Li-Fraumeni Syndrome

CLINICAL CHARACTERISTICS

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with high risks for a broad spectrum of cancers including early-onset cancers. Five cancer types account for the majority of LFS tumors: adrenocortical carcinomas, breast cancer, central nervous system tumors, osteosarcomas, and soft-tissue sarcomas. Other cancers associated with LFS include leukemia, colorectal cancer, stomach cancer, lung cancer, melanoma, pediatric head and neck cancers, pancreatic cancer, and prostate cancer. Cancer survivors are at increased risk for developing additional primary cancers and treatment-related secondary cancers. The lifetime risks of cancer for women and men with classic LFS are 90% and 70%, respectively, and 50% of cancers occur prior to age 40 years.

DIAGNOSIS/TESTING: The clinical diagnosis of LFS can be established in a proband who meets clinical diagnostic criteria, or the molecular diagnosis is established in a proband with a germline pathogenic variant in identified by molecular genetic testing.

MANAGEMENT

Bilateral mastectomy rather than lumpectomy is often recommended for LFS-related breast cancer to reduce the risk of a second primary breast cancer and to avoid radiation therapy. Radiation therapy should be avoided if possible with treatment of other cancers, to reduce the risk of secondary malignancies. Conventional cytotoxic chemotherapy may also pose an increased secondary cancer risk; however, treatment efficacy should be prioritized above concerns about late effects. Otherwise, standard oncologic management is recommended. Risk-reducing bilateral mastectomy to reduce the risk for breast cancer is an option for women with LFS; colonoscopy may be considered as surveillance as well as primary prevention of colorectal cancer; dermatologic surveillance can be used to detect and remove premalignant lesions. Comprehensive physical examination and ultrasound of abdomen and pelvis every three to four months from birth to age 18 years; comprehensive physical examination every six months in those older than age 18 years; annual whole-body MRI; females should have a clinical breast examination every six to 12 months beginning at age 20-25 years, annual breast MRI starting between age 20-30 years, and annual mammogram alternating with breast MRI from age 30 to 75 years; annual brain MRI; upper endoscopy and colonoscopy every two to five years beginning at age 25 years; annual dermatologic exam beginning at age 18 years; annual ultrasound of the abdomen and pelvis beginning at age 18 years; consider additional screening for lung, pancreatic, prostate, and thyroid cancer depending on family history and additional risk factors; assess social work and genetic counseling needs at each visit. Minimize exposure to diagnostic and therapeutic radiation; avoid known carcinogens including unprotected sun exposure, tobacco use, occupational exposures, and excessive alcohol use. If a molecular diagnosis of LFS has been established in the proband, offer molecular genetic testing to all first-degree relatives (including children) and other relatives in order to identify individuals with LFS who would benefit from increased cancer monitoring, with attention to symptoms or signs of cancer and early intervention when a cancer or precancer is identified. If a clinical diagnosis of LFS has been established in the proband but the proband does not have an identified pathogenic variant, all at-risk family members should be counseled regarding their potential increased risks for LFS-related cancers and options for surveillance and risk reduction.

GENETIC COUNSELING

LFS is inherited in an autosomal dominant manner. Most individuals diagnosed with LFS inherited a pathogenic variant from a parent. Some individuals diagnosed with LFS have the disorder as the result of a germline pathogenic variant. The frequency of pathogenic variants is estimated at between 7% and 20%. Each child of an individual with a molecular diagnosis of LFS has a 50% risk of inheriting the pathogenic variant; each child of an individual with a clinical diagnosis of LFS (in whom a pathogenic variant has not been identified) is presumed to have an increased risk for LFS. If a pathogenic variant has been identified in an affected family member, predictive testing for at-risk family members and prenatal/preimplantation genetic testing are possible.