Version August 2024
INTRODUCTION — Von Hippel-Lindau (VHL) disease is an inherited, autosomal-dominant syndrome that occurs due to germline pathogenic variants in the VHL gene. VHL disease is characterized by a variety of benign and malignant tumors.
The clinical presentation, diagnosis, and surveillance protocols of VHL disease are discussed here. The molecular biology and pathogenesis and the management of VHL disease are discussed separately.
●(See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)
●(See "Management of von Hippel-Lindau disease".)
EPIDEMIOLOGY
●Prevalence – VHL disease is an inherited, autosomal-dominant syndrome that occurs due to germline pathogenic variants in the VHL gene. VHL, the product of the VHL gene, is a tumor suppressor protein that performs a number of important cellular functions (figure 1). A pathogenic variant in the VHL gene is present in approximately 1 in 36,000 individuals [1-3] and is diagnostic for VHL disease. (See 'Diagnosis of VHL disease' below.)
●Age of onset – For patients with VHL disease, the mean age of initial presentation of any associated tumor is approximately 26 years old [1]. However, the actual age of presentation varies by tumor type (table 1), so patients may present with their first tumor in childhood, adolescence, or adulthood (table 1) [4]. Patients with known VHL disease who undergo surveillance for associated tumors may be diagnosed as early as infancy with some tumors, such as retinal capillary hemangioblastoma. (See 'Surveillance for associated tumors' below.)
All clinical manifestations associated with VHL disease are almost fully penetrant by age 60 [1,5,6]. (See 'Clinical presentation' below.)
CLINICAL PRESENTATION — VHL disease is characterized by the clinical presentation of specific benign and malignant tumors. In patients with VHL, these tumors can present at varying ages and frequencies (table 1), with clinical manifestations that differ according to tumor type. However, most occur in younger individuals (typically under the age of 40), are bilateral and/or multifocal in nature, and generally exhibit indolent growth.
Specific tumors associated with VHL disease include:
●Central nervous system (CNS) hemangioblastomas – (See 'CNS hemangioblastomas' below.)
●Retinal capillary hemangioblastomas (retinal angiomas) – (See 'Retinal capillary hemangioblastomas' below.)
●Clear cell renal cell carcinomas (RCCs) – (See 'Renal cell carcinomas' below.)
●Pheochromocytomas – (See 'Pheochromocytoma' below.)
●Pancreatic cysts and serous cystadenomas; pancreatic neuroendocrine neoplasms – (See 'Pancreatic lesions' below.)
●Endolymphatic sac tumors of the middle ear – (See 'Endolymphatic sac tumors of the middle ear' below.)
●Papillary cystadenomas of the epididymis and broad ligament – (See 'Papillary cystadenomas' below.)
CNS hemangioblastomas — CNS hemangioblastomas (or well-circumscribed, capillary vessel-rich benign neoplasms) are the most common lesions associated with VHL disease, affecting 60 to 84 percent of patients [1,2,7]. The clinical presentation and diagnosis of sporadic hemangioblastomas not associated with VHL disease is discussed separately. (See "Hemangioblastoma", section on 'Clinical manifestations'.)
●Age – VHL disease-associated hemangioblastomas tend to present in the second decade of life (table 1), with a mean age at diagnosis of 29 years and a range of 9 to 78 years [1]. Patients with VHL disease tend to present with hemangioblastoma at a younger age than those with sporadic hemangioblastomas. Surveillance for CNS hemangioblastomas in patients with VHL disease is discussed below. (See 'Surveillance for associated tumors' below.)
●Location – VHL disease-associated hemangioblastomas tend to be multiple and infratentorial. They typically occur in the spinal cord (51 percent), cerebellum (38 percent), and brainstem (10 percent) and are rare in supratentorial regions (2 percent) [1,2,7,8].
●Symptoms – Hemangioblastomas do not invade locally or metastasize. However, they can cause symptoms through pressure on adjacent structures and through hemorrhage, due to either the hemangioblastoma itself or cyst formation around the lesion.
Retinal capillary hemangioblastomas — In patients with VHL disease, the frequency of retinal capillary hemangioblastoma is high (ranging between 49 and 85 percent). Most cases of retinal capillary hemangioblastoma (up to 70 percent) are diagnosed in patients with VHL disease by age 60.
●Age – Patients with VHL disease most commonly present with retinal capillary hemangioblastoma between the ages of 12 and 25 years old (table 1), but some individuals can present as early as infancy. Patients with VHL disease-associated retinal hemangioblastoma are also much younger and more likely to have multiple tumors compared with those with sporadic retinal tumors [9].
Surveillance for retinal capillary hemangioblastoma in the pediatric population is warranted as early diagnosis and treatment can preserve vision. The early age of onset for this tumor is also one of the reasons that genetic testing is performed during infancy for VHL pathogenic variants. (See 'Surveillance for associated tumors' below.)
●Location – VHL disease-associated retinal capillary hemangioblastomas are found more commonly in the peripheral retina (85 percent) and/or less commonly in the juxtapapillary region (15 percent) [10]. They are often multifocal and bilateral.
In an observational study of 890 patients with VHL disease, the overall prevalence of retinal capillary hemangioblastoma in at least one eye was 37 percent (335 patients) [10,11]. Lesions were detected unilaterally and bilaterally in 42 and 58 percent of affected patients, respectively. No correlation was detected between the age, sex, or laterality of involvement. Among the involved eyes, a majority (87 percent) had tumors that could be individually visualized. The tumor count in the periphery averaged 2.5+/-1.8 per eye, with 25 percent of eyes having more than one quadrant of retinal involvement. Patients with VHL missense variants encoding the alpha domain of the protein are more likely to have retinal lesions whereas missense variants encoding the beta-domain result in hemangioblastomas that are more likely to be peripherally located [12]. The prevalence of retinal capillary hemangioblastomas was lowest among those with complete deletion of the VHL gene (15 percent) [11].
