Handbook of Genetic Counseling/Von Hippel-Lindau Syndrome

< Handbook of Genetic Counseling

Von Hippel-Lindau Syndrome

Overview of Cancer

Cancer is caused by a mixture of genes and environment
- All cancer is genetic, but not all cancer is hereditary
- Most cancers are sporadic
Cells in our bodies are always growing and dividing
- Genes control and regulate cell growth
- Changes in these genes result in a cell that grows out of control
  - Uncontrolled cell growth is cancer
  - Changes in DNA occur due to damage to genetic material
    - DNA contains instructions for making proteins
    - Proteins determine how cells work and regulate our development
    - DNA must be copied each time a cell divides, and mistakes can occur in this process
Hereditary cancer occurs when a person inherits one non-working copy of a gene
- One step closer to developing cancer than person with two working copies
- Features of hereditary cancer:
  - Earlier age of onset
  - Multiple generations affected
  - Bilateral or multiple primary cancers
  - Siblings both affected with related cancers

Etiology of VHL

VHL gene located on chromosome 3p26-25
- Tumor suppressor gene
- Normal gene product has several functions:
  - Transcriptional regulation by interaction with elongin
  - Post-transcriptional repression of genes induced by hypoxia
  - Regulation of p27 (cyclin-dependant kinase inhibitor)
- Over 150 mutations have been identified
Incidence is 1/35,000 to 1/40,000
- 5-20% of mutations are de novo
- Penetrance is 80-90%
Autosomal dominant inheritance
There is genotype-phenotype correlation

Clinical Features

Hemangioblastoma
- CNS hemangioblastoma
  - Characteristic lesion of VHL
  - 80% develop in brain and 20% in spinal cord
  - Clinical symptoms
    - Headache, vomiting, and gait disturbance or ataxia if in brain
    - Pain, sensory and motor loss, or asymptomatic if in spinal cord
  - Generally slow growing but may also be rapidly enlarging cysts in brain causing hydrocephalus and papilledema
- Retinal
  - Found in about 70% of patients and are often initial manifestations
  - May be detected on ophthalmoscopy
  - Clinical symptoms
    - Asymptomatic in some individuals
    - Visual field defect
    - Loss of visual activity due to retinal detachment or hemorrhage
  - Number of hemangiomas doesn't increase with age but probability of vision loss does
Renal lesions
- Multiple renal cysts are common
- Renal cell carcinoma occurs in about 40% of patients
  - Usually clear cell type
  - Develop within cyst or in surrounding parenchyma
  - Leading cause of mortality
Pheochromocytoma
- May cause sustained or episodic hypertension or be asymptomatic
- Located on one or both adrenal glands usually but may be in other places
- Rarely cause malignant degeneration
Pancreatic lesions
- Most are simple cysts and are usually multiple
- Rarely cause endocrine or exocrine insufficiency
  - Cysts in head of pancreas can cause biliary obstruction
  - Neuroendocrine tumors of pancreas can develop and become malignant
Endolymphatic sac tumors (10% of patients)
- Cause deafness of varying degrees of severity
- Vertigo or tinnitus may be presenting complaint
- Large tumors can invade other cranial nerves
Epididymal tumors
- Relatively common in males
- May cause infertility if bilateral
- Women may develop equivalent papillary cystadenoma of broad ligament - uncommon
Natural history
- Wide variation in age of onset of symptoms
- Organ system involvement and disease severity also vary greatly

Genotype - Phenotype Correlation

Type 1 - no pheo
- Partial gene deletion
- Small insertions or deletions (frameshifts)
- Nonsense mutations
- Splice site mutations
Type 2 - with pheo
- Missense mutations
- Type 2A
  - Without renal cell carcinoma and pancreatic cysts
  - Y98H, Y112H, V116F, L188V
- Type 2B
  - With renal cell carcinoma and pancreatic cysts
  - R167Q and R167W
- Type 2C
  - With pheos only
  - V155L and R238W

Diagnosis

Clinical diagnosis
- Features needed for diagnosis
  - Isolated case with two or more characteristic lesions
  - Asymptomatic individual with positive family history with one or more of following
    - Retinal hemangioblastoma
    - Spinal or cerebellar hemangioblastoma
    - Pheochromocytoma
    - Multiple pancreatic cysts
    - Epididymal cystadenoma
    - Multiple renal cysts
    - Renal cell carcinoma before age 60
- Tests used to make diagnosis
  - CT scans or MRI to look for CNS and visceral tumors
  - Ultrasound exam of epididymus, broad ligament, and possibly kidneys
  - Radioiodine labeled MIBG if extra-adrenal tumors are susected
  - Urinary catecholamine metabolite analysis
    - VMA, metanephrine, and total catecholamine
    - Suggest presence of pheos even if hypertension not present
Molecular genetic testing
- Available clinically
- For cases that meet strict clinical criteria, mutation detection nears 100%
  - Southern blotting
    - Detects complete or partial gene deletions
    - Responsible for about 28% of cases
  - DNA sequence analysis
    - Of all three exons to detect point mutations
    - Missense mutations not previously characterized must be interpreted with caution
- Indicated in all individuals with known or suspected VHLdiagnosis
- Prenatal testing
  - For pregnancies at 50% risk if mutation identified in affected parent
  - Typically adult-onset so requires careful genetic counseling

Treatment/Management

Surveillance
- DNA testing in at-risk family members can reduce need for costly screening in those who test negative
- Early recognition of manifestations may allow for improved outcome
- Ophthalmological screening beginning at age 5
- Annual blood pressure monitoring and measurement of urinary catecholamine metabolites beginning at age 5 in families with pheos
- Annual abdominal ultrasound beginning at age 16
- CT or MRI of suspicious lesions in kidney, adrenal gland, or pancreas
- Possible baseline MRI of brain and spine in young adults
Management of tumors
- CNS hemangioblastoma
  - Some advocate early surgical removal while others follow lesions with imaging
  - Most lesions eventually require intervention
  - Gamma knife surgery can be used for small tumors or those in inoperable sites
  - Surgical complications include paraplegia and operative mortality (10%)
- Retinal hemangioblastoma
  - Laser and cryosurgery used with varying degrees of success depending on location, size, and number of lesions
  - Recurrent tumors have been noted
- Renal cell carcinoma
  - Early surgery is best option
  - Renal transplantation in patients who require bilateral nephrectomy
- Pheochromocytoma
  - Surgically removed
  - Preoperative treatment with alpha-adrenergic blockade for 7-10 days
- Endolymphatic sac tumors
  - Slow growing
  - Possible deafness if removed
- Epididymal or broad ligament papillary cyst adenomas usually don't require surgery

Resources

American Cancer Society

1-800-227-2345

Web: www.cancer.org

VHL Family Alliance

1-800-767-4845

Email: info@vhl.org

Web: www.vhl.org

References

www.geneclinics.org, www.cancer.org, www.vhl.org
Hes FJ, et al. "Clinical Management of Von Hippel-Lindau (VHL) Disease." The Netherlands Journal of Medicine (2001) 59: 225-234.

Notes

The information in this outline was last updated in Oct 2002.

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