Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS)

What is Li-Fraumeni syndrome?

Li-Fraumeni syndrome, also known as Heritable TP53-related cancer (hTP53rc) syndrome, is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults. The diagnosis should be considered in four different clinical situations:

  1. Patient with a tumour suggestive of the syndrome, prior to age 46 years (soft-tissue tumour (sarcoma), bone tumour, a tumour in the outer layer of the adrenal glands (adrenocortical carcinoma), brain tumour, female breast cancer)
    AND
    at least one first- or second-degree relative with a LFS tumour before the age of 56 years or with multiple tumours;
  2. Patient with two tumours belonging to the LFS spectrum, the first being developed before 46 years or patient with a second tumour developed in a field irradiated during the treatment of a first tumour;
  3. Patient with a very rare tumour such as an adrenocortical tumour, a rare brain tumour called choroid plexus tumour, or a specific type of sarcoma called embryonal anaplastic rhabdomyosarcoma;
  4. Female patient with breast cancer before 31 years.

What causes LFS?

LFS results from the alteration of one the two parental copies of the TP53 gene encoding the p53 protein. This protein normally acts as a guardian of the genome when DNA damages occur. In patients with an alteration of the gene, the quantity of the normal protein is insufficient, and when DNA damages occur in a cell, they are not corrected and their accumulation leads to the cancerous transformation of the cell.

How is LFS inherited?

LFS is a so-called autosomal dominant syndrome: if you inherit the altered copy from only one parent, you can get the disease. In most of the families, the mutation is inherited from the mother or the father, but new alterations occurring in sperm or eggs can end up in every cell of the child and represent at least 14% of the cases.  

The risk for a mutation carrier to develop cancer is quite diverse, even within the same family, indicating that some adult mutation carriers do not develop cancer. The risk depends on the type of the mutation and probably on the presence of other genetic variations which act as modifier factors.

Radiotherapy and genotoxic chemotherapies contribute to the development of secondary tumours. Therefore radiotherapy should be avoided and surgical treatment prioritized, but only if this is possible and does not compromise the treatment of cancer.

What are the surveillance options for LFS?

The surveillance protocols are based, from the first year of life, on abdominal ultrasound every 3-6 months, annual total body MRI, annual brain MRI, and in women from 20 years on annual breast MRI. The benefits of such heavy protocols should be carefully analyzed and discussed in each family.

 
Clinical practice guideline

Written by ERN GENTURIS

Clinical practice guideline - Li-Fraumeni and Heritable TP53-related cancer syndromes

 

Care pathway

Care pathway - Li-Fraumeni and heritable TP53-related cancer (hTP53rc)

 

Patient journey

Patient journey - Li Fraumeni syndrome