Diagnostic Laboratory Testing for Von Hippel-Lindau Disease
Genetic testing for pathogenic variants in the VHL gene is the gold standard and definitive diagnostic laboratory test for von Hippel-Lindau disease, detecting mutations in 95-100% of clinically diagnosed cases. 1, 2
Primary Diagnostic Test
VHL gene molecular testing is the cornerstone laboratory diagnostic approach and should be performed in the following scenarios: 1
First-degree relatives of individuals with confirmed pathogenic VHL variants 1, 3
Any child presenting with characteristic VHL-associated tumors, including: 1
- Retinal angioma/hemangioblastoma
- CNS hemangioblastoma
- Clear cell renal cell carcinoma
- Pheochromocytoma or paraganglioma
- Endolymphatic sac tumor
- Epididymal or adnexal papillary cystadenoma
- Multiple pancreatic cysts or pancreatic neuroendocrine tumors
- Multiple renal cysts
Patients with single or multifocal retinal hemangioblastomas, even without family history 1
At-risk children should be tested early in life to enable timely surveillance 1
Genetic Testing Methodology
The VHL gene testing detects several mutation types: 2, 4
- Large germline deletions (detectable by Southern blot analysis): ~20% of cases 4
- Missense mutations: ~27% of cases 4
- Nonsense or frameshift mutations: ~27% of cases 4
- Undetectable mutations: ~20% of families may have no identifiable deletion or mutation with current techniques 4
The VHL gene contains three exons on chromosome 3p25-p26, and comprehensive sequencing should evaluate all coding regions. 2, 4, 5
Clinical Diagnosis Criteria (When Genetic Testing Unavailable)
While genetic testing is the gold standard, clinical diagnosis can be established through: 1, 3
Scenario 1 - With family history:
- Presence of one of the following: CNS hemangioblastoma, retinal hemangioblastoma, pheochromocytoma, or renal cell carcinoma 1
Scenario 2 - Without family history (simplex case):
- Two or more hemangioblastomas (retinal or CNS), OR 1
- Two or more visceral tumors, OR 1
- One hemangioblastoma AND one visceral tumor 1
Biochemical Screening Tests for Surveillance
Once VHL is diagnosed, specific biochemical tests are used for tumor surveillance (not for initial diagnosis): 1, 3
- Annual plasma or urine metanephrines starting at age 5 years to screen for pheochromocytoma 3
- These are surveillance tools rather than diagnostic tests for VHL itself 1
Important Caveats
Epididymal and renal cysts alone are NOT sufficient for clinical diagnosis of VHL, as they occur commonly in the general population and can lead to diagnostic errors. 6 Genetic testing with flanking markers has confirmed that isolated epididymal cysts should not be used as diagnostic criteria. 6
De novo mutations account for approximately 20% of VHL cases, so absence of family history does not exclude the diagnosis. 7, 3, 8 This underscores the importance of genetic testing in patients presenting with characteristic tumors even without family history. 2
Genetic counseling should accompany all VHL genetic testing, both before and after testing, to discuss implications for the patient and family members. 1, 3