What is Li-Fraumeni syndrome?

Li-Fraumeni syndrome (LFS) is a genetic condition that predisposes to the development of malignant tumors. Already in childhood or young adulthood the cancer risk is significantly increased and soft tissue and bone tumors, blood cancer, brain tumors, tumors of the adrenal gland and breast cancer in young women can occur. The LFS is one of the most aggressive cancer predisposition diseases. Therefore, it is of utmost importance to monitor and accompany people with LFS medically.

How is Li-Fraumeni syndrome diagnosed?

LFS can be diagnosed clinically on the basis of classical diagnostic criteria. In addition, there are personal and family constellations in which it makes sense to initiate genetic testing for the presence of an LFS. The diagnosis of an LFS is confirmed with such a genetic test and the detection of a TP53 mutation.

Classical Diagnostic Criteria for the LFS

  • A patient has the diagnosis of a sarcoma aged ≤45 years

  • A first-degree relative (father, mother, children) fell ill with cancer at the age of ≤45 years old

  • A first or second degree relative (grandparents, siblings, grandchildren) at the age of ≤45 years fell ill with cancer or developed a sarcoma regardless of the age of illness.

Chompret Criteria

The following criteria should be examined for the presence of an LFS (one of the following points must be fulfilled). A patient has:

  • A tumor of the LFS tumor spectrum before the age of 46 years AND at least one first or second degree relative with an LFS tumor (except breast cancer, if the patient himself has breast cancer) before the age of 56 years or in multiple tumors;

  • Several tumors (except breast cancer), two of which belong to the LFS tumor spectrum and 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 carcinoma (a rare brain tumor) or an embryonal anaplastic RMS (a special soft tissue tumor) independent of the family history;

  • Breast cancer before the age of 31.

What is the risk of cancer?

A typical feature 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 affected:

  • Bones

  • Muscles and connective tissue

  • Adrenal gland

  • Blood

  • Brain

  • Breast

Due to the large number of different tumors associated with the LFS, it is impossible to predict which tumor will occur.

Other common cancers are

  • Skin Cancer

  • Lung cancer

  • Gastrointestinal cancer

  • Neuroblastoma (tumors of the adrenal gland)

  • Lymphomas (lymph gland cancer)

  • Kidney Tumors

  • Thyroid cancer

Already in the first year of life 4% of children with LFS develop a tumor, up to the age of 5 it is almost a quarter of all children (22%) and up to 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 young women

  • Soft tissue sarcomas

Approximately half of LFS carriers suffer from cancer up to the age of 30 and half of male LFS carriers up to the age of 45. At the age of 60 the risk increases to 80-90%, at the age of 70 the probability of developing a tumor is almost 100%. In individual cases, however, it is impossible to predict when a tumor will occur. Unfortunately, some patients also develop cancer several times, especially if they were treated for a malignant disease in childhood.

What causes Li-Fraumeni syndrome?

Li-Fraumeni syndrome is caused by a genetic alteration, a mutation, in a gene called TP53. This gene has 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 carrying damaged DNA and thus false genetic information material. If this important gene is defective, uncontrolled defective cells multiply and cancer develops.

Each person carries 2 copies of the TP53 gene, one copy from the mother and one copy from the father. With the LFS one of the two copies is damaged. If now also the 2nd still healthy copy of the TP53 gene is damaged, tumors develop.

The disease is transmitted via an autosomal dominant inheritance. That means every second child gets sick. About 70% of people with LFS have inherited the disease from their mother or father. In about 5-20% of cases, the mutation is newly spontaneous, which is called de novo.

Today it is assumed that about 1 out of 5000 people carries a mutation in the LFS gene. In some areas of Brazil there are many more people.

Is there a treatment?

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

Both diagnostic and therapeutic radiation exposure should be avoided where possible as it favours the development of further tumors. However, the primary cure is always superior to the risk reduction for secondary diseases.

Please ask your attending physician if there are any open clinical trials that could be considered for you.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

The aim is the early recognition of developing complications in order to achieve the best possible treatment results. For this purpose, regular medical examinations are recommended according to the following scheme (examination recommendations of the AACR 2016):

Children and Adolescents (birth up to 18 years)

  • Physical examination every 3-4 months

  • Immediate pediatric examination in case of new medical problems

  • Ultrasound of abdomen and pelvis every 3-4 months

  • Only perform a blood test if ultrasound is not available

  • Annual MRI of the head

  • Annual whole-body MRI

Adults (from 18 years)

  • Complete physical examination every 6 months

  • Immediate recording of medical problems by family doctor or internist

  • Risk awareness for breast cancer for women over 18 years

  • Clinical breast examination twice a year over 20 years

  • Annual breast MRI screening (from 20-75 years)

  • Annual MRI of the head over 18 years

  • Annual whole-body MRI over 18 years

  • Ultrasound of abdomen and pelvis every 12 months

  • Examination of the gastrointestinal tract every 2-5 years from the age of 25

  • Annual dermatological examination from the age of 18

The breast MRI and ultrasound examination of the abdominal organs and pelvis should alternate with the annual whole-body MRI (at least one scan every 6 months).

Self-Care and Support

What should I pay special attention to?

People with Li-Fraumeni syndrome should

  • avoid known carcinogens including sun exposure, tobacco consumption, occupational exposure and excessive alcohol consumption.

  • minimise exposure to diagnostic and therapeutic radiation.

Please contact your attending physician or every LFS consultation hour and arrange a prompt appointment for new symptoms, new pain and parental uncertainties in the assessment of a clinical change. The threshold for establishing contact should be as low as possible!

Support Groups and Additional Information