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More than 1,500 mutations! What is the secret of the Von Hippel–Lindau gene?
Von Hippel–Lindau disease (VHL) is a rare genetic disorder characterized by multisystem involvement. The disease is characterized by visceral cysts and benign tumors that have the potential to transform into malignant tumors. VHL is a syndrome caused by mutations in a tumor suppressor gene located on the short arm of chromosome 3. According to the latest research, there are more than 1,500 known mutations within this gene.
Symptoms and signs
Common symptoms of VHL disease include headaches, problems with balance and walking, dizziness, weakness in the limbs, vision problems and high blood pressure.
People with VHL disease may develop the following health problems: hemangioblastoma, pheochromocytoma, renal cell carcinoma, pancreatic cysts, endolymphatic cyst tumors, and bilateral vasodilatation cysts. According to the study, approximately 37.2 percent of VHL patients develop hemangioblastomas, which usually affect the retina and cause vision loss. The disease may also lead to stroke, heart attack and other cardiovascular diseases.
Pathogenesis
The root cause of VHL disease is a mutation in the VHL tumor suppressor gene located on chromosome 3 (3p25-26). These mutations can be divided into germ cell mutations and somatic mutations, and their number exceeds 1,500. Each cell has two copies of the gene, and in VHL disease, at least one of the copies is mutated, resulting in the production of a malfunctioning VHL protein.
VHL protein
The VHL protein (pVHL) is responsible for regulating a protein called hypoxia-inducible factor 1α (HIF1α). Under normal circumstances, pVHL can recognize and bind to HIF1α in an aerobic environment and degrade it through ubiquitination. However, in VHL disease, mutations prevent pVHL from effectively binding to HIF1α, thereby activating transcription of other genes and driving tumorigenesis.
Diagnosis
The key to diagnosing VHL disease is detecting tumors with specific characteristics.
In the presence of a family history, only one case of hemangioblastoma or pheochromocytoma is required to diagnose VHL disease. Patients without a family history of the disease need to have at least two VHL-related tumors identified. Genetic diagnosis also plays an important role in the diagnosis of VHL disease, especially when screening family members.
Categories
VHL disease is divided into 2 types based on the presence or absence of pheochromocytoma: VHL type 1 includes patients without pheochromocytoma, and type 2 includes patients with pheochromocytoma. Type 2 is further divided into three subcategories: 2A, 2B, and 2C. The key to diagnosing VHL is identifying the specific combination of the patient's family history and tumor.
Treatment methods
Early recognition and treatment of VHL-related symptoms are crucial to reduce complications and improve quality of life. Regular screening is necessary, especially for retinal hemangioblastoma and CNS hemangioblastoma. In addition, surgical resection is a common measure for tumors with obvious symptoms.
EpidemiologyThe incidence of VHL disease is approximately 1 in 36,000 births, and penetrance exceeds 90% by age 65 years. The age of diagnosis ranges from infancy to 60-70 years old, with an average clinical diagnosis age of 26 years.
History Review
The disease was first described by German ophthalmologist Eugen von Hippel in 1904 and further described by Arvid Lindau in 1927, who studied hemangioblastomas in the cerebellum and spine. The name "Von Hippel–Lindau" did not come into widespread use until the 1970s.
Think about the problem
As research on VHL disease continues to deepen, will we be able to find more effective treatments in the future to improve patients' quality of life and prolong their lifespan?
