HPCGG: Lab for Molecular Medicine

VON HIPPEL-LINDAU SYNDROME (VHL)

Gene: VHL at 3p26-p25

Methodology: Bi-directional DNA sequencing of 3 exons
and splice sites and/or deletion/duplication analysis by
MLPA of the VHL gene

Clinical Sensitivity: A mutation is identified in patients
with a clinical diagnosis of VHL 100% of the time. Approximately
72% of VHL mutations will be detected by sequencing and 28%
by deletion/duplication analysis.

Turn-Around-Times:

VHL Gene Sequencing: 2 weeks

VHL Deletion/Duplication Analysis: 3 weeks

VHL Gene Sequencing and
Deletion/Duplication Analysis: 4 weeks

Familial Known Mutation (Sequencing): 2 weeks

Familial Known Mutation
(Deletion/Duplication Analysis): 3 weeks

Sample Requirements: 7cc's blood in an K₃EDTA (purple top) tube

Costs:

VHL Gene Sequencing: $500
VHL Deletion/Duplication Analysis: $600
Familial Known Mutation Test (Sequencing): $250
Familial Known Mutation Test
(Deletion/Duplication Analysis): $600

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Background:
von Hippel-Lindau (VHL) syndrome is an autosomal dominant inherited cancer condition with an incidence of approximately 1 in 36,000 in the general population. It is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal carcinoma; pheochromocytomas; endolymphatic sac tumors; and papillary cystadenomas of the epididymis or broad ligament. Clinical manifestations and disease severity can be highly variable both within and between families. About 80% of individuals diagnosed with VHL have inherited the disorder from a family member and 20% of cases are caused by a new (de novo) mutation.

Mutations in VHL are responsible for causing VHL syndrome. Over 300 mutations have been identified, with most mutations being unique to a family. Approximately 72% of mutations are point mutations detectable by DNA sequencing, with the remaining 28% being partial or complete VHL gene deletions. Genotype-phenotype correlations have been observed in VHL such that there are associations between certain mutations and the risk of either pheochromocytoma or renal cell carcinoma (see chart below).

A clinical diagnosis of VHL is established on certain clinical criteria. In an individual suspected to have VHL with no family history for the disease, two or more characteristic lesions (such as a hemangioblastoma of the retina or brain, or a single hemangioblastoma in association with a VHL-related tumor) can establish a diagnosis. However, in an individual with a positive family history for the disease, one or more VHL-related tumors diagnosed before 60 years of age can establish the diagnosis.

The American Society of Clinical Oncologists recommends that genetic testing be part of the standard management for family members at risk for VHL. In addition to confirming the diagnosis of VHL in patients with clinically evident disease, genetic testing allows for early identification and intervention of individuals at greatest risk for developing VHL prior to the expression of typical clinical manifestations. If a mutation is identified in an asymptomatic individual, regular and serial outpatient follow up is indicated. Referral to specialists with expertise in the management of VHL is highly recommended for patients with established disease as well as family members who are found to have mutations. Longitudinal study is necessary to survey for the development of clinical manifestations as well as to optimize treatment. If clinically unaffected members of a family with an identified causal mutation for VHL are found not to carry that mutation, they can be definitively diagnosed as unaffected with VHL and reassured that neither they nor their offspring will be at higher risk compared to the general population to develop this disorder, except in cases where germline mosaicism occurs.

Synonyms: von Hippel-Lindau syndrome (Online Mendelian Inheritance in Man #193300)

Other diseases caused by mutations in the same gene: Familial pheochromocytoma or nonfamilial bilateral pheochromocytoma (VHL type 2C; OMIM#608537); Chuvash polycythemia (OMIM# 263400); sporadic mutations in VHL gene can give rise to VHL-type tumors (RCC, pheochromocytoma) without other associated tumor characteristics of the heritable disease (Knudson 2 hit hypothesis)

Gene	Protein	OMIM#	Locus
VHL	Von Hippel-Lindau disease tumor suppressor	608537	3p26-p25

Epidemiology: ~1/36,000 births per year (prevalence)

Both males and females are affected in equal frequency
No known racial predilection

VHL syndrome classification exists for phenotype as well as genotype.

