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Li-Fraumeni syndrome

Synonym(s) -
Prevalence 1-9 / 100 000
Inheritance Autosomal dominant
Age of onset All ages
  • D48.9
  • C0085390
  • D016864
  • 10066795


Disease definition

Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome characterized by the early-onset of multiple primary cancers such as breast cancer, soft tissue and bone sarcomas (see these terms), brain tumors and adrenal cortical carcinoma (ACC) (see this term).


The estimated prevalence of causal deleterious germline TP53 mutations ranges from 1/10,000-1/25,000 in the U.K. and 1/20,000 in the U.S.

Clinical description

The lifetime risk of cancer in LFS is about 70% for men and close to 100% for women by age 70. The risk of a childhood cancer is about 12-20%. Core cancers observed in LFS include early-onset breast cancer, ACC, soft tissue and bone sarcomas (including rhabdomyosarcoma and osteosarcoma) and brain tumors (choroid plexus carcinoma (CPC), astrocytoma, medulloblastoma and glioblastoma) (see these terms). Other commonly observed cancers include leukemia and gastrointestinal cancers (e.g. stomach, colon) as well as ovarian and lung cancers, such as bronchoalveolar cancers. LFS patients also have about a 50% increased risk of later developing a secondary malignancy.


LFS is caused by mutations in the tumor suppressor gene TP53 (17p13.1) in about 80% of families with classic LFS. It encodes the cellular tumor antigen p53 protein, involved in many cellular processes such as DNA repair, growth arrest and apoptosis. Thus far, no other gene has been definitively associated with LFS. There is, however, much interest in finding genetic modifiers of the LFS phenotype. Individuals who have a TP53 mutation and either shorter telomeres or a specific nucleotide polymorphism in the MDM2 gene, for example, appear to be at risk for developing cancer at younger ages.

Diagnostic methods

The clinical criteria for classic LFS are: (1) sarcoma diagnosed in the patient before age 45 years, (2) first-degree relative with any cancer before age 45 years, and (3) 1st- or 2nd-degree relative with any cancer before age 45 years or a sarcoma at any age. The Chompret criteria for TP53 testing are also widely used: (1) individual with a tumor belonging to the LFS tumor spectrum before age 46 years and at least one 1st-or 2nd-degree relative with a LFS tumor before age 56 years or with multiple tumors; or (2) individual with multiple tumors (except multiple breast tumors), 2 of which belonging to the LFS tumor spectrum and the 1st of which occurred before age 46 years; or (3) individual with ACC or CPC, regardless of family history. Anyone who meets the Chompret criteria for LFS should be tested for a TP53 mutation which confirms diagnosis.

Differential diagnosis

Differential diagnoses include hereditary breast and ovarian cancer syndrome and constitutional mismatch repair deficiency syndrome (see these terms).

Antenatal diagnosis

Prenatal and preimplantation genetic diagnoses are possible in families with a known disease-causing mutation.

Genetic counseling

LFS is inherited autosomal dominantly. Genetic counseling is recommended to inform patients and family members of issues related to cancer risks, screening, and presymptomatic genetic testing and its psychological implications. About 7-20% of TP53 mutations are estimated to be de novo.

Management and treatment

LFS patients who develop breast cancer are suggested to have mastectomies over lumpectomies. Management of other cancers generally follows standard treatment protocols, except for the consideration of minimizing radiation therapy when possible. Prophylactic mastectomy can also be offered to those with a known TP53 mutation for risk reduction. Screening recommendations for those with a TP53 mutation include annual physical exams, annual clinical breast exams from age 20-25, and breast imaging starting at age 20-25 (or earlier if indicated by family history) with breast MRIs and/or mammogram. Screening for colorectal cancer is also considered starting from age 25.


Prognosis depends on the type and severity of cancers developed.

Expert reviewer(s)

  • Dr Junne KAMIHARA
  • Katherine SCHNEIDER

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Detailed information

Clinical genetics review
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