Disease characteristics. Von Hippel-Lindau syndrome (VHL syndrome) is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma; and endolymphatic sac tumors. Cerebellar hemangioblastomas may be associated with headache, vomiting, and gait disturbances or ataxia. Retinal hemangioblastomas may be the initial manifestation of VHL syndrome and can cause vision loss. Renal cell carcinoma occurs in about 40% of individuals with VHL and is the leading cause of mortality. Pheochromocytomas can be asymptomatic but may cause sustained or episodic hypertension. Endolymphatic sac tumors can cause hearing loss of varying severity, which can be a presenting symptom.
Diagnosis/testing. The diagnosis of VHL syndrome is suspected in individuals with characteristic lesions including hemangioblastomas, renal cysts and renal cell carcinoma, pheochromocytoma, and endolymphatic sac tumors. VHL is the onlyknown to be associated with VHL syndrome. of the VHL detects mutations in nearly 100% of individuals. Such testing is clinically available.
Management. Treatment of manifestations: intervention for most CNS lesions; remove spinal lesions completely; 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; consider surgical removal of endolymphatic sac tumors (particularly small tumors in order to preserve hearing and vestibular function). Prevention of secondary complications: early detection and removal of tumors to prevent/minimize secondary deficits such as hearing loss, vision loss, and neurologic symptoms. Surveillance: for individuals with known VHL syndrome or known to have a VHLand at-risk relatives with unknown genetic status: annual ophthalmologic examination, beginning before age five years; annual blood pressure monitoring and measurement of urinary catecholamine metabolites beginning at age five years in families with a high incidence of pheochromocytoma; annual abdominal ultrasound examination beginning at age 16 years with evaluation of suspicious lesions by CT scan or MRI; audiologic evaluation if hearing deficits are suspected; T1-weighted MRI of the temporal bone if hearing loss is detected. Testing of relatives at risk: If the in a family is known, can be used to clarify the genetic status of at-risk family members to eliminate the need for costly surveillance of family members who have not inherited the .
. VHL syndrome is inherited in an manner. Approximately 80% of individuals with VHL syndrome have an parent and about 20% have VHL syndrome as the result of a de novo . Parental 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 . Prenatal testing for pregnancies at risk is available if the has been identified in a family member.
The clinical diagnosis of von Hippel-Lindau syndrome (VHL syndrome) is established in:
A(i.e., an individual with no known of VHL syndrome) presenting with two or more characteristic lesions (e.g., two or more hemangioblastomas of the retina or brain or a single hemangioblastoma in association with a visceral manifestation such as kidney or pancreatic cysts; renal cell carcinoma; adrenal or extra-adrenal pheochromocytomas, and, less commonly, endolymphatic sac tumors, papillary cystadenomas of the epididymis or broad ligament, or neuroendocrine tumors of the pancreas);
An individual with a positiveof VHL syndrome in whom one or more of the following disease manifestations is present: retinal angioma, spinal or cerebellar hemangioblastoma, pheochromocytoma, multiple pancreatic cysts, epididymal or broad ligament cystadenomas, multiple renal cysts, or renal cell carcinoma before age 60 years.
The following tests are used to establish the diagnosis and determine the extent of clinical manifestations:
CT scan or MRI to establish the presence of:
Pheochromocytomas that exhibit high signal intensity on T2-weighted MRI, which may help differentiate them from adrenal cortical nodules
Endolymphatic sac tumors identified with high signal intensity with T1 imaging on MRI as a mass on the posterior wall of the petrous part of the temporal bone
Ultrasound examination for evaluation of the epididymis and broad ligament, and for less expensiveof the kidneys
Radioiodine-labeled MIBG for the evaluation of suspected extra-adrenal tumors
18F DOPA whole-body PET, which shows promise as a sensitive and specific method for detection of pheochromocytomas [Hoegerle et al 2002]
Measurement of urinary catecholamine metabolites (VMA, metanephrine, and total catecholamine) to detect elevations that may suggest pheochromocytoma even in the absence of hypertension
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in theby either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
. VHL is the only known to be associated with VHL syndrome.
