and pregnancy; MRI without contrast of the cerebellum at four months’ gestation.

Genetic counseling.

VHL syndrome is inherited in an autosomal dominant manner. Approximately 80% of individuals with VHL syndrome have an affected parent and about 20% have VHL syndrome as the result of a de novo pathogenic variant. Parental mosaicism has been described; the incidence is not known. The offspring of an individual with VHL syndrome are at a 50% risk of inheriting the VHL pathogenic variant. Prenatal testing for pregnancies at risk is possible if the pathogenic variant has been identified in a family member.

Diagnosis

Suggestive Findings

Von Hippel-Lindau syndrome should be suspected in individuals with or without a family history of VHL and:

  • Retinal angioma, especially in a young patient
  • Spinal or cerebellar hemangioblastoma
  • Adrenal or extra-adrenal pheochromocytoma
  • Renal cell carcinoma, if the patient is under age 47 years or has a personal or family history of any other tumor typical of VHL
  • Multiple renal and pancreatic cysts
  • Neuroendocrine tumors of the pancreas
  • Endolymphatic sac tumors
  • Less commonly, multiple papillary cystadenomas of the epididymis or broad ligament

Establishing the Diagnosis

The diagnosis of von Hippel-Lindau (VHL) syndrome is established in a proband with the following clinical features [Lonser et al 2003, Butman et al 2008, Maher et al 2011] and/or after the identification of a heterozygous germline VHL pathogenic variant on molecular genetic testing. Identification of a heterozygous germline VHL pathogenic variant on molecular genetic testing (Table 1) establishes the diagnosis and supports periodic follow up even if clinical and radiographic features are inconclusive.

Various tests can be used to establish the diagnosis and determine the extent of the clinical manifestations (MRI of the brain and spinal cord, fundoscopy, ultrasound examination/MRI of the abdomen, and blood/urinary catecholamine metabolites can be used to establish the clinical diagnosis). See Surveillance.

  • A simplex case (i.e., an individual with no known family history of VHL syndrome) 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 pheochromocytomas
    • Less commonly, endolymphatic sac tumors, papillary cystadenomas of the epididymis or broad ligament, or neuroendocrine tumors of the pancreas
  • An individual with a positive family history of VHL syndrome in whom one or more of the following syndrome manifestations is present:
    • Retinal angioma
    • Spinal or cerebellar hemangioblastoma
    • Adrenal or extra-adrenal pheochromocytoma
    • Renal cell carcinoma
    • Multiple renal and pancreatic cysts
      Note: 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. 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.

Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and genomic testing.

  • Single-gene testing. Sequence analysis of VHL is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multi-gene panel that includes VHL and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.
  • Genomic testing may be considered if serial single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of VHL syndrome. Such testing may include whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).
    For issues to consider in interpretation of genomic test results, click here.

Table 1.

Molecular Genetic Testing Used in von Hippel-Lindau Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
VHLSequence analysis 3~72% 4
Gene-targeted deletion/duplication analysis 5~28% 4, 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Test characteristics. See Clinical Utility Gene Card [Decker et al 2014] for information on test characteristics including sensitivity and specificity.

Clinical Characteristics

Clinical Description

Von Hippel-Lindau (VHL) syndrome is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and renal cell carcinoma; pheochromocytoma and paraganglioma; 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 syndrome phenotypes. The manifestations and severity are highly variable both within and between families, even among those with the same pathogenic variant.

Hemangioblastomas. CNS hemangioblastoma is the prototypic lesion of VHL syndrome [Catapano et al 2005, Gläsker 2005]. Multiple CNS tumors, occurring either synchronously or metachronously, are common. Roughly 80% develop in the brain and 20% in the spinal cord. Peripheral nerve hemangiomas may develop rarely [Giannini et al 1998].

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. Some hemangioblastomas do not cause symptoms and are discovered only on imaging.

Central nervous system hemangioblastoma growth appears to be associated with male sex and partial germline deletions [Lonser et al 2014, Huntoon et al 2015]. Growth patterns of these lesions can be saltatory (72%), linear (6%), or exponential (22%). Increased growth was associated with male sex, symptomatic tumors and hemangioblastoma-associated cysts.

  • Brain hemangioblastomas. 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 syndrome [Lonser et al 2009]. 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.
  • Spinal hemangioblastomas are generally intradural, most commonly occur in the cervical or thoracic regions, and occasionally may involve the entire cord. Most symptom-producing spinal hemangioblastomas are associated with cysts/syringomyelia/syrinx [Wanebo et al 2003]. Spinal hemangioblastomas usually present with pain; sensory and motor loss may develop with cord compression.
  • Retinal hemangioblastoma. These retinal lesions, sometimes called retinal angiomas, are histologically identical to CNS hemangioblastomas. They may be the initial manifestations of VHL syndrome 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 detection 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%).
  • Retinal hemangioblastomas 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 syndrome [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 syndrome [Maher et al 1990, Maher et al 1991]. Pathogenic variants in VHL are the most common cause of familial and sporadic RCC. Overall survival for renal cell carcinoma in individuals with VHL is associated with tumor size (<3 cm or ≥3 cm) and patient age [Kwon et al 2014].

Pheochromocytoma may present with sustained or episodic hypertension or be totally asymptomatic, 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].

Paragangliomas. Similar in etiology, paragangliomas can develop along the sympathetic axis in the abdomen or thorax [Schimke et al 1998, Boedeker et al 2014]; these tumors are mostly nonfunctional.

Pancreatic lesions

  • Pancreatic cysts. 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.
  • Neuroendocrine tumors. 5%-17% 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 are seen in approximately 10%-16% of individuals with VHL syndrome, and in some instances the associated uni- or bilateral hearing loss is the initial feature of the syndrome [Kim et al 2005, Binderup et al 2013b]. The onset of hearing loss is typically sudden; severity varies, but it is often severe to profound [Choo et al 2004, Kim et al 2005]. Vertigo or tinnitus is the presenting complaint. Symptoms do not appear to be related to tumor size. Large endolymphatic sac tumors can involve other cranial nerves. Endolymphatic sac tumors are rarely malignant [Muzumdar et al 2006].

Epididymal and broad ligament cystadenomas. Epididymal or papillary cystadenomas are relatively common in males with VHL syndrome. 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 Correlations

Four general VHL syndrome phenotypes (type 1, type 2A, type 2B, type 2C) 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. Note: 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 or missense pathogenic variants 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 pathogenic variant. Some missense pathogenic variants appear to correlate with a specific type 2 VHL phenotype [Weirich et al 2002, Sansó et al 2004, Abbott et al 2006, Knauth et al 2006]. (See also Molecular Genetics).

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 carcinoma
  • Type 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 syndrome have developed hemangioblastomas [Neumann & Eng 2009].

Penetrance

VHL pathogenic variants are highly penetrant. Almost all individuals who have a pathogenic variant in VHL are symptomatic by age 65 years [Maher et al 1991].

Nomenclature

Obsolete terms for VHL syndrome include: angiophakomatosis retinae et cerebelli, familial cerebello-retinal angiomatosis, cerebelloretinal hemangioblastomatosis, Hippel disease, Hippel-Lindau syndrome, Lindau disease, and retinocerebellar angiomatosis [Molino et al 2006].

Prevalence

The incidence of VHL syndrome is thought to be about one in 36,000 births with an estimated de novo mutation rate of 4.4x10-6 gametes per generation [Maher et al 1991].

