Sorted By Test Name - Mayo Medical Laboratories

Clinical Information: Von Hippel-Lindau (VHL) disease is an autosomal dominant cancer syndrome
with a birth incidence of approximately 1:36,000 live births. It predisposes affected individuals to the
development of mainly 5 different types of neoplasms: retinal angioma (>90% penetrance), cerebellar
hemangioblastoma (CHB, >80% penetrance), clear-cell renal cell carcinoma (cRCC, approximately 75%
penetrance), spinal hemangioblastoma (SHB, approximately 50% penetrance), and pheochromocytoma
(PC, approximately 30% penetrance). Angiomas in other organs, pancreatic cysts/adenomas/carcinomas,
islet cell tumors, and endolymphatic sac tumors can also occur, but at much lower frequencies.
VHL-related tumors start presenting at approximately 10 to 15 years of age (retinal angioma may present
earlier), except for cRCC, which lags about a decade behind. For each tumor type, the incidence rates rise
steadily, albeit at different slopes, throughout life. VHL disease is caused by germline loss-of-function
point mutations or deletions/insertions (approximately 80% of cases), or large germline deletions
(approximately 20% of cases) of 1 copy of the VHL gene. Approximately 20% of cases are due to new
mutations. VHL codes for a protein that is involved in ubiquination and degradation of a variety of other
proteins, most notable hypoxia-inducible factor (HIF). HIF induces expression of genes that promote cell
survival and angiogenesis under conditions of hypoxia. It is believed that diminished HIF degradation due
to inactive VHL protein causes the tumors in VHL disease. Tumors form when the remaining intact copy
of VHL is somatically inactivated in target tissues. Sporadic cRCC, unrelated to VHL disease, also shows
somatic deletions, mutations, or aberrant methylation in 80% to 100% of cases. Retinal angioma, CHB,
and SHB cause morbidity, and some mortality, through pressure on adjacent structures and through retinal
or subarachnoid hemorrhages. VHL-related cRCC and PC follow a similar clinical course as their
sporadic counterparts, with substantial morbidity and mortality. Early detection of VHL-related tumors
can reduce these adverse outcomes, and surveillance of affected individuals is therefore widely advocated.
Genetic testing is the most accurate way to identify presymptomatic individuals, who can then be entered
into a surveillance program. Genetic testing might also predict the types of tumors that will occur, and
can, therefore, be used to individualize surveillance programs. Certain combinations of the 5 major
VHL-tumors cluster in VHL families. This observation has led to a phenotype-based classification of
VHL syndrome into type 1 (cRCC with an combination of retinal angioma, CHB, or SHB), type 2A (PC
with an combination of retinal angioma, CHB, or SHB), type 2B (both cRCC and PC, with any
combination of retinal angioma, CHB, or SHB), and type 2C (isolated PC). Type 1 accounts for 60% to
80% of cases, while type 2C is exceedingly rare. However, phenotyping is only accurate in large kindreds.
In smaller kindreds, genetic testing can assist in tailoring follow-up to patient needs. For example,
missense mutations, in particular those affecting surface amino acids involved in maintaining the surface
structural integrity of VHL protein, are strongly associated with PC. By contrast, nonsense or frameshift
mutations that disrupt overall VHL protein structure and large deletions are associated with early clinical
presentation and increased age-related risks for retinal angioma and cRCC.
Useful For: Diagnosis of suspected Von Hippel-Lindau disease Screening presymptomatic members of
Von Hippel-Lindau families Tailoring optimal tumor-surveillance strategies for patients, when used in
conjunction with phenotyping
Interpretation: All detected alterations will be evaluated according to American College of Medical
Genetics and Genomics (ACMG) recommendations (Genet Med 2008:10[4]:294-300). Variants will be
classified based on known, predicted, or possible pathogenicity and reported with interpretive comments
detailing their potential or known significance. Rarely, unknown polymorphisms in primer- or
probe-binding sites can result in false-negative test results (DNA sequencing) or either false-positive or
false-negative results (multiplex ligation-dependent probe amplification [MLPA] deletion screening), due
to selective allelic drop-out. False-negative or false-positive results can occur in MLPA deletion screening
assays due to poor DNA quality.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Online Mendelian inheritance in Man-OMIM:
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=193300 2. Universal Mutation
database-UMD-VHL mutations database page: http://www.umd.be:2020/ 3. Maher ER, Kaelin WG Jr:
von Hippel-Lindau disease (Reviews in Molecular Medicine). Medicine 1997;76:381-391 4. Pack SD,
Zbar B, Pak E, et al: Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by
fluorescence in situ hybridization. Cancer Res 1999;59:5560-5564 5. Richards FM: Molecular pathology
of von Hippel-Lindau disease and the VHL tumor suppressor gene. Expert Rev Mol Med 2001;3:1-27 6.
Current as of January 4, 2013 7:15 pm CST 800-533-1710 or 507-266-5700 or MayoMedicalLaboratories.com Page 1857