: Clinical uses
Preimplantation genetic diagnosis
: Clinical methods
Table 1 summarizes for this disorder.
|Test Method||Mutations Detected||Detection Frequency 1||Test Availability|
|VHL sequence variants||~72%||Clinical|
|analysis||VHL partial or complete||~28%|
1. Proportion ofindividuals with a (s) as classified by / , , population group, genetic mechanism, and/or test method
Interpretation of test results. For issues to consider in interpretation of here.results, click
Since the detection rate for VHLmutations is nearly 100%, molecular testing may also be used to evaluate individuals with a single VHL-associated tumor and a negative of the disease.
For individuals with manifestations of VHL syndrome who do not meet strict diagnostic criteria and who do not have a detectable VHL Sgambati et al 2000]. In some instances, of the offspring of such individuals reveals a VHL ., for a de novoVHL should be considered [
Chuvash polycythemia. Individuals with Chuvash polycythemia, an Ang et al 2002]. Other individuals outside the mid-Volga region with polycythemia, some as compound heterozygotes for other VHL mutations, have been found to harbor the 598C>T [Pastore et al 2003]. The Chuvash has subsequently been found in individuals of diverse ethnic backgrounds. Mutations in the VHL may be responsible for as much as 17% of erythrocytosis; suggests that the 598C>T arose independently in at least two populations [Cario et al 2005]. VHL analysis is indicated in all persons with erythrocytosis regardless of ethnicity.disorder endemic to the mid-Volga region in central Russia, have elevated erythropoietin levels, and most are homozygous for a 598C>T (Arg200Trp) in the VHL [
Although thrombosis and/or hemorrhage has occurred in many, none of the Gordeuk et al 2004].individuals or their heterozygous relatives thus far described have developed VHL-related tumors [
Somatic mutations. Acquired mutations in the VHL Iliopoulos 2001] without other associated tumors characteristic of the heritable disease.may give rise to VHL-type tumors (i.e., clear cell RCC, pheochromocytoma) [
Von Hippel-Lindau syndrome (VHL syndrome) is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and renal cell carcinoma; pheochromocytoma; and endolymphatic sac tumors. 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.
Hemangioblastoma. CNS hemangioblastoma is the prototypic lesion of VHL syndrome [Catapano et al 2005, Glasker 2005]. Roughly 80% develop in the brain and 20% in the spinal cord. Within the brain the vast majority are infratentorial, mainly in the cerebellar hemispheres. 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].
Clinical symptoms depend upon 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 are generally slow growing, but on occasion include rapidly enlarging cysts that produce hydrocephaly with papilledema. Spinal hemangioblastomas usually present with pain, but sensory and motor loss may develop with cord compression. Most symptom-producing spinal hemangioblastomas are associated with syringomyelia [Wanebo et al 2003].
Some hemangioblastomas are not symptomatic and are discovered only with MRI. CNS hemangioblastoma has even been identified on fetal ultrasound examination [Diguet et al 2002].
Retinal hemangioblastoma. These retinal lesions, sometimes called retinal angiomas, are histologically identical to CNS hemangioblastomas. They may be the initial manifestations of VHL syndrome. About 70% of 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 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.individuals are identified as having retinal angiomas [
The number of retinal angiomas does not appear to increase with age, but the probability of vision loss increases with age [Kreusel et al 2006].
Tests of retinal function may be abnormal even in the absence of retinal angiomas [Lubinski et al 2003].
Renal lesions. Multiple renal cysts are common in VHL syndrome.
Renal cell carcinoma (RCC), specifically of the clear cell type developing either within a cyst or in the surrounding parenchyma, occurs in about 40% ofindividuals and is a leading cause of mortality in VHL syndrome.
Pheochromocytoma. 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, but may present anywhere along the sympathetic axis in the abdomen or thorax (paragangliomas) [Bender et al 1997] or head and neck (chemodectomas) [Schimke et al 1998]. They are normally greater than 2 cm in size.
