HLRCC Handbook

HLRCC Handbook


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. One of these diseases is called HLRCC, or Hereditary Leiomyomatosis and Renal Cell Cancer. HLRCC is a rare inherited condition first fully described in 2001. It is caused by a tiny alteration in one copy of the FH gene.

According to researchers at the US-NIH HLRCC is a rare inherited condition characterized by the presence of cutaneous leiomyomas, uterine fibroids, and/or kidney cancer. A person who is diagnosed with HLRCC has inherited a susceptibility to develop one or more of these symptoms.

Approximately 450 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. Considering HLRCC is a relatively new, and rare condition, there remains much to be learned.

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. So far, researchers have not been able to find any patterns that would allow one to predict which symptoms a person will develop based on the particular genotype they have. 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).

HLRCC is caused by having an alteration (mutation) in one copy of the fumarate hydratase (FH) gene. The FH gene is a section of DNA that codes for a protein called fumarase. Fumarase is an important enzyme needed for the production of energy by mitochondria, which are the tiny organelles inside our cells that produce most of our cells' energy. 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.

HLRCC is inherited in an Autosomal Dominant manner, meaning that both males and females can be affected, and each child of an affected parent has a 50% chance of inheriting the altered FH gene.

All people have two copies of the fumarate hydratase gene, one from their mother and one from their father. In a person with the condition called HLRCC, one of their two genes is normal and working well. 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. During a person's lifetime, genes can become damaged when alterations occur during cell division or from exposure to chemicals or radiation. 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. For more detailed information regarding the FH enzyme, please refer to our HLRCC Science.

Diagnostic Criteria

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:

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. A fumarase activity level less than or equal to 60% is indicative of HLRCC. 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.

There are other cancers which have been occasionally associated with HLRCC. Breast and prostate are examples. Some HLRCC family members have other health problems (an example is thyroid nodules), but it is not clear if these are related to HLRCC. At this point they are assumed to be coincidental. We are all still members of the general population.

Note: Researchers in England have discovered a chemical compound that is present in HLRCC tumors, but not in non HLRCC tumors (kidney and other tumors), so in the future we may see newer and better screening tests for HLRCC.

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. There is also a possibility of benign ovarian cystadenomas and some Wilms' tumors being associated with HLRCC.

Genetic Testing

HLRCC is an autosomal dominant disorder. "Autosomal" means that the alteration is located on one of the 22 regular chromosomes and not on a sex chromosome (X or Y). "Dominant" means that having just one copy of the altered gene is enough to cause the disorder. This means that if a person has HLRCC, there is a 50% chance that he or she will pass the altered gene to a child. There is a 50% chance that an embryo of an HLRCC parent will have the condition, depending on whether the particular egg or sperm from which that the embryo was formed contained the altered copy of the gene. You have two FH genes – one from each parent. The one healthy parent gives you one healthy unaltered FH gene. The other parent with the altered gene gives you one of their two copies of the gene: either a healthy unaltered FH gene or an altered FH gene – hence the 50% chance. You either have an altered gene or you don’t. 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. This is termed a "de novo mutation".

Parent 1 with HLRCC
A = FH Gene Mutation
B = FH Working Gene
Parent 2 without HLRCC
C = FH Working Gene
D = FH Working Gene

Each child gets one copy of the FH gene from each parent.
In this way, there are four possible arrangements of these four genes. Each arrangement has a 25% chance.

So for each child there is a 50% chance of having HLRCC and a 50% chance of not having it.

AC: Child
A=FH Gene Mutation
C=FH Working Gene
AD: Child
A=FH Gene Mutation
D=FH Working Gene
BC: Child
Without HLRCC
B=FH Working Gene
C=FH Working Gene
BD: Child
Without HLRCC
B=FH Working Gene
D=FH Working Gene

Genetic testing is the most reliable way of diagnosing HLRCC. 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.

