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Li-Fraumeni Syndrome.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
1999 Jan 19 [updated 2013 Apr 11].

Author information

1
Adult Oncology, Dana Farber Cancer Institute, Boston, Massachusetts
2
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Excerpt

CLINICAL CHARACTERISTICS:

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the development of the following classic tumors: soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemias. In addition, a variety of other neoplasms may occur. LFS-related cancers often occur in childhood or young adulthood and survivors have an increased risk for multiple primary cancers. Age-specific cancer risks have been calculated.

DIAGNOSIS/TESTING:

LFS is diagnosed in individuals meeting established clinical criteria or in those who have a germline pathogenic variant in TP53 regardless of family cancer history. At least 70% of individuals diagnosed clinically have an identifiable germline pathogenic variant in TP53, the only gene so far identified in which pathogenic variants are definitively associated with LFS.

MANAGEMENT:

Treatment of manifestations: Routine oncologic management is recommended for malignancies in individuals with LFS, with the exception of breast cancer, in which mastectomy rather than lumpectomy is recommended in order to reduce the risks of a second primary breast tumor and avoid radiation therapy. Concerns about increased risk for radiation-induced second primary tumors has led to more cautious use of therapeutic radiation in general, but most experts recommend that treatment efficacy be prioritized above concerns about late effects after careful analysis of risks and benefits. Prevention of primary manifestations: Prophylactic mastectomy to reduce the risk for breast cancer is an option for women with a germline TP53 pathogenic variant. Recent recommendations for colonoscopy may be considered surveillance as well as primary prevention of colorectal cancer. Prevention of secondary complications: Avoidance of exposure to radiation therapy, when possible, to reduce the risk of secondary radiation-induced malignancies. Surveillance: There are no definitive prospective data on the optimal methods for and efficacy of tumor surveillance for children or adults with a germline TP53 pathogenic variant. Currently, it is recommended that: (1) children and adults undergo comprehensive annual physical examination; (2) children and adults be encouraged see a physician promptly for evaluation of lingering symptoms and illnesses; (3) women undergo breast cancer monitoring, with annual breast MRI and twice annual clinical breast examination beginning at age 20-25 years. The use of mammograms has been controversial because of radiation exposure and limited sensitivity. When included, annual mammograms should alternate with breast MRI, with one modality every six months; (4) adults consider routine screening for colorectal cancer with colonoscopy every 2-3 years beginning no later than age 25 years; (5) individuals consider organ-targeted surveillance based on the pattern of cancer observed in their family. Intensified surveillance with whole-body MRI protocols for adults and children who carry a germline TP53 pathogenic variant are being evaluated in investigational settings. Agents/circumstances to avoid: People with germline TP53 pathogenic variants should: (1) avoid known carcinogens including sun exposure, tobacco use, occupational exposures, and excessive alcohol use; and (2) minimize exposure to diagnostic and therapeutic radiation. Evaluation of relatives at risk: It is appropriate to offer genetic counseling and testing to all relatives who are at risk of having a familial TP53 pathogenic variant.

GENETIC COUNSELING:

LFS is inherited in an autosomal dominant manner. The proportion of individuals with a de novo germline TP53 pathogenic variant is estimated to be between 7% and 20%. Offspring of an affected individual have a 50% chance of inheriting the pathogenic variant. Predisposition testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the heritable pathogenic variant in the family has been identified.

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