VHL disease is an autosomal dominant condition that affects approximately 1 in 36,000 live births worldwide. The VHL gene is located on the short arm of

chromosome 3 (3p25) and is the only known susceptibility locus associated with the condition. It is a well-studied tumor suppressor gene that demonstrates loss of heterozygosity in RCCs of patients with VHL disease and sporadic clear cell RCC as well.

VHL disease is a multisystem condition, and an affected individual is at risk to develop any of the following lesions: (1) hemangioblastoma of the cerebellum, spine, or retina; (2) papillary cystadenoma of the epididymis, the adnexal organs, or the endolymphatic sac; (3) adrenal pheochromocytoma and occasionally extra-adrenal paraganglioma; (4) pancreatic cysts, serous cystadenomas, and neuroendocrine tumors (NETs); and (5) multiple and/or bilateral RCC and cysts.

Although the penetrance of VHL disease is 100%, where individuals will develop at least one associated lesion by their sixth decade of life, the expressivity is highly variable even among individuals sharing the same gene mutation. The disease is phenotypically categorized into type 1 and type 2 based on risk for developing pheochromocytoma, with the latter further divided into three subtypes (2A, 2B, and 2C) based on risk for developing RCC. The genotype/phenotype correlations within each type are described in Table 10.2.

RCCs of patients with VHL disease are of exclusively clear cell histology. The lifetime risk for developing RCC is 25% to 45%, and when renal cysts are included, the
risk rises to 60%.⁵ Renal cysts and RCCs develop at an earlier age in patients with VHL in comparison to sporadic counterparts, with an average age of 39 years (range, 16 to 67 years).⁵ Cystic lesions are typically asymptomatic; however, complex cysts must be monitored closely with computed tomography (CT) or magnetic resonance imaging as they will harbor a visibly solid RCC component. RCC will often arise from noncystic parenchyma as well.

With the exception of RCC and pancreatic NETs, the malignancy risk with VHL-associated tumors is very low. Renal lesions and hemangioblastoma of the cerebellum, spine, or retina are common presenting lesions in VHL. The risk for developing a single hemangioblastoma of the spine, cerebellum, and brainstem is 60% to 80%, and the average age is 33 years (range, 9 to 73 years),⁵ although most patients can develop multiple lesions at any point in their lifetime. Patients may remain completely asymptomatic especially during periods of no growth or slow growth. Surgical resection is delayed until onset of symptoms.

Retinal hemangioblastomas (retinal angiomas) are usually multifocal and bilateral. These hypervascular tumors can lead to retinal detachment and vision loss. Retinal hemangioblastomas have been observed in 25% to 60% of patients with an average age of 25 years (range, 1 to 67 years). Approximately 5% of lesions are seen younger than 10 years, making genetic testing of at-risk children essential as affected children should undergo annual retinal examinations beginning at birth. Pheochromocytoma has also been observed in young children and can present as a hypertensive crisis. The average age at presentation is 30 years (range, 5 to 58 years), and the risk is 10% to 20%.⁵

Pancreatic manifestations include multiple simple cysts and serous cystadenomas (47% and 11%, respectively), which follow a benign course and are almost always asymptomatic in patients. Pancreatic NETs are less common (15%); however, approximately 2% undergo malignant transformation.⁶ A NET tends to be indolent and is seldom the initial presenting lesion; however, close monitoring is indicated for timing of surgical resection.

A less common manifestation of VHL is a papillary cystadenoma of the endolymphatic sac, or inner ear, which is extremely rare in the general population but more prevalent in VHL disease (∼11%). Papillary cystadenomas may also arise in the epididymis in men and less commonly in the adnexal organs in women.

The VHL gene was cloned by Latif et al.⁷ in 1993 and is the most well studied of the familial RCC syndromes. Loss of VHL function has been demonstrated to cause RCC formation in VHL disease as well as in the majority of sporadic clear cell RCCs.⁸,⁹ The VHL gene encodes the pVHL protein, which in normoxic conditions forms a complex with elongin B, elongin C, Cullin 2, and Rbx1. The VHL complex targets HIF-1α and HIF-2α for ubiquitin-mediated degradation. The HIF-1α and HIF-2α
genes, along with HIF-3a, encode the a subunit of the HIF heterodimer. In hypoxic conditions, the VHL complex does not interact with HIF-1a and HIF-2a, leading to an accumulation of these subunits and downstream transcription of HIF-dependent genes. Loss of VHL protein function in renal tumors simulates low tissue oxygen levels, or “pseudohypoxia” where HIF-1a and HIF-2a accumulate, causing upregulation of many genes involved in tumorigenesis such as vascular endothelial growth factor (proangiogenesis), epidermal growth factor receptor (cell proliferation and survival), and glucose transporter 1 (regulation of glucose uptake).

Genetic testing of the VHL gene is available on a clinical basis and involves full-gene sequencing and large gene rearrangement analysis. When both methods are used, the mutation detection rate is nearly 100% in patients with a clinical diagnosis of VHL.¹⁰ Approximately 80% of patients have a parent with VHL, and ∼20% represent de novo cases where neither parent carries the mutation. Genetic testing is recommended for a proband with a personal and family history of VHL, as the identification of causative mutations aids in determining disease subtype (Table 10.2). Disease subtype information along with a careful, detailed family history aids in guiding screening and surveillance of VHL patients. In simplex cases, where a patient has two or more VHL-associated lesions and a negative family history, genetic testing is recommended to establish a diagnosis. When a mutation is identified in a proband, at-risk family members should be offered predictive testing. Since young children with VHL are known to be at risk for retinal lesions and pheochromocytoma, genetic testing should be offered anytime after birth.

In 1977, Drs. Birt, Hogg, and Dubé first described a multigenerational kindred showing autosomal dominant transmission of fibrofolliculomas with trichodiscomas and acrochordons.¹¹ The phenotype was later expanded beyond dermatologic manifestations to include lung cysts and pneumothorax, and renal tumors.¹² The number of families with BHD syndrome described in the literature to date is small, and therefore, the exact incidence is unknown. Inherited mutations in the folliculin (FLCN) gene are associated with BHD syndrome.

An individual with BHD syndrome is at increased risk of developing multiple and bilateral renal tumors, frequently of more than one histologic type even within the same renal unit, and at younger ages compared with the general population. The lifetime risk is in the range of 27% to 45%,¹³

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