Differential Diagnosis

Isolated hemangioblastoma, retinal angioma, or clear cell renal cell carcinoma. The clinical sensitivity of molecular genetic testing of VHL makes it possible to effectively rule out von Hippel-Lindau (VHL) syndrome with a high degree of certainty in individuals with (1) isolated hemangioblastoma, retinal angioma, or clear cell renal cell carcinoma and (2) no detectable germline VHL pathogenic variant. Somatic mosaicism for a VHL pathogenic variant could still be considered in such individuals. A younger individual, especially one with multiple lesions, is more likely to have a germline VHL pathogenic variant than an older individual with a single lesion [Neumann et al 2002].

Pheochromocytoma. Approximately 25% of individuals with pheochromocytoma and no known family history of pheochromocytoma have a heterozygous pathogenic variant in one of several genes: RET, VHL, SDHD, SDHB, SDHA, SDHC, SDHAF2, TMEM127, or MAX. Germline VHL pathogenic variants are rare in simplex cases of unilateral pheochromocytoma (i.e., an affected individual with no family history of VHL syndrome), unless the individual is younger than age 20 years.

  • Multiple endocrine neoplasia type 2 (MEN2). Individuals with MEN2A are at increased risk for medullary carcinoma of the thyroid, pheochromocytoma, and parathyroid adenoma or hyperplasia. Pheochromocytomas usually present after medullary thyroid cancer (MTC) or concomitantly; however, they are the first sign in 13%-27% of individuals with MEN2A [Inabnet et al 2000, Rodriguez et al 2008]. Features of MEN2B include mucosal neuromas of the lips and tongue, distinctive facies with thick vermilion of the upper and lower lips, ganglioneuromatosis of the gastrointestinal tract, a ‘marfanoid’ habitus, and an increased risk for MTC and pheochromocytoma. Pheochromocytomas occur in 50% of individuals with MEN2B; about half are multiple and often bilateral. A heterozygous pathogenic variant of RET is associated with MEN2.
  • Hereditary paraganglioma-pheochromocytoma syndrome. Approximately 8.5% of individuals with apparently nonfamilial nonsyndromic pheochromocytoma have been shown to have a pathogenic variant in one of the genes (SDHD, SDHB, SDHA, SDHC, and SDHAF2) encoding the succinate dehydrogenase subunits that cause the hereditary paraganglioma-pheochromocytoma syndromes [Neumann et al 2002, Neumann et al 2004]. Mutation of these genes is associated with familial paragangliomas, which are also known as extra-adrenal pheochromocytomas or glomus tumors [Baysal et al 2000, Astuti et al 2001]. Korpershoek et al [2011] found an SDHA germline pathogenic variant in 3% of individuals with apparently sporadic paragangliomas and pheochromocytomas. A MAX germline pathogenic variant is seen in approximately 1% of individuals with familial or nonfamilial pheochromocytoma [Burnichon et al 2012].
  • TMEM127-associated susceptibility to pheochromocytoma (OMIM 613403). Recent studies estimate that 1%-2% of individuals with familial or nonfamilial pheochromocytoma have a germline pathogenic variant in TMEM127 [Yao et al 2010, Abermil et al 2012]. A few individuals with a germline pathogenic variant in TMEM127 have paragangliomas of the head/neck or at extra-adrenal sites [Neumann et al 2011].
  • Pheochromocytomas are observed on occasion in neurofibromatosis type 1 (NF1).

Renal cell carcinoma (RCC). Individuals with familial RCC should be examined for hereditary leiomyomatosis and renal cell cancer (HLRCC) and Birt-Hogg-Dubé (BHD) syndrome.

Endolymphatic sac tumors in VHL are often misdiagnosed as Menière disease.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with von Hippel-Lindau (VHL) syndrome, 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
  • 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.
  • Blood pressure determination, supplemented by measurement of urinary catecholamine metabolites after age five years to evaluate for pheochromocytoma
  • Audiologic evaluation for hearing loss associated with endolymphatic sac tumors
  • Consultation with a medical geneticist and/or genetic counselor

Treatment of Manifestations

No guidelines exist for the management of VHL lesions.

CNS hemangioblastoma

  • Most central nervous system hemangioblastomas can be surgically removed completely and safely [Lonser et al 2003].
  • Some advocate early surgical removal of both symptomatic and asymptomatic CNS lesions, while others follow asymptomatic lesions with yearly imaging studies.
  • Surgical intervention of cysts/syrinx in the spinal cord is recommended.
  • Preoperative arterial embolization may be indicated, especially for extensive spinal tumors.
  • The position of stereotactic therapy is still questionable [Oldfield 2015]. Gamma knife surgery may be useful with small solid 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. In a study with nearly six years of follow up of 40 hemangioblastomas in 20 patients treated with stereotactic therapy, no progression was described in 33% [Asthagiri et al 2010]. Similar results are found when analyzing the natural history of the hemangioblastomas (25%) [Lonser et al 2014]. The unpredictable growth pattern makes it difficult to determine when to start stereotactic therapy, to avoid unnecessary intervention. A recent study demonstrates a local tumor control with stereotactic therapy of 93% after three years, 89% after five years, and 79% after ten years [Kano et al 2015]. Factors associated with tumor control are solid, smaller, VHL-associated lesions and higher margin dose. Thirteen of the 186 (7%) experienced complications, 11 patients needed steroid therapy and one person died of refractory peritumoral edema. Two patients required additional surgery.

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 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 renal cell carcinoma 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, particularly <3 cm [Best et al 2012]. However, smaller lesions treated with radio frequency ablation need frequent intervention [Joly et al 2011]. The major complication rate (need for a radiologic, surgical, or endoscopic intervention) for laparoscopic and percutaneous radio frequency ablation therapy was 7.3% and 4.3%, respectively [Young et al 2012].
  • 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 syndrome and to exclude those found to have VHL syndrome.

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].
  • Partial adrenalectomy is also therapy of choice in children. In 10 VHL patients 18 successful operations were performed. After follow up (median 7.2 years), 2 patients developed a new tumor in the ipsilateral adrenal gland [Volkin et al 2012].

Pancreatic cysts and neuroendocrine tumors

  • 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 there is a high risk of metastases suggested by one of the following prognostic criteria [Blansfield et al 2007]:
    • A tumor of ≥3 cm
    • A pathogenic variant in exon 3
    • A tumor with a doubling rate <500 days

Endolymphatic sac tumors (ELST). 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, Friedman et al 2013]. Friedman et al described two patients (2/18) with postoperative decreased facial nerve function and three (3/18) patients with recurrent ELSTs (with a mean follow up of 67 months). Kim et al [2013] studied 31 patients with VHL with 33 resected ELSTs. Twenty-nine patients were symptomatic. After surgery, hearing was stabilized or improved in 97% of individuals, and tumor resection was complete in 91%. Complications occurred in three tumors: cerebrospinal fluid leakage in two (6%) and transient lower cranial nerve palsy in one (3%).

Epididymal or broad ligament papillary cyst adenomas. These generally do not require surgery, unless they are symptomatic or are threatening fertility.

Prevention of Secondary Manifestations

Early 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.

Surveillance

Individuals with known VHL syndrome, individuals without clinical manifestations but identified as having a VHL pathogenic variant, 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 syndrome.

