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The links included within the service may let you leave this site. These links are provided as a convenience only, and the inclusion of any link does not imply endorsement by HLRCCFA of the site or any association with their operators. Julie Adam, Ph. Carrington, M. Marston Linehan, M. Menko, M.

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Mier, M. Schmidt, Ph. Toro, M. Although no longer actively involved, in recognition of their contribution to the world of HLRCC the following have kindly agreed to be listed. Funding the Alliance helps support our website and any outreach we do to the medical community, including such things as domestic and international mailings, attending medical conferences related to HLRCC, or supporting travel expenses for HLRCC educators. The Alliance is funded by the generosity of its supporters. Please contact your local group and your tax advisor for specific information on guidelines for tax deductibility of donations.

Thank you! Download the Quick Facts for your convenience. In recent years, scientists have used the work of the Genome Project to help identify new connections between physical symptoms that used to be viewed as isolated or random. HLRCC is a rare inherited condition first fully described in It is caused by a tiny alteration in one copy of the FH gene. Approximately people have been evaluated at the US-NIH, along with many other people in England, France, Japan, Finland, and Australia, but it is believed that there are many more people who are undiagnosed.

There is considerable variation in symptoms from family to family and among members of the same family. Each person in a family has their own individual susceptibility to the symptoms. For example, if your parent had kidney cancer, it does not mean you will develop a kidney tumor. You have your own unique susceptibility. Even if a child inherits the altered gene, it does not necessarily mean that he or she will have any symptoms of HLRCC. There may never be any symptoms at all. Or that person may develop just one of the issues, or two, or possibly all three.

However, there do seem to be trends in some families. Some families seem to only get leiomyomatosis and other families are more likely to get RCC kidney cancer. All people have fumarase and researchers are trying to learn the normal function of fumarase and why alterations in the FH gene cause the symptoms of HLRCC. All people have two copies of the fumarate hydratase gene, one from their mother and one from their father.

The other is altered, meaning that it has a change in it and does not work very well. The altered FH gene is unable to produce the fumarase enzyme properly. When a person has only one working copy of the gene, their cells make less fumarase than normal, but enough to be healthy. Cells have the ability to repair damaged DNA, but sometimes they cannot, leaving a non-working altered gene in a cell. In a person with HLRCC, an alteration in the second copy of the FH gene can lead to biochemical changes that cause those cells to grow into benign smooth muscle tumors leiomyomas of the skin and uterus, or less often malignant tumors of the kidney.

Although there is no consensus on diagnostic criteria, the US-NIH and other experts believe that an individual has HLRCC if they have any of the major features of the condition, including:. However, fibroids are very common in the general population and are rarely diagnostically useful on their own. However, the incidence of kidney tumors in the European group is reported as much lower.

If HLRCC is suspected, but the genetic alteration cannot be found and there are no cutaneous leiomyomas, then a fumarase enzyme assay can be done on cells derived from skin or blood. This test is specialized and it is not available in most laboratories. Some laboratories that can test for fumarase activity find difficulties because of problems in calculating and interpreting the results. Breast and prostate are examples. At this point they are assumed to be coincidental.

We are all still members of the general population. Note: There are other tumor types where the number of cases is too small to allow us to categorize these tumors as diagnostic criteria for HLRCC, but when they occur in an HLRCC patient, the tumors are found to have no fumarase activity. Examples are benign adrenal tumors and Leydig testicular cancer which develops in the Leydig cells — the cells in the testes that release the male hormone, testosterone. HLRCC is an autosomal dominant disorder.

You have two FH genes — one from each parent. The one healthy parent gives you one healthy unaltered FH gene. Occasionally a person with an altered FH gene may have very few symptoms, so that it may seem to skip a generation, but if you do not have an altered FH gene you cannot pass it to a child.

It is possible for an alteration in the FH gene to be present for the first time in one family member as a result of a mutation in a germ cell egg or sperm of one of the parents or in the fertilized egg itself. Each child gets one copy of the FH gene from each parent. In this way, there are four possible arrangements of these four genes. Although a physician can often diagnose an individual with HLRCC based on the physical signs listed above, the US-NIH recommend that individuals obtain genetic testing to confirm that they actually have the gene alteration. You should also give your genetic counselor the link www.

You are at significant risk of being diagnosed with an FH gene alteration if you have a diagnosed blood relative. In other words, if one of your parents is at risk, but tests negative, then you will not be at risk. If a person does not carry the altered gene, they cannot pass it to a child.

You may wish to discuss this with your genetic counselor for more clarification. If you test positive and want to inform other family members, there is at the end of the handbook, a printable Family Letter to send to relatives of someone recently diagnosed with HLRCC.

