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 plasma or 24-hour urine for fractionated metanephrines; audiology assessment every two to three years; thin-slice MRI with contrast of the internal auditory canal in those with repeat 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 a pregnancy at risk is possible if the pathogenic variant has been identified in a family member.

Suggestive Findings

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

• Retinal angioma, especially in a young individual
• Spinal or cerebellar hemangioblastoma
• Adrenal or extra-adrenal pheochromocytoma
• Renal cell carcinoma, if the individual is younger than 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 clinical features listed below [Lonser et al 2003, Butman et al 2008, Maher et al 2011] and/or by identification of a heterozygous germline pathogenic variant in VHL on molecular genetic testing. Identification of a heterozygous germline pathogenic variant in VHL by 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.

Clinical diagnostic criteria

• 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 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 genetic testing. Approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing, exome array) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of VHL is broad, individuals with the distinctive features described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders associated with an increased risk of tumors are more likely to be diagnosed using genomic testing (see Option 2).

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. One study showed that in adulthood, men have more VHL manifestations compared to women. They also showed that the risk for manifestations was not constant, but varied throughout the affected individual's lifetime [Binderup et al 2016]. Age was the only predictor for the number of involved organs. The sex of the affected individual or type/location of the VHL pathogenic variant were not associated with the number of involved organs [Feletti et al 2016].

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 be a rare manifestation [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 (CNS) 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. CNS hemangioblastomas remain the main cause of death, although VHL-related survival has improved over the years [Binderup et al 2017b].

• 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 does [Kreusel et al 2006].

Renal lesions

• Multiple and bilateral renal cysts are common in individuals with 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 age of the individual [Kwon et al 2014].

Pheochromocytoma may cause sustained or episodic hypertension or may not cause signs/symptoms and is 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 often nonfunctional (i.e., do not secrete catecholamines or other hormones).

Pancreatic lesions

• Pancreatic cysts. Most pancreatic lesions are simple cysts and have no malignant potential. 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 >2.7 cm [Krauss et al 2018]. Tumors are described from an early age, starting from the second decade [Krauss et al 2018, O'Toole et al 2018].

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. More significant hearing loss and larger tumor size at presentation was reported in individuals with endolymphatic sac tumors not related to VHL than in individuals with VHL-related endolymphatic sac tumors [Nevoux et al 2014]. 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. Both tissues are mesonephric in origin and are likely a developmental remnant of somatic VHL loss.

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. Pathogenic truncating or missense 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 pathogenic missense variant. Some pathogenic missense 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). Pathogenic missense variants stratified by multiple in silico computational models found that variants with a high predicted risk of pathogenicity were predictive of pancreatic lesion progression in an NIH patient series [Tirosh et al 2018]. In contrast, genotype did not appear to influence the growth of renal cell carcinomas in individuals with VHL [Farhadi et al 2018].

VHL type 2 is further subdivided:

• Type 2A. Pheochromocytoma, retinal angiomas, and CNS hemangioblastoma; low risk for renal cell carcinoma
• Type 2B. Pheochromocytoma, retinal angiomas, CNS hemangioblastoma, pancreatic cysts, and neuroendocrine tumors; high risk for renal carcinoma
• Type 2C. Risk for pheochromocytomas 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 BRK1 (previously 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].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with von Hippel-Lindau (VHL) syndrome, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

No guidelines exist for the management of VHL lesions.

