Handbook of Genetic Counseling/Von Hippel-Lindau Syndrome

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-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

 * 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