Von Hippel-Lindau disease

Early diagnosis of von Hippel-Lindau disease is critical because of the prognostic implications for both patients and their families. Unless the diagnosis is considered, the physician may incorrectly assume that the patient has an isolated lesion.

Illustrative Case

After six months and a total of 11 visits to a family practice clinic, a local emergency department and offices of neurologic, urologic and otolaryngolic consultants (during which complete neurologic, funduscopic and cardiovascular evaluations, including complete blood count, SMA-20, electrocardiogram and Holter monitoring, were normal), a previously healthy 20-year-old man with a single near-syncopal event and a history of recurrent headaches, dizziness and malaise was finally diagnosed by a neurosurgeon as having von Hippel-Lindau disease. Medical and surgical histories were unremarkable except for three small epididymal cysts, the significance of which went unrealized by the neurologist, urologist and primary care physicians. The neurosurgeon based the diagnosis on a magnetic resonance image (MRI) showing a heterogeneous midline mass inferior to the fourth ventricle and on a previously unavailable historic detail - the patient's maternal grandmother had an intercranial hemangioblastoma removed during her childhood. After excision of the tumor, a computed tomographic (CT) scan of the abdomen was performed to detect pancreatic and hepatic neoplasms, lesions that commonly affect patients with von Hippel-Lindau disease. The CT scan revealed pancreatic cysts but there was no evidence of hepatic, pancreatic or renal malignancy.

Definition and Diagnosis

Von Hippel-Lindau disease is a rare phakomatosis that in the majority of cases is inherited in an autosomal dominant fashion, with penetrance approaching 100 percent.[1-4] The incidence of von Hippel-Lindau disease is difficult to determine because of varying definitions of what constitutes the disease, underreporting and underdiagnosis. The gene frequency is approximately one person per 100,000 population.[3] Patients with von Hippel-Lindau disease are predisposed to the development of hemangioblastomas of the cerebellum, retina and spinal cord; renal, pancreatic and epididymal cysts; renal carcinoma, and pheochromocytoma.[1-4]

The pathogenesis of von Hippel-Lindau disease is unknown. Geneticists have consistently observed allelic depletion on the short arm of chromosome 3.[5] Presumably the gene at the von Hippel-Lindau disease locus acts as a tumor-suppressor gene.[6] Von Hippel-Lindau disease behaves according to Knudson's "two-hit" theory of carcinogenesis: when one allele is defective due to an inherited genomic trait or a sporadic genetic event, only a mutation in the remaining allele is needed for tumor-suppressor activity to be lost. Therefore, the risk of malignancy is high in patients who inherit the first defect.[5-7]

Initial manifestations of von Hippel-Lindau disease are varied. As in the illustrative case, epididymal cysts can be an early sign of the disease.[7] Retinal hemangiomatosis was the most frequent initial manifestation in Neumann's analysis of 338 cases of von Hippel-Lindau disease.[8] However, in Huson and colleagues' study, cerebellar hemangioblastomas accounted for the majority of the presenting lesions.[9]

Other presentations of von Hippel-Lindau disease (in descending order of frequency) include renal cell carcinoma, pheochromocytoma, and spinal hemangioblastoma.[1-3] The most common abdominal lesions (in descending order of frequency) are renal cysts, pancreatic cysts, renal cell carcinoma and pheochromocytoma.[4] In Lamiell's study of 43 members of the same kindred, renal cysts and renal adenocarcinoma were the most frequent manifestations of the disease.[7] Pancreatic cysts are usually not premalignant in patients with von Hippel-Lindau disease. Renal cysts frequently undergo malignant degeneration in patients with von Hippel-Lindau disease, but these cysts do not always develop into renal cell carcinoma.

Von Hippel-Lindau disease should be suspected in any patient with renal, hepatic, pancreatic or epididymal neoplasms, or in a patient with a family history of von Hippel-Lindau disease, pheochromocytoma or renal cell carcinoma.[2] It is more probable in patients with retinal or central nervous system hemangioblastomas. Renal adenocarcinoma in the presence of renal cysts is virtually pathognomonic for von Hippel-Lindau disease.[7]

Early symptoms of the most common lesions of von Hippel-Lindau disease include occipital or frontal headache, intermittent vomiting, leg weakness, loss of sensation, impaired proprioception, back pain, syncope, vertigo, ataxia, decreased visual acuity, floaters, microscopic hematuria, intermittent blood pressure elevation or palpitations.[2] Gait disturbances, slurred speech, papilledema, nystagmus, paraplegia, subarachnoid hemorrhage, urinary incontinence, glaucoma, blindness and palpable abdominal masses are late manifestations.[2]

Most investigators use the widely accepted criteria proposed in 1964 by Melmon and Rosen[10]: the presence of two or more hemangioblastomas or a single hemangioblastoma in association with at least one visceral manifestation.[7,10] In a patient whose family history includes a retinal or central nervous system hemangioblastoma, only one hemangioblastoma or visceral manifestation is required to make a diagnosis of von Hippel-Lindau disease.[7,10] (Table 1). Patients who do not fulfill all criteria (i.e., a patient with a single hemangioblastoma and no visceral abnormality or family history) are considered to have an incomplete or arrested form of von Hippel-Lindau disease.[2,7]

Screening and Management

To help identify relatives who may be at risk of von Hippel-Lindau disease, a family pedigree is essential. DNA testing has become standard in the identification of the von Hippel-Lindau disease gene and in more accurate prediction of the probability of von Hippel-Lindau disease in a relative who is at risk.[7]

First degree relatives of patients with von Hippel-Lindau disease run a 50 percent risk of the disease.[11] Therefore, at risk relatives (i.e., siblings, children and parents) should undergo thorough screening protocols to detect silent lesions.