CNS hemangioblastoma

• Most central nervous system (CNS) hemangioblastomas can be surgically removed completely and safely [Gläsker et al 2013].
• Some advocate early surgical removal of both symptomatic and asymptomatic CNS lesions, while others follow asymptomatic lesions with yearly imaging studies. A recent study of 15 symptomatic individuals with cauda equina hemangioblastomas revealed a worse outcome in only one individual six months after surgery. The other individuals were stable or improved [Mehta et al 2017]. A retrospective study with a mean follow-up time of 21 months confirmed that microsurgical treatment of symptomatic spinal cord hemangioblastomas was safe and effective. Intraoperative fluorescence angiography was helpful in reducing intraoperative bleeding and preventing spinal swelling.
• Surgical intervention of cysts/syrinx in the spinal cord is recommended.
• Preoperative arterial embolization may be indicated, especially for extensive spinal tumors.
• Pathologic findings during intraoperative neurophysiologic monitoring appear to predict worse long-term outcome after microsurgical removal of spinal cord hemangioblastomas [Siller et al 2017].
• Stereotactic therapy is increasingly popular, but there is still a need for prospective studies [Pan et al 2018]. 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. The unpredictable growth pattern makes it difficult to determine when to start stereotactic therapy in order to avoid unnecessary intervention. A recent study with a mean follow up of 54 months in 19 individuals with 34 tumors revealed that 94% of tumors were radiographically stable or showed signs of regression. Local control rates at one, three, and five years were 96%, 92%, and 92%, respectively. Clinically 13 of 16 (81.2%) tumors had symptomatic improvement [Pan et al 2017].
• Similar results were demonstrated for local tumor control after stereotactic therapy: 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 individuals needed steroid therapy and one person died of refractory peritumoral edema. Two individuals required additional surgery.
• Another study showed a recurrence-free survival in six of eight individuals at a mean follow up of 48 months. Two individuals required additional surgery for persisting cerebellar symptoms. One individual showed an increase in cyst volume along with a decrease of the size of the mural nodule [Goyal et al 2016].
• A case study showed complete loss of stromal cells after a standard dose of SRS for hemangioblastoma, indicating the effectiveness of the treatment [Nambu et al 2018].

Retinal hemangioblastoma

• Most ophthalmologists favor prospective treatment of retinal (but not optic nerve) angiomas to avoid blindness, although spontaneous regression has occurred.
• Ultra-widefield fluorescein angiography can be useful in the evaluation and management of retinal hemangioblatoma. This technique appears to detect more hemangioblastomas than ophthalmoscopy and conventional angiography [Chen et al 2018].
• 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]. In individual reports early surgical resection and intravitreal treatment with bevacizumab and propranolol were considered safe and effective [Agarwal et al 2016, van Overdam et al 2017, Karimi et al 2020].
• There is no evidence to support the use of sunitinib for retinal hemangioblastomas.

Renal cell carcinoma

• Early surgery is the best option for renal cell carcinoma, although close monitoring is recommended for lesions <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].
• A recent study reported no complications after 19 radio frequency ablation treatments in individuals with VHL [Allasia et al 2017].
• 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 with VHL syndrome.

Pheochromocytomas

• Pheochromocytomas should be surgically removed. Laparoscopic approaches have been shown to be effective and safe [Dickson et al 2011, Agarwal et al 2012].
• 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.
• Adrenal-sparing surgery could be considered and has been regarded as a successful treatment option. A multinational observational retrospective population-based study of individuals with multiple endocrine neoplasia type 2 showed recurrence in four (3%) of 53 individuals six to 13 years after adrenal-sparing surgery. Forty-seven (57%) of 82 patients did not become steroid dependent [Castinetti et al 2014].
• 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].
• Adrenal-sparing surgery is also therapy of choice in children. In ten individuals with VHL, 18 successful operations were performed. After follow up (median 7.2 years), two individuals developed a new tumor in the ipsilateral adrenal gland [Volkin et al 2012].

Pancreatic cysts and neuroendocrine tumors. Pancreatic cysts are common, rarely influence endocrine function, and have no malignant behavior. Therefore, surgical removal is not generally required [Sharma et al 2017].

Pancreatic neuroendocrine tumors need to be differentiated from cysts and serous cystadenomas. Pancreatic tumors are generally slow growing and are not hormonally active, although they can cause metastatic disease. Surgery should be strongly considered when there is a high risk of metastases, as suggested by one of the following prognostic criteria [Krauss et al 2018]:

• A tumor of ≥2.5 cm
• 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 [Friedman et al 2013]. Friedman et al described two individuals (2/18) with postoperative decreased facial nerve function and three (3/18) individuals with recurrent ELSTs (with a mean follow up of 67 months). Kim et al [2013] studied 31 individuals with VHL with 33 resected ELSTs; 29 individuals 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 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 summarized in Table 3.

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 Alliance has worked extensively with health care professionals to assemble guidelines which are generally accepted throughout the world [VHL Handbook]. Other guidelines originate from Denmark and the Netherlands and may differ. For example: Dutch guidelines recommend screening for ELST only on indication, examination by a primary care physician and assessment of metanephrine levels starting at age ten years, and ophthalmologic examination beginning 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 CNS 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 individuals with VHL can start at age 12 years. For CNS 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 more than 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

Avoid the following:

• Tobacco products, as they are considered a risk factor for kidney cancer
• Chemicals and industrial toxins known to affect VHL-involved organs
• Contact sports 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 [Robson et al 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 in an at-risk family member 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 proband 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. A recent study showed a decrease in new VHL manifestations during pregnancy [Binderup et al 2015]. In another study pregnancy did not correlate with the development of new hemangioblastomas or hemangioblastoma/cyst growth [Ye et al 2012]; the data suggested that 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 proven effective in treating retinal hemangioblastomas in individuals with VHL [Hrisomalos et al 2010]. Stabilization of some (but not all) CNS hemangioblastomas has also been demonstrated [Madhusudan et al 2004].