Pheochromocytomas are usually benign, but malignant behavior has been reported [Chen et al 2001].
Pancreatic lesions. Most pancreatic lesions are simple cysts and are frequently multiple. They rarely cause endocrine or exocrine insufficiency unless extensive. Occasionally, cysts in the head of the pancreas cause biliary obstruction.
Rarely, neuroendocrine tumors of the pancreas develop. They are usually not hormonally active and are slow growing, but more malignant behavior has been observed, particularly in tumors greater than 3 cm [Marcos et al 2002].
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 [Manski et al 1997]. Large tumors can involve other cranial nerves. Endolymphatic sac tumors are seen in approximately 10% of individuals with VHL syndrome, 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].
Epididymal tumors. 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.
Four classic VHL disease phenotypes have been described based on the likelihood of pheochromocytoma or renal cell carcinoma [Zbar et al 1996].
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 is characterized by a high risk for pheochromocytoma. Individuals with VHL type 2 almost invariably have a Zbar et al 1996, Weirich et al 2002, Sanso et al 2004, Abbott et al 2006, Knauth et al 2006].. Some missense mutations seem to correlate with a specific type 2 VHL [
VHL type 2 is further subdivided:
Type 2A, characterized by a low risk of renal cell carcinoma;
Type 2B, carrying a high risk of renal carcinoma; and
Type 2C, carrying a risk for pheochromocytoma only.
More recently, two groups reported a reduced risk for renal cell carcinoma in individuals with a complete Cybulski et al 2002, Maranchie et al 2004]. This group of individuals defines a new VHL characterized by a low risk for both renal cell carcinoma and pheochromocytoma.of the VHL [
VHL mutations are highly penetrant. Almost all individuals who have ain the VHL express disease-related symptoms by age 65 years.
is not observed with VHL syndrome.
Obsolete terms for VHL syndrome include: angiophakomatosis retinae et cerebelli, Molino et al 2006].cerebello-retinal angiomatosis, cerebelloretinal hemangioblastomatosis, Hippel disease, Hippel-Lindau syndrome, Lindau disease, and retinocerebellar angiomatosis [
The incidence of VHL syndrome is thought to be about one in 36,000 births per year with an estimated de novo Maher et al 1991].rate of 4.4x10-6 gametes per generation [
For current information on availability of genetic testing for disorders included in this section, see. —ED.
The level of Neumann et al 2002].detection obtained by of the VHL makes it possible to effectively rule out von Hippel-Lindau syndrome (VHL syndrome) with a high degree of certainty in individuals with hemangioblastoma, retinal angioma, or clear cell renal cell carcinoma, who have no detectable VHL disease-causing ; for a VHL still needs to be considered in such individuals. A younger individual, especially one with multiple lesions, is more likely to have a VHL than an older individual with a single lesion [
Since pheochromocytoma is part of the VHL syndrome spectrum and may occur as the exclusive manifestation of VHL syndrome (type 2C), individuals with a Richards et al 1998]. VHL mutations are rare in simplex cases of unilateral pheochromocytoma (i.e., an individual with no of VHL syndrome), unless the individual is younger than age 20 years. Exceptions are those individuals with a that is more consistent with paragangliomas of the head and neck, which are caused by mutations in various subunits of the encoding succinic dehydrogenase (SDH) [Maher & Eng 2002, Bryant et al 2003], or those individuals who have features of other heritable diseases associated with pheochromocytoma such as multiple endocrine neoplasia type 2A or 2B or neurofibromatosis type 1 [Neumann et al 2002].of these tumors, or those in whom the disease is bilateral or multifocal, should be offered for VHL mutations [
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is characterized by cutaneous leiomyomata. females usually develop uterine leiomyomata (fibroids) at an early age. Predisposition to renal tumors occurs in a subset of families. Most renal tumors are classified as 'type 2' papillary renal cancer, displaying distinct papillary architecture and characteristic histopathology. Other types of renal tumors include a spectrum ranging from tubulo-papillary renal cell carcinomas to collecting-duct renal cell carcinomas. Inheritance is . Heterozygous defects in the FH, encoding fumarate hyphatase, are causative [Lehtonen et al 2006].
