There are variable estimates of the prevalence of HLRCC, but genetic testing suggests that the condition is much more common than previously thought. According to the article ‘Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer’ is the most common hereditary kidney cancer syndrome and 1/2,500 people have the condition.

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.

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.

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 the activation of certain signaling pathways. It is also believed that additional genetic and environmental factors may contribute to the development and progression of HLRCC-related tumors.

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.

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, as early detection and treatment can improve outcomes and reduce the risk of complications.

Individuals who have a family history of HLRCC, kidney cancer, skin leiomyomas, or multiple uterine leiomyomas may be candidates for genetic testing for HLRCC. Additionally, individuals with one or more skin leiomyomas or early-onset kidney cancer may choose to get genetic testing.

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. If the cancer has spread, there are specific medical therapies that are highly effective for treating this type of kidney cancer. Additionally, it allows for appropriate counseling of family members to undergo kidney cancer surveillance if they also have the condition.

Abdominal MRI surveillance for HLRCC should begin at age 8 and continue throughout the individual’s life. If a tumor is detected on MRI, immediate surgical resection is recommended because HLRCC related kidney cancer (also known as FH deficient renal cell carcinoma) are highly aggressive and can spread quickly.

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 50 years old). Piloleiomyomas typically manifest as a singular dermal nodule or multiple dermal nodules arranged in a clustered, linear, dermatomal, or dispersed pattern.

The recurrence rate and lack of successful pharmacological treatment for piloleiomyomas make treatment challenging for both patients and physicians. The treatment approach depends on the number and location of lesions and the degree of discomfort experienced by the patient. Surgical excision is the preferred treatment for patients with a limited number of localized lesions. However, patients should be informed of the high chance of local recurrence. Other treatment options include cryosurgery and carbon dioxide (CO2) laser ablation.

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.

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 ensure the best possible outcomes for patients.

The Urologic Oncology division at NIH, headed by Dr. Marston Linehan, is interested in evaluating/managing patients affected with, or at risk for, Hereditary Leiomyoma and Renal Cell Carcinoma (HLRCC). The NIH has evaluated > 700 patients from 350 families with the condition and has a long term interest in the disorder.

The NIH performs genetic testing/counseling, surveillance and surgical management of localized/locally advanced disease (when present) in individuals with HLRCC. Those affected with advanced disease would be evaluated by the NIH’s therapeutic team, headed by Dr. Srinivasan. The NIH has protocols and are actively recruiting individuals with advanced HLRCC for treatment trials here at NCI.

The people here to contact are Debbie Nielsen or Lidenys O’Brien.  Their contact information is:

Debbie Nielsen, R.N.

Research Nurse Specialist

Urologic Oncology Branch

Bldg. 10 -Room 2-5750

Bethesda, MD  20892

Office (240) 760-6247

Fax (301) 480-2869

deborah.nielsen@nih.gov

Lidenys O’Brien, R.N.

Research Nurse Specialist

Urologic Oncology Branch

National Cancer Institute

Lidenys.O’Brien@nih.gov

There is no charge for any form of evaluation or treatment at the National Institutes of Health, and, for most patients the NIH can help defray travel expenses. TeleMedicine appointments are also an option and the NIH can often help defray the additional costs associated with imaging done outside of the NIH.

There are several treatment options available for HLRCC, including EGFR inhibition with Erlotinib combined with Bevacizumab, a VEGF inhibitor, which has shown exceptional responses. 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.