# 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

## 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.