Von HippelLindau

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Von Hippel-Lindau

• A Hereditary Cancer Syndrome

Diane Stirling
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Von Hippel-Lindau

• What is it?
• Natural history
• Genetics
• Expression
• Genetic testing

• Diagnostic criteria
• Screening
• Family experiences
• Clinical experience /service development

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What is vHL?

• An inherited genetic change which predisposes the
  individual to a wide variety of tumours, both
  benign and malignant
• First identified 100 years ago
• Incidence (gene frequency) 1 in 100 000

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Natural History

• Mean age of expression 26 years
• 97 expressing the disease by age 60 years
• Studies estimate a life expectancy of less than
  50 years
• (before surveillance programs introduced)

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Genetics

• Autosomal dominant tumour suppressor gene
• Gene identified in 1993
• Chromosome 3p25-26
• Coding region
• contains 3 Exons
• Gene product
• recently linked to epithelial growth factor

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Autosomal Dominant Inheritance
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Conforms to Knudsons 2 hit hypothesis

• Individuals with the disease are born with one
  mutated copy of the vHL gene
• Tumours develop when the other normal copy is
  inactivated in a susceptible cell
• (people with 2 normal copies of the vHL gene can
  develop sporadic CH or RCC if both copies are
  inactivated)

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Expression of the disease

• cerebellar haemangioma
• retinal angioma
• renal cell carcinoma
• spinal haemangioma
• phaeochromocytoma
• Renal, pancreatic and epidydimal cysts
• frequently found but incidence not accurately
  assessed
• Endolymphatic sac tumours
• (Mayer et al 1990)

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Cerebellar Haemangioma

• Most frequent complication (59)
• Mean age at diagnosis 29 years (or-10)
• Benign
• MRI scanning more sensitive than CT
• Treatment - surgical (? Symptomatic lesions)
• (approx 30 of all CH occur as part of vHL)

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Retinal Angioma

• Joint most frequent complication (59)
• Earliest age of onset of all complications
• Estimation of risk (Maher et al 1990)
• age 5 years - lt1
• age 10 years - 5
• Small lesions - asymptomatic
• Treatment - laser therapy
• (untreated lead to retinal detachment,
  haemorrhage and visual loss)

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Renal Cell Carcinoma (RCC)

• Occurs in 28 of individuals
• Leading cause of death in vHL
• (secondary to CH)
• vHL related RCC occurs at an earlier age than
  sporadic RCC
• often multiple and bilateral
• CT scanning is more sensitive than U/S
• Treatment - surgical
• (with preservation of renal tissue if possible)

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RCC (2)

• Diagnosis before symptoms occur confers a better
  prognosis
• Symptomatic - metastatic disease is present in
  20-30 of presenting cases
• Relapse - most commonly to lung, bone, distal
  nodes and liver
• (Familial Non-vHL renal cell carcinoma)

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Spinal Haemangioma

• Occurs in 13 of individuals
• MRI more sensitive than CT
• Treatment surgical
• Symptoms may include pain, sensory loss and
  muscle weakness

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Phaeochromocytoma

• Occurs in 9 of individuals
• major risk is hypertensive crisis during surgery
• treatment - surgical
• Genotype/phenotype correlation
• Type 1 vHL / absence of phaeo
• deletions or premature termination mutations
• Type 2 vHL / presence of phaeo
• missense mutations

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Others

• Pancreatic lesions
• usually asymptomatic
• cancers unusual but can occur

• Endolymphatic tumours
• tinnitus or deafness

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Diagnosis in individuals without a family history

• Clinical diagnosis is made based on -
• Two or more retinal or cerebellar haemangiomas
• OR
• One retinal or cerebellar haemangioma and one
  visceral tumour

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Diagnosis in Individuals with a Family History

• Clinical diagnosis is made based on
• - a single retinal angioma
• or a cerebellar haemangioma
• or a renal cell carcinoma
• or a phaeochromocytoma
• or possibly multiple pancreatic cysts
• ( Renal and epydidymal cysts are not sufficient )

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Genetic Testing

• Direct gene test
• about 20 of families have large deletions
• about 60 have missense, nonsense or frameshift
  mutations
• about 20 of families will have no mutation or
  deletion identified
• Linkage analysis
• may be possible

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Genetic Testing - Advantages

• Informs medical care
• removal from screening if negative
• emphasizes need for screening if positive
• Early detection of complications improves
  prognosis
• Removes uncertainty

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Genetic Testing - Disadvantages

• Living with the knowledge of risk
• Preventative treatment not available
• Treatment only after expression of the disease

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Service Development Outcomes

• Identified co-ordinator for screening
• Protocol for screening
• Improved screening service (arranged in one day)
• convenience for the individual
• lower anxiety provoking events
• vHL database
• for recall
• audit of screening protocol
• audit of natural history of vHL

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Screening

• What
• How often
• When to start
• When to stop

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Developing a Screening Protocol
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Edinburgh Screening Protocol
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Screening Considerations

• Disadvantages - mutagenic radiation, stress and
  anxiety
• Sensitivity and reliability - false positive and
  false negative rates
• Cost
• Availability

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Family 2 - issues

• ? Informed consent for testing
• ? Directiveness of counselling
• Service provision
• Confidentiality

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Database

• Data recorded on 97 individuals ( 5 main
  Families)
• 28 gene carriers or affected individuals
• 17 individuals at 50 risk
• 4 individuals at 25 risk
• TOTAL OF 37 INDIVIDUALS ON WGH SCREENING PROGRAMME

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Future Developments

• Patient held records
• Collate and publish data

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Summary

• Autosomal dominant
• Predisposition to a variety of tumours
• cerebellar haemangioma
• retinal angioma
• renal cell carcinoma
• spinal haemangioma
• phaeochromocytoma
• Single gene 3p25-26
• Presymptomatic testing if mutation identified in
  an affected member
• Screening for individuals at increased risk