Benefits of genetic testing to confirm HLRCC:

Things to keep in mind regarding genetic testing:

If you are in the worldwide HLRCC clinical study at the US-NIH (Bethesda, Maryland, USA):

If you are not in the US-NIH study, you should look for a genetic counselor from your area online. The best links to use are:
US - http://www.nsgc.org/
World - http://geneclinics.org and go to the link for Clinic Directory

You will want to bring a copy of a clinical paper about HLRCC such as the Toro article http://www.ncbi.nlm.nih.gov/books/NBK1252/ with you to your genetic counselor and your genetic counselor is welcome to contact Lindsay Middelton at US-NIH or another expert consultant to obtain further information. You should also give your genetic counselor the link www.hlrccinfo.org so that they can make sure you get the screening you need when they connect you with the proper physicians, should your test be positive.


The risk of developing the features of HLRCC increases with age. You are at significant risk of being diagnosed with an FH gene alteration if you have a diagnosed blood relative. The actual risk figure depends on the closeness of the relationship starting as high as 50% with a first degree relative (parent, child or sibling). There is a lower risk of 25% with a second degree relative (uncle/aunt, niece/nephew or a grandparent) and a still lower risk with a third degree relative (first cousin) or even a first cousin's child. The alteration cannot however skip generations so the more genetic testing a family has the more precise the risk figure will be for each individual ranging from 0% to 50%. 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. 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. Tests in some countries are faster than others. Please consider the following PROS and CONS when considering genetic testing as well:



Life and Health Insurance

A useful link describing the general implications for insurance (applies to all genetic conditions not just to Birt-Hogg-Dubé) is http://www.bhdsyndrome.org/for-families/additional-resources/insurance/ and there is information for different US States in http://www.healthinsuranceinfo.net/

Concerns about Genetic Discrimination of Health Insurers

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. You can access information about your state law by accessing: http://genome.gov > Issues in Genetics > Statute and Legislation Database http://www.genome.gov/PolicyEthics/LegDatabase/pubsearch.cfm

In 2008 the Genetic Information Nondiscrimination Act (GINA) was signed into law. The GINA Act prohibits discrimination by health insurance companies and employers based on "genetic information", including information about genetic testing or your results (and those of your family members) or information about family history of any disease or disorder.

Health insurance protection:

Employment protection:

What does GINA NOT do?

Employers with fewer than 15 employees and the military are not required to abide by the employment protections.

Having Children

Deciding whether to have children when there is a 50% chance of inheriting a problem is a difficult decision to make. Before making any decision you may wish to speak with a geneticist or genetic counselor about possible testing options and its implications. One option may be Pre-implantation Genetic Diagnosis (PGD). There is information on the VHL Family Alliance website about PGD. See http://www.vhl.org/?s=pgd

Other options may include Chorionic Villus Sampling (CVS) or amniocentesis.

Cutaneous Leiomyomas (Skin Bumps)

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.

Cutaneous Leiomyomas
Figure 2 On the Back
Cutaneous Leiomyomas
Figure 3 On the Back
Cutaneous Leiomyomas
Figure 4 Segmental on the Chest
Cutaneous Leiomyomas
Figure 5 On the Leg

Photos 2, 3 and 4 courtesy of Dr. Ed Cowen, NIH, NCI.

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. These are the muscles that allow your hairs to "stand up" when you are cold or fearful. When benign tumors grow from arrrectores pilorum, they are called piloleiomyomas. They also may be called cutaneous leiomyomas. It is estimated that most people with HLRCC will get one or more piloleiomyomas in their lifetime.

Piloleiomyomas are very helpful for identifying people who are likely to have HLRCC.

Individuals who have HLRCC tend to have cutaneous leiomyomas by the time they are in their 30’s, but some have gotten them as early as 11 years old; some people report finding their first one in their 50’s.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. A smaller percentage of people develop wide distribution of leiomyomas over a chest or back ("segmental distribution"). 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. If one has a first-degree relative with HLRCC, then a single confirmed cutaneous leiomyoma is sufficient for the diagnosis of 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. 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. 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.

Currently researchers at US-NIH are experimenting with Botox therapy to help with the pain (see Clinical Trials). If you have painful cutaneous leiomyomas, you may want to get a contact name from info@hlrccinfo.org or talk with your own dermatologist about options.

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.

http://www.lyrica.com/PHN/phn-introduction.aspx and http://arthritis.about.com/od/pregabalin/a/Lyrica.htm and http://en.wikipedia.org/wiki/Pregabalin

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.

