Written by Valeria Carla VIGITELLO
INTRODUCTION
Von Hippel-Lindau disease (VHL) is a rare, genetic disease that causes tumors and cysts to grow in the body. The tumors can be either cancerous or benign. They can grow in brain and spinal cord, kidneys, pancreas and, in men, their genital tract. Symptoms of VHL vary and depend on the size and location of the tumors. They may include headaches, problems with balance and walking, dizziness, weakness of the limbs, vision problems and high blood pressure.
Detecting and treating VHL early is important. Treatment usually involves surgery or sometimes radiation therapy. The goal is to treat growths while they are small and before they do permanent damage.
DEFINITION
Von Hippel-Lindau disease is a heritable multisystem cancer syndrome that is associated with a germline mutation of the VHL tumour suppressor gene on the short arm of chromosome 3. This disorder is inherited as a highly penetrant autosomal dominant trait. Affected individuals are at risk of developing various benign and malignant tumours of the central nervous system, kidneys, adrenal glands, pancreas, and reproductive adnexal organs.
EPIDEMIOLOGY
The incidence of von Hippel-Lindau syndrome is estimated to be 1 in 36,000 individuals
GENETICS
The disease is caused by mutations of the Von Hippel–Lindau tumor suppressor (VHL) gene on the short arm of chromosome 3 (3p25-26).
As long as one copy of the VHL gene is producing functional VHL protein in each cell, tumors do not form. Since both alleles need to be mutated in order for the disorder to develop, the second allele must develop the mutation in at least one other cell in their bodies. This is known as the two-hit hypothesis. If a mutation occurs in the second copy of the VHL gene, the cell will have no working copies of the gene and will produce no functional VHL protein. A lack of this protein allows tumors characteristic of von Hippel–Lindau syndrome to develop.
An inherited mutation of the VHL gene is responsible for about 80 percent of cases. In about 20 percent of cases, however, the altered gene is the result of a new mutation that occurred during the formation of reproductive cells (eggs or sperm) or early in fetal development. This is quite rare because the probability of a mutation occurring in a cell where both alleles are previously normal is quite small. Whether by new mutation or inherited mutation, the aforementioned second hit still needs to occur in order for a tumor to appear.
There is a wide variation in the age of onset of the disease, the organ system affected and the severity of effect. This suggests that the second mutation can occur in different types of cells and at various times of a person's life.
SYMPTOMS
Those who inherit a mutated gene are at greatly increased risk for retinal hemangioblastoma; cerebellar hemangioblastoma; pheochromocytoma; pancreatic and renal cysts; spinal hemangioblastoma; renal cell carcinoma (RCC); hemangiomas of the adrenals, liver, and lungs; endolymphatic sac tumors; and papillary cystadenoma of the epididymis or broad ligament. Up to 50% of patients in VHL families show only one manifestation of the syndrome. Expressivity is variable among families; however, some clinical features are similar within families. Clear cell RCC has been found to occur in up to 70% of patients. In early studies the most common causes of death were complications of cerebellar hemangioblastoma (53%) and metastatic RCC (32%). The retinal lesions may cause retinal detachment or hemorrhage, leading to blindness, but they usually respond to treatment with laser therapy or cryotherapy if detected early.
The ages of onset of typical findings are listed in Table 1. If pheochromocytoma is present in the family it may be the initial presentation. A registry started in northwest England in 1990 has registered 83 patients. In that population the mean age of onset of the first sign or symptom was 26.25 years, with a mean age at diagnosis of 30.87 years. The most common initial manifestation was cerebellar hemangioblastoma (34.9%). The mean age at death was 40.9 years, and the most common cause of death was complications of cerebellar hemangioblastoma (47.7%). In this population the cumulative occurrence of cerebellar hemangioblastoma was 60.2%, that of retinal hemangioblastoma was 41%, that of RCC was 25.3%, that of spinal hemangioblastoma was 14.5%, and that of pheochromocytoma was 14.5%
DIAGNOSIS
Clinical Diagnosis
The diagnosis of VHL may be made on clinical grounds. In a patient with a positive family history of VHL, the finding of a single retinal or cerebellar hemangioblastoma, pheochromocytoma, or RCC is sufficient to make the diagnosis. Some have argued that the presence of multiple pancreatic cysts is also sufficient. Renal or epididymal cysts alone are not sufficient because they occur frequently in the general population.
