"Li-Fraumeni Syndrome" – What Is It?

Li-Fraumeni syndrome (LFS) is a genetic, i.e., hereditary, predisposition to the development of malignant tumors. The risk of cancer is already significantly increased in childhood or young adulthood. It can lead to soft tissue and bone tumors, blood cancer, brain tumors, adrenal gland tumors, and, in young women, breast cancer.

LFS is one of the most aggressive cancer predisposition diseases. Therefore, providing good medical monitoring and support for people with LFS is extremely important.

Overview of the Chapters on This Page:

  • Li-Fraumeni Syndrome – What Is It? (This Section)
  • How Is "Li-Fraumeni Syndrome" Diagnosed?
  • What Is the Risk of Cancer?
  • What Is Known About the Development of "Li-Fraumeni Syndrome"
  • Is There Any Treatment Available?
  • Medical Measures for Early Detection
  • Li-Fraumeni Syndrome – What You Can Do Yourself
  • Links and Further Information (e.g., From Support Groups)
  • Li-Fraumeni Syndrome – What Is It? (This Section)
  • How Is "Li-Fraumeni Syndrome" Diagnosed?
  • What Is the Risk of Cancer?
  • What Is Known About the Development of "Li-Fraumeni Syndrome"?
  • Is There Any Form of Treatment Available?
  • Medical Measures for Early Detection
  • Li-Fraumeni Syndrome – What You Can Do Yourself
  • Links (e.g., From Support Groups) and Further Information

How Is "Li-Fraumeni Syndrome" Diagnosed?

LFS can be diagnosed clinically based on classic diagnostic criteria. There are also personal and familial constellations in which it makes sense to arrange genetic testing for the presence of LFS. Such a genetic test and the detection of a TP53 mutation confirm the diagnosis of LFS.

Classic Diagnostic Criteria for the LFS

  • A patient has been diagnosed with sarcoma at the age of ≤45 years
    AND
  • A first-degree relative (father, mother, children) fell ill with cancer at the age of ≤45 years
    AND
  • A first- or second-degree relative (grandparent, sibling, grandchild) developed cancer at the age of ≤45 years or developed sarcoma regardless of the age of onset.

Chompret Criteria

If the following criteria are met, an examination for the presence of LFS should be carried out (one of the following points must be fulfilled). A patient has:

  • A tumor of the LFS tumor spectrum before the age of 46 AND at least one first- or second-degree relative with an LFS tumor (except breast cancer, if the patient has breast cancer) before the age of 56 or in the case of multiple tumors;
  • Several tumors (except breast cancer), two of which belong to the LFS tumor spectrum, the first of which occurred before the age of 46;
  • An adrenocortical carcinoma (ACC, the adrenal gland is a small organ located above the two kidneys), a choroid plexus tumor (a rare brain tumor), or embryonal anaplastic RMS (a specific soft tissue tumor) regardless of family history;
  • Breast cancer before the age of 31.

What Is the Risk of Cancer?

Typical of Li-Fraumeni syndrome is the occurrence of various types of cancer at an unusually young age. The “core” tumors, i.e., the most frequently occurring cancers, are:

  • Bones
  • Muscles and connective tissue
  • Adrenal gland
  • Blood
  • Brain
  • Chest

Due to the many different tumors associated with LFS, it is impossible to predict which tumor will occur in an individual case.

Other Common Types of Cancer Are

  • Skin cancer
  • Lung cancer
  • Gastrointestinal cancer
  • Neuroblastomas (tumors of the adrenal gland)
  • Lymphoma (cancer of the lymph glands)
  • Kidney tumors
  • Thyroid cancer

Already in the first year of life, 4% of children with LFS develop a tumor; by the age of 5, it is almost a quarter of all children (22%), and by the age of 18, over 40% of children and adolescents with LFS have already developed a tumor.

Typical Tumors in Childhood Are

  • Sarcomas (osteosarcomas, soft tissue sarcomas)
  • ACC
  • Brain tumors (choroid plexus tumors, SHH medulloblastomas)
  • ALL (especially hypodiploid), AML, MDS
  • ALL relapses

Typical Tumors in Adulthood Are

  • Breast cancer, especially among young women
  • Soft tissue sarcomas

Around half of female LFS carriers develop cancer by the age of 30, and around half of male LFS carriers by the age of 45. At 60, the risk increases to 80-90%. At 70, the probability of developing a tumor is almost 100%. In individual cases, however, predicting when a tumor will occur is impossible. Unfortunately, some patients develop cancer several times, especially if they have already been treated for a malignant disease in childhood.

What Is Known About the Development of "Li-Fraumeni Syndrome"?

Li-Fraumeni syndrome is caused by a genetic change, a mutation, in a gene called TP53. This gene plays a key role in controlling cell growth and tumor development. It determines the fate of cells and initiates a repair process or self-destruction for cells that carry damaged DNA and, therefore, incorrect genetic information. If this important gene is defective, faulty cells multiply uncontrollably, and cancer develops.