Significant pain relief has also been reported with pulsed hysocine butyl bromide see http://www.ncbi.nlm.nih.gov/pubmed/20049277. This article mentions many calcium channel blockers like nifedipine, phenoxybenzamine, doxazocine, gabapentin and topical 9% hyoscine hydrobromide.

Cutaneous leiomyomas
Courtesy of Ryan N, HLRCC patient - showing significant growing back after 3 years.

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). There has been one reported case of a solitary angioleiomyoma with multiple piloleiomyomas see http://www.ncbi.nlm.nih.gov/pubmed/10356411.

Uterine Fibroids

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).

In the general population, up to 80% of women develop uterine fibroids by the age of 50 years. 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. More often fibroids are simply "innocent bystanders" during pregnancy and cause no problems at all.

Uterine fibroids are often the first physical symptom to develop in a female who has HLRCC. Although a nuisance, they provide a clue to individuals who are at risk, as well as a warning to be looking for skin leiomyomas, which are often the second physical symptoms of HLRCC.

The growth of uterine fibroids is believed to be affected by hormones (byespecially the female hormones estrogen and progesterone). The occurrence of fibroids is genetic. Uterine fibroids that are associated with HLRCC tend to be larger and to occur at earlier ages than in the general population.

If you are planning to have children, it may be better to have them in your 20's rather than to wait until your 30's, as over time fibroids may begin to create issues which can complicate fertility or pregnancy.

Fibroid Symptoms

Fibroids are so common - and can be so small - that many women do not even know that they have them. Women with HLRCC often have moremore and much larger fibroids that are accompanied by other symptoms, including:


Ways to find out if you have uterine fibroids:

  • A pelvic ultrasound scan is usually performed transvaginally. However, when the uterus is very large, a transabdominal pelvic ultrasound may be needed to measure the full size of the fibroids and uterus. Some radiologists and gynecologists also perform a sonohysterogram in which a catheter is placed in the cervix into the uterus and fluid (sterile water or saline) is infused. Sonohysterograms can be helpful in determining whether there are fibroids within the uterine cavity.
  • Hysterosalpingogram is an x-ray test done during testing for infertility, and is used to investigate the shape of the uterine cavity and whether the fallopian tubes may be blocked. During hysterosalpingograms, radio-opaque material is injected into the uterine cavity and x-rays are done. Hysterosalpingograms can be helpful in determining whether there are fibroids within the uterine cavity or whether these fibroids compress the opening to the fallopian tubes. However they are not useful in looking at the fibroids themselves, and not all centers perform this procedure.
  • A gynecologist should continue these annual checks and consider adding radiological examination. Once a woman with HLRCC is known to have fibroids, a gynecologist should perform an annual examination to check for increasing uterine size suggestive of fibroid growth. Having imaging studies done over time (ultrasound or MRI) will also enable the radiologist and gynecologist to determine whether the fibroids have grown in size or number. Significant growth in fibroid size might suggest the development of a malignant type of fibroids called leiomyosarcoma. Thus, when fibroids grow rapidly, surgical treatment is usually recommended. Hysterosonograms and hysterosalpingograms may be helpful as a preoperative assessment for myomectomy (described below). While the first reports of HLRCC suggested that leiomyosarcoma might occur in women with fibroids, a large study at US-NIH has shown that fibroids may be atypical, but no cases of leiomyosarcoma have been observed.

    Fibroid tumors seen during surgery
    From http://en.wikipedia.org/wiki/Uterine_fibroid

    A moving story : "I was at the University of Michigan as a high risk patient while I was pregnant with my first child," said Julie Sherwood, a 39-year-old HLRCC patient. "I had a vertical c-section and they still could not find my baby because I had so many fibroids in the way. They had to do a second incision and the baby was saved. During my second pregnancy my fibroids tripled within weeks and the baby couldn’t survive. I had an emergency hysterectomy weeks later."

    Julie's moving story, along with many other discussions about a variety of health-related topics, can be found in a recent radio interview at:


    There are several options of managing fibroids. Many factors are considered to determine which option is the best one for each individual.

    Sometimes a hysterectomy is recommended. During hysterectomy the uterus and cervix are removed, and sometimes the ovaries are removed as well. It is not possible to carry a pregnancy after the uterus is removed.