If no known family history of VHL exists, two or more retinal or cerebellar hemangioblastomas or one hemangioblastoma plus one visceral tumor must be present to justify the diagnosis. New mutations are thought to account for 1% to 3% of VHL cases.
Symptoms of cerebellar hemangioblastoma may include headache, vomiting, wide-based gait, slurred speech, nystagmus, labile hypertension (without pheochromocytoma), positional vertigo, and dysmetria. Erythrocytosis occurs in 5% to 20% of patients. Up to 30% of patients with cerebellar hemangioblastoma have VHL disease.5, Spinal hemangioblastomas are more specific for VHL disease, and about 80% are caused by VHL disease. They occur in 13% to 59% of VHL patients.
Renal cell carcinomas may occur in renal cysts. The tumors tend to grow slowly, less than 2 cm per year, and it has been recommended they by followed with computed tomography scans every 6 months.
Summarizing, 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 .
Genetic Testing
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.
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
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.
PATHOGENESIS
Role of the VHL Gene
Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. It has been demonstrated that the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL plays a critical role in HIF-1 regulation. In VHL-defective cells, HIF alpha-subunits are constitutively stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitate, and pVHL is present in the hypoxic HIF-1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF-1 is dissociated from pVHL. These findings indicate that the interaction between HIF-1 and pVHL is iron dependent, and thatit is necessary for the oxygen-dependent degradation of HIF alpha-subunits. Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing.
Role of 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. The alpha subunits of HIF are hydroxylated at conserved proline residues by HIF prolyl-hydroxylases, allowing their recognition and ubiquitination by the VHL E3 ubiquitin ligase, which labels them for rapid degradation by the proteasome. This occurs only in normoxic conditions. In hypoxic conditions, HIF prolyl-hydroxylase is inhibited, since it utilizes oxygen as a cosubstrate 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.
THERAPY
Medical Care
An annual physical examination, with specific attention to possible neurologic manifestations of CNS hemangioblastoma, is suggested for individuals with von Hippel-Lindau (VHL) disease, or von Hippel-Lindau syndrome, for individuals with suspected von Hippel-Lindau disease, or for at-risk relatives.
Focal neurologic signs should prompt imaging of the brain, spinal cord, or both. MRI is the preferred modality because of the preponderance of subtentorial and posterior fossa tumors.
Medical care for patients with von Hippel-Lindau disease is dictated entirely by the specific complications that are present. Most therapies for complications of von Hippel-Lindau disease are surgical (eg, excision of tumors of the CNS, adrenal glands). Thus, the most crucial aspect of medical care in these patients is close surveillance and prompt evaluation with appropriate imaging.
A substantial number of patients eventually require renal dialysis because the presence of tumors necessitates nephrectomy.
The increasing knowledge about the molecular role of von Hippel-Lindau proteins (pVHL) has led to clinical trials of several antiangiogenic drugs designed to reduce or prevent tumorigenesis in von Hippel-Lindau disease. These drugs remain under investigation and are not available outside of a research protocol.
Annual ophthalmologic examination is recommended because of the risk for retinal hemangioblastomas.
Surgical Care
Surgery is the mainstay of treatment for tumors that arise in patients with von Hippel-Lindau disease. The standard of care is organ-sparing surgery.
- The most significant life-threatening tumor that occurs in individuals with von Hippel-Lindau disease is renal cell carcinoma. Partial nephrectomy or radiofrequency ablation is preferred to spare renal function, if tumor involvement is not extensive. However, total nephrectomy is often necessary because of extensive tumor involvement.
- Since multiple primary tumors are common in von Hippel-Lindau disease, bilateral nephrectomies may ultimately be required. Bilateral nephrectomies necessitate renal dialysis or transplantation.
- CNS hemangioblastomas are typically not malignant; thus, they can be monitored if their size is stable and they are not producing neurologic symptoms or signs. However, if these tumors cause neurologic symptoms, neurosurgical excision is required.
- Retinal hemangioblastomas should be monitored by an ophthalmologist. Treatment typically consists of laser treatment or cryotherapy to preserve vision.
