Li-Fraumeni Syndrome

What is Li-Fraumeni syndrome?

Li-Fraumeni syndrome (LFS) is a rare hereditary condition that increases a person's risk for a wide spectrum of tumors. In LFS, the tendency to develop cancer is inherited, meaning that it can be passed from an affected parent to a child. There are several types of cancer that are commonly associated with Li-Fraumeni syndrome:

  • Soft-tissue sarcomas — Tumors that develop in tissues that connect, support or surround other organs and structures of the body, specifically the muscles, fat, blood vessels, nerves and joints
  • Osteosarcomas — Tumors that form in the cells of the bone
  • Breast cancer
  • Brain tumors
  • Adrenocortical tumors — A type of tumor that forms in the adrenal gland (a small organ located on top of each kidney that secretes specific hormones)
  • Acute leukemias — Cancers of the blood which tend to progress rapidly

Some people with Li-Fraumeni syndrome develop other types of cancer such as:

  • Melanoma (skin cancer)
  • Lung
  • Cancers of the stomach, colon, pancreas and esophagus
  • Thyroid
  • Germ cell tumors
  • Lymphomas

In most cases, cancers associated with Li-Fraumeni syndrome develop in children or young adults, but they can occur during any stage of life. People with Li-Fraumeni syndrome are typically younger when they develop cancer compared to healthy individuals in the general population. People with Li-Fraumeni syndrome are also at increased risk for multiple cancers in their lifetimes.


Li-Fraumeni syndrome is caused by alterations, also known as mutations, at specific locations in an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes." Genes provide the necessary instructions that our cells require to perform different functions within our bodies.

There is a specific gene known as TP53, located on chromosome 17, which is altered in patients with Li-Fraumeni syndrome. The normal role of the TP53 gene is to produce a protein that regulates cell growth and division. When both copies of this gene mutate within a cell, the affected cell can grow and divide in an abnormal fashion, which can ultimately lead to tumor formation.

How is Li-Fraumeni syndrome inherited?

With rare exceptions, each person has two copies of every gene, including TP53. In most cases, Li-Fraumeni syndrome is caused when an individual inherits one abnormal or “mutated” copy of the TP53 gene from an affected parent. A person carrying an alteration in one TP53 gene copy has a 50 percent — or one in two — chance of passing this same alteration on to his or her future children. Children who inherit the altered gene copy have Li-Fraumeni syndrome and therefore are at increased risk to develop cancer.

Li-Fraumeni syndrome is commonly seen in several generations of an affected family. LFS does not skip generations. However, certain people found to carry an alteration in TP53 are the first ones in their family to have this genetic change. In this situation, a new mutation has occurred in one of the two TP53 gene copies carried by these individuals. The affected individuals can pass these new mutations in TP53 on to future generations.


A careful and detailed review of a person's medical and family history is important when attempting to make a diagnosis of Li-Fraumeni syndrome. A doctor or genetic counselor may construct a pedigree, or a multi-generation family tree, that shows which members of the family have developed cancer, the types of cancer, and their ages when the cancer first occurred. Some indicators suggesting a possible diagnosis of Li-Fraumeni syndrome in the family may include:

  • Individuals who developed cancer at a younger than expected age
  • Many family members with cancer in two or more generations
  • Family members who have had two or more cancers during their lifetime
  • Individuals in the family with rare forms of cancer

Several different classification schemes have been developed to aid in making a clinical diagnosis of Li-Fraumeni syndrome. The classic diagnostic criteria for LFS were defined in 1969 by Drs. Li and Fraumeni and include:

  • A proband (the first affected family member who seeks medical attention for a genetic disorder) diagnosed with a sarcoma and younger than 45 years old
  • A first-degree relative younger than 45 years old with any cancer
  • Another first- or second-degree relative younger than age 45 with any cancer (or a first- or second-degree relative at any age with a sarcoma)

Approximately 70 percent of families meeting classic criteria for Li-Fraumeni syndrome carry mutations in the TP53 gene.

