What Is Li-Fraumeni Syndrome or LFS?
Li-Fraumeni is a rare genetic disorder that increases the risk of developing different types of cancer in young children and adults, such as soft tissue sarcoma, cancer of the breast, leukemia, and adrenocortical carcinoma. It was first recognized by two American physicians, Frederick Pei Li and Joseph F. Fraumeni, Jr., and therefore it was named after them. It is an autosomal dominant disorder that can be passed on to children from parents. People who are affected by Li-Fraumeni syndrome have the risk of developing more than one type of cancer in their lifetime. Common cancers affecting people with Li-Fraumeni syndrome include soft tissue sarcoma, breast cancer, neuroblastoma, acute myeloid leukemia, etc.
What Causes Li-Fraumeni Syndrome?
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Li-Fraumeni syndrome is mainly caused by the mutation in the TP53 gene that contains the genetic information for making a protein called tumor protein 53 or P53. Tumor protein 53, or P53, is a tumor suppressor gene that plays a crucial role in regulating DNA repair and controlling cell division. Therefore a mutation in the TP53 gene allows the cells with damaged DNA to divide uncontrollably and become tumors.
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Some cases of Li-Fraumeni syndrome are also reported with mutations in the CHEK2 gene. However, the risk of cancer development in Li-Fraumeni syndrome is less common in patients with CHEK2 gene mutation.
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Li-Fraumeni syndrome is an autosomal dominant disorder, which means a person will have Li-Fraumeni syndrome even if there is a mutation in any of the two copies of the TP53 gene or CHEK2 gene. However, some reports suggest that nearly 25 % of people with Li-Fraumeni syndrome have no family history of the condition. Still, they have a de novo (new) mutation in the TP53 or CHEK2 gene.
What Are the Symptoms of Li-Fraumeni Syndrome?
Developing different types of cancers at an early age is the most common symptom of Li-Fraumeni syndrome. There are many different types of cancers associated with Li-Fraumeni syndrome, out of which some are the core cancers that are seen commonly in Li-Fraumeni syndrome-affected individuals, which include;
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Breast Cancer: Females affected by Li-Fraumeni syndrome have a high risk of breast cancer. The common symptoms of breast cancer include a breast lump, a change in the shape of the breast, swelling and redness on the skin of the breast, and blood discharge from the nipple.
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Soft Tissue Sarcoma: Soft tissue sarcoma is rare cancer in soft tissues such as muscles, nerves, tendons, lymph nodes, and blood vessels. Common symptoms include a lump growth anywhere in the body, abdominal pain, trouble breathing, cough, nausea, and vomiting.
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Neuroblastoma: It is a rare type of childhood cancer that develops in nerve tissue. It most commonly arises in the adrenal glands' neuroblast cells (nerve-forming cells). However, it can also develop in the spinal cord, neck, chest, and abdomen. It most commonly causes symptoms like abdominal pain, diarrhea, and change in bowel habits. Chest pain and wheezing are the other most common symptoms of neuroblastoma in the chest.
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Adrenocortical Carcinoma: It is an endocrine malignancy that develops in the outer layer of the adrenal glands (a small triangular-shaped gland attached to the top of both kidneys). Symptoms of adrenocortical carcinoma include weight gain, muscle weakness, deepening of the voice, and trouble sleeping.
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Acute Myeloid Leukemia: It is a type of blood cancer that develops in the blood-forming cells of bone marrow. The most common symptoms include recurrent infections, fever, night sweats, fatigue, and pale skin.
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Osteosarcoma: It is the most common bone tumor that develops in the osteoblast cells that form bone. Osteosarcoma leads to symptoms including swelling in the bone, bone pain or joint pain, restricted movements, and limping (difficulty walking).
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Glioblastoma: Glioblastoma is a malignant tumor that develops in a brain cell called an astrocyte. The signs and symptoms of glioblastoma include headache, blurred vision, memory problems, personality or mood changes, and seizures.
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Medulloblastoma: Medulloblastoma is a malignant brain tumor that develops in the cerebellum (a part of the brain). Medulloblastoma symptoms are headache, nausea, vomiting, dizziness, fatigue, and blurred vision.