●Symptoms – Visual loss from retinal capillary hemangioblastomas is generally caused by exudation from the tumor, causing retinal edema, or by tractional effects, in which glial proliferation on the surface of the tumor induces retinal striae and distortion [13]. In addition, retinal capillary hemangioblastomas can hemorrhage, leading to retinal detachment, glaucoma, and loss of vision. The risk of vision loss increases with age [11].
Renal cell carcinomas — Among patients with VHL disease, approximately two-thirds are at risk for developing multiple kidney cysts and RCC [1,2,14].
●Age – The diagnosis of RCC is rare in a patient with VHL disease prior to age 20, although it can present during the teenage years (table 1) [15,16]. RCC occurs with increasing frequency thereafter. Surveillance for RCC in patients with VHL disease is discussed below. (See 'Surveillance for associated tumors' below.)
In one observational study of 152 patients with VHL disease, the probability of developing RCC by age 60 was estimated at 69 percent [1]. The incidence of RCC is lower in patients with specific pathogenic variants in the VHL gene. (See 'Types of VHL disease' below.)
●Location and association with kidney cysts – RCCs are often multicentric and bilateral and can arise either in conjunction with cysts or de novo from noncystic kidney parenchyma. Although kidney cysts may be benign, they are thought to represent a premalignant lesion. Solid components within otherwise benign-appearing kidney cysts almost always contain RCC [17]. (See "Simple and complex kidney cysts in adults".)
●Histology – Virtually all VHL disease-associated RCCs are clear cell tumors [2]. Histopathologic changes in the kidney parenchyma are widespread and are not limited to kidney cysts [18]. Systematic microscopic analysis identified numerous clear cell abnormalities, which are thought to be precursors for clear cell RCC. Similar clear cell precursors were not seen in the kidney parenchyma from patients with sporadic RCC or from patients without RCC. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Clear cell carcinomas'.)
RCCs of non-clear cell histologies are generally not associated with VHL disease but can be seen in other hereditary kidney cancer syndromes [19,20]. Clear cell papillary RCC in patients with VHL disease have been observed [21,22], but the prevalence of these lesions appears to be low. (See "Hereditary kidney cancer syndromes".)
●Symptoms – VHL disease-associated RCC typically exhibits indolent tumor growth, although some lesions can present with more rapid disease progression. An observational series evaluated 64 patients with VHL disease who had a total of 96 kidney tumors with analyzed germline pathogenic variants. A majority (54 patients) were treated, and the remainder (10 patients) underwent surveillance over a mean follow-up of 55 months [23]. Among the 96 tumors, the mean growth rate was 4.4 mm/year and the mean volume doubling time was 26 months.
Further details on the clinical manifestations and diagnosis of RCC are discussed separately. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma", section on 'Clinical manifestations'.)
Pheochromocytoma — Pheochromocytoma is a catecholamine-secreting tumor that arises from chromaffin cells of the adrenal medulla and the sympathetic ganglia. (See "Clinical presentation and diagnosis of pheochromocytoma".)
Among all patients with VHL disease, the frequency of pheochromocytoma ranges from 10 to 20 percent [1,24,25]. The frequency of pheochromocytoma also varies depending upon the type of VHL disease. (See 'Types of VHL disease' below.)
Pheochromocytoma can also occur sporadically or in association with other genetic syndromes, such as multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1, and pathogenic variants in the genes for succinate dehydrogenase subunits, among others [26]. Genetic syndromes associated with pheochromocytomas are discussed separately. (See "Pheochromocytoma in genetic disorders".)
●Age – In patients with VHL disease, the median age of presentation with a pheochromocytoma is 30 years old (table 1). However, these tumors have also been reported in pediatric patients with VHL disease [27,28].
●Location – VHL disease-associated pheochromocytomas often present with multiple tumors, which may be located in the adrenal gland (approximately 90 percent) or extra-adrenally (ie, paragangliomas; approximately 10 percent) [29].
●Symptoms – Patients with VHL disease-associated pheochromocytoma can either be symptomatic or asymptomatic, as the production of catecholamines is highly variable in these tumors [29-33].
Most patients with VHL disease-associated pheochromocytoma produce catecholamines and may present with classic symptoms of pheochromocytoma, such as hypertension, diaphoresis, tachycardia, and apparent mood changes. VHL disease-associated pheochromocytomas that produce catecholamines almost exclusively make normetanephrine (indicating norepinephrine production) [34]. Biochemical testing typically demonstrates a high normetanephrine to metanephrine ratio. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Clinical presentation'.)
In contrast, approximately one-third of patients with VHL disease-associated pheochromocytoma have biochemically silent tumors and present with no symptoms or evidence of excess catecholamine production [29,31]. Such patients may have their tumors detected as part of imaging studies during surveillance protocols or as an incidental adrenal mass on imaging studies performed for other reasons.
In patients with VHL disease who require surgery and have not recently had surveillance for pheochromocytoma, clinicians should evaluate for occult pheochromocytoma due to the potential risk of anesthesia complications, including sympathetic overactivity and severe hypertension. (See 'Surveillance for associated tumors' below.)
Further details on the clinical presentation, appropriate imaging studies, and diagnosis of pheochromocytoma are discussed separately (algorithm 1). (See "Clinical presentation and diagnosis of pheochromocytoma".)
Pancreatic lesions — Pancreatic abnormalities are identified in 30 to 70 percent of patients with VHL disease [35]. The most frequently encountered pancreatic lesions are [35,36]:
●Pancreatic cysts (70 percent) – (See 'Pancreatic cysts and serous cystadenomas' below.)
