von Hippel-Lindau Syndrome
In the past several years, patients with von Hippel-Lindau syndrome have been able to stretch their life to 75 to 80 years.

The survival rate of von Hippel-Lindau (VHL) syndrome has improved over time, and it has become closer to that of the general population without VHL syndrome. Patients with VHL syndrome have lower life expectancy than those with other tumor syndromes.

Patients with VHL syndrome have a life expectancy of 40 to 52 years, and VHL-syndrome-related death is most usually caused by complications from renal cell carcinoma and central nervous system malignancies

VHL syndrome affects about 1 in 36,000 people and can manifest in childhood, adolescence, or adulthood, with a mean age of onset at 26 years.

  • Men have a slightly longer life expectancy than women, with 59.4 and 48.4 years, respectively.
  • Age and type of presentation may affect the outcome; this might be due to the aggressive nature of the disease. 

According to recent studies and research, mortality and morbidity have decreased significantly as a result of improved screening, early diagnosis, and treatment. Early discovery, genetic testing, and systemic therapy can increase the life expectancy of afflicted individuals.

The treatment of this disease necessitates the collaboration of clinicians from several specialties, including those who treat central nervous system and kidney malignancies. Although there are various potential therapies for VHL syndrome, early diagnosis of tumors is the top objective for disease management and has been found to lower the incidence of complications and death rates.

The overall life expectancy of patients with VHL syndrome was previously limited, with a median survival of about 50 years. However, the introduction of clinical screening enabled timely diagnosis and prophylactic treatment of VHL syndrome lesions, resulting in significantly improved life expectancy. Modern management of VHL-disease-associated lesions has resulted in an additional 10 years of life expectancy.

With an improved understanding of the disease and modern management strategies, the outcomes should be even better in the future.

What is von Hippel-Lindau syndrome?

Von Hippel-Lindau (VHL) syndrome is a rare genetic condition that makes a person prone to certain types of cancer. Tumors and cysts associated with VHL syndrome are most common in young adulthood, but they can appear at any age.

VHL syndrome may commonly affect the following organs:

  • Kidneys
  • Adrenal glands
  • Brain
  • Pancreas
  • Eyes
  • Inner ears
  • Spine
  • Reproductive tract
  • Liver
  • Lungs

Most VHL-syndrome-related tumors are benign, meaning they are unlikely to spread elsewhere in the body, but they can still be dangerous. As they grow in size, they push into surrounding structures, causing pain and interfering with the function of the affected organ or tissue.

What are the common signs and symptoms of von Hippel-Lindau syndrome?

Von Hippel-Lindau (VHL) syndrome is a familial disorder. Some people with VHL syndrome have no symptoms. When symptoms do appear, they differ from patient to patient, even within the same family.

Signs and symptoms of VHL syndrome vary depending on the organ or organs affected by the disease. 

Typical signs and symptoms of VHL syndrome

What types of tumors are seen in von Hippel-Lindau syndrome?

Von Hippel-Lindau (VHL) syndrome is characterized by the development of several benign and malignant tumors (at least 40 types) in various organs. VHL disease is a result of mutations in the VHL tumor suppressor gene.

Growths can occur in the retina, specific parts of the brain, or other sections of the nervous system. These tumors are not cancerous. Other forms of growth can occur in the spinal cord, adrenal glands, kidneys, or pancreas. 

VHL syndrome is commonly associated with the following tumors:

  • Angiomas or enlarged blood vessels
    • Occur in the eye or on the retina (back of the eye).
    • When they are small, they do not cause any problems and can only be seen by an ophthalmologist (eye specialist).
    • However, if an angioma is not detected and treated, it can grow, damage the retina, and eventually impair vision.
  • Hemangioblastomas or cysts or benign tumors
    • Frequently seen in the brain and spinal cord, causing symptoms such as headaches, weakness, ataxia (lack of muscle coordination), nausea, and vomiting. They may occur in the cerebellum or spinal cord and are not dangerous and do not spread.
    • They usually cause a headache and unsteadiness while walking if they occur in the cerebellum. Spinal hemangioblastomas can cause pain or numbness.
    • A CT or an MRI brain scan, as well as an MRI spine scan, can detect these cysts.
  • Renal and pancreatic tumors
    • Are common in VHL syndrome. They are harmless and do not cause any symptoms. However, a solid tumor may form in certain cases. 
    • These tumors are readily removed and do not cause concerns if identified early. If the tumor is not found and treated, it might develop into cancer and spread throughout the body. 
    • Pancreatic cysts are common, and pancreatic tumors can form in rare cases.
  • Pheochromocytoma
    • Adrenal gland tumors are normally noncancerous and do not cause any symptoms. 
    • However, due to increased hormone release, an abrupt elevation in blood pressure might develop that is resistant to therapy. Other signs include a headache, panic episodes, and excessive perspiration.
  • Renal cell carcinoma (RCC)
  • Endolymphatic sac tumors
    • Benign tumors develop in the inner ear. These tumors form in about 10 percent of patients with VHL syndrome. Hearing loss, tinnitus (ringing/buzzing in the ears), and difficulties maintaining balance when standing and/or walking are among the symptoms.
  • Pancreatic neuroendocrine tumors
    • Islet cell tumors are a type of endocrine (hormonal) tumor that develops in the pancreas and are one of the most frequent neuroendocrine tumors. The hormones released by the tumors cause symptoms such as hypoglycemia (low blood sugar), stomach ulcers, gallstones, and severe diarrhea.

VHL syndrome is highly variable; although one family member may have an eye problem, another family member with the same genetic change may develop a kidney problem. 

Similarly, although numerous members of the same family may acquire difficulties at a young age, another member may not get an issue until they are much older. Pheochromocytoma has a propensity to run in certain families.