Birt-Hogg-Dubé (BHD) syndrome is characterized by cutaneous findings (fibrofolliculomas, trichodiscomas, and acrochordons). Pulmonary cysts/history of pneumothorax, and various types of renal tumors are frequently found in persons with BHD syndrome and/or their families. The most common tumors are a hybrid of oncocytoma and chromophobe histologic cell types, so-called oncocytic hybrid tumor (67%), chromophobe renal cell carcinoma (23%), and renal oncocytoma (3%). Only renal oncocytoma is considered a benign tumor. Other types of renal tumors reported in lower frequency include clear cell renal cell carcinoma and papillary renal carcinoma. Mutations in FLCN (BHD) are causative. Inheritance is .
Individuals with RCC and no other evidence of VHL syndrome are unlikely to have Richards et al 1998].VHL mutations [
To establish the extent of disease in an individual diagnosed with von Hippel-Lindau syndrome (VHL syndrome):
Neurologic history and physical examination for evidence of CNS or peripheral nerve hemangioblastomatosis
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 in those families with a high incidence of 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.
A baseline MRI of the brain and spine in young adulthood has been suggested by some; however, this procedure is expensive and the overall value in an asymptomatic individual remains questionable.
Nervous system hemangioblastoma
Some advocate early surgical removal of both symptomatic and asymptomatic CNS lesions, while others follow asymptomatic lesions with yearly imaging studies. Most CNS lesions eventually require intervention.
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. While this technique may reduce the size of the solid tumor, it does not seem to prevent cyst formation. Overall operative mortality is roughly 10%, with higher figures for brain stem tumors.
It is recommended that spinal lesions be completely removed. Paraplegia is the major complication following removal of spinal tumors.
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 upon 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. Depending on the size and location of the tumor, nephron-sparing or partial nephrectomy may be possible without compromising survival [Grubb et al 2005].
Cryoablation is being increasingly used for small lesions or in individuals at high risk for a surgical procedure [Shingleton & Sewell 2002].
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 should be surgically removed. Laparascopic approaches have been shown to be effective.
Preoperative treatment with alpha-adrenergic blockade for seven to ten days is appropriate even in individuals with no known hypertension.
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.
Early detection through surveillance and removal of tumors may prevent or minimize deficits such as hearing loss, vision loss, and neurologic symptoms.
Individuals with known VHL syndrome, individuals without clinical manifestations but known to have a VHL, and at-risk relatives who have not undergone need regular clinical monitoring by a physician or medical team familiar with the spectrum of VHL syndrome.
Monitoring includes the following:
Annual ophthalmologic Kreusel et al 2006], preferably beginning before age five years [
Annual blood pressure monitoring supplemented by measurement of urinary catecholamine metabolites beginning at age five years in those families with a high incidence of pheochromocytoma
Annual abdominal ultrasound examination beginning at 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.
Audiologic evaluation of individuals with any recognized hearing deficit, followed by T1-weighted MRI of the temporal bone if abnormalities are found [Kim et al 2005]
Use of at-risk family members improves diagnostic certainty and reduces the need for costly procedures in those at-risk family members who have not inherited the [Priesemann et al 2006]. The American Society of Clinical Oncologists (ASCO) identifies VHL syndrome as a Group 1 disorder, i.e., a hereditary syndrome for which genetic testing is considered part of the standard management for at-risk family members [ASCO 2003].for early identification of
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.
See Genetic Counseling for issues related to testing of at-risk relatives for purposes.
Certain VHL mutations fail to down-regulate HIFα, leading to overexpression of vascular endothelial growth factor (VEGF). A VEGF receptor inhibitor, SU5416, has been used with some success, particularly in individuals with retinal hemangioblastomas who have either failed local therapy or whose lesions are not amenable to local therapy [Aiello et al 2002, Girmens et al 2003]. Stabilization of some, but not all, CNS hemangioblastomas has also been demonstrated [Madhusudan et al 2004]. However, paradoxical secondary polycythemia has occurred in some individuals with VHL syndrome in whom this drug has been used [Richard et al 2002].