●Serous cystadenomas (9 percent) – (See 'Pancreatic cysts and serous cystadenomas' below.)
●Pancreatic neuroendocrine neoplasms (9 to 17 percent) – (See 'Pancreatic neuroendocrine neoplasms' below.)
Mucinous cysts of the pancreas are not seen with VHL disease. (See "Classification of pancreatic cysts".)
Patients with VHL disease also do not have an increased risk of pancreatic adenocarcinoma. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer".)
Pancreatic cysts and serous cystadenomas
●Age – VHL disease-associated pancreatic cysts and serous cystadenomas typically present between the ages of 24 and 35 years (table 1).
●Location – VHL disease-associated pancreatic cysts are frequently multiloculated. In one observational study of 122 patients with VHL disease and various pancreatic lesions, most multiloculated pancreatic cysts were disseminated throughout the pancreas (80 percent), followed by the body/tail (16 percent) and the head/neck (4 percent) regions [35].
In the same study, among those with VHL disease-associated serous cystadenomas (image 1), most were located in the head/neck and body/tail regions (40 percent each) and the remainder were disseminated throughout the pancreas (20 percent) [35].
●Symptoms – Pancreatic cysts and serous cystadenomas in VHL disease may be asymptomatic (even large lesions) and may be diagnosed incidentally on imaging studies. However, some lesions can cause epigastric pain [37,38], biliary obstruction [39], or portal hypertension [35] through compression of adjacent organs and blood vessels.
Pancreatitis and pancreatic failure are exceedingly rare, although exocrine pancreatic dysfunction has been reported. Patients may be asked about stool characteristics and digestive patterns during surveillance for VHL disease-associated tumors. (See "Exocrine pancreatic insufficiency" and 'Surveillance for associated tumors' below.)
Pancreatic neuroendocrine neoplasms
●Location – Pancreatic neuroendocrine neoplasms associated with VHL disease can be unifocal or multifocal. In one observational series of 122 patients with VHL disease and various pancreatic lesions, most neuroendocrine neoplasms were located in the head/neck region of the pancreas (60 percent), followed by the body/tail region (33 percent), and disseminated (7 percent) [35].
While most VHL-disease associated pancreatic neuroendocrine neoplasms are localized to the pancreas, some may metastasize, typically to the locoregional nodes or liver. In one observational series of 108 patients with VHL disease and pancreatic neuroendocrine neoplasms, 9 patients (8 percent) had metastatic disease [36]. Neoplasms that are most likely to metastasize are those that are >3 cm in diameter, have a rapid tumor doubling time (<500 days), and have VHL missense and/or exon 3 pathogenic (or likely pathogenic) variants [36,40-42]. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Classification and terminology'.)
●Histology – While most VHL disease-associated pancreatic neuroendocrine neoplasms are well-differentiated (G1 or G2 pancreatic neuroendocrine tumors [pNETs]) [41,42], high-grade well-differentiated (ie, pNET, G3) and high-grade poorly differentiated tumors (neuroendocrine carcinomas) have also been described (table 2) [43,44].
●Symptoms – Most VHL disease-associated pancreatic neuroendocrine neoplasms are nonfunctional (ie, do not secrete peptides) and grow slowly without producing symptoms related to peptide overproduction [35,45]. Most asymptomatic pancreatic neuroendocrine neoplasms are diagnosed during imaging surveillance [36]. (See 'Surveillance for associated tumors' below.)
When symptomatic, common symptoms include abdominal pain, weight loss, anorexia, nausea, and obstructive jaundice, among others. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Nonfunctioning tumors'.)
However, rare patients with functional pancreatic neuroendocrine neoplasms may present with symptoms related to secreted peptides, such as diarrhea from vasoactive intestinal peptide and hypoglycemic episodes from insulin [35]. Once the diagnosis of a functional pancreatic neuroendocrine neoplasm is confirmed, such patients can be monitored using tumor-specific pancreatic polypeptide levels to assess disease burden [39]. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Functioning tumors'.)
Further details on the clinical presentation and diagnosis of pancreatic neuroendocrine neoplasms are discussed separately. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms".)
Endolymphatic sac tumors of the middle ear — Endolymphatic sac tumors (ELSTs) of the middle ear are highly vascular lesions arising within the posterior portion of the temporal bone [46]. In patients with VHL disease, the frequency of ELSTs ranges between 10 and 25 percent [46-53].
●Age – Although these tumors also occur sporadically, they arise at a younger age in patients with VHL disease [48]. ELST is most commonly diagnosed between 24 and 35 years old but can occur as early as 12 years old (table 1).
●Location – ELSTs are located within the posterior portion of the temporal bone and are more likely to be bilateral in patients with VHL disease than those without the disease [48]. In two other reports in VHL patients, 5 of 34 tumors (15 percent) were bilateral [46,47].
●Symptoms – ELSTs are indolent, slow-growing tumors but they can still cause symptoms by impacting locoregional structures. Common clinical manifestations of ELSTs include auditory and vestibular symptoms, such as changes in hearing or hearing loss, tinnitus, and vertigo [54]. Less commonly, these lesions can present with ear pain or facial muscle weakness due to facial nerve palsy [46-49,53]. Patients with auditory or vestibular symptoms should be referred for auditory testing. Any patient with abnormalities in auditory tests should be screened for ELSTs by computed tomography (CT) of the skull base or magnetic resonance imaging (MRI) with fine cuts of the temporal bones [46]. (See 'Surveillance for associated tumors' below.)
The following mechanisms can cause hearing loss and other symptoms [49].
