Hippel-Lindau disease: what is it, symptoms, causes, treatment, prognosis

What is Hippel-Lindau disease?

Hippel-Lindau disease (or von Hippel-Lindau syndrome, eng. Von Hippel – Lindau disease — VHL) Is an autosomal dominant genetic disorder resulting from a deletion or mutation in a gene VHL. Hippel-Lindau syndrome affects 1 in 36,000 people (200,000 cases worldwide), and 20% of patients are the first in the family (ie, a new mutation). The median age of onset is 26, and 97% of people with the gene mutation VHL have symptoms by age 65. Hippel-Lindau disease affects men and women and all ethnic groups equally and occurs in all parts of the world. Patients with the disease may develop tumors and / or cysts in ten parts of the body, including the brain, spine, eyes, kidneys, pancreas, adrenal glands, inner ear, reproductive tract, liver and lungs with subsequent symptoms / complications:

• Hemangioblastoma of the brain / spine: headache, ataxia, nystagmus, back pain, numbness, hiccups;
• Retinal hemangioblastoma: floating opacities - "flies" in the eyes, retinal detachment;
• Tumors of the endolymphatic sac: hearing loss tinnitus (ringing /noise in ears), dizziness;
• Cysts / tumors /cancer pancreas glands:pancreatitis (due to blockage of the bile ducts), diabetes (due to blockage of insulin delivery), irritability of the digestive system, intestinal malabsorption, jaundice;
• Pheochromocytoma, paraganglioma: high blood pressure (arterial hypertension), panic attacks (or postoperative adrenal insufficiency);
• Kidney cysts, renal cell carcinoma: back pain, hematuria, fatigue;
• Cystadenoma (in men and women): pain, rupture, bleeding, torsion (possible ovarian cancer)

Most of these tumors are benign, but this does not mean that they are harmless. In fact, benign tumors of Hippel-Lindau syndrome can still be very serious. As they grow in size, these tumors and their associated cysts can put increased pressure on the structure around them. This pressure can cause symptoms, including severe pain or even more serious complications.

Hippel-Lindau disease is different for each patient, even within the same family. Since it is impossible to accurately predict how and when each person will develop the disorder, it is very important to regularly check for possible manifestations of the disorder throughout the person's life.

Currently, there is no drug (pharmacological) treatment; surgical removal is the main treatment. The organ-sparing approach is the best approach to reduce irreparable damage while minimizing organ removal. With careful monitoring, early detection and appropriate treatment, the most harmful effects of a VHL gene mutation can be significantly reduced and, in some people, completely prevented.

Because the disease can cause malignant tumors, it is considered one of the genetically transmitted risk factors for familial cancer. The goal is to find the tumor early, watch for signs of tumor growth, and remove or heal the tumor before it invades other tissues. Benign tumors may also need treatment or removal if their growth is causing symptoms.

Signs and symptoms

Hippel-Lindau disease does not have a single primary symptom. This is partly due to the fact that it occurs in more than one organ of the body. The syndrome also does not always occur in a particular age group. It is a hereditary disorder, but its manifestations can vary greatly from person to person, despite the same genetic mutation. In addition, the appearance and severity of lesions vary so much from person to person that many members of the same family may only have some relatively harmless problems, while others may have severe complications.

The age of onset varies from family to family and from person to person. Pheochromocytoma (adrenal cancer) is very common in some families, while clear cell renal cell carcinoma ([kidney tumor]) is more common in other families.

The most common symptom of Hippel-Lindau syndrome is hemangioblastoma. These are benign tumors of the brain, spinal cord and retina. Hemangioblastomas are benign. In the brain or spinal cord, hemangioblastoma can sometimes be found inside a cyst or fluid-filled sac. Hemangioblastomas or surrounding cysts can press on a nerve or brain tissue and cause symptoms such as:

• headache;
• balance problems when walking;
• weakness of the arms and legs.

Hemorrhage in the eye or leakage of fluid from hemangioblastomas can interfere with vision. Early detection, close eye observation, and timely treatment are essential to maintain healthy vision.

Early signs of tumors adrenal glands may have high blood pressure, panic attacks, or heavy sweating. Early signs of cysts and tumors pancreas may include digestive complaints such as bloating or impaired bowel and bladder function. Some of these tumors are benign while others may become cancerous.

Kidney tumors and cysts (clear cell renal cell carcinoma) can lead to decreased kidney function, but usually there are no symptoms in the early stages. If the kidney tumor is not removed, metastases will spread when they reach about 3 cm in diameter.

Hippel-Lindau disease can also cause a benign tumor in the inner ear called an endolymphatic sac tumor. If this tumor is not removed, it can lead to hearing loss in the affected ear, as well as imbalance. Less common manifestations of the syndrome include benign tumors of the genital tract in both men and women. However, these tumors can lead to problems with fertilization or pregnancy.

Tumors in the liver and lungs are considered harmless.

Causes

Hippel-Lindau disease is an autosomal dominant disorder resulting from a gene deletion or mutation VHLlocated on the short arm of chromosome 3. Every child of a person with the syndrome has a 50% risk of inheriting an altered copy of the gene. VHL.

Normal gene VHL acts as a tumor suppressor gene with the function of preventing the formation of tumors. The gene acts as a key regulator of cellular hypoxia signaling through its product, the VHL protein (pVHL). pVHL through the HIF complex (hypoxia-inducible factor) is indirectly responsible for increased levels of growth factors, including vascular endothelial factor, platelet-derived growth factor and transforming growth factor alpha.

