Discussion Author: MS-4 USU Teaching File
Von Hippel-Lindau Syndrome (VHL) is an autosomal dominant disorder (with incomplete penetrance) caused by deletions or mutations in a tumor suppressor gene mapped to chromosome 3p25. This is a relatively rare disease with an estimated prevalence of 1 in 45,000 (approx 6,000-7,000 pts in USA). It is characterized clinically by vascular tumors, including retinal and CNS hemangioblastomas (cerebellar, spinal, and brainstem), cystic lesions of the kidneys, liver, and pancreas. Clear cell renal cell carcinoma occurs in up to 70% of patients with VHL and is a frequent cause of death. Additionally, some families possess a VHL pattern that includes pheochromocytoma. Patients with VHL may also develop endolymphatic sac tumors. Table 1 summarizes a classification scheme for different family patterns proposed by the NCI.
Clinically, the patient with VHL will develop different manifestations of the disease at different ages. The mean age of diagnosis of retinal hemangioblastoma is 25 years (range 1-67 yrs), of cerebellar hemangioblastoma is 30 years (range 11-78 yrs), and of renal cell carcinoma 37 years (range 16-67 years). Symptoms of cerebellar hemangioblastoma may include headache, vomiting, wide-based gait, slurred speech, nystagmus, labile hypertension, positional vertigo, and dysmetric. Erythrocytosis occurs in 5-20% of patients due to erythropoietin generated by hemangioblastomas. Retinal hemangioblastomas are usually asymptomatic if they are in a peripheral location, but if they are centrally located or become large, they can cause profound blindness. Complications include macular edema, glaucoma, and cataract. Renal lesions are asymptomatic and are detected by imaging studies. Endolymphatic sac tumors may cause tinnitus or deafness. In particularly involved cases, pancreatic replacement by cystic lesions may result in IDDM. Up to 50% of patients show only one manifestation of the syndrome.
Diagnosis on clinical grounds requires either a positive family history and the finding of a single retinal or cerebellar hemangioblastoma, pheochromocytoma, or RCC. Pancreatic cysts have been argued to be adequate by some researchers. Renal or epididymal cysts are to common in the general population to make the diagnosis. In the abscence of a family history, two or more retinal or cerebellar hemangioblastomas or one hemangioblastoma plus one visceral tumor must be present to justify the diagnosis. The diagnosis can be confirmed by genetic testing. Screening of family members is imperative.
The VHL gene encodes a protein that inhibits transcription elongation and functions as a tumor suppressor molecule. Loss of the protein allows the unregulated growth of vascular tumors in multiple tissues.
Historically, studies of the natual history of VHL have shown a life expectancy of less than 50 years, with death frequently due to complications of cerebellar hemangioblastoma (47.7%) or metastatic clear cell renal cell carcinoma (32%). This is not believed to represent current expectations, and is expected to be improved because of earlier diagnoses and development of surveillance protocols.
Current recommendations for the surveillance of patients with VHL is summarized in Table 2.
A brief historical note: in 1904, yon Hippel (a German ophthalmologist) first recognized the familial nature of retinal hemangioblastomas. It was not until 1926 that Arvid Lindau (a Swedish ophthalmologist) observed that cerebellar and retinal hemangioblastomas are part of a larger "angiomatous lesion of the CNS", and that the condition was heritable.
Table 1: National Cancer Institute VHL Classification Scheme
I. VHL without pheochromocytomas (most common)
IIA. VHL with pheochromocytomas, retinal and CNS mangioblastoma, and islet cell tumor of pancreas. No pancreatic or renal cysts, milder clinical course.
IIB. VHL with pheochromocytomas, retinal and CNS hemangioblastomas, renal cancers, and
Table 2: Recommendations for monitoring patients with VHL and family members
Age (yrs) Recommendation
0-2 Annual physical and ophthalmologic examination
2 Urinary catecholamines every 1-2 years
11 Biannual MRI of brain and spine, annual ultrasound of abdomen; if renal cysts or tumor
present, CT scans every 6 months
20 Change annual abdominal ultrasound examination to annual CT scan
60 If no evidence of VHL, change MRI of brain and spine to every 3-5 years, change CT scan of abdomen to every other year
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