The letter should only come from the person with the HLRCC diagnosis, or the next-of-kin if the person has died, in order to respect their privacy.

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It is important to keep in mind that your family members may be overwhelmed when they receive this information. We tried to keep this in mind when creating our printable letter and to offer the support of the HLRCC Family Alliance as a way of supporting each and every person associated with this condition.

If your genetic test is negative, but you have symptoms of HLRCC you should check that your genetic test covered the possibility of FH deletions, in addition to bidirectional sequencing. This is usually through a technique called MLPA or multiplex ligation probe amplification. Some companies only offer sequencing. It can sometimes take several months to obtain genetic testing results, but once one genetic alteration is identified within the family, testing of additional family members is faster and less costly.

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Tests in some countries are faster than others. Many people who learn they may have HLRCC are concerned that their health insurance company will either terminate their policy or deny coverage if the insurer learns of their genetic status. Many states have enacted state laws to protect their citizens from genetic discrimination by health insurers. However, the protection offered varies widely among state laws. Employers with fewer than 15 employees and the military are not required to abide by the employment protections.

Before making any decision you may wish to speak with a geneticist or genetic counselor about possible testing options and its implications. There is considerable variation in the appearance of cutaneous leiomyomas as can be seen in the following photographs making it difficult to diagnose by sight unless you are a specialist. Just as uterine leiomyomas grow from smooth muscle of the uterus, cutaneous leiomyomas are rare benign tumors that grow from smooth muscles in the skin.

The arrectores pilorum singular arrector pili, also called piloerectus muscles are small smooth muscles that are attached to hair follicles. When benign tumors grow from arrrectores pilorum, they are called piloleiomyomas. They also may be called cutaneous leiomyomas. They tend to grow anywhere on the body and limbs, but rarely on the face, hands or feet. These bumps can be very small, but sometimes large, can range in color from skin-colored to light brown to red, and tend to grow in mosaic clusters, but can also be solitary. Some people have a single leiomyoma, but many people develop small clusters of leiomyomas.

Once a leiomyoma appears, it does not go away. Leiomyomas can be mistaken for post-acne scarring. They are very firm to the touch and discrete as compared to acne or eczema. They are not common skin lesions in the general population, but dermatologists are starting to recognize them more easily as potential indicators of HLRCC.

A skin biopsy must be done to confirm a leiomyoma, as relying on appearance is inconclusive. A skin biopsy involves minor surgical removal of some of the skin bump, after which the tissue is sent to a pathology lab. An anesthetic agent is injected under the skin around the leiomyoma and once the area is numb, a small sample of tissue is taken.

Slides are prepared from the tissue and examined under a microscope by a pathologist to determine whether the diagnosis is piloleiomyoma or some other type of growth. Cutaneous leiomyomas can be the only clue to a physician about whether a person is at risk for HLRCC. As with all the conditions associated with HLRCC there is considerable variation not only in the appearance of cutaneous leiomyomas, but also in the experience of pain in them. The exact cause of pain has not been understood, but there is a thought that the leiomyoma has trapped nerve cells.

The variation is not just from patient to patient, but also within one patient and can increase over time. Some patients find a cold sensitivity to such an extent that they even consider moving to a warmer country. Some find that if a pain develops in one leiomyoma it acts as a trigger to all the others to become also painful for hours or days at a time.

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Sometimes a leiomyoma that grows initially without having any pain symptom can start to become irritable and painful. Pain can sometimes occur as a result of exertion, or by touch or rubbing clothes. When pain does occur most patients describe it as excruciating, like having a knifepoint stab. Cutaneous leiomyomas are often sensitive to cold and touch, but many people do not find them painful.

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However, in some people leiomyomas are very painful. Most dermatologists do NOT recommend surgically removing all these growths, except as needed for biopsies, as it tends to cause scarring and divots in the skin where the procedure is performed. However painful or unsightly leiomyomas, if there are not too many close together, can be surgically removed using CO2 laser or freezing with cryosurgery.

Preferably the removal is by a skilled plastic surgeon to minimize scarring. Use of a super-fine thread avoids the dots on either side of the line of surgery. Removal will normally be done under a local anesthetic. There is a reported case of extensive multiple piloleiomyomas being successfully removed by surgery and reconstructed with a flap technique.

Sometimes the leiomyomas will grow back after removal, possibly because some tissue was left behind, or there were new ones growing when in a cluster. You should talk with a dermatologist about what is best for your type of skin growth. One of our members has found significant relief using Lyrica. As with any treatment you should first discuss and agree its suitability with your physician and or dermatologist. The links below have a lot of information about Lyrica including descriptions of warnings and side effects which seem important to study before deciding to take it.