  • Annual 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 pupils
  • Annual blood pressure monitoring starting at age one year

Monitoring for complications is as follows:

  • CNS lesions. MRI of the brain and total spine 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.
  • Visceral lesions. Annual abdominal ultrasound; MRI scan of the abdomen (kidney, pancreas and adrenal glands) every two years starting at age 16 years
  • Retinal angiomas. Annual ophthalmology evaluation with indirect ophthalmoscope starting at age one year
  • Pheochromocytoma. Annual blood or urinary fractionated metanephrines starting at age five years
  • Endolymphatic sac tumors (ELST). The best way to detect ELST is unknown.
    • 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 (to detect hydrops), using thin slices of the internal auditory canal is recommended in symptomatic individuals. Butman et al [2013] found that FLAIR MRI is useful to find ELST-associated hydrops.
    • Butman et al [2013] described three pathophysiologic ways in which ELST can cause symptoms: optic capsule invasion, hemorrhage, and endolymphatic hydrops. Symptoms can be caused by all three mechanisms and hemorrhage or hydrops can be present even without any lesion being visible on MRI (<3 mm).
    • Audiology assessment every two to three years (annually if hearing loss, tinnitus, or vertigo is present) starting at age five years. Audiology can be used to detect (early) hearing loss. Binderup et al [2013b] described a male patient with demonstrable hearing loss by audiometric data whose ELST was only detectable with MRI more than one year later, after the patient already suffered from complete right-sided hearing loss. Results from a large study on audiometric data in individuals with VHL are pending.

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 on 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.

Two recent studies evaluated tumor progression. In one study, new tumor development was compared to age and genotype [Binderup et al 2013b]. According to their results, surveillance for retinal angiomas is essential during teenage years and central nervous system hemangioblastomas is mainly important in adults. In the other study, the optimal lesion-specific age to start surveillance and the optimal screening interval per organ system was analyzed [Kruizinga et al 2013]. The optimal time to start metanephrine measurements is age five years; retinal screening in patients with VHL can start at age 12 years. For central nervous system hemangioblastomas and visceral lesions, starting age was in line with current surveillance guidelines. Furthermore, to attain a 5% detection rate, surveillance intervals for retinal tumors can be twice as long, and for the adrenal gland, four times as long.

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 Risk

Early recognition of manifestations of VHL syndrome may allow for timely intervention and improved outcome; thus, clinical surveillance of asymptomatic at-risk individuals (including children) for early manifestations of VHL syndrome is appropriate. The American Society of Clinical Oncology identifies VHL syndrome as a Group 1 disorder – a hereditary disease for which genetic testing is considered part of the standard management for at-risk family members [American Society of Clinical Oncology 2010] (full text).

If the VHL pathogenic variant in the family is known, molecular genetic testing can be used for early identification of at-risk family members to improve diagnostic certainty and reduce the need for screening procedures in those at-risk family members who have not inherited the pathogenic variant [Priesemann et al 2006].

If the VHL pathogenic variant in the family is not known and/or at-risk individuals decline genetic testing for religious or financial reasons, continued screening for VHL lesions is warranted (see Surveillance).

The use of molecular genetic testing for determining the genetic status of presumably at-risk relatives when a family member with a clinical diagnosis of VHL syndrome is not available for testing is not straightforward. Such test results need to be interpreted with caution. A positive test result signals the presence of a VHL pathogenic variant in the at-risk family member and indicates that the same molecular genetic testing method can be used to assess the genetic status of other at-risk family members. However, a negative test for a VHL pathogenic variant under such circumstances suggests one of the following possibilities:

  • The at-risk family member has not inherited a VHL pathogenic variant.
  • The familial VHL pathogenic variant may not be detectable by the assays used.
  • The clinical diagnosis of VHL syndrome in the affected family member is questionable.

In this situation, the presumably at-risk family member has a small, but finite, residual risk of having inherited a pathogenic allele (i.e., VHL syndrome or other hereditary disorder). In counseling such individuals, careful consideration should be given to the strength of the clinical diagnosis of VHL syndrome in the affected family member, the relationship of the at-risk individual to the affected family member, the perceived risk of an undetected VHL (or other gene) pathogenic variant, and the potential need for some form of continued clinical surveillance.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Recommended medical surveillance for pregnant women with VHL is still debated. 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 2012]. Intensified surveillance could therefore be recommended in a specialized medical center during preconception care and pregnancy. Special attention should be paid to pheochromocytoma and cerebellar hemangioblastoma. In another study pregnancy was not related with the development of new hemangioblastomas or hemangioblastoma/cyst growth [Ye et al 2012]. Their data suggest no extra precautions need to be taken during gestation. The VHL Handbook recommends MRI of the cerebellum without contrast at four months’ gestation.

Therapies Under Investigation

Certain VHL pathogenic variants fail to downregulate HIFα, leading to overexpression of downstream effectors such as vascular endothelial growth factor (VEGF) which contribute to pathogenesis. Many experimental therapies target these misregulated signaling pathways. 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]. Intravitreal injections of bevacizumab, another VEGF inhibitor, have also been shown to be effective in treating retinal hemangioblastomas in patients with VHL [Hrisomalos et al 2010]. Stabilization of some (but not all) CNS hemangioblastomas has also been demonstrated [Madhusudan et al 2004].

A tyrosine kinase inhibitor that inhibits the action of growth factor receptors, sunitinib, 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]. Sunitinib has also been shown to effectively treat clear cell renal cell carcinomas – but not hemangioblastomas – in patients with VHL [Jonasch et al 2011].

Checkpoint inhibitors such as antibodies targeting PD-L1 have shown promise in managing tumor load; however, these treatments have unknown toxicity in patients with VHL, who will likely have dozens to thousands of small subclinical lesions present throughout their body. .

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. No such treatment for VHL currently exists, although it will be exciting to follow the example set by other monogenic diseases causing blindness. Encouragingly, gene replacement therapy strategies have been used successfully for other diseases of the eye including Leber congenital amaurosis, retinitis pigmentosa, and Usher syndrome [Ashtari et al 2011, Trapani et al 2014, Deng et al 2015]. 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 variants 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 variants 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Von Hippel-Lindau (VHL) syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • About 80% of individuals diagnosed with VHL syndrome have an affected parent.
  • A proband with VHL syndrome may have the disorder as the result of de novo VHL pathogenic variant. The proportion of individuals with VHL syndrome due to a de novo pathogenic variant is about 20%.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or de novo mutaiton in the proband. The incidence of germline mosaicism is as of yet unknown. However, some results suggest that mosaicism contributes more to VHL syndrome than is currently thought. Next-generation sequencing, with its improved sensitivity, will increase detection of mosaicism in VHL [Wu et al 2013, Coppin et al 2014].
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant. If the VHL pathogenic variant in the proband is not known, ophthalmologic screening and abdominal ultrasound evaluation, at a minimum, should be offered to both parents.
  • The family history of some individuals diagnosed with VHL syndrome may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the syndrome in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Note: If the parent is the individual in whom the pathogenic variant first occurred, (s)he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected and/or has the VHL pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
  • If the parents are clinically unaffected and are at least 35 years old, the risk to the sibs of a proband appears to be low.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for VHL syndrome because of the possibility of failure to recognize the disorder or late onset of the syndrome in an affected parent.
  • If the VHL pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
  • Mosaicism has been described; the incidence is not known [Murgia et al 2000, Sgambati et al 2000, Santarpia et al 2007, Wu et al 2013, Coppin et al 2014].

Offspring of a proband. Each child of an individual with VHL syndrome is at a 50% risk of inheriting the VHL pathogenic variant; the degree of clinical severity is not predictable.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ®, National Cancer Institute).

Testing of at-risk asymptomatic family members. Molecular genetic testing of at-risk family members is appropriate in order to determine the need for continued clinical surveillance. Interpretation of molecular genetic test results is most accurate when a germline VHL pathogenic variant has been identified in an affected family member (see Evaluation of Relatives at Risk).

Because early detection of at-risk individuals affects medical management, testing of asymptomatic individuals during childhood is beneficial [Hes et al 2001, Lonser et al 2003, Binderup et al 2013a, VHL Handbook]. As ophthalmologic screening for those at risk for VHL syndrome begins as early as possible, certainly before age five years, molecular genetic testing may be considered in young children. Molecular genetic testing may be performed earlier if the results would alter the medical management of the child.

Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures in a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and their children. The authors recommend the VHL handbook for children by the VHL Family Alliance [VHL Handbook - Kids’ Edition].

Other issues to consider. It is recommended that physicians ordering VHL molecular genetic testing and individuals considering undergoing testing understand the risks, benefits, and limitations of the testing prior to sending a sample to a laboratory. A study demonstrated that for almost one third of individuals assessed for familial adenomatous polyposis, an autosomal dominant colon cancer disease, the physician misinterpreted the test results [Giardiello et al 1997]. Referral to a genetic counselor and/or a center in which testing is routinely offered is recommended.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband has VHL syndrome and/or has the VHL pathogenic variant, the VHL pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
  • Preconception considerations include possible male infertility due to cysts of the epididymis.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the VHL pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) has been successfully used in pregnancies at risk for VHL syndrome [Rechitsky et al 2002, Simpson et al 2005] and may be available for families in which the VHL pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Cancer.Net
    Phone: 571-483-1780; 888-651-3038
    Fax: 571-366-9537
    Email: contactus@cancer.net
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • The VHL Handbook: What You Need to Know About VHL
    A reference handbook for people with von Hippel-Lindau, their families, and support personnel.
  • VHL Alliance
    2001 Beacon Street
    Suite 208
    Boston MA 02135-7787
    Phone: 800-767-4845 (toll-free); 617-277-5667
    Fax: 858-712-8712
    Email: info@vhl.org
  • American Cancer Society (ACS)
    1599 Clifton Road Northeast
    Atlanta GA 30329-4251
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • CancerCare
    275 Seventh Avenue
    Floor 22
    New York NY 10001
    Phone: 800-813-4673 (toll-free); 212-712-8400 (administrative)
    Fax: 212-712-8495
    Email: info@cancercare.org
  • Kidney Cancer Association
    PO Box 96503
    Washington DC 20090
    Phone: 800-850-9132 (toll-free); 312-436-1455
    Fax: 847-332-2978
    Email: kidney.cancer@hotmail.com

Molecular Genetics

Information 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 Syndrome: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
VHL3p25​.3Von Hippel-Lindau disease tumor suppressorVHL @ LOVDVHL

Data 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 Syndrome (View All in OMIM)

193300VON HIPPEL-LINDAU SYNDROME; VHL
608537VHL GENE; VHL

Gene structure. VHL, which comprises three exons spanning about 10 kb of genomic DNA, is highly conserved among worms, flies, rodents, zebrafish, and humans [Kaelin 2002, Gossage et al 2015]. 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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. More than 500 germline pathogenic variants have been identified in families with von Hippel-Lindau (VHL) syndrome (see Table A) [Nordstrom-O'Brien et al 2010]. They consist of partial- and whole-gene deletions and frameshift, nonsense, missense, and splice site variants. Single nucleotide variants have been identified in all three exons. Codon 167 is considered a mutational "hot spot."

Nordstrom-O'Brien et al [2010] describes detailed phenotype and pathogenic variant information for 945 families with VHL. The spectrum of pathogenic variants found: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice site mutations. In families whose described phenotype includes pheochromocytoma, 83.5% had a pathogenic missense variant. Families without pheochromocytoma had 6.6% more pathogenic truncating variants than pathogenic missense variants.

Normal gene product. Von Hippel-Lindau syndrome 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 proteasomes. 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.

Figure 1. . Schematic view of pVHL and HIF

A.

Figure 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 pathogenic variant; 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 syndrome [Gossage et al 2015].

Abnormal gene product. Pathogenic variants in VHL either prevent its expression (i.e., deletions, frameshifts, nonsense variants, and splice site variants) or lead to the expression of an abnormal protein (i.e., pathogenic missense variants). The type of VHL that results from a pathogenic missense variant depends on its effect on the three-dimensional structure of the protein [Stebbins et al 1999]. Pathogenic variants in VHL cause misfolding and subsequent chaperonin-mediated breakdown [Feldman et al 2003]. Pathogenic missense variants 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. Pathogenic missense variants 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).

Pathogenic missense variants 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 pathogenic variants that result in VHL syndrome 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].

Cancer and benign tumors. Acquired somatic pathogenic variants 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 syndrome.

References

Published Guidelines/Consensus Statements

  1. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2003. Accessed 8-4-15.
  2. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online; registration or institutional access required. 2010. Accessed 8-4-15.
  3. Binderup ML, Bisgaard ML, Harbud V, Møller HU, Gimsing S, Friis-Hansen L, Hansen Tv, Bagi P, Knigge U, Kosteljanetz M, Bøgeskov L, Thomsen C, Gerdes AM, Ousager LB, Sunde L; Danish vHL Coordination Group (2013b) Von Hippel-Lindau disease (vHL). National clinical guideline for diagnosis and surveillance in Denmark. 3rd edition. Dan Med J 60:B4763. [PubMed: 24355456]
  4. Hes FJ, van der Luijt RB, Lips CJ. Clinical management of Von Hippel-Lindau (VHL) disease. Neth J Med. 2001;59:225–34. [PubMed: 11705642]
  5. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH. von Hippel-Lindau disease. Lancet. 2003;361:2059–67. [PubMed: 12814730]
  6. VHL Family Alliance. The VHL Handbook. 4 ed. Available online. 2012. Accessed 8-4-15.

