Li Fraumeni syndrome

• The early start of numerous primary malignancies, including as brain tumors, adrenocortical carcinoma (ACC), leukemias, breast cancer, soft tissue and bone sarcomas, and other cancers, is the hallmark of this uncommon genetic cancer predisposition disease.

Incidence

How common is Li Fraumeni syndrome?

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

Inheritance

Autosomal dominant 

Age of Onset

Any age

What are the symptoms of Li Fraumeni syndrome?

• Brain tumors, soft tissue sarcomas, osteosarcomas, early-onset breast cancer, and SCC are the main malignancies associated with Li-Fraumeni syndrome (LFS).
• Numerous additional malignancies, including lymphomas, leukemias, and colorectal cancer, have also been documented.
• There is a 50% chance that someone with LFS will have another cancer.

Very Common Symptoms

Neoplasm

Common Symptoms

Breast carcinoma 

Occasional Symptoms

• Adrenocortical carcinoma
• Astrocytoma
• Central primitive neuroectodermal tumor
• Choroid plexus carcinoma
• Colorectal polyposis 
• Ependymoma
• Glioblastoma multiforme
• Leukemia 
• Lymphoma
• Neoplasm of the central nervous system
• Neoplasm of the gastrointestinal tract
• Osteosarcoma
• Rhabdomyosarcoma
• Stomach cancer

Rare Symptoms

• Acute lymphoblastic leukemia
• Acute myeloid leukemia
• Choriocarcinoma
• Colon cancer 
• Hodgkin lymphoma
• Medulloblastoma
• Melanoma
• Myelodysplasia
• Neoplasm of head and neck
• Neoplasm of the larynx
• Neoplasm of the lung
• Neoplasm of the pancreas
• Neoplasm of the rectum
• Non-Hodgkin lymphoma
• Ovarian neoplasm
• Prostate cancer
• Renal neoplasm
• Testicular neoplasm
• Thyroid carcinoma 

What are the causes of this condition?

• In most families with classic LFS, LFS is caused by germline mutations in the tumor suppressor gene TP53 (17p13.1).
• The tumor antigen protein p53, which is involved in numerous cellular functions such DNA repair, growth arrest, and apoptosis, is encoded by this gene.
• Between 7 and 20% of TP53 mutations are thought to be de novo. No further genes have been linked to LFS as of yet.

How to diagnose Li Fraumeni syndrome?

• Genetic testing and the discovery of a TP53 mutation confirm the diagnosis. If an individual satisfies the traditional LFS requirements, which include the following: (1) an individual whose sarcoma was diagnosed prior to the age of 45; (2) a first-degree relative whose cancer was diagnosed prior to the age of 45; and (3) a first- or second-degree relative whose cancer was diagnosed prior to the age of 45 or whose sarcoma was diagnosed at any age.
• TP53 testing may also be recommended for people who meet the following Chompret criteria: (1) a person with a tumor that falls within the LFS tumor spectrum before the age of 46, as well as a first- or second-degree relative who also has an LFS tumor (excluding multiple breast cancer tumors or breast cancer before the age of 56); (2) a person who has multiple tumors (excluding multiple breast tumors), two of which fall within the LFS tumor spectrum, with the first occurring before the age of 46; (3) a person who, regardless of family history, has an ACC, CPC, or anaplastic embryonal rhabdomyosarcoma; or (4) a person who has breast cancer before the age of 31.

What is the differential diagnosis?

Differential diagnoses include

• hereditary breast and ovarian cancer syndrome
• CHEK2 cancer susceptibility syndrome
• Constitutional mismatch repair deficiency syndrome

How is this treated?

• Treatment measures are typically followed to minimize radiation exposure for malignancies linked to Lynch syndrome. When treating breast cancer, mastectomies are preferred over lumpectomies.
• For risk reduction, a prophylactic mastectomy may also be recommended to those with a known TP53 mutation. It is advised that persons with TP53 mutations undergo routine surveillance, which incorporates screening using biochemical and imaging modalities, as adopted from the “Toronto protocol.”
• From birth until age 18, it is advised to have thorough physical examinations and pelvic and abdominal ultrasonography every three to four months. It is recommended that adults and children have annual brain and whole-body magnetic resonance imaging (MRI).
• It is advised that women undergo annual mammograms at age 30, yearly breast MRIs starting at age 20, and clinical breast exams every six to twelve months.
• Annual dermatologic examinations and physical examinations every 6 to 12 months starting at age 18 are advised for further cancer concerns.
• Every two to five years starting at age 25 (or five years prior to the earliest colon cancer in the family), colonoscopies and upper endoscopies are advised. Additional screening might also be advised.

What is the prognosis of Li Fraumeni syndrome?

• The type and severity of the tumors that grow determine the prognosis.
• The 5-year survival rates of patients who underwent the Toronto screening protocol were found to be higher.

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.