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.