Literature Cited

  1. Abadie C, Croupier I, Bringuier-Branchereau S, Mercies G, Deveaux S, Richard S. Role of pregnancy on hemangioblastomas in von Hippel-Lindau disease: A retrospective French study. Rio de Janeiro, Brazil: 9th International Medical Symposium on VHL. 2010.
  2. Abbott MA, Nathanson KL, Nightingale S, Maher ER, Greenstein RM. The von Hippel-Lindau (VHL) germline mutation V84L manifests as early-onset bilateral pheochromocytoma. Am J Med Genet A. 2006;140:685–90. [PubMed: 16502427]
  3. Abermil N, Guillaud-Bataille M, Burnichon N, Venisse A, Manivet P, Guignat L, Drui D, Chupin M, Josseaume C, Affres H, Plouin PF, Bertherat J, Jeunemaître X, Gimenez-Roqueplo AP. TMEM127 screening in a large cohort of patients with pheochromocytoma and/or paraganglioma. J Clin Endocrinol Metab. 2012;97:E805–9. [PubMed: 22419703]
  4. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010;28:893–901. [PubMed: 20065170]
  5. Ang SO, Chen H, Gordeuk VR, Sergueeva AI, Polyakova LA, Miasnikova GY, Kralovics R, Stockton DW, Prchal JT. Endemic polycythemia in Russia: mutation in the VHL gene. Blood Cells Mol Dis. 2002;28:57–62. [PubMed: 11987242]
  6. Ashtari M, Cyckowski LL, Monroe JF, Marshall KA, Chung DC, Auricchio A, Simonelli F, Leroy BP, Maguire AM, Shindler KS, Bennett J. The human visual cortex responds to gene therapy-mediated recovery of retinal function. J Clin Invest. 2011;121:2160–8. [PMC free article: PMC3104779] [PubMed: 21606598]
  7. Asthagiri AR, Metha GU, Zach L, Li X, Butman JA, Camphausen KA, Lonser RR. Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease. Neuro Oncol. 2010;12:80–6. [PMC free article: PMC2940550] [PubMed: 20150370]
  8. Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Sköldberg F, Husebye ES, Eng C, Maher ER. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001;69:49–54. [PMC free article: PMC1226047] [PubMed: 11404820]
  9. Auld DS, Lovell S, Thorne N, Lea WA, Maloney DJ, Shen M, Rai G, Battaile KP, Thomas CJ, Simeonov A, Hanzlik RP, Inglese J. Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124. Proc Natl Acad Sci U S A. 2010;107:4878–83. [PMC free article: PMC2841876] [PubMed: 20194791]
  10. Banks RE, Tirukonda P, Taylor C, Hornigold N, Astuti D, Cohen D, Maher ER, Stanley AJ, Harnden P, Joyce A, Knowles M, Selby PJ. Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. Cancer Res. 2006;66:2000–11. [PubMed: 16488999]
  11. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard CW 3rd, Cornelisse CJ, Devilee P, Devlin B. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000;287:848–51. [PubMed: 10657297]
  12. Benhammou JN, Boris RS, Pacak K, Pinto PA, Linehan WM, Bratslavsky G. Functional and oncologic outcomes of partial adrenalectomy for pheochromocytoma in patients with von Hippel-Lindau syndrome after at least 5 years of follow-up. J Urol. 2010;184:1855–9. [PMC free article: PMC3164541] [PubMed: 20846682]
  13. Bertelsen M, Kosteljanetz M. An evaluation of Danish national clinical guidelines for von Hippel-Lindau (VHL). Acta Neurochir (Wien) 2011;153:35–41. [PubMed: 20865287]
  14. Best SL, Park SK, Youssef RF, Olweny EO, Tan YK, Trimmer C, Cadeddu JA. Long-term outcomes of renal tumor radio frequency ablation stratified by tumor diameter: size matters. J Urol. 2012;187:1183–9. [PubMed: 22335865]
  15. Binderup ML, Bisgaard ML, Harbud V, Møller HU, Gimsing S, Friis-Hansen L, Hansen Tv, Bagi P, Knigge U, Kosteljanetz M, Bøgeskov L, Thomsen C, Gerdes AM, Ousager LB, Sunde L; Danish vHL Coordination Group (2013a) Von Hippel-Lindau disease (vHL). National clinical guideline for diagnosis and surveillance in Denmark. 3rd edition. Dan Med J 60:B4763. [PubMed: 24355456]
  16. Binderup ML, Gimsing S, Kosteljanetz M, Thomsen C, Bisgaard ML. von Hippel-Lindau disease: deafness due to a non-MRI-visible endolymphatic sac tumor despite targeted screening. Int J Audiol. 2013b;52:771–5. [PubMed: 24003980]
  17. Blansfield JA, Choyke L, Morita SY, Choyke PL, Pingpank JF, Alexander HR, Seidel G, Shutack Y, Yuldasheva N, Eugeni M, Bartlett DL, Glenn GM, Middelton L, Linehan WM, Libutti SK. Clinical, genetic and radiographic analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs). Surgery. 2007;142:814–8. [PubMed: 18063061]
  18. Boedeker CC, Hensen EF, Neumann HP, Maier W, van Nederveen FH, Suárez C, Kunst HP, Rodrigo JP, Takes RP, Pellitteri PK, Rinaldo A, Ferlito A. Genetics of hereditary head and neck paragangliomas. Head Neck. 2014;36:907–16. [PubMed: 23913591]
  19. Burnichon N, Abermil N, Buffet A, Favier J, Gimenez-Roqueplo AP. The genetics of paragangliomas. Eur Ann Otorhinolaryngol Head Neck Dis. 2012;129:315–8. [PubMed: 23078982]
  20. Butman JA, Linehan WM, Lonser RR. Neurologic manifestations of von Hippel-Lindau disease. JAMA. 2008;300:1334–42. [PMC free article: PMC3487164] [PubMed: 18799446]
  21. Butman JA, Nduom E, Kim HJ, Lonser RR. Imaging detection of endolymphatic sac tumor-associated hydrops. J Neurosurg. 2013;119:406–11. [PubMed: 23472846]
  22. Catapano D, Muscarella LA, Guarnieri V, Zelante L, D'Angelo VA, D'Agruma L. Hemangioblastomas of central nervous system: molecular genetic analysis and clinical management. Neurosurgery. 2005;56:1215–21. [PubMed: 15918937]
  23. Chen MY, Chew EY, Reynolds JC, Chao DL, Oldfield EH. Metastatic brainstem pheochromocytoma in a patient with von Hippel-Lindau disease. J Neurosurg. 2001;94:138. [PubMed: 11147885]
  24. Choo D, Shotland L, Mastroianni M, Glenn G, van Waes C, Linehan WM, Oldfield EH. Endolymphatic sac tumors in von Hippel-Lindau disease. J Neurosurg. 2004;100:480–7. [PubMed: 15035284]
  25. Coppin L, Grutzmacher C, Crépin M, Destailleur E, Giraud S, Cardot-Bauters C, Porchet N, Pigny P. VHL mosaicism can be detected by clinical next-generation sequencing and is not restricted to patients with a mild phenotype. Eur J Hum Genet. 2014;22:1149–52. [PMC free article: PMC4135403] [PubMed: 24301059]
  26. Corcos O, Couvelard A, Giraud S, Vullierme MP. Dermot O'Toole, Rebours V, Stievenart JL, Penfornis A, Niccoli-Sire P, Baudin E, Sauvanet A, Levy P, Ruszniewski P, Richard S, Hammel P. Endocrine pancreatic tumors in von Hippel-Lindau disease: clinical, histological, and genetic features. Pancreas. 2008;37:85–93. [PubMed: 18580449]
  27. Cybulski C, Krzystolik K, Murgia A, Gorski B, Debniak T, Jakubowska A, Martella M, Kurzawski G, Prost M, Kojder I, Limon J, Nowacki P, Sagan L, Bialas B, Kaluza J, Zdunek M, Omulecka A, Jaskolski D, Kostyk E, Koraszewska-Matuszewska B, Haus O, Janiszewska H, Pecold K, Starzycka M, Slomski R, Cwirko M, Sikorski A, Gliniewicz B, Cyrylowski L, Fiszer-Maliszewska L, Gronwald J, Toloczko-Grabarek A, Zajaczek S, Lubinski J. Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene. J Med Genet. 2002;39:E38. [PMC free article: PMC1735187] [PubMed: 12114495]
  28. Decker J, Neuhaus C, Macdonald F, Brauch H, Maher ER. Clinical utility gene card for: von Hippel-Lindau (VHL). Eur J Hum Genet. 2014 Apr;22(4) [PMC free article: PMC3953906] [PubMed: 23982691]
  29. Deng WT, Dyka FM, Dinculescu A, Li J, Zhu P, Chiodo VA, Boye SL, Conlon TJ, Erger K, Cossette T, Hauswirth WW. Stability and Safety of an AAV Vector for Treating RPGR-ORF15 X-Linked Retinitis Pigmentosa. Hum Gene Ther. 2015 Jul 29 Epub ahead of print. [PubMed: 26076799]
  30. Dollfus H, Massin P, Taupin P, Nemeth C, Amara S, Giraud S, Beroud C, Dureau P, Gaudric A, Landais P, Richard S. Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study. Invest Ophthalmol Vis Sci. 2002;43:3067–74. [PubMed: 12202531]
  31. Feldman DE, Spiess C, Howard DE, Frydman J. Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding. Mol Cell. 2003;12:1213–24. [PubMed: 14636579]
  32. Frantzen C, Kruizinga RC, van Asselt SJ, Zonnenberg BA, Lenders JWM, de Herder WW, Walenkamp AME, Giles RH, Hes FJ, Sluiter WJ, van Pampus MG, Links TP. Pregnancy-related hemangioblastoma progression and complications in von Hippel-Lindau disease. Neurology. 2012;79:793–6. [PubMed: 22875085]
  33. Friedman RA, Hoa M, Brackmann DE. Surgical management of endolymphatic sac tumors. J Neurol Surg B Skull Base. 2013;74:12–9. [PMC free article: PMC3699165] [PubMed: 24436884]
  34. Giannini C, Scheithauer BW, Hellbusch LC, Rasmussen AG, Fox MW, McCormick SR, Davis DH. Peripheral nerve hemangioblastoma. Mod Pathol. 1998;11:999–1004. [PubMed: 9796730]
