Von Hippel-Lindau syndrome - VHL gene

Von Hippel-Lindau syndrome (VHL syndrome), also known as retinal angiomatosis, is a hereditary process in which affected people have a high predisposition to the development of tumors in different organs: multiple hemangioblastoma in the central nervous system (CNS), medulla and retina; clear cell carcinoma in the kidney, pheochromocytoma -see Pheochromocytoma - VHL, NF1, MEN2, SDHB, SDHC and SDHD genes-; neuroendocrine pancreatic tumor; endolymphatic sac tumor; renal, hepatic and pancreatic cysts. Hemangioblastoma is the most frequent lesion in this syndrome, which despite being benign and slow growing, is the leading cause of death, since access to a possible surgical intervention is not always possible. This is, among others, one of the main reasons for early detection by genetic analysis in healthy individuals with a family history.

Clinical symptoms depend on the location of the tumor. The symptoms in CNS hemangioblastomas vary depending on the exact location. Infratentorial tumors usually cause headache, ataxia, vertigo and vomiting; in spinal hemangioblastoma there is usually pain, bladder and intestinal dysfunction, sensory and motor loss of the limbs, bladder dysfunction and orthostatic hypotension. 20% of patients have tumor production of erythropoietin and polycythemia. Retinal hemangioblastoma may be the first manifestation of VHL syndrome, and may arise during childhood. The initial symptoms are loss of visual acuity and, if not detected early by molecular analysis, evolves to retinal detachment, hemorrhages, glaucoma, cataracts and blindness. The symptoms that usually accompany pheochromocytoma are tachycardia, diaphoresis (major sweating) and headache. Pancreatic tumor is manifested by obstructive jaundice and abdominal pain. Endolymphatic sac tumor (present in about 10% of people with this syndrome) is clinically manifested by progressive hearing loss, tinnitus (noise or ringing in the ears), vertigo, and facial paralysis and/or vocal cords. On the other hand, clear cell carcinoma in the kidney is usually asymptomatic.

Von Hippel-Lindau syndrome is due to mutations in the VHL tumor suppressor gene, located on the short arm of chromosome 3 (3p25.3). This gene encodes a protein that acts as part of a complex called VCB-CUL2. This complex directs other proteins to be degraded by the cell when they are no longer needed. One of the objectives of the VCB-CUL2 complex is a protein called hypoxia-inducible factor 2-alpha (HIF-2α). HIF-2α is a subunit of the HIF complex, which plays a critical role in oxygen homeostasis. HIF controls several genes involved in cell division, the formation of new blood vessels, and the production of erythrocytes. In addition, it is the main regulator of the hormone erythropoietin, which controls the production of erythrocytes. The function of the HIF complex is particularly important when oxygen concentrations are lower than normal (hypoxia). However, when the right amount of oxygen is available, the VCB-CUL2 complex causes HIF to accumulate inappropriately in the cells. VHL protein probably plays a role in other cellular functions, including the regulation of other genes and the control of cell division. Based on this function, VHL protein is classified as a tumor suppressor, preventing cells from growing and dividing too quickly or uncontrollably. VHL protein is also involved in the formation of the extracellular matrix, which provides structural support to tissues.

More than 370 inherited mutations in the VHL gene have been identified in people with VHL syndrome. VHL gene mutations associated with this syndrome inhibit the synthesis of VHL protein or lead to the synthesis of an abnormal version of the protein. The inactivation of the pVHL protein, as a consequence of mutations in the sequence that encodes it, causes the alteration of these processes and induces the development of highly vascularized tumors. Generally, its inactivation causes overexpression of Vascular Endothelial Growth Factor (VEGF), Growth Transformation Factor (FTC), HIF and erythropoietin. All this generates numerous anomalies in the extracellular matrix, in the differentiation and control of the cell cycle, which generate angiogenesis and vascularization alterations, and induce the formation of tumors.

The search for mutations associated with Von Hippel-Lindau syndrome can be very useful, without being excessively expensive given the small size of the VHL gene, especially in cases with a family history -also in the absence of symptoms-, or in patients without previous family history, but with characteristic symptoms or injuries. Confirmation to patients with mutations in the VHL gene allows their continuous and specific surveillance, as well as the elucidation of individual predisposition to the development of each type of tumor associated with this syndrome.

Mutations in the VHL gene are inherited with an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to increase the risk of developing tumors and cysts. Most people with von Hippel-Lindau syndrome inherit an altered copy of the gene from an affected parent. However, in approximately 20% of cases the altered gene is due to a new mutation that occurs during the formation of reproductive cells or early in development. Unlike other autosomal dominant processes, in which one altered copy of a gene in each cell is sufficient to express the alteration, two copies of the VHL gene must be altered to trigger the development of a tumor and the formation of cysts in the VHL syndrome. A mutation in the second copy of the VHL gene occurs during the life of a person in certain cells in organs such as the brain, retina and kidneys. Cells with two altered copies of this gene inhibit functional VHL protein coding, which allows the development of tumors and cysts. Almost all people who inherit a VHL mutation eventually acquire a mutation in the second copy of the gene in some cells, leading to the characteristics of VHL syndrome.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Von Hippel-Lindau syndrome, by means of the complete PCR amplification of the exons of the VHL gene, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).