    Another option for treating fibroids is a surgical procedure called myomectomy. During a myomectomy only the fibroids are removed, and thus the ability to carry a pregnancy may be preserved. When fibroids are within the uterine cavity, they may be removed through a hysteroscopic myomectomy procedure (operating using a viewing instrument through the cervix). When the fibroids are large and within the wall of the uterus, an abdominal myomectomy is usually performed. While some gynecologists perform this procedure laparoscopically or robotically (operating using a viewing instrument in the abdomen), it is important that the fibroids are not morcellated (mechanically cut up into pieces) inside your body. Removing the fibroid intact will enable the pathologist to examine it for atypical features or possible leiomyosarcoma. Additionally, there is a concern that many fibroids associated with HLRCC are atypical and cellular. With morcellation, small pieces of tissue left in your body may attach and grow. Another concern is the number of myomectomy procedures done prior to attempting pregnancy. If a woman undergoes several myomectomy procedures prior to attempting pregnancy, she may have difficulty becoming pregnant or may be at risk of miscarriage. These effects may occur because, for example, of scarring in the uterine wall. Thus, timing myomectomy surgery just before attempting pregnancy may be a preferable strategy.

    Non-surgical treatments of uterine fibroids include Uterine Artery Embolization (UAE) or High Intensity Focused Ultrasound Ablation (HIFU) of fibroids. Both procedures are performed by an interventional radiologist. These physicians are trained in a medical sub-specialty of radiology which utilizes minimally-invasive image-guided procedures to treat diseases. At the present time, neither procedure is recommended for women with HLRCC as they will not investigate whether fibroids are atypical or cancerous. These strategies either lessen the flow of blood to the uterus (UAE) or physically destroy part of the fibroid (HIFU). In some patients with HLRCC who have undergone UAE, their fibroids have rapidly increased in size.

    Birth control pills and the levonorgestrel (MirenaTM) IUD decrease menstrual bleeding in women regardless of whether they have fibroids, and are effective methods of contraception. Women with the HLRCC gene defect are able to use these treatments for these indications. While fibroids do appear to be hormone-sensitive, it is unknown at this time whether using hormones like birth control pills or the levonorgestrel IUD will be effective in decreasing fibroid size in women with HLRCC.

    There are many organizations and links that will assist in your understanding of uterine fibroids. Keep in mind that we are currently trying to educate these organizations about HLRCC and that you most likely will not find information specific to HLRCC on these websites.

    The Center for Uterine Fibroids

    The National Uterine Fibroids Foundation
    Colorado Springs, Colorado

    The following links provide additional information about fibroids:





    There are additional links for fibroids to be found in the HLRCC Science document.

    Renal (Kidney) Tumors

    Research indicates that only a proportion of individuals with HLRCC develop malignant (cancerous) kidney tumors. There is a higher proportion in the US-NIH study possibly because they are recruiting as kidney cancer specialists. The variation in incidence figures is considerable and may depend on several factors including methods of recruitment. It will take more studies to determine the true risk of kidney tumors in a particular individual. Meanwhile, since this is such a potentially lethal tumor, we recommend that everyone be screened for kidney tumors. See Suggested Screening Guidelines.


    Kidney cancer often develops with no initial symptoms, and by the time symptoms such as pain or blood in the urine appear, it has often already become a danger to life.

    In the general population kidney cancer accounts for about 3% of all cancers. Whereas the cell type of most kidney cancers is Clear Cell, HLRCC tumors are most often called Type II Papillary, sometimes Tubulopapillary, occasionally Collecting Duct Carcinoma, and rarely Clear Cell. Dr. Maria Merino of the US-NCI described the typical features of the HLRCC tumors in "The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome", 2007 Merino MJ, Torres-Cabala C, Pinto P, Linehan WM. http://www.ncbi.nlm.nih.gov/pubmed/17895761

    A person with a diagnosis of HLRCC has a much higher risk of developing lesions in the kidney compared to the general population. There are three kinds of lesions in the kidney: benign cysts, hard tumors, and hard lumps developing inside a cyst. Unlike other genetic syndromes associated with kidney cancer, HLRCC kidney tumors can metastasize (spread) when the tumor is relatively small (less than 1 cm). These tumors usually spread to the lungs, bone and brain. It was thought that HLRCC was generally unilateral in that only one kidney is initially affected. However as people are living longer after surgery, problems can develop in the remaining kidney. Like all kidney tumors they often initially have few, if any, noticeable symptoms, which is why scanning is essential in order to detect them at an earlier stage.

