The most common manifestations of VHL are retinal, cerebellar, spinal and medullary hemangioblastomas, renal cysts and carcinoma, pancreatic cysts, pheochromocytoma and papillary cystadenoma of the epididymis. The clinical diagnostic criteria for VHL were proposed by Melmon and Rosen in 1964 (8). If a family history of retinal or central nervous system hemangioblastoma (Hb) exists, only one Hb or visceral lesion (renal tumors, pancreatic cysts or tumors, pheochromocytoma, papillary cystadenomas of the epididymis) is required to make the diagnosis of VHL (4). Renal cysts and epididymal cysts are too frequent in the general population to be reliable markers of VHL. For isolated cases without a clear family history, two or more Hbs or one Hb and a visceral manifestation is required (1). Relatively few patients exhibit all the manifestations of VHL; about 50% of VHL patients will only have one manifestation of VHL (2,4).
The age of onset of VHL is variable and depends on the expression of the disease within an individual, within a family and the intensity with which asymptomatic lesions are sought. An intensive screening program can greatly increase the number of known affected individuals in a family. Retinal lesions generally occur first. The mean ages (and ranges) of diagnosis of retinal Hb, cerebellar Hb, and renal cell carcinoma are 25 years (1-67), 30 years (11-78), and 37 years (16-67), respectively (4,17), however, only a minority of patients are discovered before age 10 (Figure 1). Families with pheochromocytoma as a principle feature of their disease often develop pheochromocytomas before other manifestations of VHL.
Figure 1. Cumulative probability of developing specific features of
VHL with age. Note that the earliest lesion in VHL is the retinal hemangioblastoma
(RET) followed closely by cerebellar hemangioblastoma (CHB). Renal cell
carcinoma (RCC) manifests later. (reprinted with permission from Maher ER,
Yates JRW, Harries R, Benjamin C, Harris R, Moore AT, Ferguson-Smith MA.
Quart. J of Medicine,1990, 77:1151-63.) It is unusual to make the diagnosis
of VHL for the first time after age 60, however, VHL is a life long diagnosis
and there is no age beyond which new lesions cannot occur (4,12,17,18).
Indeed, if the findings of VHL are sought in elderly asymptomatic family
members, the disease can be found in nearly 100% of those carrying the gene
(1,14).
There are at least three phenotypes of VHL and the NCI has proposed a classification system (Table 1). The first pattern of VHL includes retinal and CNS Hb, renal cysts and cancers, and pancreatic cystic disease but not pheochromocytoma (VHL Type I).
This is the most common form. The second most common pattern of VHL also includes retinal and CNS Hb, but additionally exhibits pheochromocytoma and islet cell tumors of the pancreas; neither cystic disease of the pancreas nor renal cysts or cancers are present (VHL Type IIA). This type of VHL has a milder clinical course. The third and most unusual phenotype of VHL manifests retinal and CNS Hb, pheochromocytoma, renal and pancreatic disease (2).
Historically, the median age of survival is 49 years and the most common cause of death in VHL are from neurologic complications of cerebellar Hb, or metastatic renal carcinoma (1). Approximately 53% die of complications of cerebellar Hb and 32% die of metastatic renal cell carcinoma (4,18,19,20). However, these statistics are likely already out of date due to better diagnostic and surgical techniques.
The diagnosis of VHL may be missed by physicians unaware of the typical constellation of findings. Even when diagnosed, relatives of the patient may not be properly screened and genetic counselling may not be offered. The radiologist may play an important role in recognizing this entity and ensuring that family members are screened. Moreover, radiologists may be the first to recognize the risk of surgery on an organ without assessing the status of other potential sites of disease, particularly pheochromocytoma and CNS hemangioblastomas (18).
The psychological and financial impact of the disease on individuals and families can be devastating. Denial, anxiety, guilt, isolation, overprotectiveness and general personality disturbances can be observed (21). These represent adaptations to the severe chronic stress imposed upon individuals and families with VHL. Fortunately, with careful and early medical attention many complications of VHL can either be avoided or ameliorated. There is growing optimism that the diagnosis of lesions such as hemangioblastomas and renal cell carcinoma, formerly lethal, can be made earlier and more accurately with genetic testing.
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