The presence of visceral cysts of the kidney, pancreas,
and epididymis occurs not only as features of VHL but also in the general
population; however, the association of those cysts with retinal, CNS
hemangioblastoma may represent a more significant association for the
disease. The use of markers as presymptomatic diagnosis of VHL in patients
with epididymal cysts has been demonstrated to be not suitable as a
diagnostic criterion. Similarly, the genetic studies suggested that VHL with
or without pheochromocytomas is caused by defects within the same gene may
be misleading. Renal cell carcinoma occurs as part of VHL; a second more
proximal region of chromosome 3, 3p14.2, is responsible for “pure familial
renal cell carcinoma.” It has been suggested that the likelihood of VHL
being present in an individual showing a single ocular angioma is
conditional upon the age of presentation, results of DNA analysis, family
history of VHL, and results of systemic screening. The presence of a
positive VHL family history can lead to the diagnosis in a patient with at
least 1 typical VHL tumor. Typical VHL tumors are retinal, spinal, and
cerebellar hemangioblastoma; renal cell carcinoma; and pheochromocytoma.
Endolymphatic sac tumors and multiple pancreatic cysts suggest a positive
carriership in the presence of a positive VHL family history because they
are uncommon in the general population. In contrast, renal and epididymal
cysts occur very frequently in the general population and are, as sole
manifestations, not reliable indicators for VHL disease. In patients with a
negative family history of VHL-associated tumors, a diagnosis of VHL disease
can also be made on the basis of two or more hemangioblastomas or a single
hemangioblastoma in association with a visceral manifestation (e.g.,
pheochromocytoma or renal cell carcinoma). The suspicion for VHL can also be
raised in a patient with classic VHL disease (meeting clinical diagnostic
criteria) and/or first-degree family members; and/or a person from a family
in which a germline VHL gene mutation has been identified (presymptomatic
test). Also, a VHL-suspected patient, i.e., one with multicentric tumors in
one organ, bilateral tumors, two organ systems affected, or one
VHL-associated tumor at a young age (less than 50 years for hemangioblastoma
and pheochromocytoma or less than 30 years for renal cell carcinoma); or a
patient from a family with hemangioblastoma, renal cell carcinoma, or
pheochromocytoma only can also be diagnosed.