More recently, another set of criteria, known as the Chompret criteria, has been proposed to identify families who may not meet classic Li-Fraumeni syndrome diagnostic criteria but may still be affected:

  • A proband with a tumor belonging to the LFS spectrum (e.g., soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, lung cancer) before age 46 AND at least one first- or second-degree relative with a tumor belonging to the LFS spectrum, OR
  • A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS spectrum and the first of which occurred before age 46, OR
  • A patient with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history

It is estimated that at least 20 percent of families meeting Chompret criteria for LFS carry mutations in the TP53 gene.

Individuals who do not meet classic Li-Fraumeni syndrome or Chompret criteria, but nonetheless exhibit some features of LFS, may be diagnosed with Li-Fraumeni-like (LFL) syndrome. Two sets of diagnostic criteria for LFL syndrome have been proposed:

Birch definition of Li-Fraumeni-like syndrome:

  • A proband with any childhood cancer or sarcoma, brain tumor, or adrenocortical carcinoma diagnosed before age 45, AND
  • A first- or second-degree relative with a typical Li-Fraumeni syndrome cancer (sarcoma, breast cancer, brain tumor, adrenocortical carcinoma, or leukemia) at any age, AND
  • A first- or second-degree relative with any cancer before age 60 

Eeles definition of syndrome:

  • Two first- or second-degree relatives with LFS-related malignancies at any age

Approximately 22 percent of families meeting Birch or Eeles criteria for LFL syndrome carry mutations in the TP53 gene.

Even in cases where a family does not meet all of the diagnostic criteria for Li-Fraumeni syndrome, it may still be recommended that a person at risk undergo counseling and consider genetic testing to detect the presence of a TP53 gene alteration.

Testing for Li-Fraumeni syndrome

In order to confirm that a person has LFS, a genetic test must be completed. First, a blood or saliva sample is obtained from an affected individual with cancer. DNA is isolated from the sample and the two copies of the TP53 gene are evaluated by direct DNA sequencing. Sequencing is a process by which a person’s genetic code is compared to a “normal” reference code.

In the case of Li-Fraumeni syndrome, the patient’s two copies of the TP53 gene are evaluated and compared to the normal reference sequence for TP53. If an alteration is identified, a genetic counselor can next examine whether the alteration has been previously reported in other individuals with LFS. TP53 genetic test results can provide important information for other family members. Knowing the specific alteration that is present in a person with cancer allows other family members to be tested to determine if they also carry this alteration in the TP53 gene.

Options for people considering pregnancy

There are several options for individuals with a mutation TP53 and who does not want to pass this alteration onto his or her future children:

  • Prenatal diagnosis — Available for pregnancies that have a 50 percent chance of inheriting the TP53 alteration from one parent. DNA is isolated from the cells of the developing baby though one of two procedures — chorionic villus sampling (CVS) or amniocentesis. Each type of prenatal test is offered at a different time during the pregnancy.
  • Preimplantation genetic diagnosis (PGD) — Available to individuals who are known to have a genetic alteration that causes a condition such as Li-Fraumeni syndrome. PGD is performed in combination with in vitro fertilization (IVF) and offers a way to test a patient's embryos for genetic disorders before transferring them into the uterus. The procedure is particularly useful for patients with a serious inherited disorder such as LFS, who wish to avoid passing the disorder onto their children. The familial TP53 mutation must be identified before either prenatal testing or PGD can be performed.

Genetic tests for cancers not associated with Li-Fraumeni syndrome

It is possible that an individual may not have an alteration in TP53 despite having developed cancer(s) suggestive of Li-Fraumeni syndrome. In these cases, it is likely that other, as yet unknown, genes besides TP53 are responsible for the development of the cancers.

Alterations in one other gene, known as CHEK2, were originally reported as a possible cause of Li-Fraumeni syndrome in a few families; however, more recent studies have revealed that CHEK2 mutations are unlikely to be a cause of Li-Fraumeni syndrome (Evans, Birch & Narod, 2008).