•Tumors can invade the otic capsule, resulting in destruction of the membranous labyrinth and disruption of endolymphatic flow.
•Sudden, irreversible hearing loss may be due to intralabyrinthine hemorrhage.
•Gradual onset of hearing loss, tinnitus, and vertigo can be caused by blockage of endolymphatic sac resorption of fluid (hydrops).
In an observational study of 40 patients with VHL disease, the diagnosis of ELSTs was suspected based on audiovestibular symptoms (34 percent), audiometry (30 percent), and MRI (12.5 percent) [54]. Most ELSTs diagnosed on imaging (90 percent) were also associated with abnormal audiometric findings [54].
●Radiographic findings – The diagnosis of ELST is typically confirmed on specialized imaging studies. Visualization of ELSTs on imaging studies requires dedicated images, such as CT of the skull base or MRI of the internal auditory canal with fine cuts of the temporal bone. Of note, ELSTs may be missed on surveillance MRIs ordered for CNS hemangioblastomas. Characteristic radiographic findings for these tumors include a retrolabyrinthine location; on CT, intratumoral calcification; and on MRI, hyperintense focal signals on T1-weighted (non-contrast-enhanced) images and a heterogeneous signal on T2-weighted images [55,56].
Surveillance for ELST in VHL disease is discussed below. (See 'Surveillance for associated tumors' below.)
Papillary cystadenomas — In patients with VHL disease, papillary cystadenomas can occur in both the epididymis in males and the broad ligament in females (also known as adnexal papillary tumors of probable mesonephric origin) [57].
●Papillary cystadenomas of the epididymis – In males with VHL disease, papillary cystadenomas of the epididymis are typically diagnosed between the ages of 14 and 40 years old (table 1). The frequency of these lesions ranges between 25 and 60 percent [58]. Most are asymptomatic and diagnosed either on physical examination or scrotal ultrasound. Rarely, these lesions can present as painless scrotal swelling [59] or, if bilateral, cause infertility [60].
Bilateral papillary cystadenomas of the epididymis are almost pathognomonic of VHL disease [2,58]. In contrast, single epididymal cysts are common in the general male population and should not raise suspicion for VHL disease in the absence of other VHL-related findings.
●Papillary cystadenomas of the broad ligament – In females with VHL disease, papillary cystadenomas of the broad ligament are typically diagnosed between the ages of 16 and 46 years old (table 1). The true incidence of these lesions is unknown as most are asymptomatic and diagnosed on physical examination or imaging studies (such as transvaginal ultrasound, CT of the pelvis, or MRI of the pelvis [61]). The estimated frequency of this lesion among females with VHL disease is approximately 10 percent [62,63]. Those who are symptomatic have reported abdominal pain, dyspareunia, and menorrhagia.
DIAGNOSIS OF VHL DISEASE
When to suspect the diagnosis — The diagnosis of VHL disease should be suspected in young patients who present with characteristic VHL-associated tumors, individuals with a family history of VHL disease, and those with secondary pathogenic (or likely pathogenic) variants in the VHL gene, as described below.
Individuals who are suspected to have VHL disease (table 3) should be referred to specialized centers for comprehensive evaluation, genetic counseling, and definitive diagnosis through genetic testing of the VHL gene. Approved VHL Clinical Care Centers are available at the VHL Alliance website [64]. These centers have been approved for standards of care that were developed by the VHL Alliance's medical advisory board. The VHL Alliance also provides recommendations for ongoing surveillance of patients diagnosed with VHL disease (table 4). (See 'Genetic counseling' below and 'Surveillance for associated tumors' below.)
●Patients with characteristic VHL disease-associated tumors — Individuals who present with one or more characteristic tumors associated with VHL disease should have a genetic evaluation for VHL disease, including (table 3) [2,65] (see 'Clinical presentation' above):
•Clear cell renal cell carcinoma (RCC) diagnosed at age 40 or younger [65].
•Hemangioblastomas of the central nervous system [65,66] or retinal capillary hemangioblastoma (regardless of the number of lesions for either condition).
•Pheochromocytoma or paraganglioma [65,67].
•Endolymphatic sac tumors (ELSTs).
•Multiple pancreatic cysts or serous cystadenomas.
•Pancreatic neuroendocrine neoplasms.
•Papillary cystadenomas involving the epididymis (particularly those that are bilateral [2,58]) or broad ligament.
•Individuals with other combinations of tumors as well as a family history of VHL disease-associated tumors (eg, those with a diagnosis of clear cell RCC over the age of 40 but with a strong family history of kidney cancer or other tumors associated with VHL disease). (See "Diagnostic approach, differential diagnosis, and management of a small renal mass", section on 'Genetic counseling'.)
If access to genetic investigations is limited, testing can be focused on individuals who present with these lesions under the age of 50 years as a germline VHL pathogenic variant is more likely to be detected in younger patients.
●At-risk relatives — At-risk relatives are defined as any individual with a family history of VHL disease where the diagnosis has been confirmed through genetic testing of the affected relative(s) [65] or those whose relative has a clear clinical diagnosis of VHL disease, but no confirmatory genetic testing (eg, an individual with a parent who died of VHL disease prior to having genetic testing).
●Patients with secondary pathogenic (or likely pathogenic) variants — Patients with secondary (previously referred to as "incidental") findings of pathogenic (or likely pathogenic) variants in the VHL gene. (See "Gene test interpretation: VHL", section on 'Classification of variants'.)
With the use of next-generation sequencing (NGS), a secondary pathogenic (or likely pathogenic) variant in the VHL gene could be unexpectedly discovered when genetic testing is performed for other reasons, such as a large hereditary cancer panel, tumor sequencing in the care of a cancer patient, whole exome or genome sequencing for other indications, or commercial testing for a broad range of genetic conditions [68].
