HLRCC FAQ

There are variable estimates of the prevalence of HLRCC, but genetic testing suggests that the condition is much more common than previously thought. Newer research suggests about 1 in 1,000 people may carry a harmful change in the FH gene. ^[9] In a study of more than 120,000 people who had genetic testing for inherited cancer risk, about 1 in 2,668 people who had no clear sign of HLRCC were found to have a harmful FH change. ^[10] Not everyone who carries the change develops signs of HLRCC^[1].

HLRCC, also known as hereditary leiomyomatosis and renal cell carcinoma syndrome, is called a syndrome because it involves a cluster of symptoms and manifestations that may occur together. HLRCC is caused by a mutation in the FH gene, which leads to the development of benign tumors called leiomyomas in the skin and uterus, as well as a higher risk of developing kidney cancer. The severity of symptoms and the risk of cancer can vary widely among individuals with HLRCC, even within the same family. ^{[1, 2]}

A fumarate hydratase (FH) mutation is a genetic alteration that affects the function of the FH protein. FH is an enzyme that plays a critical role in the Krebs cycle, which is responsible for generating energy in cells. When FH is mutated, it can lead to a buildup of fumarate, a metabolite that is normally broken down by the FH enzyme. This buildup of fumarate is thought to be responsible for the development of tumors in individuals with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. ^{[1, 2]}

The exact mechanism by which FH mutations lead to the development of tumors is not fully understood, but it is thought to be related to the disruption of cellular metabolism and changes in how cells sense oxygen. ^{[1, 50]} A tumor can start when the second copy of the FH gene in a cell also changes, which can happen by chance or from environmental factors such as sun exposure. ^{[35, 50]}

Yes, HLRCC can be passed on to other family members. HLRCC is an autosomal dominant genetic disorder, which means that an individual with a mutation in the FH gene has a 50% chance of passing the mutation on to each of their children. ^{[1, 2]}

Genetic testing can be used to identify individuals who carry the FH mutation and who may be at increased risk of developing HLRCC-related tumors. If a family member is found to carry the mutation, they can work with their healthcare provider to develop a personalized plan for monitoring and managing their health. Regular screening for kidney tumors is recommended for individuals with HLRCC so that tumors can be found early and removed while they are small. Studies have not yet proven that this helps people live longer, but it is what experts recommend. ^{[1, 2, 5]}

NCI says FH gene testing is advised for anyone who has HLRCC or may have it, whatever their family history. ^[2]

Talk with your doctor about genetic counseling if you have:

• one or more skin leiomyomas confirmed by a biopsy^[2]
• a kidney cancer that looks like the HLRCC type (FH-deficient) under the microscope^{[1, 2]}
• fibroids that test FH-deficient in the lab, or fibroids needing surgery before age 40, especially with a family history of HLRCC signs^{[1, 2, 15, 45]}
• a blood relative with a known harmful FH change^{[1, 2]}

A genetic counselor can help you decide whether testing is right for you. ^[2]

Knowing that you have HLRCC is beneficial because it enables appropriate surveillance with abdominal MRI for early detection of kidney cancers that can be surgically removed with curative intent. ^{[1, 3, 5]} If the cancer has spread, some drug treatments have shrunk this type of kidney cancer in many people in studies. For example, in one NIH study of 43 people, bevacizumab plus erlotinib shrank the cancer in 31 (72%)^[12]. Additionally, it allows for appropriate counseling of family members to undergo kidney cancer surveillance if they also have the condition. ^[1]

Abdominal MRI surveillance for HLRCC should begin at age 8 and continue throughout the individual’s life; your urologic oncologist or medical oncologist will decide the exact timing. ^{[1, 3, 5]} If a scan shows a possible tumor, it needs prompt follow-up by a team that knows HLRCC. If it is a tumor, experts advise prompt surgery, even if it is small, rather than waiting. ^{[1, 2, 3, 5]}

There are several treatment options available for HLRCC, including EGFR inhibition with Erlotinib combined with Bevacizumab, a VEGF inhibitor. In an NIH study of 43 people with HLRCC-related kidney cancer, this combination shrank the cancer in 31 of them (72%); the study did not compare it with other treatments. ^[12] Additionally, tyrosine kinase inhibitors and immunotherapy can also be used. Clinical trials may also be an option to improve outcomes. It is important to discuss all available treatment options with an oncologist familiar with HLRCC to determine the best course of action for each individual case. ^{[1, 3, 23]}

HLRCC is caused by a mutation in the FH gene. It leads to benign tumors called leiomyomas in the skin and uterus and a higher risk of kidney cancer. ^{[1, 5]} From age 8, experts recommend a yearly kidney MRI for life. Your urologic oncologist or medical oncologist will decide the exact timing. ^{[1, 3, 5]} If a kidney tumor is found, experts advise prompt surgery, even if it is small, rather than waiting. ^{[1, 5]}

When piloleiomyomas (skin leiomyomas) occur as a result of HLRCC, they tend to appear earlier in life, with the average onset age of 25 years (ranging from 10 to 47 years old)^[2]. Piloleiomyomas typically manifest as a singular dermal nodule or multiple dermal nodules arranged in a clustered, segmental (limited to one area of the body), or widespread pattern. ^{[1, 2]}

Skin leiomyomas can be hard to treat, and medicines help some people's pain but not everyone's. ^{[2, 14]} The treatment approach depends on the number and location of lesions and the degree of discomfort experienced by the patient. Bumps that cause no problems usually need no treatment. ^{[2, 20]} Surgery to remove the bump is a standard treatment when there are one or a few painful bumps, but bumps often come back. ^[1] Other treatment options include cryosurgery and carbon dioxide (CO2) laser ablation. ^{[1, 2, 14]}

With appropriate management by an experienced OB/GYN physician, uterine fibroids in women with HLRCC can often be monitored closely and managed on an as needed basis. Compared to non-hereditary uterine leiomyomas, those associated with HLRCC tend to be larger, more numerous, develop at a younger age, and are more likely to require surgical removal or hysterectomy. ^{[1, 2, 32]}

It is crucial to seek expert guidance when dealing with HLRCC due to the complexity of interpreting MRI imaging and determining the timing and approach for surgical intervention. These nuances require specialized knowledge and experience to help patients get the best possible care. ^{[1, 2, 3]}

The Urologic Oncology Branch of the National Cancer Institute at NIH, headed by Dr. W. Marston Linehan, is interested in evaluating/managing patients affected with, or at risk for, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). The NIH has a long-term interest in the disorder and runs a long-term study of HLRCC (NIH protocol 03-C-0066; ClinicalTrials.gov NCT00050752). ^{[17, 52]}

Those affected with advanced disease would be evaluated by the NIH’s therapeutic team, led by Ramaprasad Srinivasan, M.D., Ph.D. The NIH also runs a treatment trial for advanced HLRCC-related kidney cancer (NCT04981509). Enrollment can change at each site, so check the ClinicalTrials.gov listing for current status. ^{[23, 52]}

To ask about the NIH HLRCC study (NCT00050752), the contact listed on ClinicalTrials.gov is Deborah A. Nielsen, R.N., (240) 760-6247, deborah.nielsen@nih.gov. ^[17]