Another antiangiogenic drug, halofuginone, has been shown to inhibit growth of a VHL-related pheochromocytoma transplanted in mice [Gross et al 2003]. This drug may have some utility in the rare, unresectable malignant pheochromocytomas, but simple surgical excision is clearly preferable for the usual benign tumors.
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Genetics clinics are a source of information for individuals and families regarding the natural history, treatment,, and genetic risks to other family members as well as information about available consumer-oriented resources. See the .
Support groups have been established for individuals and families to provide information, support, and contact with other Resources section may include disease-specific and/or umbrella support organizations.individuals. The
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 and the use of 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. To find a genetics or clinic, see the .
Von Hippel-Lindau syndrome (VHL syndrome) is inherited in anmanner.
Parents of a
About 80% of individuals diagnosed with VHL syndrome have anparent.
De novo mutations of the VHLare estimated to occur in about 20% of probands.
Recommendations for the evaluation of parents of awith an apparent de novo include if the VHL in the is known. If the disease-causing VHL in the is not known, ophthalmologic and abdominal ultrasound evaluation, at a minimum, should be offered to both parents.
Note: Themay appear to be negative because of failure to recognize the disorder in family members, reduced , early death of the parent before the onset of symptoms, or late onset of the disease in the parent. If the parent is the individual in whom the first occurred, (s)he may have for the and may be mildly/minimally .
Sibs of a
The risk of VHL syndrome to sibs depends upon the genetic status of the parents.
If a parent of ais clinically or has a disease-causing VHL , the sibs of the are at 50% risk of inheriting the altered .
If neither parent has the disease-causing VHLidentified in the , the sibs have a small risk of VHL syndrome because of the possibility of in one parent.
Offspring of a. Each offspring of an individual has a 50% risk of inheriting the mutant VHL ; the degree of clinical severity is not predictable.
Other family members. The risk to other family members depends upon their biological relationship to thefamily member and can be determined by analysis and/or .
Genetic cancerand counseling. For comprehensive descriptions of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer with or without , see:
(part of PDQ®, National Cancer Institute)
Testing at-risk asymptomatic family members. surveillance. Interpretation of molecular genetic test results is most accurate when a disease-causing has been identified in an family member. Those who have the require regular surveillance, whereas family members who have not inherited the and their offspring need have no future concern.of at-risk family members is appropriate in order to determine the need for continued clinical
Because early detection of at-risk individuals affects medical management, testing of asymptomatic individuals during childhood is beneficial [ASCO 2003]. As ophthalmologic for those at risk for VHL syndrome begins as early as possible, certainly before age five years, may be considered in young children. 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 initiatingin order to avoid unnecessary procedures in a child who has not inherited the altered . 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 use offor 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 less straightforward. Such test results need to be interpreted with caution. A positive test result signals the presence of a VHL in the at-risk family member and indicates that the same method can be used to assess the genetic status of other at-risk family members. However, a negative test for a VHL under such circumstances suggests one of the following possibilities:
The at-risk family member has not inherited a VHL;
TheVHL may not be detectable by the assays used; or
The diagnosis of VHL syndrome in thefamily member is questionable.
In this situation, the presumably at-risk family member has a small, but finite, residual risk of having inherited a disease-causing(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 family member, the relationship of the at-risk individual to the family member, the perceived risk of an undetected VHL (or other) , and the potential need for some form of continued clinical surveillance.
Other issues to consider. It is recommended that physicians ordering VHL familial adenomatous polyposis, an colon cancer syndrome, 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.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
Considerations in families with an apparent de novo. When neither parent of a with an condition has the or clinical evidence of the disorder, it is likely that the has a de novo . However, possible non-medical explanations including or maternity (i.e., with assisted reproduction) or undisclosed adoption could also be carefully explored.