Recommendations are available from the American College of Medical Genetics and Genomics (ACMG) for the reporting of secondary findings of pathogenic (or likely pathogenic) variants. The VHL gene is included in this list of secondary pathogenic variants that are thought to be medically actionable, even if the original indication for testing was unrelated to a cancer diagnosis [68-70]. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease", section on 'Pathogenic variants and clinical manifestations of disease'.)
Genetic testing (diagnosis) — The diagnosis of VHL disease is established through genetic testing for a germline pathogenic variant in the VHL gene. Pathogenic variants in the VHL gene are typically a loss-of-function nonsense or frameshift variant or a missense variant that interferes with VHL activity. Rarely, for patients without access to genetic testing, the diagnosis of VHL disease can be based on clinical criteria (eg, individuals with one VHL disease-associated lesion and a family history of VHL disease or those with multiple VHL-disease associated tumors). The molecular biology and pathogenesis of VHL disease is discussed separately. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)
How to perform and interpret genetic testing — Genetic testing is typically performed on isolated DNA from a fresh blood sample, which is obtained primarily from lymphocytes. Many laboratories can also perform this testing from DNA isolated from saliva or buccal samples. Most DNA diagnostic laboratories rely on NGS techniques, whether assessing a single gene or panel of hereditary cancer genes. Deletions (either intragenic or whole gene) are assessed using read-depth from NGS data [71] or confirmed directly using a targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification [72]. Many patients undergo genetic testing using larger multigene panels by NGS analysis that include the VHL gene as one of the cancer susceptibility genes under study, including those cancer patients undergoing paired tumor/normal sequencing [73]. (See "Gene test interpretation: VHL".)
For at-risk relatives, genetic testing should include the VHL pathogenic variant identified in the affected relative, an approach called "known familial pathogenic variant" testing. However, laboratories often use automated sequencing platforms and may re-evaluate the entire VHL gene for each family member. If the relative had a clinical diagnosis of VHL disease, but no confirmatory genetic testing, the at-risk relative should receive comprehensive genetic testing for all possible VHL pathogenic variants.
A molecular diagnosis of VHL disease is based on the identification of a pathogenic (or likely pathogenic) variant in the VHL gene using the ACMG classification scheme [74]. Considerations include the following:
●Pathogenic variants in the VHL gene can be inherited or arise de novo. In early studies of patients with VHL disease, the frequency of de novo pathogenic variants in the VHL gene can be high as 20 percent [75].
●The VHL gene is included on the ACMG list of genes recommended for reporting as a secondary pathogenic variant. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease", section on 'Pathogenic variants and clinical manifestations of disease'.)
●It can be particularly challenging to have a patient with a single VHL-associated tumor and a variant of uncertain significance (VUS) in the VHL gene. Many clinicians will use their own judgment to decide whether to pursue VHL disease surveillance in that setting. Patients are advised to follow up with the ordering clinician or the ordering laboratory every few years to determine if a reclassification of the VUS has been made. The Clinical Genome Resource (ClinGen) has launched a VHL Variant Classification Expert Panel to try to further improve evaluation of germline variants in VHL and reduce the number of VUS results [76,77]. (See "Gene test interpretation: VHL", section on 'Classification of variants'.)
●Rare patients may have the clinical features of VHL disease but lack a detectable pathogenic variant from analysis of a blood sample. This may be due to somatic mosaicism for the VHL pathogenic variant. (See 'Approach to patients who test negative for the VHL pathogenic variant (somatic mosaicism)' below.)
Approach to patients who test negative for the VHL pathogenic variant (somatic mosaicism) — Rarely, some patients present with VHL disease-associated tumors but test negative for a VHL pathogenic variant based on a blood or saliva sample analysis. Such patients should be evaluated for the possibility of somatic mosaicism using testing strategies such as NGS, if not done previously, and genetic testing of other tissues.
In a patient with somatic mosaicism (figure 2), a pathogenic variant occurs during embryonic development after fertilization; in these circumstances, some cells will have two normal copies of the VHL gene while others carry the pathogenic variant. In contrast to detecting germline pathogenic variants, diagnostic difficulties are more likely as the clinical presentation depends on the proportion of cells that carry this mosaic VHL pathogenic variant [78,79]. Although an individual with somatic mosaicism may present with classic VHL disease, the disease-associated variant may not be detectable in the peripheral blood because the hematologic stem cells do not carry the pathogenic variant.
Somatic mosaicism is a possible explanation in patients presenting with VHL disease-associated tumors and a negative VHL genetic test using peripheral blood cells. The disease manifestations in such patients are dependent upon when the de novo pathogenic variant event occurred in embryogenesis. The earlier that the new pathogenic variant occurred, the more tissue types that are likely to be affected.
For patients who are suspected to have somatic mosaicism, NGS provides increased sensitivity to detect VHL pathogenic variants that exist at very low levels in the blood sample compared with Sanger sequencing methods [80]. Genetic testing of skin fibroblasts or buccal mucosal cells can also be performed. Testing of multiple tumors from the same patient with somatic mosaicism can sometimes provide information on the causative pathogenic variant shared across tumors, but it should be interpreted by an experienced geneticist or genetic counselor.
Genetic counseling — Patients who have (or are suspected to have) VHL disease should be referred for appropriate genetic counseling in conjunction with genetic testing for VHL pathogenic variants [65]. (See 'Pregnancy and VHL disease' below.)
VHL disease is inherited in an autosomal-dominant fashion, and affected individuals have a 50 percent probability of transmitting the VHL pathogenic variant to each offspring. Given the variable age of tumor onset, most individuals with VHL disease live into adulthood and have children, often before the diagnosis is made. Therefore, multigenerational VHL disease pedigrees can have many affected individuals, each having slightly different patterns of tumor diagnoses and variable ages of onset.