Another pain relief drug that is being used is niphediprine. As with the use of all drugs you should consult with your medical team — especially so if intending to become pregnant. A dermatologist should conduct an annual inspection of all cutaneous leiomyomas to detect changes which might lead to malignant leiomyosarcoma which is a rare cancer.

Like the skin, the uterus contains smooth muscle tissue, and uterine fibroids are smooth muscle tumors that grow in the wall of the uterus or womb, myometrium and with the ligament of the womb. They are almost always benign non-cancerous and can be as small as an apple seed or as large as a grapefruit. Other medical terms for fibroids are myoma fibromyoma leiofibromyoma fibroleiomyoma and fibroma the dual of myoma is myomas or myomata.

Uterine fibroids are the leading reason for hysterectomies in the United States 1 in 3 have fibroids. Women with fibroids may be at greater risk of having a cesarean section when they give birth. Other women with fibroids may have difficulty becoming pregnant or carrying a pregnancy.

Von Hippel-Lindau Disease - NORD (National Organization for Rare Disorders)

The main action of the VHL protein is thought to be its E3 ubiquitin ligase activity that results in specific target proteins being 'marked' for degradation. The most researched of these targets is hypoxia inducible factor 1a HIF1a , a transcription factor that induces the expression of a number of angiogenesis related factors. HIF is necessary for tumor growth because most cancers demand high metabolic activity and are only supplied by structurally or functionally inadequate vasculature. Activation of HIF allows for enhanced angiogenesis , which in turn allows for increased glucose uptake.

This leads to increased survival due to lower rates of apoptosis and increased proliferation due to the activation of cyclin D1. This indicates that the HIF transcription factor distribution in kidney cancer is of major importance in determining the outcome of the patients. This heterodimer of HIF is a transcription factor that activates genes that encode for proteins such as vascular endothelial growth factor VEGF and erythropoietin, proteins that are both involved in angiogenesis.

Cells with abnormal pVHL are unable to disrupt the formation of these dimers, and therefore behave like they are hypoxic even in oxygenated environments. It has been theorized that constitutively activating HIF in any cell could lead to cancer, but that there are redundant regulators of HIF in organs not affected by VHL syndrome. This theory has been disproved multiple times since in all cell types loss of VHL function leads to constitutive activation of HIF and its downstream effects.

Another theory holds that although in all cells loss of VHL leads to activation of HIF, in most cells this leads to no advantage in proliferation or survival. Additionally, the nature of the mutation in the VHL protein leads to phenotypic manifestations in the pattern of cancer that develops. Nonsense or deletion mutations of VHL protein have been linked to type 1 VHL with a low risk of pheochromocytoma adrenal gland tumors. Type 2 VHL has been linked to missense mutations and is linked to a high risk of pheochromocytoma.

Type 2 has also been further subdivided based on risks of renal cell carcinoma. The involvement in VHL in renal cell cancer can be rationalized via multiple characteristics of renal cells. First, they are more sensitive to the effects of growth factors created downstream of HIF activation than other cells. Secondly, the link to Cyclin D1 as mentioned above is only seen in renal cells. Finally, many cells in the kidney normally operate under hypoxic conditions. This may give them a proliferative advantage over other cells while in hypoxic environments. This function plays a key role in the stabilisation of the spindle during mitosis.

Deletion of VHL causes a drastic increase of misorientated and rotating spindles during mitosis. Through a not yet known mechanism, VHL also increases the concentration of MAD2 , an important protein of the spindle checkpoint. Thus VHL-loss leads to a weakened checkpoint and subsequently chromosome missegregation and aneuploidy.

In turn, this leads to unregulated blood vessel growth, one of the prerequisites of a tumor. Additionally, VHL has been implicated in maintaining the differentiated phenotype in renal cells. This evidence suggests that VHL has a central role in maintaining a differentiated phenotype in the cell. Additionally, pVHL is important for extracellular matrix formation. These ideas are extremely important in the metastasis of VHL-deficient cells. In classical VHL disease a single wild-type allele in VHL appears to be sufficient to maintain normal cardiopulmonary function.

Since iron, 2-oxoglutarate and oxygen are necessary for the inactivation of HIF, it has been theorized that a lack of these cofactors could reduce the ability of hydroxlases in inactivating HIF. Disease Resources Resources can help guide your quest for factual and reliable information. Displaying of 3 results. Added On: Jun 20, Category: General. The newsletter is designed to educate and empower patients and all those impacted by VHL. Category: Blogs.

There are no true rules for the VHL journey. It is different for everyone. Read how others are living through and thriving during their journey. Publish Date: Jun 20, A reference handbook patients, caregivers and healthcare providers; it explains how VHL occurs, how to monitor and test for possible medical issues, and common treatment options to consider.