Handbook of Genetic Counseling/Von Hippel-Lindau Syndrome

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Von Hippel-Lindau Syndrome

Overview of Cancer[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

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