Phenotype	Genotype
Type 1: low risk for pheochromocytoma	Truncating or missense mutations, deletions
Type 2: high risk for pheochromocytoma	Missense mutations
Type 2A: low risk of renal cell carcinoma and pancreatic cysts	Missense mutations
Type 2B: high risk of renal carcinoma and pancreatic cysts	Missense mutations
Type 2C: risk for pheochromocytoma only	Missense mutations

Inheritance Pattern: Autosomal dominant

Each child of an affected individual has a 50% (or 1 in 2) chance of inheriting the mutation.
Reduced penetrance and variable expressivity exists.
80% of cases are inherited and about 20% are due to a de novo (new) mutation.
Germline mosaicism has been reported but the incidence is unknown.

Test Indications:

Patients who have clinical features associated with VHL syndrome (confirmatory diagnostic testing). A positive test result confirms a diagnosis of VHL in a symptomatic individual. If a familial mutation is known, a positive test result confirms the presence of the mutation in an asymptomatic family member.
Patients with family history of pheochromocytoma, bilateral/multifocal pheochromocytomas, or unilateral pheochromocytoma before 20 years of age.
Predictive testing for at-risk family members (parents, siblings, and children) of an individual diagnosed with VHL and an identified VHL mutation.

Test Outcomes:

The detection of a pathogenic mutation in one copy of the VHL gene is considered a positive test result.
Knowledge of a specific mutation may provide information about age of onset, certain clinical characteristics, and disease severity in symptomatic individuals.
A negative test result does not rule out VHL. Germline mosaicism for a VHL mutation has been reported. Large deletions and gene rearrangements of the gene or regulatory mutations could be responsible for the individual's clinical features.

Turn-Around-Times:

	VHL Gene Sequencing:	2 weeks
	VHL Deletion/Duplication Analysis:	3 weeks
	VHL Gene Sequencing and Deletion/Duplication Analysis:	4 weeks
	Familial Known Mutation (Sequencing):	2 weeks
	Familial Known Mutation (Deletion/Duplication Analysis):	3 weeks

Methodology: Bi-directional sequence analysis is performed on 3 exons and splice sites in the VHL gene. Gross deletions and duplications of the VHL gene are detected by Multiplex Ligation-dependent Probe Amplification (MLPA).

Analytical and Clinical Sensitivity: The gene sequencing assay is greater than 99.9% accurate in detecting mutations in the sequence analyzed. MLPA is 98% accurate in detecting deletions and/or duplications at the analyzed locus. According to current literature, approximately 72% of VHL mutations are point mutations or small deletions/insertions and 28% are large deletions of the gene. VHL is the only known gene to be associated with von Hippel-Lindau syndrome. A mutation is identified in individuals with a clinical diagnosis of VHL 100% of the time.

Cost and CPT codes:

VHL Gene Sequencing

Cost: $500
CPT codes: 83891(1), 83894(1), 83898(3), 83904(3), 83909(1), 83912(1)

VHL Deletion/Duplication Analysis

Cost: $600
CPT codes: 83891(1), 83896(8), 83900(1), 83901(6), 83909(1), 83912(1)

Testing for Familial Known Mutation (Sequencing)

Cost: $250
CPT codes: 83891(1), 83894(1), 83898(1), 83904(1), 83909(1), 83912(1)

Testing for Familial Known Mutation (Deletion/Duplication Analysis)

Cost: $600
CPT codes: 83891(1), 83896(8), 83900(1), 83901(6), 83909(1), 83912(1)

If you have any questions, please call the Laboratory for Molecular Medicine at 617-768-8500 or email us at LMM@partners.org