    Treatment / Management of the Kidneys

    This is an area which is still being actively researched and there are many factors to be considered for every individual. The key to managing HLRCC kidney tumors is surveillance to find tumors when they are small. Surgical removal if possible is currently the treatment of choice when a tumor is found. Some families report a currently healthy grandparent who had a nephrectomy many years ago, and there are people who had tumors removed 10 years ago who are healthy and well.

    Once an HLRCC kidney tumor has metastasized, the prognosis changes, and the course of metastatic kidney cancer is similar to the experience of others in the general population. There are targeted molecular treatments that are currently in clinical trials. At the US-NIH there is a clinical trial of a combination of bevacizumab (Avastin) and erlotinib (Tarceva). In 2014 the initial report of the trial was very favorable. The spectrum of available drugs and the recommendations for primary and secondary therapies for papillary kidney cancer is evolving rapidly. Check with an oncologist experienced in kidney cancer and make contact with an HLRCC specialist with advice from info@hlrccinfo.org.

    The type of kidney surgery is dependent on many factors. Sometimes it may be necessary to remove the entire kidney (nephrectomy) or a partial nephrectomy may be performed. A partial nephrectomy is nephron sparing surgery in which only the tumor and a little surrounding margin of tissue is removed. With HLRCC a wider margin should be used.

    Follow-up after RCC

    The exact follow-up procedure for every patient will vary from center to center and should be discussed and agreed with your physicians. We will only describe here examples of what you may expect.

    If you have had a nephrectomy, then initially for the first 2 years a full chest and abdominal CT scan with contrast may be carried out every 6 months to check for any metastasis (spread). ALWAYS TELL THE RADIOLOGIST THAT YOU HAVE ONLY ONE KIDNEY AND PLEASE TO REDUCE THE AMOUNT OF CONTRAST.

    A PET/CT and a bone scan may also be ordered if metastasis is thought likely. Kidney cancer will often metastasize to the lungs or bone. Note this is then called secondary kidney cancer in the lung or bone and NOT lung cancer or bone cancer.

    After two years the screening interval may be increased to yearly, but there continues to be a life-time risk of either recurrence or metastasis requiring long-term surveillance. See http://www.ncbi.nlm.nih.gov/pubmed/21903243


    There are four types of Kidney Imaging: Magnetic Resonance Imaging (MRI), Computed Tomography (CT), Positron Emission Tomography (PET) and Ultrasound. Some centers will alternate MRI with CT scans. The kidney cancer of HLRCC can metastasize (spread to other organs or bone) even when small, which makes early detection essential. There are several well used methods to visualize kidney tumors. There are pros and cons for each.

    Magnetic Resonance Imaging (MRI)

    MRI scans with and without contrast is an acceptable method to examine kidneys. This process creates images using magnetic waves. No radiation is used.

    The MRI scan for HLRCC patients should use pre-and post- contrast 3D acquisition with 3mm slice reconstruction. Clinicians at the National Institutes of Health are currently evaluating the potential utility of 1mm slice reconstruction in this population. The preferred option is to use MRI with gadolinium contrast, because it is the contrast medium that identifies soft tissue. MRI scanners have recently improved with "Open MRI" and shorter and wider tunnels making the experience less problematic even for people with mild claustrophobia. However there is some concern that the image quality may be reduced with some open large bore MRI scanners. The objective is to get the best possible picture quality. If you feel you need calming medication for anxiety or discomfort, a larger bore to accommodate larger body mass, or any other requests, negotiate a solution that will give the doctor the picture quality needed while addressing your concerns. Ask: Is it possible to enter the MRI machine feet first? People find this is an improvement on the unpleasant experience.

    Computed Tomography (CT Scan)

    CT scans with and without contrast is an acceptable method of visualizing kidneys. However, images are created through the use of radiation. Annual CT scans over a life span raises concerns about using up your lifetime maximum of radiation exposure.

