von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by a mutation in VHL, a tumor suppressor gene.1 VHL is found on chromosome 3 and, when mutated, can lead to uncontrolled cellular growth and oncogenesis. Lack of VHL protein also increases angiogenesis, which makes many subsequent tumors highly vascular malignancies.2,3

The incidence of VHL disease is about 1 per 36,000 live births. The most common VHL-related tumors are found in the central nervous system (CNS) and include hemangioblastomas and endolymphatic sac tumors. Tumors outside the CNS are most commonly found within the pancreas, adrenals (pheochromocytomas), and kidneys (renal cell carcinomas; RCC).

Close to 60% of all patients with VHL will develop RCC or renal cysts. Both are typically bilateral and found in multiple locations within the kidney. RCCs are found in 24% to 45% of patients with VHL and are the primary inherited renal cancer. They are always of the clear cell subtype.4

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The mean age of RCC onset is 39 years old, which is 25 years less than the mean age of the typical patient.5 As onset can range from 16 to 67 years old, screening for RCC is recommended when patients are as young as 10.

Compared with RCCs, renal cysts are less common (15%) in patients with VHL disease, though they must be closely monitored as they can be premalignant. If the renal cyst is complex (has solid components), there is a significant chance that the solid components are harboring RCC cells.

Patients with VHL disease who develop RCC can be asymptomatic for years before clinically presenting. These patients can develop similar symptoms to those with sporadic RCC, including flank pain, hematuria, weight loss, and a palpable flank mass. Although RCC-specific symptoms may be similar, patients with VHL-associated RCC could have other symptoms linked directly to the syndrome.

When performing a history and physical, it is therefore crucial to focus on the potential neurologic, ophthalmic, abdominal, and genitourinary findings that may help to identify patients with VHL disease.

Contrast-enhanced cross sectional imaging such as computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen is optimal for diagnosing RCC in patients with VHL disease. It is important, however, to consider the patient’s kidney function, age, and potential cumulative exposure to radiation before proceeding with either test. For patients age 10 and above, ultrasound and MRI with and without contrast is recommended yearly (unless the patient is pregnant).