Every person carries two copies of the TP53 gene, one from the mother and one from the father. In LFS, one of the two copies is defective. If the second, still healthy copy of the TP53 gene is also damaged, tumors develop.

The disease is passed on via autosomal dominant inheritance, which means that every second child is affected. Around 70% of people with LFS have inherited the disease from their mother or father. In around 5-20%, the mutation arises spontaneously, which is known as “de novo.”

It is now assumed that around 1 in 5,000 people carry a mutation in the LFS gene. In some areas of Brazil, there are many more people.

Is There Any Form of Treatment Available?

The therapy depends on the cancer and is, at least so far, basically the same as for patients without LFS. However, there is one exception: in the case of LFS-associated breast cancer, a mastectomy (breast amputation) would be preferred to a lumpectomy (breast-conserving surgery) to reduce the risks of a second primary breast cancer and to avoid radiotherapy.

Both diagnostic and therapeutic exposure to radiation should be avoided if possible, as it promotes the development of further tumors. However, the primary cure always takes precedence over reducing the risk of secondary diseases.

Please ask your attending physician whether any open clinical studies could be considered for you.

Diagnosis of " Li-Fraumeni Syndrome" What's Next?

If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.

Diagnosis of " Li-Fraumeni Syndrome" What's Next?

If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.

Medical Measures for Early Detection

The aim is to detect developing complications at an early stage in order to achieve the best possible treatment outcomes. According to the current guidelines of the AACR (American Association of Cancer Research), the following screening measures are redommended:

Children and adolescents (from birth to 18 years)

  • In general:
    • Detailed physical examination every 3-4 months, including blood pressure measurement, documentation of weight and height, observation of external abnormalities, and neurological examination.
    • Immediate recording of any medical concerns with the paediatrician.
  • Abdominal and pelvic ultrasound every 3-4 months
    • In case of insufficient availability or quality of ultrasound → Blood tests every 3-4 months (total testosterone, dehydroepiandrosterone sulphate and androstenedione)
    • If there is an overlap with the whole-body MRI, the ultrasound may be omitted.
  • CNS tumour: Annual head MRI (first MRI with contrast, then without contrast if previous findings are normal)
  • Soft tissue and osteosarcoma: Annual whole-body MRI
  • Melanoma: Annual full-body skin examination for new or growing moles with abnormal features
  • Leukaemia: Complete blood count every 3-4 months in patients with previous exposure to leukaemia-causing agents

Adults (aged 18 and older)

  • In general
    • Full physical examination every 6  m onths, including neurological examination, skin examination and digital rectal examination by a urologist from the age of 35
    • Immediate reporting of medical concerns to family doctor or internist
  • Breast cancer
    • Risk awareness and treained self-examination from age 18
    • Clinical breast examination twice a year (from age 20)
    • Annual breast MRI from age 20
    • Consider risk-reducing surgical removal of both breasts
    • (Annual mammography from age 30, could alternate with breast MRI – in consultation with the familial breast and ovarian cancer centre)
  • CNS tumour: Annual head MRI (first MRI with contrast, then without contrast if previous findings are normal)
  • Soft tissue and osteosarcoma, ACC
    • Annual whole body MRI
    • Abdominal and pelvic ultrasound every 6 months
    • If there is an overlap in time with the whole-body MRI, the ultrasound may be omitted
    • If the quality or availability of ultrasound is insufficient, a specific blood test can be done every 3-4 months (total testosterone, dehydroepiandrosterone sulphate and androstenedione)
  • Tumours of the digestive tract
    • Endoscopy of the upper digestive tract and bowel every 2-5 years from the age of 25, earlier in patients who have had therapeutic whole-body or abdominal radiotherapy 
  • Melanoma
    • Annual full-body skin examination for new or growing moles with abnormal features
  • Prostate
    • Annual measurement of serum PSA from the age of 35. Rapid assessment by a urologist is recommended in the event of a rapid increase

 

Notes

  • Whole-body MRI = head to toe, including upper and lower extremities
  • Alternate chest MRI/ultrasound of abdomen and pelvis with annual whole-body MRI (at least one scan every 6 months)
  • The effectiveness of biochemical monitoring for the detection of adrenocortical carcinoma has not been established

Li-Fraumeni Syndrome – What You Can Do Yourself

You Should Pay Attention to This

  • Avoid known carcinogens, including sun exposure, tobacco use, occupational exposure, and excessive alcohol consumption.
  • Minimize exposure to diagnostic and therapeutic radiation.

Please get in touch with your attending physician or any LFS consultation and make an appointment as soon as possible in the event of new symptoms, new pain, and parental uncertainty in the assessment of a clinical change. The threshold for making contact should be as low as possible!

Further Information

Li-Fraumeni syndrome is also being researched in our companion projects Liquid Biopsy and ADDRess, so we encourage patients to sign up for this in addition to the CPS Registry.

Any further questions?

You can reach us by e-mail and telephone, or you can come to our consultation hours in person. For more information, please visit our contact page.