  35. Giardiello FM, Brensinger JD, Petersen GM, Luce MC, Hylind LM, Bacon JA, Booker SV, Parker RD, Hamilton SR. The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. N Engl J Med. 1997;336:823–7. [PubMed: 9062090]
  36. Gläsker S. Central nervous system manifestations in VHL: genetics, pathology and clinical phenotypic features. Fam Cancer. 2005;4:37–42. [PubMed: 15883708]
  37. Gordeuk VR, Sergueeva AI, Miasnikova GY, Okhotin D, Voloshin Y, Choyke PL, Butman JA, Jedlickova K, Prchal JT, Polyakova LA. Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. Blood. 2004;103:3924–32. [PubMed: 14726398]
  38. Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer. 2015;15:55–64. [PubMed: 25533676]
  39. Grubb RL III, Choyke PL, Pinto PA, Linehan WM, Walther MM. Management of von Hippel-Lindau-associated kidney cancer. Nat Clin Pract Urol. 2005;2:248–55. [PubMed: 16474836]
  40. Hes FJ, van der Luijt RB, Lips CJ. Clinical management of Von Hippel-Lindau (VHL) disease. Neth J Med. 2001;59:225–34. [PubMed: 11705642]
  41. Hoebeeck J, van der Luijt R, Poppe B, De Smet E, Yigit N, Claes K, Zewald R, de Jong GJ, De Paepe A, Speleman F, Vandesompele J. Rapid detection of VHL exon deletions using real-time quantitative PCR. Lab Invest. 2005;85:24–33. [PubMed: 15608663]
  42. Hrisomalos FN, Maturi RK, Pata V. Long-term use of intravitreal bevacizumab (avastin) for the treatment of von hippel-lindau associated retinal hemangioblastomas. Open Ophthalmol J. 2010;4:66–9. [PMC free article: PMC3032222] [PubMed: 21293730]
  43. Huntoon K, Oldfield EH, Lonser RR. Dr. Arvid Lindau and discovery of von Hippel-Lindau disease. J Neurosurg. 2015;6:1–5. [PubMed: 25748307]
  44. Iliopoulos O. von Hippel-Lindau disease: genetic and clinical observations. Front Horm Res. 2001;28:131–66. [PubMed: 11443850]
  45. Inabnet WB, Caragliano P, Pertsemlidis D. Pheochromocytoma: inherited associations, bilaterality, and cortex preservation. Surgery. 2000;128:1007–11. [PubMed: 11114636]
  46. Jimenez C, Cabanillas ME, Santarpia L, Jonasch E, Kyle KL, Lano EA, Matin SF, Nunez RF, Perrier ND, Phan A, Rich TA, Shah B, Williams MD, Waguespack SG. Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors. J Clin Endocrinol Metab. 2009;94:386–91. [PubMed: 19017755]
  47. Joly D, Méjeam A, Corréas JM, Timsit MO, Verkarre V, Deveaux S, Landais P, Grünveld JP, Richard S. Progress in Nephron Sparing Therapy for Renal Cell Carcinoma and von Hippel-Lindau Disease. J Urol. 2011;185:2056–60. [PubMed: 21496837]
  48. Jonasch E, McCutcheon IE, Waguespack SG, Wen S, Davis DW, Smith LA, Tannir NM, Gombos DS, Fuller GN, Matin SF. Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease. Ann Oncol. 2011;22:2661–6. [PMC free article: PMC4542805] [PubMed: 22105611]
  49. Kaelin WG. von Hippel-Lindau disease. Annu Rev Pathol. 2007;2:145–73. [PubMed: 18039096]
  50. Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002;2:673–82. [PubMed: 12209156]
  51. Kano H, Shuto T, Iwai Y, Sheehan J, Yamamoto M, McBride HL, Sato M, Serizawa T, Yomo S, Moriki A, Kohda Y, Young B, Suzuki S, Kenai H, Duma C, Kikuchi Y, Mathieu D, Akabane A, Nagano O, Kondziolka D, Lunsford LD. Stereotactic radiosurgery for intracranial hemangioblastomas: a retrospective international outcome study. J Neurosurg. 2015;122:1469–78. [PubMed: 25816088]
  52. Kim HJ, Butman JA, Brewer C, Zalewski C, Vortmeyer AO, Glenn G, Oldfield EH, Lonser RR. Tumors of the endolymphatic sac in patients with von Hippel-Lindau disease: implications for their natural history, diagnosis, and treatment. J Neurosurg. 2005;102:503–12. [PubMed: 15796386]
  53. Kim HJ, Hagan M, Butman JA, Baggenstos M, Brewer C, Zalewski C, Linehan WM, Lonser RR. Surgical resection of endolymphatic sac tumors in von Hippel-Lindau disease: findings, results, and indications. Laryngoscope. 2013;123:477–83. [PubMed: 23070752]
  54. Kim WY, Kaelin WG. Role of VHL gene mutations in human cancer. J Clin Oncol. 2004;22:4991–5004. [PubMed: 15611513]
  55. Knauth K, Bex C, Jemth P, Buchberger A. Renal cell carcinoma risk in type 2 von Hippel-Lindau disease correlates with defects in pVHL stability and HIF-1alpha interactions. Oncogene. 2006;25:370–7. [PubMed: 16261165]
  56. Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L, Badoual C, Gadessaud N, Venisse A, Bayley JP, van Dooren MF, de Herder WW, Tissier F, Plouin PF, van Nederveen FH, Dinjens WN, Gimenez-Roqueplo AP, de Krijger RR. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab. 2011;96:E1472–6. [PubMed: 21752896]
  57. Kreusel KM. Ophthalmological manifestations in VHL and NF 1: pathological and diagnostic implications. Fam Cancer. 2005;4:43–7. [PubMed: 15883709]
  58. Kreusel KM, Bechrakis NE, Krause L, Neumann HP, Foerster MH. Retinal angiomatosis in von Hippel-Lindau disease: a longitudinal ophthalmologic study. Ophthalmology. 2006;113:1418–24. [PubMed: 16769118]
  59. Kruizinga RC, Sluiter WJ, de Vries EG, Zonnenberg BA, Lips CJ, van der Horst-Schrivers AN, Walenkamp AM, Links TP. Calculating optimal surveillance for detection of von Hippel-Lindau-related manifestations. Endocr Relat Cancer. 2013;21:63–71. [PubMed: 24132471]
  60. Kwon T, Jeong IG, Pak S, You D, Song C, Hong JH, Ahn H, Kim CS. Renal tumor size is an independent prognostic factor for overall survival in von Hippel-Lindau disease. J Cancer Res Clin Oncol. 2014;140:1171–7. [PubMed: 24671227]
  61. Lammens CR, Aaronson NK, Hes FJ, Links TP, Zonnenberg BA, Lenders JW, Majoor-Krakauer D, Van Os TA, Gomez-Garcia EB, de Herder W, van der Luijt RB, van den Ouweland AM, Van Hest LP, Verhoef S, Bleiker EM. Compliance with period surveillance for von Hippel-Lindau disease. Genet Med. 2011a;13:519–27. [PubMed: 21415761]
  62. Lammens CR, Bleiker EM, Verhoef S, Ausems MG, Majoor-Krakauer D, Sijmons RH, Hes FJ, Gómez-García EB, Van Os TA, Spruijt L, van der Luijt RB, van den Ouweland AM, Ruijs MW, Gundy C, Nagtegaal T, Aaronson NK. Distress in partners of individuals diagnosed with or at high risk of developing tumors due to rare hereditary cancer syndromes. Psychooncology. 2011b;20:631–8. [PubMed: 21384469]
  63. Lammens CR, Bleiker EM, Verhoef S, Hes FJ, Ausems MG, Majoor-Krakauer D, Sijmons RH, van der Luijt RB, van den Ouweland AM, Van Os TA, Hoogerbrugge N, Gómez García EB, Dommering CJ, Gundy CM, Aaronson NK. Psychosocial impact of Von Hippel-Lindau disease: levels and sources of distress. Clin Genet. 2010;77:483–91. [PubMed: 20184621]
  64. Lee S, Nakamura E, Yang H, Wei W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin WG Jr, Schlisio S. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell. 2005;8:155–67. [PubMed: 16098468]
  65. Lonser RR, Butman JA, Huntoon K, Asthagiri AR, Wu T, Bakhtian KD, Chew EY, Zhuang Z, Linehan WM, Oldfield EH. Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease. J Neurosurg. 2014;120:1055–62. [PubMed: 24579662]
  66. Lonser RR, Butman JA, Kiringoda R, Song D, Oldfield EH. Pituitary stalk hemangioblastomas in von Hippel-Lindau disease. J Neurosurg. 2009;110:350–3. [PMC free article: PMC2770699] [PubMed: 18834262]
  67. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH. von Hippel-Lindau disease. Lancet. 2003;361:2059–67. [PubMed: 12814730]
  68. Madhusudan S, Deplanque G, Braybrooke JP, Cattell E, Taylor M, Price P, Tsaloumas MD, Moore N, Huson SM, Adams C, Frith P, Scigalla P, Harris AL. Antiangiogenic therapy for von Hippel-Lindau disease. JAMA. 2004;291:943–4. [PubMed: 14982909]
  69. Maher ER, Iselius L, Yates JR, Littler M, Benjamin C, Harris R, Sampson J, Williams A, Ferguson-Smith MA, Morton N. Von Hippel-Lindau disease: a genetic study. J Med Genet. 1991;28:443–7. [PMC free article: PMC1016952] [PubMed: 1895313]
  70. Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19:617–23. [PMC free article: PMC3110036] [PubMed: 21386872]
  71. Maher ER, Yates RJ, Harries R, Benjamin R, Moorre AT, Ferguson-Smith MA. Clinical features and natural history of von Hippel-Lindau disease. Q J Med. 1990;77:1151–63. [PubMed: 2274658]
  72. Maranchie JK, Afonso A, Albert PS, Kalyandrug S, Phillips JL, Zhou S, Peterson J, Ghadimi BM, Hurley K, Riss J, Vasselli JR, Ried T, Zbar B, Choyke P, Walther MM, Klausner RD, Linehan WM. Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location. Hum Mutat. 2004;23:40–6. [PubMed: 14695531]
  73. Marcos HB, Libutti SK, Alexander HR, Lubensky IA, Bartlett DL, Walther MM, Linehan WM, Glenn GM, Choyke PL. Neuroendocrine tumors of the pancreas in von Hippel-Lindau disease: spectrum of appearances at CT and MR imaging with histopathologic comparison. Radiology. 2002;225:751–8. [PubMed: 12461257]