In a disease-free relative, the probability of developing von Hippel-Lindau disease decreases progressively with age.[7] However, as shown by Neumann[8] and Horton and associates,[12] there is no age at which a family member can be considered completely free of the risk of developing manifestations of von Hippel-Lindau disease. Initial manifestations have been reported as late as 69 years of age.[6] Continued screening is encouraged, even when those at risk reach 50 years of age and older.[3]

Presymptomatic screening of patients with von Hippel-Lindau disease and their at-risk relatives using a version of the screening protocol in Table 2 has been supported by numerous studies.[2-4,7-9,11,13] No author has suggested that the cost or risk of complications from screening outweighs the benefits of early detection. Early detection can prevent serious complications, such as irreversible neurologic damage or blindness.

Indirect ophthalmoscopy is the screening test of choice for the detection of retinal lesions.[7] Retinal detachment and blindness can be prevented with early identification of retinal lesions.[7] Most retinal lesions are treated with laser photocoagulation or cryotherapy.[1,7]

Jennings and Gaines[4] have proposed a roentgenographic screening and surveillance protocol in which the frequency of CT scanning is every three to five years. For initial screening, complete cranial CT scanning is performed. If the results are negative, then only the posterior fossa is regularly scanned.[4]

Intracranial hemangioblastomas and renal cell carcinomas are best detected by MRI or CT scanning. Ultrasound may not elucidate characteristics of renal cell carcinoma when there are coexistent renal cysts.[4] Lamiell and colleagues[7] found that imaging studies are invaluable for screening and surveillance, but blood tests are of little or no value, and urine testing is of uncertain value.

Physicians, especially family physicians, should be mindful of the psychologic impact of screening. In two studies, fear, guilt, blame, anxiety, depression and fatalism were exacerbated by screening.[14.15]

Patients with von Hippel-Lindau disease usually die of complications of cerebellar tumors or renal cell cancer.[2,3] With neurosurgical advancements, renal cell cancer is becoming the most common cause of death.[2,3,16] Unlike renal cysts, pancreatic cysts are rarely premalignant.[2,3] Surgery is unnecessary for benign cysts, and does not prevent malignant degeneration, but biopsy may help to rule out malignancy.[7]

Cerebellar hemangioblastomas are benign tumors and do not metastasize,[9,12,16] are not amenable to irradiation, and are resected only if symptomatic.[3,10,16] This should be explained to the neurologically asymptomatic patients before cranial CT imaging is performed, since some patients may prefer not to know if they harbor a quiescent lesion.

EMIL P. LESHO, CPT, MC, USA is stationed at Ft. Lewis, Tacoma, Wash., where he is a resident in the Department of Medicine at Madigan Army Medical Center. He received his medical degree from the Philadelphia College of Osteopathic Medicine, and he served one year in the family practice residency program at Warren Hospital, Phillipsburg, N.J., before being called to active duty during the Persian Gulf War.

REFERENCES

[1.] Cannon M, Boyd-Monk H. Nursing grand rounds: von Hippel-Lindau disease. J Ophthalmic Nurs Technol 1986;5:174-9. [2.] Martz CH. Von Hippel-Lindau disease: a genetic condition predisposing tumor formation. Oncol Nurs Forum 1991;18:545-51. [3.] Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT, et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med 1990;77:1151-63. [4.] Jennings CM, Gaines PA. The abdominal manifestation of von Hippel-Lindau disease and a radiological screening protocol for an affected family. Clin Radiol 1988;39:363-7. [5.] Seizinger BR, Smith DI, Filling-Katz MR, Neumann H, Green JS, Choyke PL, et al. Genetic flanking markers refine diagnostic criteria and provide insights into the genetics of Von Hippel Lindau disease. Proc Natl Acad Sci USA 1991;88:2864-8. [6.] Maher ER, Yates JR, Ferguson-Smith MA. Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma. J Med Genet 1990;27:311-4. [7.] Lamiell JM, Salazar FG, Hsia YE. Von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine 1989;68:1-29. [8.] Neumann HP. Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. VASA 1987;16:220-6. [9.] Huson SM, Harper PS, Hourihan MD, Cole G, Weeks RD, Compston DA. Cerebellar haemangioblastoma and von Hippel-Lindau disease. Brain 1986;109(Part 6):1297-310. [10.] Melmon KL, Rosen SW. Lindau's disease: review of the literature and study of a large kindred. Am J Med 1964;36:595-617. [11.] O'Connor GM, Littler MJ, Beck L. Von Hippel-Lindau disease: preventable morbidity by screening. J R Coll Surg Edinb 1989;34:282. [12.] Horton WA, Wong V, Eldridge R. Von Hippel-Lindau disease: clinical and pathological manifestations in nine families with 50 affected members. Arch Intern Med 1976;136:769-77. [13]. Goldhammer L. 20-year survival of von Hippel-Lindau hemangiomatosis: case report. Va Med 1990;117:255-8. [14.] Yuen J, Jewell R, Lamiell MJ, Hsia YE. Impact of a late-onset autosomal dominant precancerous disease on the knowledge and attitudes of a large kindred. Birth Defects 1984;20:135-46. [15.] Neumann HP. Prognosis of von Hippel-Lindau syndrome. VASA 1987;16:309-11. [16.] Neumann HP, Eggert HR, Weigel K, Friedburg H, Wiestler OD, Schollmeyer P. Hemangioblastomas of the central nervous system. A 10-year study with special reference to von Hippel-Lindau syndrome. J Neurosurg 1989;70:24-30.

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