Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome

Also called: HLRCC syndrome, Reed’s syndrome, HLRCC, FH Tumor Predisposition Syndrome, Multiple Cutaneous and Uterine Leiomyomatosis (MCL/MCUL)

What is hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome?

Hereditary leiomyomatosis and renal cell carcinoma syndrome is a rare condition that makes a person more likely to develop certain types of tumors. These tumors can be either benign (not cancerous) or malignant (cancerous).

People with HLRCC syndrome may develop the following:

  • Leiomyomas of the skin: benign tumors of the skin. They may be single or multiple and look like raised flesh-colored nodules.
  • Leiomyomatosis of the uterus (uterine fibroids): benign tumors of the uterus with very low risk of becoming cancerous.
  • Kidney tumors: includes tumors of different types ranging from papillary tumors to renal cell carcinoma (kidney cancer).

HLRCC syndrome can be passed from an affected parent to his or her children. Not everyone with HLRCC syndrome has the same features, even among people in the same family.

What causes hereditary leiomyomatosis and renal cell carcinoma syndrome?

HLRCC syndrome is caused by changes in a gene known as fumarate hydratase (FH). Genes carry information that tell the cells of the body how to function. The FH gene tells the cells of the body how to make fumarate hydratase. Fumarate hydratase is a protein important for normal cell function.

Most people without HLRCC syndrome carry two working copies of the FH gene in their cells. One copy of the FH gene is inherited from each parent. People with HLRCC syndrome have one working copy of the FH gene and one changed copy of the FH gene in each cell of their body. The change in the FH gene causes the gene to stop working properly. It is called an FH mutation.

Most children with HLRCC syndrome inherit an FH mutation from a parent who also has the syndrome. HLRCC syndrome is inherited as an autosomal dominant condition. That means only one FH mutation is required to cause the syndrome.

Sporadic HLRCC syndrome cases can result from new (de novo) mutations in the FH gene. People with a de novo FH mutation have no history of the syndrome in their family. In these cases, the change either happened in the egg or sperm cell when the child was formed, or the change occurred in one of the child’s cells early in development. These children are the first in their families to have HLRCC syndrome.

No matter how they acquired the FH mutation, people with HLRCC syndrome have a 50% (or 1 in 2) chance of passing it on to each of their children. It is unknown how many people have HLRCC syndrome. About 300 families around the world have been reported with HLRCC syndrome.

As people with HLRCC syndrome get older, the working copy of their FH gene often becomes changed within some of their cells. When both copies of the gene are changed, benign tumors or cancers can develop. The features of people with HLRCC syndrome can vary between families and among members of the same family.

People who are born with changes in both copies of their FH genes have a genetic condition called fumarate hydratase deficiency (FH deficiency). During infancy, patients with FH deficiency can have:

  • trouble feeding,
  • low muscle tone,
  • seizures,
  • abnormal head size,
  • various brain abnormalities, and
  • distinct facial features.

FH deficiency is completely different than HLRCC syndrome. If two people with HLRCC syndrome have a child together, there is a 1 in 4 (25%) chance for each of their children to have FH deficiency. A genetic counselor can discuss this condition in more detail.

What are the tumor risks for people with hereditary leiomyomatosis and renal cell carcinoma syndrome?

Most of the tumors related to HLRCC syndrome occur in adults. Even so, some cases of kidney cancer have been reported in children with HLRCC syndrome. The risk of developing kidney cancer in patients younger than 20 is 1%–2%. Lifetime risk of kidney cancer in patients with HLRCC syndrome is 10%–16%. Typically, kidney cancers in HLRCC syndrome are aggressive and metastatic—spread to other parts of the body. For this reason, finding and treating kidney cancer early in HLRCC syndrome patients leads to better outcomes.

The skin tumors (cutaneous leiomyomas) related to HLRCC syndrome usually develop during the teen years. Most skin leiomyomas are not cancerous, but some can develop into a type of cancer called leiomyosarcoma.

Adults with HLRCC syndrome are also at a higher risk of developing skin tumors and in females uterine tumors. Adult females with HLRCC syndrome usually develop uterine fibroids in their 30s. Often, these tumors are removed to treat anemia resulting from excessive blood loss.

Some HLRCC syndrome patients also have a slightly increased risk for certain nerve cells tumors (paragangliomas) and adrenal gland hormone-secreting tumors (pheochromocytomas). HLRCC patients with an increased risk of these types of tumors usually have specific changes in their FH genes or have a family history of those tumor types.  

Doctors also have seen other tumor types in patients with HLRCC syndrome, but the connection with HLRCC syndrome is still being researched.

How are people with hereditary leiomyomatosis and renal cell carcinoma syndrome screened for tumors?

Patients with HLRCC syndrome should be managed by a health care provider who knows this condition well and can coordinate tumor screening. The goal of screening is to find and treat tumors early to allow for the best outcome for patients.