Among the rare patients with somatic mosaicism, the risk to offspring depends upon whether or not the germline tissue carries the pathogenic variant (figure 2). Patients with documented somatic mosaicism should be counseled that their risk of having an affected child may be as high as 50 percent. Additionally, any affected child will inherit the VHL pathogenic variant in 100 percent of their cells and will potentially have more severe manifestations of the disease (ie, typical features of VHL disease compared with their mosaic parent who may show milder or no features). (See 'Approach to patients who test negative for the VHL pathogenic variant (somatic mosaicism)' above.)
The diagnosis of VHL disease in a child of unaffected parents can be concerning. Clinicians should carefully explain the concept of de novo pathogenic variants or variable expressivity (eg, where the parent may not yet have been diagnosed with a VHL-associated tumor). Clinicians should not assume that the biological parents are negative for the VHL variant without comprehensive genetic testing. When discussing de novo pathogenic variants, the biological parents should be reassured that it is unlikely any action that they took prior to or during the pregnancy caused VHL disease in their child. (See "Genetic counseling: Family history interpretation and risk assessment".)
Parents may ask about when to provide information about the diagnosis of VHL disease to children with a positive VHL genetic test. In general, it is best for this information to be conveyed in multiple settings as the child's maturity increases. Parents may benefit from the support of a clinician or genetics counselor to initiate these discussions [65]. The VHL Alliance provides resources that help explain the disease to children, parents, and other health care professionals [64].
Types of VHL disease — VHL disease is classified into two categories, type 1 and 2 [81], based on the risk of developing certain VHL-associated tumors when there is substantial family data. These classifications should be used as guides rather than absolute categories.
●Type 1 – Patients in families with type 1 disease are at substantially lower risk of pheochromocytoma:
•Type 1A – Low risk for pheochromocytoma, high risk for other VHL-associated tumors.
•Type 1B – Low risk for both pheochromocytomas and RCC, high risk for all other VHL-associated tumors. Type 1B is due to a specific type of deletion that includes the nearby BRK1 gene (previously called C3orf10) [82].
●Type 2 – Patients in families with type 2 disease are at high risk for developing pheochromocytoma and are also more likely to have missense (rather than truncating or null) pathogenic variants in the VHL gene. (See "Pheochromocytoma in genetic disorders", section on 'VHL syndrome'.)
Further subclassifications of type 2 VHL disease include:
•Type 2A – High risk for pheochromocytoma and low risk of RCC.
•Type 2B – High risk for pheochromocytoma and high risk of RCC.
•Type 2C – High risk for pheochromocytoma only. Such patients do not develop RCC or hemangioblastoma.
Surveillance protocols and management apply independently of the type of pathogenic variant [83]. For example, individuals with VHL disease who present with type 2C characteristics should continue surveillance for other VHL disease-associated tumors. (See 'Surveillance for associated tumors' below.)
SURVEILLANCE FOR ASSOCIATED TUMORS — All patients with VHL disease, including those who are asymptomatic, should initiate lifelong surveillance for tumors associated with this condition. Surveillance is important for early diagnosis of new tumors that may require treatment, to monitor small asymptomatic tumors for evidence of progression, and to reduce disease-related morbidity and mortality [6]. The management of VHL disease by tumor type is discussed separately. (See "Management of von Hippel-Lindau disease".)
Surveillance protocols mainly focus on central nervous system hemangioblastoma, retinal capillary hemangioblastoma, renal cell carcinoma, pheochromocytoma, endolymphatic sac tumors (ELSTs) of the middle ear, and pancreatic lesions. Surveillance for each tumor type is typically initiated based on the age of onset. (See 'Clinical presentation' above.)
On history, a review of systems (as appropriate based on the age of the patient) includes neurologic symptoms, auditory and vestibulo-neural symptoms, visual symptoms, abdominal pain, and symptoms of catecholamine excess (headaches, palpitations, diaphoresis, hyperactivity, anxiety, and polyuria). Patients with any signs or symptoms suggestive of a VHL disease-associated tumor should be evaluated with appropriate testing, regardless of age. Surveillance protocols may also need to be adapted to the individual patient to account for active or prior tumor diagnoses.
Comprehensive surveillance guidelines for VHL disease are available from several organizations [6,15,16,64,84]. The following summarizes surveillance guidelines for asymptomatic patients with VHL disease based on a consensus statement from the International VHL Surveillance Guidelines Consortium and the VHL Alliance (table 4) [6,64].
Ages 0 to 4
●Every 6 to 12 months
•Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist skilled in diagnosis and management of retinal disease, especially for children known from infancy to carry the VHL pathogenic variant
●Annually
•From age 1 year – History and physical examination by a clinician informed about VHL disease
•From age 2 years – Blood pressure and pulse measurements
Ages 5 to 10
●Every 6 to 12 months
•Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist informed about VHL disease, using a dilated exam
●Annually
•History and physical examination by a clinician informed about VHL disease
•Blood pressure and pulse measurements
•Assessment of plasma metanephrines or 24-hour urinary metanephrines
Age 11 and beyond
●Every 6 to 12 months
•Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist informed about VHL disease, using a dilated exam
●Annually
•History and physical examination by a clinician informed about VHL disease
•Blood pressure and pulse measurements
•Assessment of plasma metanephrines or 24-hour urinary metanephrines
●Every 2 years
•MRI with and without contrast of brain, cervical, thoracic, and lumbar spine
•Audiogram performed by an audiologist
Age 15 and beyond
●Every 6 to 12 months
•Dilated eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist informed about VHL disease
●Annually
•History and physical examination by a clinician informed about VHL disease
•Blood pressure and pulse measurements
•Assessment of plasma metanephrines or 24-hour urinary metanephrines
●Every 2 years
•MRI with and without contrast of brain, cervical, thoracic, and lumbar spine
-A one-time MRI of the brain with thin cuts through inner ear/petrous temporal bones (internal auditory canal) to assess for ELST of the middle ear
•MRI abdomen with and without contrast
•Audiogram performed by an audiologist
Beginning age 30
●Decrease frequency of screening eye examination to annually. All other testing remains the same.