    The CT scan is done with a contrast agent usually containing iodine and you should drink plenty of water afterwards to flush the contrast agent out of your body. If there is any doubt about your kidney function (creatinine levels above 1.6) you may be given 500cc of saline solution first and Visipaque(iodixanol) or Omnipaque (iohexol) contrast which have lower iodine content.

    Positron Emission Tomography (PET)

    For ordinary RCC, PET scans are normally less effective than CT scans with contrast and have been known to give false negatives. A PET scan is often combined with a CT scan. However, with HLRCC any tumors present are glucose hungry and PET can be a useful diagnostic tool especially for detecting metastases. There can be false positives in both the adrenal glands and the uterus because of the presence of benign HLRCC related tissue. Cancer cells upregulate glucose metabolism, which is a phenomenon known as the Warburg effect. This is the basis for PET in which a glucose analog tracer FDG (2-18fluoro-2-deoxy-D-glucose), a radioactive modified hexokinase substrate, is used to differentiate between normal and tumor tissue.


    Ultrasound can be effective in visualizing some kidney tumors, but can easily miss the small tumors associated with HLRCC or does not detect some types of tumor tissue. Ultrasound is used occasionally when a tumor is present to determine the amount of fluid in the mass. Note: Ultrasound as a screening (surveillance) method is not recommended for people with HLRCC.

    Bone Scan

    A bone scan consists of taking a camera image of your body about 3 to 4 hours after giving you an injection of a radioactive isotope. This can detect any metastasis that has spread to the bones.


    There is now a published guideline by the world's experts which corresponds generally to the information presented in this HLRCC Handbook.

    Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Menko FH, Maher ER, Schmidt LS, Middelton LA, Aittomäki K, Tomlinson I, Richard S, Linehan WM, 2014

    The HLRCC Family Alliance has taken a stronger position based on input from its members.

    1) As informed patients or as parents we should be able to strongly suggest FH genetic testing from any age starting from birth. This is justified from the fact that new research has shown that some pheochromocytoma and paraganglioma are associated with FH and can manifest from birth. This also means that children under the age of 16 can either be warned that they have HLRCC FH mutation or are clear and don't need to worry because they don't have it. Many children become worried about not knowing and are able to cope well with a positive diagnosis.

    2) As informed patients or as parents we should be able to strongly suggest that screening with an initial MRI test can start from any age from birth for anyone at risk. For a child of a HLRCC patient the child is at risk either known from a genetic test or because of parenthood if no genetic test has been made, or if no family FH mutation is known which occurs in a few families. To screen every year with MRI may be considered excessive if the initial MRI is clear and maybe 2 or 3 year intervals is more appropriate with ultrasound in between. This of course slightly increases the risk of something developing and being undetected for a period of time.


    The one common guideline we do recommend is that you take charge. Be informed, discuss openly with your medical professionals and consider the pros and cons. Please e-mail us at info@hlrccinfo.org if you want more information about the published guideline above or you have unanswered questions and we will always try to help you.

    HLRCC is a relatively young condition in that there are few people who have been followed medically from childhood through adulthood with today's screening technologies. We have lots of questions, but few firm answers at this time. However everyone with HLRCC can assist us in learning what we need to know to protect ourselves and our children from the worst effects of HLRCC.

    The purpose of screening guidelines is to help patients and their local physicians watch out for foreshadowing of problems, before they get to a critical stage. By intervening at earlier stages, hopefully these problems never become threatening to life or quality of life. Note that screening means that you do not yet have any issues in the area being screened. Once you have a diagnosed issue, then you will need to follow the guidance of your health care team in deciding what course of action to take. Feel free to seek a second opinion from a doctor more familiar with HLRCC, even in another country. Scans can easily be sent through the mail, and the experts are quite willing to provide their opinion. Note: e-mailing scans is not satisfactory. There are many file formats used by the various vendors, so the receiving doctor will likely not be able to read the file. On the CD they include the viewer software to read the file, so the receiving doctor can open the file and read it quite nicely. Sending a universal format (like a .pdf) reduces the quality of the image, making it hard to determine what is a cyst and what is a tumor - a critical distinction for us.

