Li-Fraumeni Syndrome

It is an autosomal dominant pathology characterized by an increased risk of developing different types of cancer at early ages. It is caused by alterations in the TP53 gene which is one of the main tumor suppressor genes.

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults, such as soft tissue sarcoma, osteosarcoma, pre-menopause breast cancer, cerebral tumors, adrenocortical carcinoma (ACC) and leukemia. In addition a variety of other neoplasms can be developed. Multiple cancers and tumors linked to LFS are often produced in childhood or as young adults and the survivors have a greater risk of various primary cancers.

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 germ line pathogenic variant in TP53, the only gene so far identified in which mutation is definitively associated with LFS.

It is difficult to estimate the incidence of this rare disease since its definition raises a problem of nosologic classification.

The most characteristic tumors are osteosarcomas, soft tissue sarcomas, breast cancer in young people, leukemia/ lymphoma, cerebral tumors and adenocarcinoma; however, any type of tumor can be observed.

The germ mutation of the TP53 gene is found in 70% of the families with LFS, as well as in some families or patients with patterns suggestive of the disease, even without strictly fulfilling the criteria. The risk of a carrier of a deleterious mutation on the TP53 gene of developing cancer is 15% at 15 years of age, 80% for women of 50 years and 40% for men of the same age. The significant difference between sexes can be explained almost completely owing to breast cancer. The risk of developing a second cancer, especially a radiation-induced type, is high.

Classic LFS is diagnosed when a person has all of the following criteria:

  • A sarcoma diagnosed before age 45
  • A first-degree relative, meaning a parent, sibling or child, with any cancer before age 45

A first-degree relative or second-degree relative, meaning a grandparent, aunt/uncle, niece/nephew, or grandchild, with any cancer before age 45 or a sarcoma at any age


Any genetic counseling is difficult because of the wide spectrum of tumors and their appearance at any age, especially during infancy. No measure of surveillance can be considered effective, with the exception of those for breast cancer in women over 20.

The doctors and the families should be aware that currently there are no monitoring regimes that have definitely been proved of benefit to the children and adults with the germ line TP53 mutation. However, this is an ongoing important area of research.

The following are some recommendations:

  • Children and adults should have a physical examination, including skin care and neurologic tests, annually. Doctors should be aware of the high risks for early onset of rare cancer and also of secondary malignant neoplasms in cancer survivors.
  • People should pay more attention to any persistent symptoms and illnesses, especially headaches, bone pain and abdominal pains. If these symptoms occur, the person should be checked by a doctor immediately.
  • Women should undergo breast cancer monitoring, with annual breast MRI and twice-yearly clinical breast examination beginning at age 20 to 25. The use of mammograms has been controversial because of radiation sensitivity concerns. If available, annual mammograms should alternate with breast MRI every six months.

Also suggested:

  • Adults should have a colonoscopy every two or three years starting, at the latest, at 25 years of age to checked for colorectal cancer
  • People should consider an organ-specific monitoring based on the pattern of cancer observed in their family.

There is substantial evidence that Li-Fraumeni Syndrome patients may have an increased sensitivity to ionizing radiation [Hisada et al 1998, Varley 2003, Wang et al 2003, Cohen et al 2005]. Therefore, those persons with TP53 germ line mutations should avoid or reduce to the minimum exposure to diagnostic and therapeutic radiation whenever possible.

Those persons with LFS are encouraged to avoid or reduce exposure to known or supposed carcinogens, among them, exposure to sunlight, smoking, occupation exposure to certain substances and the excessive use of alcoholic beverages since the effects of cancer-causing exposure and the TP53 germ line mutations can be accumulative. For example, it has been shown that individuals with a TP53 germ line mutation and who smoke significantly increase their risk of developing lung cancer over those who have the same mutation but do not smoke.

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