Beginning age 65
●Annually
•For areas that have active disease, continue imaging at a frequency that allows follow-up and management of lesions in question. Surveillance examination frequency is described as follows.
•Dilated eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist informed about VHL disease.
•History and physical examination by a clinician informed about VHL disease.
•Blood pressure and pulse measurements.
•If pheochromocytoma has not been detected, stop assessment of plasma or urinary metanephrines.
•If ELST has not been detected, stop audiogram.
•Stop surveillance MRI imaging for areas that have not shown any disease manifestations.
SPECIAL POPULATIONS
Pregnancy and VHL disease
Surveillance for tumors prior to and during pregnancy — Female patients with VHL disease should undergo surveillance to assess for VHL disease-associated tumors prior to attempting conception and during pregnancy. (See 'Surveillance for associated tumors' above.)
Although it is controversial whether VHL disease-associated tumors demonstrate new or accelerated growth during pregnancy [85-87], surveillance is still warranted in patients who are pregnant or planning pregnancy due to the risk of pregnancy complications, particularly those associated with pheochromocytoma.
Surveillance in this population is as follows (table 4):
●Pheochromocytoma – All patients with VHL disease who are planning pregnancy should have surveillance for pheochromocytoma prior to conception including history and physical examination, blood pressure and pulse check, MRI of the abdomen with and without contrast, and biochemical tests (plasma or 24-hour urinary metanephrines). For pregnant patients with VHL disease who did not receive such surveillance for pheochromocytoma prior to conception, plasma metanephrines and normetanephrines are generally tested in the first trimester and then early in the third trimester of pregnancy.
Patients with VHL who are diagnosed with pheochromocytoma need to have the tumor fully treated before attempting pregnancy. The growth or development of pheochromocytomas can have catastrophic consequences during pregnancy and delivery, such as the release of metanephrines due to pressure on the tumor during labor and subsequent blood pressure instability [85,86].
Further details on the management of pheochromocytoma in pregnancy and in adults are discussed separately. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Pheochromocytoma in pregnancy' and "Treatment of pheochromocytoma in adults".)
●Other VHL disease-associated tumors
•All patients with VHL disease who are planning pregnancy should undergo surveillance for all tumors associated with VHL disease prior to attempting conception. All surveillance MRI studies should ideally be obtained prior to conception (table 4).
•Retinal examinations should be performed prior to conception and then every 6 to 12 months throughout the pregnancy.
•Physical examination (including blood pressure and pulse) and laboratory testing should continue during pregnancy. All MRI studies obtained during pregnancy (eg, as part of routine surveillance or for a suspected VHL disease-associated tumor) should be performed without contrast.
Females with VHL disease and existing retinal, brain, and spinal cord lesions may be at increased risk for tumor growth during pregnancy [83,86]. An observational study of VHL disease progression during and after pregnancy demonstrated accelerated growth of cerebellar hemangioblastomas [86], although this was not observed in a second series [83]. Detecting such tumors through surveillance can influence decisions regarding the management of labor and delivery. (See "Neurologic disorders complicating pregnancy", section on 'Brain tumors'.)
Assessing fetal VHL disease genetic status — Patients who are planning or carrying a pregnancy at risk for VHL disease should be offered genetic counseling. (See 'Genetic counseling' above.)
They should also be informed about reproductive technologies that minimize the risk of having a child with VHL disease, such as preimplantation genetic diagnosis, and methods to obtain the VHL pathogenic variant status of the fetus. Surveillance should be promptly initiated in all infants diagnosed with VHL disease. (See 'Surveillance for associated tumors' above.)
Prenatal diagnosis — For patients who are planning pregnancy, reproductive technologies are available that greatly lower the risk of having a child with VHL disease. These include sperm or oocyte donation (depending on which parent is affected with VHL disease), and preimplantation genetic testing [88].
Preimplantation genetic testing involves testing embryos fertilized in vitro for the familial VHL pathogenic variant, usually on a single cell of a blastocyst, and selecting unaffected embryos for implantation [89]. In one observational study, a parental history of VHL disease was one of the most common reasons that parents sought preimplantation genetic testing [90]. (See "Preimplantation genetic testing".)
Patients may also choose prenatal diagnosis after an in utero pregnancy is initiated, using a sample obtained by amniocentesis or chorionic villus sampling. Noninvasive testing of a maternal blood sample routinely used to detect aneuploidy does not typically detect genetic conditions caused by small genetic sequence differences, as seen in VHL disease. (See "Diagnostic amniocentesis" and "Chorionic villus sampling".)
Postnatal diagnosis — Pregnant patients whose child is at risk for VHL disease may choose to know their child's VHL disease genetic status after birth. If prenatal genetic testing is not performed, then all at-risk children should be offered testing in infancy for the VHL pathogenic variant.