Recommended screening for patients with HLRCC include the following:

Yearly physical exams by a health care provider who knows the condition well

Yearly skin exams beginning at diagnosis to look for leiomyomas and signs of leiomyosarcoma

Yearly pelvic exams and pelvic MRI or transvaginal ultrasound beginning at 20 years of age or at first gynecologic exam (whichever happens first) to look for fibroids and rare signs of leiomyosarcoma

  • Yearly renal MRI beginning at 8 years of age to look for kidney tumors
  •  There are no uniform guidelines to look for signs of pheochromocytomas or paragangliomas. However, the following tests may be done:
    • Baseline blood pressure*
    • MRI from skull base through pelvis*
    • Plasma fractionated metanephrines*

*Only for patients with specific FH gene changes related to paragangliomas or pheochromocytomas or patients with a family history of paragangliomas or pheochromocytomas

How is genetic testing for hereditary leiomyomatosis and renal cell carcinoma syndrome done?

A health care provider may suspect HLRCC syndrome after reviewing a patient’s medical or family histories. In most cases, a health care provider, like a genetic counselor, will ask questions about a person’s health and the health of other family members.

The genetic counselor or health care provider will record which family members have developed tumors, the types of tumors, and at what ages the tumors occurred. From this information they will create a family tree. Health care providers will examine the family tree to look for patterns that might suggest HLRCC syndrome.

If HLRCC syndrome is suspected in a child or other family members, the health care provider will likely recommend genetic testing of the FH gene.

Diagnostic genetic testing

If a health care provider suspects a person has HLRCC syndrome, diagnostic testing may take place as follows:

  • A blood sample is collected.
  • DNA is isolated from the cells in the sample. A person’s genes are made of DNA.
  • Both copies of the FH gene are checked for possible changes. A genetic specialist compares the two copies of the patient’s FH gene to a normal FH gene. If there are differences, the specialist decides if they might be a cause of HLRCC syndrome.
  •  If an FH mutation is found, the genetic counselor will work with the family in the following ways:
    • To help the family understand the tumor risks related to HLRCC syndrome.
    • To find out if other family members should consider testing.
    • To help with decisions about prenatal genetic testing.

Prenatal genetic testing

Parents may undergo prenatal testing to find out if the pregnancy is affected with a known FH mutation in the family. Testing may take place either before pregnancy occurs or during pregnancy.

People considering prenatal testing should work with a prenatal genetic counselor to review the pros and cons of the testing options. The genetic counselor can also help parents consider how they wish to handle the results of the testing.

Testing that occurs before pregnancy —Testing that happens before pregnancy is called preimplantation genetic testing (PGT). This special type of genetic testing is done along with in vitro fertilization (IVF). PGT offers a way to test embryos for a known FH mutation before placing them into the uterus.

Testing that occurs during pregnancy Testing can be used to see if a pregnancy is affected with a known FH mutation. A doctor gathers cells from the pregnancy in one of two ways:

  • Chorionic villus sampling (CVS) — during the first trimester (first three months)
  • Amniocentesis — during the second trimester or later (last six months)

Collected tissue can be checked for the presence of the FH mutation identified in the family.

Both of these tests carry risks and should be discussed with an experienced doctor or genetic counselor.

Special concerns

Genetic testing for HLRCC syndrome is a complex process. Those thinking about testing should take time to consider the benefits and risks. They should discuss the process with a genetic counselor before testing is done. If they choose to have testing, they should review the test results with a genetic health care provider to be sure they understand the meaning of the results.

Sometimes children or adults with HLRCC syndrome can feel sad, anxious, or angry. Parents who pass on a FH mutation to one or more of their children can feel guilty. Some people with a FH mutation could have trouble getting disability coverage, life insurance, or long-term care insurance in some states. More information about genetic discrimination can be found at www.ginahelp.org.

Are there other special health care needs for children with hereditary leiomyomatosis and renal cell carcinoma syndrome?

Children with HLRCC syndrome are at risk of developing tumors during their lifetimes. They should monitor their health and adopt healthful habits throughout life. It is important to continue to have regular physical checkups and screenings. That way, any tumor can be found early at the most treatable stage.

People with this syndrome should watch closely for general signs or symptoms that could signal tumors:

  • Aches, pains, lumps, or swelling that cannot be explained
  • In women: Heavy menstrual bleeding or irregular menstrual cycles
  • Pain in the abdomen or the pelvis
  • Blood in the urine

Other ideas to reduce the risk of tumors include the following:

  • Eat a healthful diet with lots of fruits and vegetables
  • Get regular exercise
  • Avoid smoking or using tobacco products
  • Avoid secondhand smoke
  • Avoid excess sun exposure and always wear sunscreen, hat and protective clothing when out in the sun

Updated 6/2020

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