von Hippel-Lindau disease (vHL) is a heritable disorder that manifests as multiple abnormalities of various organ systems.  It is believed to result when there is inactivation of a tumor suppressor gene.  Cerebellar hemangioblastomas, retinal angiomas, pheochromocytoma, renal cell carcinoma, renal cysts, pancreatic cysts, papillary cystadenomas of the epididymis and endolymphatic sac tumors are the clinical manifestations that are encountered in this disorder.  The genetic abnormality in this disease has been located on the short arm of chromosome 3.

     Central nervous system and retinal lesions are the most common manifestations.  CNS lesions consist of hemangioblastomas with the most common site of involvement being the cerebellum; however, the brain stem and spinal cord are often involved.  Hemangioblastomas consist of vascular channels lined with endothelium plus the surrounding stromal cells and pericytes.  These tumors are not malignant and do not metastasize.  Retinal angiomas are often multiple and located in the periphery; however, the optic disk or ora serrata may be involved.  Complications include retinal detachment and hemorrhaging, which may result in blindness.  Early detection often allows effective therapy with either lasers or cryotherapy.

     Renal involvement ranges from cystic disease to renal cell carcinoma.  Renal malignancies are common and usually multicentric.  Renal cell carcinomas are the most common cause of death in patients with vHL and constant surveillance along with early detection is imperative..

     Another form of tumor associated with this disorder is pheochromocytoma.  Once patients have been diagnosed with a pheochromocytoma, a search for tumors in sites other than the adrenals is prudent as up to 20% of all cases of pheochromocytoma are the result of underlying vHL.

     Pancreatic cystic lesions are common in vHL.  Nonsecretory islet cell tumors may occur also, and when present may be malignant.  Insulin secreting pancreatic islet cell tumors may also occur in patients with vHL.

     The presence of a retinal or cerebellar hemangioblastoma or a pheochromocytoma or renal cell carcinoma establishes the diagnosis of vHL in a patient with a positive family history.  In cases where there is no family history of vHL, the presence of at least two retinal or cerebellar hemangioblastomas or the presence of one hemangioblastoma plus one visceral tumor establishes the diagnosis.  The National Cancer Institute has proposed the following classification system:

               Type I disease:  vHL without pheochromocytoma;

               Type IIA disease:  pheochromocytomas plus retinal and CNS hemangioblastomas;

               Type IIB disease:  pheochromocytomas, retinal and CNS hemangioblastomas, renal cancers and pancreatic involvement.

     Once the diagnosis is established, strict surveillance to detect disease progression is important to allow early intervention.  An aggressive work-up should be pursued in any patient manifesting specific symptoms.  The Cambridge screening protocol calls for the following:

     Established Diagnosis:

          Annual physical examination and urine testing;

          Annual direct and indirect ophthalmoscopy with fluoroscein angioscopy or angiography;

          Brain MRI or CT scanning every three years until age 50 then every five years;

          Annual renal ultrasound with CT scanning performed every third yeat;

          Annual 24 hour urine VMA testing

     Screening of at Risk Relatives:

          Annual physical examination and urine testing;

          Annual direct and indirect ophthalmoscopy starting at age five.  Annual fluorescein angioscopy or

               angiography from age 10 until age 60;

          Brain MRI or CT scanning every three years ages 15 to 40 then every five years until age 60;

          Annual renal ultrasound with CT scanning performed every third year between the ages of

               20 to 65 years;

          Annual 24 hour urine VMA testing.

     Specific therapy is dependant on the organ system involved.  Cerebellar hemangioblastomas are surgically resected quite frequently with good results; whereas, tumors of the brain stem and spinal cord are much more difficult to treat.  Retinal lesions when detected early, may respond to laser or cryotherapy, but vitrectomy may be required in extreme cases.  Early detection and regular follow-up allows for nephron sparring resection of renal tumors greater than 3 cm in size.  Pheochromocytomas should be resected.

     Genetic testing may be used to identify a pathologic mutation in the vHL gene.  Once the genetic defect has been identified, family members may be screened for the same abnormality.  If the abnormal gene is found in a family member, the appropriate screening tests to monitor for disease should be instituted.  If a family member is negative for the abnormality found in the affected relative, then they may be assured that they are free of disease and screening is unnecessary.  Also, if a patient without a family history is suspected of having vHL, genetic testing may be helpful.  If a gene mutation known to be associated with vHL is identified then certainly an aggressive work up is warranted.