    The screening guidelines shown in this section are the best advice we were able to assemble at this time from the major research teams studying this condition, and from patient experience. We are hopeful that using these guidelines as a starting point, and with feedback from patients and physicians worldwide, we can evolve these guidelines over the next several years to make them increasingly cost-effective.

    Upon HLRCC Diagnosis (At Any Age Greater Than 8)

    For Children at Risk Under 8

    Children are "at risk" if they are not genetically tested or if they are in the 3% of families which have clear evidence of HLRCC symptoms, but no DNA alteration can be found.

    Annually from age 1

    Annually beginning at age 8

    Feedback - You Can Help Us Learn

    Each time you do your annual check for any family member, would you please keep a log of the results? It is just as important for us to know that "all is well" as it is to hear that something was found. We are working to have a web-accessible, secure patient registry ready for your use within the next 1-2 years. Meanwhile, if you could please keep a paper notebook of this information, you will be able to add it when the online service is available. You will have an account and password to enter your information. Our goal is to analyze the medical information (without your personally identifying information) to determine at what ages the various issues are likely to emerge, and whether earlier intervention might be helpful. For example, there are new treatments for fibroids that might be used on smaller fibroids so that they never advance to the stage where hysterectomy is the only remaining option. See the fibroid section for treatment recommendations.


    Who has HLRCC?

    Males and females from birth, but most symptoms occur after puberty, which may begin as early as 8-9 years of age.

    Should I get tested?

    If one of your parents is positive for HLRCC, it is very important that you obtain a genetic test for yourself, either through the study at the US-NIH or through a genetic counselor. Remember - there is a 50% chance that you are negative. You will not be able to advocate for yourself and your family until you know for certain if you have HLRCC.

    What is FH and why is it important to HLRCC?

    FH stands for Fumarate Hydratase, an enzyme associated with the Krebs Cycle that naturally suppresses tumors. Individuals with HLRCC have a lower FH level than those without HLRCC.

    Is there anything I can do about an FH enzyme deficiency?

    At this point there is no enzyme replacement for FH, but refer to our HLRCC Science document for the current research on enzyme replacement.

    If I have HLRCC and have a child, should I have him/her tested?

    This is a complex issue and there is no single answer or recommendation. We have written in this handbook a complete section on testing and screening as it is such an important issue.

    What do I tell a child?

    The level of information must be chosen to correspond to the child's age and their ability to understand. A genetic counselor is trained to help you in this and often is involved in an interview with the child. Obviously you don't want to scare the child, but hiding the simple facts by not discussing them may cause problems, especially with older children who can find out information by themselves and be more alarmed than is necessary. Children often have a surprising ability to cope with difficult news. Older children may be very angry with their parents if they feel that information was withheld from them when they were younger.

    Is HLRCC a cancer?

    Despite its name the majority of people with HLRCC never get kidney cancer and many people will go through life never knowing that they have HLRCC. Most of the tumors associated with HLRCC are not cancerous. The cutaneous leiomyoma (skin bumps) and uterine fibroids are problematic but benign. Some people (a minority) develop kidney cancer; but knowing about a genetic alteration and being able to screen for a cancer is a gift - an early warning system that most people do not have. It is best to find and treat kidney cancer before it has spread (called metastasis).

    I am scared, how can I support myself and my family emotionally?

    You have come to the right place. The HLRCC Family Alliance, found on the http://www.hlrccinfo.org site, has the information that you need. We also offer an e-mail address to send your questions to, a telephone number to discuss your concerns, and an online discussion at INSPIRE and RareConnect HLRCC Community in conjunction with other hereditary kidney cancers. We hope that you'll use these resources!

    Further Reading - Internet Sites

    Please refer to our HLRCC Science document for an extensive list of research articles. If you find an interesting article, please feel free to e-mail it to us as well!


    Copyright © 2004 - 2018 Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)Family Alliance
    c/o VHL Alliance, 1208 VFW Parkway // Suite 303, Boston, MA 02132
    +1-617-277-5667 ext. 3 or +1-800-767-4845, ext. 3 hlrcc@vhl.org

    Last modified: December 13 2017 22:29:30.