Things to consider before having genetic testing

Deciding to pursue genetic testing for Li-Fraumeni syndrome can be complex. Individuals who are found to have an altered TP53 gene may experience depression, anxiety, anger and fear of the future when they receive the test results. Family relationships can be affected both positively and negatively by this genetic information. There is also the possibility that a person who is found to have an altered TP53 gene could have more difficulty obtaining disability or life insurance from certain insurance companies. The decision to undergo TP53 genetic testing should be carefully considered and discussed thoroughly with a physician and/or genetic counselor before the testing takes place. Once results are available, they should be disclosed with the help of a genetic counselor.

Cancer risks

It is estimated that 50 percent of people with Li-Fraumeni syndrome will develop a cancer by age 30 and up to 90 percent will develop cancer by the time they are 60 years old. Men with LFS may have a lower lifetime risk of cancer compared to women with LFS. People with LFS are also at increased risk for developing multiple primary tumors and may be at increased risk for developing radiation-induced cancers.

Unfortunately, it is hard to predict which cancers will develop in children and adults with TP53 mutations and when these cancers will occur.

By undergoing regular check-ups and cancer screening tests, individuals at risk can ensure that cancers will be detected at their earliest and most treatable stages. It is also important that parents of children with TP53 mutations, and adults with TP53 mutations, be on the lookout for signs of illness that cannot otherwise be explained. Individuals should be evaluated promptly by their doctors if such signs develop, as these could be evidence of an underlying cancer.

Parents of a child with a cancer associated with Li-Fraumeni syndrome should consider surveillance measures even if they decide not to pursue testing for TP53 mutations in their family.

Cancer screening protocol

For children

For children, recommended surveillance measures include:

  • Annual physical examination by a doctor, including careful skin and neurologic examinations 

Other screening measures, which are currently under investigation, include:

  • Annual brain MRI (to monitor for development of brain tumors)
  • Annual total body MRI (as surveillance for sarcomas and other tumors)
  • Abdominal ultrasound every 3-4 months (as surveillance for adrenocortical tumors)
  • Urinalysis, complete blood counts, and other blood tests (your doctor will determine how often), including chemistries; lactate dehydrogenase; and adrenal hormones such as cortisol, testosterone, 17-hydroxyprogesterone, androstenedione and dehydroepiandrosterone

Children should be encouraged to lead as healthy a lifestyle as possible. They should eat a balanced diet, avoid excess sun exposure and always wear sun block and a hat when outdoors in the sunlight. As adolescents, they should be discouraged from smoking cigarettes or cigars and should not be exposed to secondhand smoke. Parents should watch for symptoms of illness and have their children evaluated promptly if these occur.

For adults

Adults within the family should also pursue a healthy lifestyle, avoid tobacco use and excess alcohol consumption, use protective measures when in the sun and follow published guidelines for cancer surveillance, which include:

  • A complete physical examination every 12 months, including careful skin and neurologic examinations.
  • Consider colonoscopy every 2-5 years starting no later than age 25.
  • Beginning at age 20-25 — or 5-10 years before the earliest age of breast cancer diagnosis in the family, whichever is earlier — women should undergo a clinical breast examination every 6 months, an annual mammogram (X-ray of the breast) and an annual breast magnetic resonance imaging (MRI) examination.
  • Consider organ-targeted surveillance based on the pattern of cancer in the family. However, there is currently no data to support this recommendation.

Adults with Li-Fraumeni

Adults who have Li-Fraumeni syndrome or who would like more information about Li-Fraumeni syndrome may contact the Medical Genetics Team at the Hospital of the University of Pennsylvania.


Evans, D.G., Birch, J., & S.A. Narod. (2008). Is CHEK2 a cause of Li-Fraumeni syndrome? Journal of Medical Genetics, 45, 63-64.


Reviewed by Kristin Zelley, MS, LCGC

Providers Who Treat Li-Fraumeni Syndrome