  74. McNeill A, Rattenberry E, Barber R, Killick P, MacDonald F, Maher ER. Genotype-phenotype correlations in VHL exon deletions. Am J Med Genet A. 2009;149A:2147–51. [PubMed: 19764026]
  75. Molino D, Sepe J, Anastasio P, De Santo NG. The history of von Hippel-Lindau disease. J Nephrol. 2006;19 Suppl 10:S119–23. [PubMed: 16874724]
  76. Murgia A, Martella M, Vinanzi C, Polli R, Perilongo G, Opocher G. Somatic mosaicism in von Hippel-Lindau Disease. Hum Mutat. 2000;15:114. [PubMed: 10612832]
  77. Muzumdar DP, Goel A, Fattepurkar S, Goel N. Endolymphatic sac carcinoma of the right petrous bone in Von Hippel-Lindau disease. J Clin Neurosci. 2006;13:471–4. [PubMed: 16678727]
  78. Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C, Eng C. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459–66. [PubMed: 12000816]
  79. Neumann HP, Eng C. The approach to the patient with paraganglioma. J Clin Endocrinol Metab. 2009;94:2677–83. [PMC free article: PMC2730863] [PubMed: 19657044]
  80. Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C., European-American Paraganglioma Study Group. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004;292:943–51. [PubMed: 15328326]
  81. Neumann HP, Sullivan M, Winter A, Malinoc A, Hoffmann MM, Boedeker CC, Bertz H, Walz MK, Moeller LC, Schmid KW, Eng C. Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites. J Clin Endocrinol Metab. 2011;96:E1279–82. [PubMed: 21613359]
  82. Nordstrom-O'Brien M, van der Luijt RB, van Rooijen E, van den Ouweland AM, Majoor-Krakauer DF, Lolkema MP, van Brussel A, Voest EE, Giles RH. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010;31:521–37. [PubMed: 20151405]
  83. Oldfield EH. Editorial: Management of hemangioblastomas in patients with von Hippel-Lindau disease: stereotactic radiosurgery compared to surgical excision. J Neurosurg. 2015;122:1466–8. [PubMed: 25816089]
  84. Pastore Y, Jedlickova K, Guan Y, Liu E, Fahner J, Hasle H, Prchal JF, Prchal JT. Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia. Am J Hum Genet. 2003;73:412–9. [PMC free article: PMC1180379] [PubMed: 12844285]
  85. Priesemann M, Davies KM, Perry LA, Drake WM, Chew SL, Monson JP, Savage MO, Johnston LB. Benefits of screening in von Hippel-Lindau disease--comparison of morbidity associated with initial tumours in affected parents and children. Horm Res. 2006;66:1–5. [PubMed: 16651847]
  86. Raja D, Benz MS, Murray TG, Escalona-Benz EM, Markoe A. Salvage external beam radiotherapy of retinal capillary hemangiomas secondary to von Hippel-Lindau disease: visual and anatomic outcomes. Ophthalmology. 2004;111:150–3. [PubMed: 14711727]
  87. Rechitsky S, Verlinsky O, Chistokhina A, Sharapova T, Ozen S, Masciangelo C, Kuliev A, Verlinsky Y. Preimplantation genetic diagnosis for cancer predisposition. Reprod Biomed Online. 2002;5:148–55. [PubMed: 12419039]
  88. Roberts AM, Ohh M. Beyond the hypoxia-inducible factor-centric tumour suppressor model of von Hippel-Lindau. Curr Opin Oncol. 2008;20:83–9. [PubMed: 18043261]
  89. Rodriguez JM, Balsalobre M, Ponce JL, Ríos A, Torregrosa NM, Tebar J, Parrilla P. Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World J Surg. 2008 Nov;32(11):2520–6. [PubMed: 18795243]
  90. Sansó G, Rudaz MC, Levin G, Barontini M. Familial isolated pheochromocytoma presenting a new mutation in the von Hippel-Lindau gene. Am J Hypertens. 2004 Dec;17(12 Pt 1):1107–11. [PubMed: 15607616]
  91. Santarpia L, Sarlis NJ, Santarpia M, Sherman SI, Trimarchi F, Benvenga S. Mosaicism in von Hippel-Lindau disease: an event important to recognize. J Cell Mol Med. 2007;11:1408–15. [PMC free article: PMC4401302] [PubMed: 18205710]
  92. Sardi I, Sanzo M, Giordano F, Buccoliero AM, Mussa F, Aricò M, Genitori L. Monotherapy with thalidomide for treatment of spinal cord hemangioblastomas in a patient with von Hippel-Lindau disease. Pediatr Blood Cancer. 2009;53:464–7. [PubMed: 19415739]
  93. Schimke RN, Collins DL, Rothberg PG. Functioning carotid paraganglioma in the von Hippel-Lindau syndrome. Am J Med Genet. 1998;80:533–4. [letter] [PubMed: 9880225]
  94. Sgambati MT, Stolle C, Choyke PL, Walther MM, Zbar B, Linehan WM, Glenn GM. Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. Am J Hum Genet. 2000;66:84–91. [PMC free article: PMC1288351] [PubMed: 10631138]
  95. Shingleton WB, Sewell PE Jr. Percutaneous renal cryoablation of renal tumors in patients with von Hippel-Lindau disease. J Urol. 2002;167:1268–70. [PubMed: 11832711]
  96. Simone CB, Lonser RR, Ondos J, Oldfield EH, Camphausen K, Simone NL. Infratentorial craniospinal irradiation for von Hippel-Lindau: a retrospective study supporting a new treatment for patients with CNS hemangioblastomas. Neuro Oncol. 2011;13:1030–36. [PMC free article: PMC3158017] [PubMed: 21798886]
  97. Simpson JL, Carson SA, Cisneros P. Preimplantation genetic diagnosis (PGD) for heritable neoplasia. J Natl Cancer Inst Monogr. 2005;34:87–90. [PubMed: 15784832]
  98. Stebbins CE, Kaelin WG Jr, Pavletich NP. Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science. 1999;284:455–61. [PubMed: 10205047]
  99. Stolle C, Glenn G, Zbar B, Humphrey JS, Choyke P, Walther M, Pack S, Hurley K, Andrey C, Klausner R, Linehan WM. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat. 1998;12:417–23. [PubMed: 9829911]
  100. Trapani I, Colella P, Sommella A, Iodice C, Cesi G, de Simone S, Marrocco E, Rossi S, Giunti M, Palfi A, Farrar GJ, Polishchuk R, Auricchio A. Effective delivery of large genes to the retina by dual AAV vectors. EMBO Mol Med. 2014;6:194–211. [PMC free article: PMC3927955] [PubMed: 24150896]
  101. Volkin D, Yerram N, Ahmed F, Lankford D, Baccala A, Gupta GN, Hoang A, Nix J, Metwalli AR, Lang DM, Bratslavsky G, Linehan WM, Pinto PA. Partial adrenalectomy minimizes the need for long-term hormone replacement in pediatric patients with pheochromocytoma and von Hippel-Lindau syndrome. J Pediatr Surg. 2012;47:2077–82. [PMC free article: PMC3846393] [PubMed: 23164001]
  102. Wanebo JE, Lonser RR, Glenn GM, Oldfield EH. The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg. 2003;98:82–94. [PubMed: 12546356]
  103. Webster AR, Maher ER, Moore AT. Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation. Arch Ophthalmol. 1999;117:371–8. [PubMed: 10088816]
  104. Weirich G, Klein B, Wohl T, Engelhardt D, Brauch H. VHL2C phenotype in a German von Hippel-Lindau family with concurrent VHL germline mutations P81S and L188V. J Clin Endocrinol Metab. 2002;87:5241–6. [PubMed: 12414898]
  105. Wilding A, Ingham SL, Lalloo F, Clancy T, Huson SM, Moran A, Evans DG. Life expectancy in hereditary cancer predisposing diseases: an observational study. J Med Genet. 2012;49:264–9. [PubMed: 22362873]
  106. Wilschanski M, Lovell S, Thorne N, Lea WA, Maloney DJ, Shen M, Rai G, Battaile KP, Thomas CJ, Simeonov A, Hanzlik RP, Inglese J. Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis. Eur Respir J. 2011;38:59–69. [PubMed: 21233271]
  107. Wong WT, Liang KJ, Hammel K, Coleman HR, Chew EY. Intravitreal ranibizumab therapy for retinal capillary hemangioblastoma related to von Hippel-Lindau disease. Ophthalmology. 2008;115:1957–64. [PMC free article: PMC3034164] [PubMed: 18789534]
  108. Wu P, Zhang N, Wang X, Li T, Ning X, Bu D, Gong K. Mosaicism in von Hippel-Lindau disease with severe renal manifestations. Clin Genet. 2013;84:581–4. [PubMed: 23384228]
  109. Yao L, Schiavi F, Cascon A, Qin Y, Inglada-Pérez L, King EE, Toledo RA, Ercolino T, Rapizzi E, Ricketts CJ, Mori L, Giacchè M, Mendola A, Taschin E, Boaretto F, Loli P, Iacobone M, Rossi GP, Biondi B, Lima-Junior JV, Kater CE, Bex M, Vikkula M, Grossman AB, Gruber SB, Barontini M, Persu A, Castellano M, Toledo SP, Maher ER, Mannelli M, Opocher G, Robledo M, Dahia PL. Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA. 2010 Dec 15;304(23):2611–9. [PubMed: 21156949]
  110. Ye DY, Bakhtian KD, Asthagiri AR, Lonser RR. Effect of pregnancy on hemangioblastoma development and progression in von Hippel-Lindau disease. J Neurosurg. 2012;117:818–24. [PubMed: 22937928]
  111. Young EE, Castle SM, Gorbatiy V, Leveillee RJ. Comparison of safety, renal function outcomes and efficacy of laparoscopic and percutaneous radio frequency ablation of renal masses. J Urol. 2012;187:1177–82. [PubMed: 22357170]