Family planning. The optimal time for determination of genetic risk andregarding prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
. is the storage of (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking , particularly in situations in which the of currently available testing is less than 100%. See for a list of laboratories offering this service.
for pregnancies at 50% risk is possible by analysis of extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing of an family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for conditions such as VHL syndrome that do not affect intellect and have some treatment available are not common. 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, careful 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 has been identified in an family member. For laboratories offering PGD, see .
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
|VHL||3p26-p25||Von Hippel-Lindau disease tumor suppressor|
Data are compiled from the following standard references:from ; chromosomal , , , complementation group from ; protein name from .
|VON HIPPEL-LINDAU SYNDROME; VHL|
For a description of the genomic databases listed, click here.
Normal allelic variants: The VHL 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 from an internal methionine at position 54. Both protein appear to be functional., which consists of three exons spanning about 10 kb of genomic , is highly conserved among worms, flies, rodents, and humans (reviewed in
Pathologic allelic variants: Over 300 Beroud et al 1998]. They consist of partial and complete deletions and frameshift, nonsense, missense, and splice site mutations. The mutations occur in all three exons, with only a handful of mutations found in four or more families (i.e., delPhe76, Asn78Ser, Arg161X, Arg167Gln, Arg167Trp, Leu178Pro). 167 is a "hot spot." A database of mutations in the VHL is maintained on the .mutations have been identified in families with von Hippel-Lindau syndrome (VHL syndrome) [
Normal Kaelin 2002). The role of pVHL in the regulation of hypoxia-inducible genes through the targeted ubiquitinylation and degradation of HIF1α has been elucidated, leading to a model of how disruption of the VHL results in renal cell carcinoma and the production of highly vascularized tumors.: Von Hippel-Lindau disease tumor suppressor protein (pVHL) has been implicated in a variety of functions including transcriptional regulation, post-transcriptional expression, protein folding, extracellular matrix formation, and ubiquitinylation (reviewed in
Normal pVHL binds to elongin C, which forms a complex with elongin B and cullin-2 (CUL-2). 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 two specific proline residues by a member of the EGLN family of prolyl hydroxylase enzymes.
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 Kaelin 2002].of a variety of hypoxia-inducible genes (i.e., VEGF, EPO, TGF α, PDGF β). Likewise, when pVHL is absent or mutated, HIF1α subunits accumulate, resulting in cell proliferation and the neovascularization of tumors characteristic of VHL disease [
Abnormal Stebbins et al 1999]. Missense mutations that result in VHL syndrome type 1 are predicted to destabilize packing of the alpha-helical domains, decrease the stability of the alpha-beta interface, interfere with binding of elongin C and HIF1α, or disrupt hydrophobic core residues, thereby leading to loss of protein function.: Mutations in the VHL either prevent its expression (i.e., deletions, and frameshifts, nonsense mutations, splice site mutations) or lead to the expression of an abnormal protein (i.e., missense mutations). The effect of missense mutations may be deduced from the three-dimensional structure of the protein [
Missense mutations that cause VHL syndrome type 2 include those not predicted to unravel the protein structure completely. Most type 2 mutations map either to residues that contact elongin C or to solvent-exposed residues that make up a second protein-binding site. Missense mutations that lead to pheochromocytoma with a low (or no) risk of RCC (types 2A and 2C) may encode a VHL protein that retains the ability to ubiquinate (and so down-regulate) HIF1α in the presence of molecular oxygen to a greater degree than mutations that result in VHL syndrome with pheochromocytoma and RCC (type 2B). Alternatively, mutant pVHL may predispose to pheochromocytoma by up-regulating JunB, which antagonizes c-Jun, resulting in an inability to regulate apoptosis which is mediated by c-Jun [Kaelin 2005].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search for the most up-to-date Resources information.—ED.for this disorder and select
National Library of Medicine Genetics Home Reference
NCBI Genes and Disease
VHL Family Alliance
2001 Beacon St Suite 208
Boston MA 02135-7787
Phone: 800-767-4VHL; 617-277-5667
Kidney Cancer Association
1234 Sherman Avenue Suite 203
Evanston IL 60202-1375
Phone: 800-850-9132; 847-332-1051
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