Version May 2024
INTRODUCTION — This monograph summarizes the interpretation of germline testing for the von Hippel-Lindau disease gene, VHL. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or in the clinical care of the individual who was tested. These subjects are discussed separately [1].
OVERVIEW
How to read the report — There are several important caveats to reviewing a genetic test report; these are summarized in the checklist (table 1). Another table provides a glossary of relevant terminology (table 2).
Testing involves two steps: Analyzing the gene to identify variants and interpreting the pathogenicity of the variant(s) identified.
●Analysis – Identifies variant(s) that differ from a reference sequence. VHL testing includes whole gene sequencing and deletion/duplications analysis. It may evaluate only a subset of possible disease variants in the VHL gene. While variants are expected to be identified if present, current testing technologies may not identify every existing variant.
Testing should be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory if the results were obtained by direct-to-consumer testing or a research study in any individual with a personal and/or family history suspicious of VHL.
We expect a proportion of positive results from health testing in the general population, especially those obtained from laboratories that are not CLIA-certified and are using microarrays, to be false positives that will not be identified on retesting in a CLIA-certified laboratory using sequencing [2].
●Interpretation – Determines pathogenicity of the variants identified using available data. Variant interpretation may change over time and may require updating as new information becomes available. (See 'Classification of variants' below.)
For questions regarding the interpretation of a specific variant, the testing laboratory can be contacted for further review.
Classification of variants — The pathogenicity of each variant (or lack thereof) is classified by the testing laboratory into one of five categories based on information available to them at the time (table 3) [3]. It is possible for laboratories to have a different classification for the same variant.
●Positive – Pathogenic or likely pathogenic results indicating von Hippel-Lindau (VHL) disease.
●Negative – Benign or likely benign results.
●Uncertain – A variant of uncertain significance (VUS) is a result that needs more information (eg, data from family studies or bench research) before it can be classified as positive or negative.
The classification continues to be updated, especially for VUS results, as more information becomes available regarding their associations with disease. Some laboratories routinely provide updates and others require a request for variant reclassification. The uncertainty reflects the available evidence for disease association, not the accuracy of genotyping or the likelihood of disease in a particular individual. Some laboratories may ask for additional clinical information from affected individuals or offer family studies to support or reclassify a variant. Many VUSs are reclassified as benign. Individuals with a VUS in the VHL gene are encouraged to reach out to their ordering clinician or the ordering laboratory every couple of years to determine if a reclassification has been made.
To learn more about a particular variant, individuals may consult a database such as ClinVar or a specialist (clinical geneticist, genetic counselor, or specialist in VHL disease). (See 'Locating an expert' below.)
Variants determined to be benign or likely benign are not reported (or are reported as negative). The report may include special interpretations of variants and must be read in its entirety.
Disease associations — VHL disease is an autosomal dominant disease caused by a germline pathogenic variant in the VHL gene that predisposes affected individuals to several types of malignant and benign tumors:
●Central nervous system
•Hemangioblastomas (cerebellum, brainstem, spinal cord, retina)
•Middle ear endolymphatic sac tumors
●Visceral
•Renal cell carcinomas (clear cell) and renal cysts
•Pheochromocytomas and paragangliomas
•Pancreatic cysts, serous cystadenomas, and neuroendocrine tumors
•Epididymal (males) and broad ligament of the uterus (females) papillary cystadenomas
The frequency of tumors and mean age of presentation are summarized in the table (table 4).
VHL is a tumor suppressor gene; development of tumors is thought to occur when a cell (or group of cells) that is heterozygous for a pathogenic variant in VHL loses the normal copy of the gene. There are differences in disease spectrum with different types of pathogenic variants (deletion versus frameshift mutation versus premature stop codon). This creates variable expressivity in disease presentation among individuals and family members with VHL. The mechanisms are discussed separately. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease", section on 'Molecular biology and pathogenesis'.)
SURVEILLANCE FOR VHL TUMORS — Individuals with a germline pathogenic or likely pathogenic variant in VHL that has been confirmed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (see 'How to read the report' above) require active surveillance for associated tumors to allow early intervention when indicated. Surveillance for individuals begins at birth; therefore, confirming a VHL diagnosis in any at-risk family members is important. (See 'At-risk relatives' below.)
VHL disease is rare, and most guidance is based on observational studies and expert opinion. Professional societies may differ slightly in the details of the age at which to start screening, frequency of screening, or screening modality [4-6]. We generally adhere to the recommendations of the VHL Alliance (VHL.org/clinicians/surveillance/), a patient organization that solicits input from a large group of clinicians with VHL disease expertise [6]. Family history may also be used to tailor screening recommendations. However, VHL can affect individuals differently, even within the same family.
Caring for individuals with VHL requires a multidisciplinary approach, involving expertise not only in the medical aspects of VHL but also social, genetic, and emotional considerations. History and physical examination is conducted annually from birth (or from the time of diagnosis), including age-appropriate history for visual, vestibuloneural, and catecholamine symptoms and neurologic examination. Recommended surveillance tests are summarized below and in the table (table 5).
