Handbook of Genetic Counseling/Von Hippel-Lindau Syndrome
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-dependent 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
- CNS hemangioblastoma
- 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
- Features needed for diagnosis
- 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
- Southern blotting
- 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
- CNS hemangioblastoma
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
editThe information in this outline was last updated in Oct 2002.