In the case of a non-functioning gene, for example, in Hippel-Lindau disease, the HIF complex is not regulated. As a result, the level of various growth factors increases, which contributes to the growth of blood vessels (angiogenesis) and the formation of tumors. This is the same process as in other more common cancers such as kidney, breast, pancreas, and adrenal cancers.

The researchers believe that interfering with growth factor and / or HIF activity will be an effective treatment for Hippel-Lindau syndrome and other forms of cancer.

Affected populations

The disease is a hereditary genetic disorder, but 20% of all patients are the first in the family. The incidence is 1 in 36,000 births, affecting men and women equally, as well as all ethnic groups, and occurs in all parts of the world.

Related disorders

Hippel-Lindau disease is a complex disease that causes tumors to grow in 10 different parts of the body: the kidneys, adrenal glands, pancreas, brain, spine, retina, inner ear, reproductive tract, liver and lungs. Due to the damage to many organs, the symptoms and manifestations of the syndrome coincide with a wide range of diseases. These include the following:

• Kidneys: sporadic kidney cancer, Burt-Hog-Dube syndrome, hereditary leiomyomatosis and renal cell carcinoma, complex tuberous sclerosis, excess of succinate dehydrogenase.
• Adrenal gland or pheochromocytoma: excess succinate dehydrogenase, multiple endocrine neoplasia 2 types, types A and B (MEN2A and MEN2B).
• Inner ear:Meniere's disease.
• Pancreas: pancreas cancer.
• Retina: retinal hemangioblastomas are unique to Hippel-Lindau disease. The presence of retinal hemangioblastoma leads to a clinical diagnosis of the disease.
• Brain or spine: hemangioblastomas in the brain or spinal cord are different from other forms of brain or spinal cord tumors and therefore their diagnosis is considered a criterion for genetic analysis VHL. Note that research on other types of brain tumors is not relevant to Hippel-Lindau hemangioblastomas.

Diagnostics

Anyone who has a parent with Hippel-Lindau Syndrome and most people who have a sibling with the disease have a 50% chance of getting the disease. Anyone who has an aunt, uncle, cousin, or grandfather or grandmother with a medical condition may also be at risk. The only way to know for sure if someone doesn't have a gene mutation VHL Is a DNA test. A clinical diagnosis can also be made when a person has a tumor specific to a disease.

After the diagnosis of Hippel-Lindau disease has been made, it is important to start a follow-up examination as early as possible, before any symptoms appear. Most tumors / cysts are much easier to treat when they are small. A number of possible complications of Hippel-Lindau disease do not show symptoms until the problem develops to a critical level. Treatment can only stop the symptoms that appear; it is not always possible to undo changes and return to normal.

Standard treatments

There is no one-size-fits-all treatment recommendation. Treatment options can only be determined by carefully assessing the individual patient's overall situation - symptoms, test results, imaging studies, and general physical condition. The following are suggested as general recommendations for a possible treatment.

- Hemangioblastomas of the brain and spinal cord.

Symptoms associated with hemangioblastomas of the brain and spinal cord depend on the location, size of the tumor and the presence of an associated edema or cysts. Symptomatic lesions grow faster than asymptomatic lesions. Cysts often cause more symptoms than the tumor itself. Once the lesion is removed, the cyst will collapse. If any part of the tumor remains in place, the cyst will fill up again. Small hemangioblastomas that are asymptomatic and not associated with a cyst are sometimes treated with stereotaxic radiosurgery, but this is more prevention than treatment, and long-term results seem to show only little benefit. In addition, symptoms may not improve during the recovery period.

- Neuroendocrine tumors of the pancreas.

Careful analysis is required to differentiate serous cystadenomas from pancreatic neuroendocrine tumors (pancreatic NET). Cysts and cystadenomas usually do not require treatment. The pancreatic NET should be assessed for size, behavior, and specific genetic mutation.

- Renal cell carcinoma.

Hippel-Lindau disease kidney tumors are often found when they are very small and very early in development. The strategy to ensure that a person has a sufficiently functioning kidney throughout their life begins with careful observation and the choice of surgery only when the size of the tumor or the high growth rate suggests that the tumor may acquire a metastatic potential (by about 3 cm). At the same time, the method of organ-preserving surgery is widely used. Radiofrequency ablation (RFA) or cryosurgery (cryotherapy) may be considered, especially for small tumors in the early stages. Care must be taken not to damage adjacent structures and to limit scarring that can complicate subsequent operations.

- Hemangioblastoma of the retina.

Small peripheral lesions can be successfully treated with minimal or no vision loss with a laser. Large lesions often require cryotherapy. If the hemangioblastoma is located on the optic nerve head, there are several treatment options available to help maintain vision successfully.

- Pheochromocytomas.

Surgical removal is performed after adequate blockage with medication; laparoscopic partial adrenalectomy is preferred. Vital signs are closely monitored for at least a week after surgery while the body adjusts to its "new normal". Special care is required during any type of surgery, as well as during pregnancy and childbirth. Even pheochromocytomas that do not appear to be active or cause symptoms should be considered for removal, ideally before pregnancy or non-emergency surgery.

- Tumors of the endolymphatic sac.

Patients who have a tumor or hemorrhage visible on MRI, but who can still hear, require surgery to prevent their condition from worsening. Deaf patients with tumor imaging data should undergo surgery if other neurologic symptoms are present to prevent impairment of balance. Not all endolymphatic sac tumors are visible on imaging; some are found only during the operation.

Forecast

The prognosis of Hippel-Lindau disease depends on the occurrence of multiple tumors. Renal cell carcinoma is the leading cause of death, followed by central nervous system hemangioblastomas. Life expectancy was previously estimated at 50 years; however, regular surveillance, early detection and treatment of tumors have now reduced morbidity and mortality.