Sunitib, a tyrosine kinase inhibitor (TKI) that inhibits the action of VEGF receptors, 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 individuals with VHL [Jonasch et al 2011].

Pazopanib showed favorable effects on the clinical condition of individuals with recurrent and rapidly progressive VHL-associated hemangioblastomas [Migliorini et al 2015]. A pilot study to assess the safety and efficacy of another TKI, dovitinib, for the treatment of asymptomatic hemangioblastomas in individuals with VHL resulted in termination of the study after adverse events in all six individuals. Maculopapular rash, diarrhea, and fatigue were most common [Pilié et al 2018]. In a series of 22 individuals with VHL with a total of 311 lesions, good identification of VEGF-producing lesions suggest that (89)Zr-bevacizumab PET could offer a tool to select individuals for anti-VEGF therapy [Oosting et al 2016].

Somatostatin analogs could be of use in the treatment of hemangioblastomas. Nine hemangioblastomas demonstrated expression for at least three somastatin receptor subtypes (1, 2a, 3, 4, or 5). One individual with a symptomatic irresectable suprasellar hemangioblastoma was treated with octreotide long-acting release, which resulted in clinical stability and radiographic response after nine months of treatment [Sizdahkhani et al 2017].

Propranolol could be an efficient treatment to control hemangioblastoma growth in individuals with VHL because of its antiangiogenic effects demonstrated in infantile hemangioma and the hypothetic impact on HIF levels.

Checkpoint inhibitors such as antibodies targeting PD-L1 have shown promise in managing tumor load; however, these treatments have unknown toxicity in individuals 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.

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 [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 I and II 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.

An in vivo study of HIF2a inhibitor in vhl-/- zebrafish showed promising results in suppressing erythrocytosis and abnormal vascular proliferation in the brain and trunk. Furthermore, it promoted erythroid differentiation and decreased the number of early erythroid progenitors circulating in the peripheral blood. Therefore, there is a rationale for performing preclinical and clinical studies in optimized HIF2A inhibitors [Metelo et al 2015].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

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%.
• 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.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are a de novo pathogenic variant in the proband or germline mosaicism in a parent. The incidence of germline mosaicism is as-yet unknown. However, some results suggest that mosaicism contributes more to VHL syndrome than is currently thought.
• 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 clinical/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 have not undergone molecular genetic testing but are clinically unaffected and are at least age 35 years, the risk to the sibs of a proband appears to be low; however; the sibs 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 recurrence risk to sibs is low but greater than that of the general population because of the possibility of parental germline mosaicism. Parental 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 and/or has the VHL pathogenic variant, 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 [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 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/preimplantation genetic 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. 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 from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic alteration/s are unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the VHL pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing (PGT) for VHL syndrome are possible [Dommering et al 2017]. PGT has been successfully used in pregnancies at risk for VHL syndrome [Rechitsky et al 2002, Simpson et al 2005].

Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Published Guidelines / Consensus Statements

• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003. [PubMed: 12692171]
• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2010. [PubMed: 12692171]
• 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 (2013) Von Hippel-Lindau disease (vHL). National clinical guideline for diagnosis and surveillance in Denmark. 3rd edition. [PubMed: 24355456]
• 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]
• 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]
• VHL Alliance. The VHL Handbook. 4 ed. Available for purchase online. 2015. Accessed 10-13-21.

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Author History

Saya Ahmad, BSc (2018-present)
Debra L Collins, MS; University of Kansas Medical Center (2000-2012)
Carlijn Frantzen, MD; University Medical Center Groningen (2012-2018)
Timothy Klasson, BSc; University Medical Center Utrecht (2015-2018)
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)
Rachel S van Leeuwaarde, MD (2018-present)

Revision History

• 6 September 2018 (sw) Comprehensive update posted live
• 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 live
• 1 December 2004 (me) Comprehensive update posted live
• 14 November 2002 (tk,cg) Comprehensive update posted live
• 17 May 2000 (me) Review posted live
• 17 September 1999 (rns) Original submission