Li-Fraumeni Syndrome

A rare, inherited, cancer predisposition syndrome characterized by the early-onset of multiple primary cancers including breast cancer, soft tissue and bone sarcomas, brain tumors, adrenal cortical carcinoma (ACC), leukemias, and other cancers.


More than 400 families with Li-Fraumeni (LFS) have been reported in the literature. The estimated prevalence of pathogenic and likely pathogenic germline TP53 mutations is not well defined but has been estimated to range between 1/3,555-5,476.

Clinical description

The core cancers in Li-Fraumeni syndrome (LFS) are early-onset breast cancer, ACC, soft tissue sarcomas, osteosarcomas, and brain tumors. Also seen in LFS are leukemias, lymphomas, colorectal cancer, and many other cancers. People with LFS have about a 50% increased risk of developing a second cancer.


LFS is caused by germline mutations in the tumor suppressor gene TP53 (17p13.1) in the majority of families with classic LFS. This gene encodes the tumor antigen p53 protein involved in many cellular processes such as DNA repair, growth arrest and apoptosis. 7-20% of TP53 mutations are estimated to be de novo. No other gene has been associated with LFS thus far.

Diagnostic methods

Diagnosis is confirmed by genetic testing and identification of a TP53 mutation. Individuals may also be clinically diagnosed with LFS if they meet classic LFS criteria which include: (1) a person with a sarcoma diagnosed before age 45 years and (2) a first-degree relative with any cancer diagnosed before age 45 years and (3) a first- or second degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age. The Chompret criteria may also be used to identify individuals for whom TP53 testing is indicated: (1) an individual with a tumor belonging to the LFS tumor spectrum before age 46 years and a first- or second-degree relative with an LFS tumor (except multiple breast cancer tumors or breast cancer before 56 years of age); (2) an individual with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum , with the first occurring before 46 years of age; (3) an individual with ACC or CPC, or anaplastic embryonal rhabdomyosarcoma regardless of family history; or (4) an individual with breast cancer before 31 years of age.

Differential diagnosis

Differential diagnoses include hereditary breast and ovarian cancer syndrome, CHEK2 cancer susceptibility syndrome, and constitutional mismatch repair deficiency syndrome.

Antenatal diagnosis

Prenatal and preimplantation genetic diagnoses are available for families with a TP53 mutation.

Genetic counseling

The pattern of inheritance is autosomal dominant; the risk of inheriting the mutation from a carrier is 50%. The lifetime risk of cancer in LFS is estimated to be about 70% for men and over 90% for women, although these may be overestimates. The age-related cancer risks are estimated at 22% between 0-15 years, 51% between 16-50 years, and 27% between 51-80 years. Genetic counseling is recommended to inform individuals of issues related to genetic testing, cancer risks, medical surveillance, and psychosocial and family impact.

Management and treatment

Management of LFS-related cancers generally follows standard treatment protocols, with minimizing radiation when possible. Mastectomies are recommended over lumpectomies for the treatment of breast cancer. Prophylactic mastectomy can also be offered to those with a known TP53 mutation for risk reduction. Regular surveillance (adapted from the ''Toronto protocol'') is recommended for individuals with TP53 mutations, and incorporate screening with biochemical and imaging modalities. Complete physical exams and ultrasound of the abdomen and pelvis is recommended every 3-4 months from birth until age 18. Children and adults are advised to have annual whole-body and brain magnetic resonance imaging (MRI). Women are recommended to have clinical breast exams every 6-12 months, an annual breast MRI from age 20 and an annual mammogram from age 30. For other cancer risks, physical exam is recommended every 6-12 months from age 18 years, with annual dermatologic exam. Colonoscopy and upper endoscopy are recommended every 2-5 years from age 25 (or 5 years before the earliest colon cancer in the family). Other screening may also be recommended.


Prognosis depends on the type and severity of cancers developed. Patients followed on the Toronto screening protocol were reported to have higher 5-year survival rates.