Suggested Reading

  1. Capodano AM, Richard S. Von-Hippel Lindau. Atlas of Genetics and Cytogenetics Oncology and Haematology. Available online. 2001. Accessed 8-4-15.
  2. Kruger M, Chan-Smutko G, Doyle C, Eckerman A. The VHL Handbook - Kids’ Edition. VHL Family Alliance. Available online. 2009. Accessed 8-4-15.
  3. Linehan WM, Zbar B, Klausner DR. Renal carcinoma. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 41. New York, NY: McGraw-Hill. Available online. Accessed 8-4-15.
  4. Woodward ER, Maher ER. Von Hippel-Lindau disease and endocrine tumour susceptibility. Endocr Relat Cancer. 2006;13:415–25. [PubMed: 16728571]

Chapter Notes

Author History

Debra L Collins, MS; University of Kansas Medical Center (2000-2012)
Carlijn Frantzen, MD (2012-present)
Timothy Klasson, BSc (2015-present)
Rachel Giles, PhD (2012-present)
Thera P Links, MD, PhD (2012-present)
R Neil Schimke, MD; University of Kansas Medical Center (2000-2012)
Catherine A Stolle, PhD; The Children’s Hospital of Philadelphia (2000-2012)

Revision History

  • 6 August 2015 (me) Comprehensive update posted live
  • 21 June 2012 (me) Comprehensive update posted live
  • 22 December 2009 (me) Comprehensive update posted live
  • 20 March 2007 (me) Comprehensive update posted to live Web site
  • 1 December 2004 (me) Comprehensive update posted to live Web site
  • 14 November 2002 (tk,cg) Comprehensive update posted to live Web site
  • 17 May 2000 (me) Review posted to live Web site
  • 17 September 1999 (rns) Original submission
Copyright © 1993-2015, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1463PMID: 20301636
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...