Von Hippel-Lindau Syndrome
(VHL)

Von Hippel-Lindau Syndrome (VHL) is a hereditary cancer syndrome characterized by the often multifocal occurrence of retinal, cerebellar, and/or spinal hemangioblastomas (HAB), pheochromocytomas, and renal cell carcinomas (RCC)(1,2). In addition, numerous other visceral neoplasms have been observed in patients with VHL. Incidence of VHL has been estimated at 1 in 36,000 births (3).

Clinical diagnosis of VHL is based on the presence of at least two characteristic tumors. Therefore, diagnosis of VHL often lags several years behind onset of the first characteristic symptoms (4). However, early diagnosis of VHL has been shown to increase survival of patients with VHL-associated RCC, one of the leading causes of mortality in VHL (5). Similarly, timely treatment of retinal HAB can prevent vision loss and blindness (1). Since VHL has been associated with autosomal dominant mutations in the gene VHL (6), genetic testing can confirm a diagnosis of VHL and identify family members at risk for developing the disease before they become symptomatic.

Types and Causes of VHL

VHL is associated with loss-of-function mutations in the gene VHL. VHL is believed to act as a tumor suppressor gene, i.e., defects in both copies of the VHL gene within the same cell dramatically increase the risk for certain neoplasms. While in the general population two independent somatic events are necessary to disable both copies of the VHL gene in a given cell, only one such somatic event is required in carriers of a germline loss-of-function mutation in VHL. Therefore, VHL carriers have a greatly increased risk of developing tumors compared to the general population. They typically develop tumors early and in several different tissues, and their tumors tend to be multifocal. The first VHL-associated neoplasms typically appear in the third decade of life, and almost all carriers are symptomatic by 65 years of age (7).

Several subtypes of VHL are distinguished based on the associated risk for pheochromocytoma and RCC (1,2). Cerebellar, spinal, or retinal HAB are seen in all subtypes of VHL, except for Type 2C, which presents as familial pheochromocytoma. A high risk of RCC has been correlated to large deletions or truncations in the VHL gene (8).
 

Of note, certain loss-of-function mutations in VHL are associated in a recessive mode of inheritance with congenital polycythemia, and may account for up to 50% of congenital polycythemia with normal to elevated level of erythropoietin (9). Risk of VHL-associated tumors is low in patients with congenital polycythemia.

The VHL Protein

VHL codes for the VHL protein, which binds to the transcription factors elongin B and C and acts as a component of an E3-ubiquitin ligase complex involved in targeting hypoxia-inducible factor 1alpha (HIF-1alpha) for degradation (see reference 2 for review). Loss-of-function mutations in VHL allow HIF-1alpha to persist in absence of hypoxic conditions and lead to increased transcription of hypoxia-inducible genes, resulting in the overexpression of proteins such as vascular endothelial growth factor and transforming growth factor alpha. VHL protein may also play a role in extracellular matrix formation and cell cycle control.

VHL typically presents in the third decade of life (1,2,5). The most common initial manifestation of VHL is retinal HAB, presenting with vision loss, or cerebellar HAB with symptoms such as headache, slurred speech, nystagmus, positional vertigo, labile hypertension (in the absence of pheochromocytoma), vomiting, or dysmetria. In patients with VHL type 2, pheochromocytoma may be the initial manifestation, leading to palpitations, tachycardia, headaches, or nausea. Other VHL-associated tumors include spinal HAB, RCC, endolymphatic sac tumors, pancreatic neuroendocrine tumors, and renal, pancreatic, epididymal, and broad ligament cysts. Rarely, VHL may present as atypical autosomal dominant polycystic kidney disease (1,10)

VHL is believed to account for 4-36% of apparently sporadic cerebellar HABs, 30-58% of retinal HABs, and 11% of apparently sporadic pheochromocytomas (11-14).

Clinical diagnosis of VHL is based on the presence of two characteristic tumors or, in the presence of a family history of VHL, occurrence of one characteristic tumor. However, a family history is often difficult to recognize due to the variability in clinical presentation of VHL both between and within affected families. In addition, up to 20% of VHL occurs in patients without a family history (7). Genetic testing can confirm a diagnosis of VHL after the appearance of only one characteristic tumor and can identify family members at risk for VHL before they become symptomatic.

Symptomatic cerebellar and spinal HABs, pheochromocytomas, RCC, and other visceral tumors typically require surgery. Treatment with laser photocoagulation or cryotherapy can prevent vision loss due to retinal HAB (1,2). Once a diagnosis of VHL or the risk of VHL has been established, patients and at-risk family members of patients should undergo regular screening for symptoms of VHL. such as annual ophthalmologic examination from age 6, biochemical screening for raised urinary catecholamines from age 10, and MRI and CT scanning from age 15 years (1).

VHL belongs to the familial cancer syndromes and is inherited in an autosomal dominant manner. Loss-of-function mutations in VHL are the only known cause of VHL, and germline VHL mutations can be detected in up to 100% of VHL families (7). Mutations are scattered throughout the coding region of the gene, with large deletions accounting for about 30% of mutations (15). Such large deletions or truncations in the VHL gene are associated with a high risk of RCC (8). The de novo mutation rate is estimated at 20%, and mosaicism may occur in a small percentage of VHL patients.

Somatic mutations on both copies of VHL play role in sporadic occurrence of RCC and endolymphatic sac tumors (16,17).

The von Hippel-Lindau Evaluation detects mutations other than large deletions in the gene VHL and can confirm a diagnosis of VHL in patients presenting with only one of the characteristic manifestations. The von Hippel-Lindau Evaluation can also identify pre-symptomatic carriers of a VHL-associated mutation among family members of patients. Individuals with a confirmed diagnosis of or predisposition to developing VHL can then be screened regularly for developing neoplasms, facilitating timely diagnosis and treatment. Conversely, the von Hippel-Lindau Evaluation can also identify members of VHL families who do not carry the familial pathogenic VHL mutation, eliminating the need for screening in these individuals.

How Is Genetic Testing for VHL Performed?

DNA for sequencing is obtained from leukocytes present in a small blood sample. The coding sequences of VHL are amplified in a highly specific manner through a polymerase chain reaction (PCR), and all PCR products are fully sequenced. Sequencing results are interpreted, and a detailed result report is sent to the patient’s physician.

Ordering testing von Hippel-Lindau Syndrome, click here.

Download a printable pdf version of this review.