Li-Fraumeni syndrome is also linked to several other cancers, but the risks of developing these cancers are lower than the core cancers. They include:
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Lung adenocarcinoma.
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Pancreatic cancer.
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Kidney cancer.
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Colon cancer.
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Thyroid cancer.
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Ovarian cancer.
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Testicular cancer.
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Prostate cancer.
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Melanoma (a type of skin cancer).
How Is Li-Fraumeni Syndrome Diagnosed?
Genetic mutations cause Li-Fraumeni syndrome; therefore, healthcare providers use genetic testing for diagnosis. Before genetic testing, the healthcare providers check the patient's medical history and family history to look for familial inheritance. Healthcare providers use different types of criteria for the diagnosis of Li-Fraumeni syndrome, it includes;
1. Classic Clinical Criteria:
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The patient has sarcoma, which is diagnosed before 45 years of age.
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Any first-degree relative of the patient meaning a parent, siblings, or children affected with any cancer before the age of 45 years.
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Any of the first-degree or second-degree relatives of the patient, meaning a grandparent, aunt or uncle, niece or nephew, or grandchild, is affected with any cancer before age 45 or sarcoma at any age.
2. Chompret Criteria:
Chompret criteria have been proposed to identify Li-Fraumeni syndrome-affected families beyond the classic criteria mentioned above. It consists of three criteria which are as follows;
A. Criterion 1:
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A person diagnosed with a tumor that belongs to the Li-Fraumeni syndrome tumor spectrum before the age of 46. It includes any of the following diseases: soft tissue sarcoma, premenopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia, osteosarcoma, or lung cancer.
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At least any one of the first-degree or second-degree family members is diagnosed with a Li-Fraumeni syndrome-related tumor, except breast cancer, if the individual has breast cancer before the age of 56 or with multiple tumors.
B. Criterion 2:
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A person diagnosed with multiple tumors except for multiple breast tumors, two out of multiple tumors belong to the Li-Fraumeni syndrome tumor spectrum, and the first of which occurred before age 46.
C. Criterion 3:
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An individual who is diagnosed with either adrenocortical carcinoma or a choroid plexus tumor regardless of family history.
3. Li-Fraumeni Like Syndrome (LFL) Criteria:
It is another similar criterion for identifying Li-Fraumeni syndrome-affected families beyond classic criteria. It has two sets of definitions that include the following:
A. LFL Definition 1: LFL definition 1 is also called the Birch definition.
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A person diagnosed with any childhood cancer, brain tumor, sarcoma, or adrenocortical tumor before age 45.
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A first-degree or second-degree family member is diagnosed with typical Li-Fraumeni syndrome-associated cancers such as breast cancer, brain cancer, sarcoma, leukemia, or adrenocortical tumor at any age.
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A first-degree or second-degree family member is diagnosed with any cancer before age 60.
B. LFL Definition 2: LFL Definition 2 is also called Eeles definition:
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Two first-degree or second-degree family members are diagnosed with Li-Fraumeni syndrome-associated cancer, such as breast cancer, pancreatic cancer, brain cancer, adrenal cortical tumor, or leukemia, at any age.
Apart from genetic testing and clinical criteria, the doctor will suggest specific tests, such as imaging tests, blood tests, biopsies, etc., for diagnosing different cancers associated with Li-Fraumeni syndrome.
How Is Li-Fraumeni Syndrome Treated?
The treatment options for Li-Fraumeni syndrome depend on the different cancers that are associated with it. Some of the common treatment options used for treating cancers linked with Li-Fraumeni syndrome include surgery, chemotherapy, and immunotherapy. Some reports suggest that TP53 genetic mutation in Li-Fraumeni syndrome can increase the patient's sensitivity to ionizing radiation. Therefore radiation therapy is not included as a part of the treatment.
Conclusion:
Li-Fraumeni syndrome cannot be prevented, but early and regular screenings will help treat the condition early. There is no specific treatment for Li-Fraumeni syndrome, and the treatment options depend on the associated cancers. The main aim of the treatment is to alleviate the symptoms of the different cancers related to Li-Fraumeni syndrome and help improve the overall survival and quality of life in patients. However, researchers are trying to identify new ways of treatment for Li-Fraumeni syndrome using genetic testing.