Sporadic tumors due to somatic VHL pathogenic variants — Sporadic renal cell carcinomas (RCCs), hemangioblastomas, pheochromocytomas, and endolymphatic sac tumors frequently have acquired somatic (as opposed to germline) abnormalities involving the VHL gene, supporting a role for the VHL gene in tumorigenesis in sporadic cases [19,52,91-95]. These "two hits" or loss-of-function events are required in VHL disease for both hereditary and sporadic tumors. The hits can result from a combination of inherited plus somatic pathogenic variants, or, in the case of sporadic tumors, both hits may be somatic. The second hit is often loss of heterozygosity or loss of gene expression caused by promoter hypermethylation. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)
Somatic VHL pathogenic variants can occur at the following frequencies in sporadic tumors:
●Sporadic RCCs – Abnormalities of the VHL gene are found in 50 to 60 percent of patients with sporadic RCCs. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Von Hippel-Lindau gene'.)
●Sporadic hemangioblastomas – Somatic pathogenic variants of the VHL gene and/or allelic deletion may be present in as many as 50 percent of sporadic hemangioblastomas. (See "Hemangioblastoma", section on 'Molecular biology'.)
●Sporadic pheochromocytoma – VHL gene abnormalities in sporadic pheochromocytoma are observed less commonly (up to 17 percent of such tumors in one observational series [93]). However, some of these patients may actually have true VHL disease due to known VHL germline pathogenic variants [67]. (See 'Pheochromocytoma' above.)
Surveillance for other tumors associated with VHL disease is generally not required in patients with a sporadic tumor. However, patients at high clinical suspicion for VHL disease, such as a young patient with a strongly VHL disease-associated tumor, should receive the appropriate diagnostic evaluation. (See 'Diagnosis of VHL disease' above.)
ADDITIONAL RESOURCES — Summary information concerning VHL disease may be useful for counseling patients and affected families. The following organization can provide such information:
VHL Alliance
2001 Beacon Street, Suite 208
Boston, MA 02135
Telephone: 617-277-5667
Toll free number in the United States and Canada: 800-767-4VHL
Fax: 858-712-8712
The VHL Handbook is available in various languages as a download or through the VHL Alliance office. The handbook is a reference guide for patients and their health care teams.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cancer of the kidney and ureters" and "Society guideline links: Primary brain tumors" and "Society guideline links: Well-differentiated gastroenteropancreatic neuroendocrine tumors" and "Society guideline links: Pheochromocytoma and paraganglioma".)
SUMMARY AND RECOMMENDATIONS
●Definition – Von Hippel Lindau (VHL) disease is an inherited, autosomal-dominant syndrome that occurs due to germline pathogenic variants in the VHL gene. VHL disease is characterized by a variety of benign and malignant tumors, which include:
•Central nervous system hemangioblastomas – (see 'CNS hemangioblastomas' above)
•Retinal capillary hemangioblastomas – (see 'Retinal capillary hemangioblastomas' above)
•Clear cell renal cell carcinomas – (see 'Renal cell carcinomas' above)
•Pheochromocytomas – (see 'Pheochromocytoma' above)
•Pancreatic cysts and serous cystadenomas; pancreatic neuroendocrine neoplasms – (see 'Pancreatic lesions' above)
•Endolymphatic sac tumors of the middle ear – (see 'Endolymphatic sac tumors of the middle ear' above)
•Papillary cystadenomas of the epididymis and broad ligament – (see 'Papillary cystadenomas' above)
●Clinical presentation – In patients with VHL disease, tumors can present at varying ages and frequencies (table 1), with clinical manifestations that differ according to tumor type. However, most occur in younger individuals (typically under the age of 40), are bilateral and/or multifocal in nature, and generally exhibit indolent growth. (See 'Clinical presentation' above.)
●When to suspect the diagnosis of VHL disease – The diagnosis of VHL disease should be suspected in young patients who present with characteristic VHL-associated tumors, individuals with a family history of VHL disease, and those with secondary pathogenic (or likely pathogenic) variants in the VHL gene. (See 'When to suspect the diagnosis' above.)
●Genetic testing (diagnosis) – The diagnosis of VHL disease is typically established through detection of a germline pathogenic variant in the VHL gene. (See 'Genetic testing (diagnosis)' above and "Molecular biology and pathogenesis of von Hippel-Lindau disease".)
•Somatic mosaicism – Somatic mosaicism (figure 2) is a possibility in the rare patient who presents with a VHL disease-associated tumor but tests negative for a VHL pathogenic variant based on a blood sample analysis. Such patients may be evaluated using next-generation sequencing and genetic testing of other tissues (eg, skin fibroblasts, buccal mucosal cells, or multiple tumors from the same patient). (See 'Approach to patients who test negative for the VHL pathogenic variant (somatic mosaicism)' above.)
●Surveillance for VHL-associated tumors – All patients with VHL disease, including those who are asymptomatic, should initiate lifelong surveillance for tumors associated with this condition (table 4). Surveillance is important for early diagnosis of new tumors that may require treatment, to monitor small asymptomatic tumors for evidence of progression, and to reduce morbidity and mortality. (See 'Surveillance for associated tumors' above.)
●Pregnancy and VHL disease
•Assessing fetal VHL genetic status – Patients who are planning or carrying a pregnancy at risk for VHL disease should be offered genetic counseling. They should also be informed about reproductive technologies that lower the risk of having a child with VHL disease and methods to obtain the VHL pathogenic variant status of the fetus. Surveillance should be promptly initiated in all infants diagnosed with VHL disease. (See 'Genetic counseling' above and 'Assessing fetal VHL disease genetic status' above.)
•Surveillance for VHL-associated tumors prior to and during pregnancy – Female patients with VHL disease should undergo surveillance to assess for VHL disease-associated tumors prior to attempting conception and during pregnancy (table 4). (See 'Surveillance for tumors prior to and during pregnancy' above.)
●Management of VHL disease – The management of VHL disease by tumor type is discussed separately. (See "Management of von Hippel-Lindau disease".)
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