What are the possible causes of and risk factors for von Hippel-Lindau syndrome?

Von Hippel-Lindau (VHL) syndrome is caused by a gene mutation. Instead of growing in branches, blood vessels in patients with VHL syndrome form a tiny loop or knot. The knot develops into growth or tumor, most commonly in the eye and brain.

VHL syndrome has been connected to cancer and cysts in the body. This condition runs in family and is usually inherited

Genetic condition and mutation

  • VHL disease is a genetic condition that can be passed down from generation to generation. A mutation in the VHL gene on chromosome 3p25.3 causes it. 
  • This gene is a tumor suppressor gene, meaning it prevents uncontrolled cell division and thus tumor formation. The presence of the mutation knocks out this gene, resulting in uncontrolled cell proliferation and the formation of the various types of tumors seen in patients with VHL syndrome. 
  • VHL syndrome is inherited in an autosomal dominant manner, which means that even a single mutation in the VHL gene (or only one affected parent) can increase the risk of the disease (or transmit the disease to the child—risk is 50 percent per generation).

80 percent inherited

  • VHL disease is inherited in approximately 80 percent of cases. It is inherited in an autosomal dominant pattern, meaning that an affected parent has a 50 percent chance of passing the affected gene to each of their offspring. 
  • Children who inherit an erroneous copy of the gene will eventually develop cysts and tumors.

Rarely new mutation

  • VHL syndrome is not inherited from a parent in the other 20 percent of cases. Instead, mutations in both copies of the gene create "de novo" (new) genetic coding in the patient.
  • One in every five patients with VHL syndrome has a novel VHL mutation that did not come from either parent. 
  • These patients may have no family history of the condition. In some circumstances, the alteration occurs either during the formation of an egg or a sperm cell or during pregnancy in one of the child's cells. 
  • These patients are the first in their families to be diagnosed with VHL syndrome. 

People with VHL syndrome have a 50 percent or one in two probability of passing the VHL mutation to their offspring regardless of how they got it. As patients with VHL syndrome age, the remaining functioning copy of the VHL gene in some of their cells changes. When both copies of a gene are altered, benign tumors or cancer can form. Almost everyone who possesses the VHL gene mutation will develop the illness by the age of 65 years.

How is von Hippel-Lindau syndrome diagnosed?

Von Hippel-Lindau (VHL) disease is diagnosed by doctors based on certain clinical criteria (signs and symptoms) or when molecular genetic testing indicates a change (mutation) in the VHL gene.

The following tests can assist establish an accurate clinical diagnosis:

  • An MRI scan of the brain and spinal cord
  • Fundoscopy or dilated eye exam
  • Ultrasound examination or MRI of the abdominal area
  • Blood and urinary catecholamine metabolites

Other tests may also be recommended to either rule out or confirm the disease. A thorough diagnosis, followed by appropriate therapy, is critical for improving the VHL syndrome prognosis.

What are the treatment options for von Hippel-Lindau syndrome?

There is no universally accepted therapy for this illness. Only a comprehensive review of the individual's whole situation, including symptoms, test results, imaging exams, and general physical state, can identify therapy alternatives.

Depending on the difficulties and concerns, the treatment techniques might be noninvasive or surgical.

Nonsurgical treatment approaches

  • Nonsurgical therapeutic options avoid problems and offer planned follow-up. 
  • Because of the risk of retinal hemangioblastomas, it is suggested that the affected person should undergo an annual ophthalmologic checkup. 
  • It is feasible to reduce the risk of vision loss by diagnosing and treating retinal lesions early.

Monitoring and evaluation 

  • Treating the clinical finding alone is not adequate for individuals with only one symptom of von Hippel-Lindau (VHL) syndrome because the patient is at risk of acquiring other, possibly life-threatening consequences that are not immediately evident. 
  • As a result, the most important parts of medical care for these people are closely monitoring and quick assessment with adequate diagnostic imaging.

Surgical management

  • Depending on the location of the tumor or cyst, surgical therapy may involve ocular, neurological, and renal procedures.

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How is treatment for von Hippel-Lindau syndrome determined?

Because of the vast range of possible symptoms of the condition, treatment choices vary widely, and a treatment course can only be chosen after a detailed review of each person's situation as a whole. Some people may have a single tumor that needs rapid removal; others may have many tumors, one of which requires immediate care and still others may just have cysts or tumors that require monitoring.

The main goal of therapy for VHL syndrome is to locate and remove tumors as soon as possible to prevent them from damaging health.

The doctor will identify the best way to remove these tumors by:

Previously, patients with VHL syndrome lived about 52 to 54 years. In the past several years, patients were able to stretch their life to 75 to 80 years.

Participating in clinical trials and complying with the imaging and appointments is the best way to beat this disease. Although it is not feasible to undo the effects of VHL gene mutations, it is possible to manage the symptoms so that patients have a better quality of life. MK-6482 or belzutifan was designated as a breakthrough therapy by the FDA in July 2020 for VHL disease.

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Medically Reviewed on 9/27/2022
Image Source: iStock image

Von Hippel-Lindau Syndrome: https://www.cancer.net/cancer-types/von-hippel-lindau-syndrome

Von Hippel-Lindau Syndrome: https://www.ncbi.nlm.nih.gov/books/NBK1463/

Von Hippel-Lindau Disease: https://rarediseases.org/rare-diseases/von-hippel-lindau-disease/

VON HIPPEL-LINDAU SYNDROME; VHLS: https://www.omim.org/entry/193300

Von Hippel-Lindau disease (VHL) is an inherited mutation of the von Hippel-Lindau gene. The mutation causes tumors and cysts to form in several locations throughout the body: https://www.mdanderson.org/cancer-types/von-hippel-lindau-disease.html