FeedbackPolymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Polymerase Chain Reaction/Sequencing
- Acceptable initial test to confirm a suspected diagnosis of VHL syndrome
- Preferred test to confirm a suspected diagnosis of VHL-associated polycythemia
Related Tests
Polymerase Chain Reaction/Sequencing
Useful when a familial pathogenic variant identifiable by sequencing is known
Multiplex Ligation-dependent Probe Amplification
Use to assess for large deletion/duplication previously identified in a family member
Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
Confirm diagnosis of a hereditary cancer syndrome with personal or family history consistent with features of more than one cancer syndrome
Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
Preferred test to confirm a diagnosis of hereditary renal cancer syndrome in individuals with personal or family history of renal cancer
Von Hippel-Lindau (VHL) syndrome is an inherited genetic disorder characterized by the formation of tumors and cysts throughout the body. Tumors may be benign or malignant and appear most often during youth or early adulthood, but can occur throughout life.
Hemangioblastomas are typically benign but can cause serious or life-threatening complications depending on location within the body. Hemangioblastomas that develop in the brain and spinal cord can cause headaches, vomiting, weakness, and a loss of muscle coordination (ataxia). Hemangiomas of the retina, called retinal angiomas, can cause vision loss.
Cysts and tumors may also occur in the kidneys, pancreas, and genital tract. Individuals with VHL syndrome are at increased risk of developing clear-cell renal cell carcinoma and pancreatic neuroendocrine tumors. Pheochromocytomas can occur and most commonly develop in the adrenal glands. Endolymphatic sac tumors as well as epididymal and broad ligament cysts have also been associated with VHL syndrome.
Disease Overview
VHL Syndrome
Incidence
Symptoms
- Manifestations and severity are highly variable within and between families; may be influenced by age and sex
- Characteristic tumor manifestations of VHL syndrome with estimated penetrance in affected individuals, if available :
- CNS hemangioblastoma: common
- 80% occur in brain
- 20% occur in spinal cord
- Retinal hemangioblastoma: 70%
- Renal cell carcinoma: 70% by 60 years of age
- Endolymphatic sac tumor: 10-16%
- Pancreatic endocrine tumor: 5-17%
- Pheochromocytoma or paraganglioma
- CNS hemangioblastoma: common
- Other manifestations
- Hemangiomas in glands, lungs, and liver
- Cysts in kidneys, pancreas, and epididymis
VHL-Associated Polycythemia
Prevalence
Rare worldwide, endemic in the Chuvash region of Russia
Symptoms
- Increased serum erythropoietin levels and hemoglobin concentrations during normoxia
- Leads to increased circulating red blood cell mass
- Increased risk for mortality caused by thrombosis and/or hemorrhage
- No increased risk for tumors that are associated with VHL syndrome
Genetics
Gene
VHL
Inheritance
- VHL syndrome: autosomal dominant
- VHL-associated polycythemia: autosomal recessive
Penetrance
Nearly complete by age 65 for VHL syndrome
De novo Variants
Pathogenic Variants
- Specific VHL sequence variants have been associated with VHL-associated polycythemia (eg, c.598C>T, p.R200W)
Test Interpretation
Sensitivity/Specificity
- Clinical sensitivity:
- Analytical sensitivity/specificity of sequencing: 99%
- Analytical sensitivity of deletion/duplication analysis: 90%
- Analytical specificity of deletion/duplication analysis: 98%
Results
- Positive
- One VHL pathogenic variant detected
- Diagnosis of VHL syndrome
- Two VHL pathogenic variants associated with polycythemia are identified
- VHL-associated polycythemia is confirmed
- One VHL pathogenic variant detected
- Negative
- No VHL pathogenic gene variant detected.
- VHL-related syndrome is unlikely, but not excluded
- No VHL pathogenic gene variant detected.
- Inconclusive
- VHL gene variant detected, but whether variant is benign or pathogenic is unknown
Limitations
- Not detected
- Deep intronic or regulatory region variants
- Large deletion/duplication breakpoints will not be determined
- Diagnostic errors can occur due to rare sequence variations
References
-
NIH - Von Hippel-Lindau Syndrome
National Institutes of Health, U.S. National Library of Medicine. Genetics home reference: von Hippel-Lindau syndrome. [Reviewed: Oct 2018; Accessed: Apr 2020]
Online -
1895313
Maher ER, Iselius L, Yates JR, et al. Von Hippel-Lindau disease: a genetic study. J Med Genet. 1991;28(7):443-447.
PubMed -
GeneReviews - Von Hippel-Lindau Syndrome
van Leeuwaarde RS, Ahmad S, Links TP, et al. Von Hippel-Lindau syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2021. [Last update: Sep 2018; Accessed: Apr 2020]
Online -
20151405
Nordstrom-O'Brien M, van der Luijt RB, van Rooijen E, et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010;31(5):521-537.
PubMed -
15642664
Cario H, Schwarz K, Jorch N, et al. Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and VHL-haplotype analysis in patients with presumable congenital erythrocytosis. Haematologica. 2005;90(1):19-24.
PubMed
Preferred test to confirm a suspected diagnosis of VHL syndrome