Many of the tumors associated with VHL are benign; however, some have the potential to become malignant.
●Central nervous system tumors
•Ophthalmology (including dilated retinal examination) every 6 to 12 months, starting before age 1 year.
•Audiology every 2 years, starting at age 11 years.
•Magnetic resonance imaging (MRI) with and without contrast of the brain and spine every two years, starting at age 11 years.
•MRI of the internal auditory canal once at age 15 years.
●Visceral tumors
•Pheochromocytoma and paragangliomas
-Blood pressure and pulse annually, starting at age 2 years.
-Metanephrines (plasma free [preferred] or 24-hour urine) annually, starting at age 5 years.
•Renal cell cancer, pancreatic tumors, pheochromocytoma, and paragangliomas
-MRI of the abdomen with and without contrast every two years, beginning at age 15 years.
The frequency may be adjusted based on findings (eg, more frequent MRI of the abdomen to monitor tumors <3 cm). MRI contrast is avoided during pregnancy. Surveillance tests can be stopped at age 65 years for individuals who have never had a VHL disease-associated tumor; routine physical examinations and ophthalmology examinations are continued indefinitely.
VHL confers a significant psychological burden due to uncertainties about when and where a tumor will develop, the need for multiple surgeries over a lifetime, and surgical morbidities. Some individuals may develop postoperative functional impairment or chronic pain. Strategies for stress reduction, counseling, psychosocial support, and/or treatment for depression, anxiety, or opioid use disorder may be indicated.
For individuals with a family history consistent with VHL disease, negative genetic testing of VHL does not eliminate the need for active surveillance. Alternatively, if a VHL gene mutation is identified in a family and a relative tests negative for the familial mutation with caveats as noted (table 1), this is considered to be a true negative result and the individual is not considered to have increased risks associated with VHL disease.
Referral to a genetic counselor or other individual with expertise in familial cancer syndromes may be especially helpful for advice on additional genetic testing (of VHL or other genes) and/or other clinical surveillance. (See 'Locating an expert' below.)
MANAGEMENT OF SPECIFIC TUMORS — Management of tumors (malignant or benign) in patients with VHL disease is best performed at a VHL clinical care center or a comprehensive cancer center, where optimal approaches can be discussed and implemented. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)
These experts can take a team decision-making approach that incorporates the individual's complete clinical picture. If in-person care at a VHL center is not possible, consultation with VHL center experts is advised. (See 'Locating an expert' below.)
The following aspects of management may be affected by the presence of a pathogenic or likely pathogenic variant in VHL:
●Possible changes in surgical approach, such as:
•Nephron-sparing surgery for renal cell cancer due to the risk of multifocal, bilateral, and chronologically spaced recurrences or second primary tumors.
•Neurosurgical approaches that strike a balance between providing sufficient treatment to prevent or reduce symptoms while also minimizing surgical morbidity.
●Possible use of the oral hypoxia-inducible factor (HIF)-2alpha inhibitor belzutifan, which acts downstream of VHL.
●Possible investigational therapy or clinical trial targeting VHL-specific mechanism of tumorigenesis or drug sensitivity.
Individuals with VHL-related tumors require ongoing surveillance for other tumors (or initiation of surveillance if the VHL diagnosis was previously unknown). (See 'Surveillance for VHL tumors' above.)
GENETIC TESTING AND COUNSELING
VHL disease is caused by a pathogenic or likely pathogenic variant in the VHL gene. VHL is an autosomal dominant disease and can be inherited by males and females equally. Children of affected individuals have a 50 percent chance of inheriting the causative variant from their parent.
At-risk relatives — Approximately 80 percent of individuals with VHL disease have an affected parent; the remaining 20 percent have a de novo mutation (new in an individual for the first time) [7]. Thus, it is reasonable when a new diagnosis is made in a family to test the parents for the variant first (algorithm 1), with subsequent testing of other first-degree relatives and cascade testing of their first-degree relatives based on the results.
Genetic counseling and genetic testing for first-degree relatives are important as they help to identify which individuals have increased risks necessitating additional surveillance and which do not.
Individuals with a pathogenic or likely pathogenic variant in VHL should inform their first-degree relatives about the importance of genetic counseling and testing. Results should be shared within a family to ensure accurate single-site genetic testing for at-risk relatives.
Testing should be performed as soon as possible for family members who are at risk for carrying a germline pathogenic or likely pathogenic variant in VHL. Testing can occur soon after birth for newborn children of affected individuals based on the early onset of disease manifestations.
Preconception counseling — Some individuals may choose to pursue reproductive options such as donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "Preimplantation genetic testing".)
RESOURCES
UpToDate topics
●Pathogenesis – (See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)
●Diagnosis and management – (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)
Locating an expert — Listings are available from the following organizations:
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
●Genetic counselors – National Society of Genetic Counselors (NSGC)
●National Institutes of Health (NIH) – Cancer Genetics Services Directory
●VHL Clinical Care Centers – The VHL Alliance has lists for the United States and International
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