Li-Fraumeni Syndrome (LFS) is a rare genetic disorder that affects children when they are young. Children suffering from Li-Fraumeni are likely to develop multiple types of cancers, such as bone cancer (osteosarcoma), brain tumours (medulloblastoma, choroid plexus carcinoma), adrenal gland cancer, and breast cancer.¹

According to the Children's Hospital of Philadelphia, Li-Fraumeni syndrome is an inherited disease. This condition does not skip generations and is likely to cause the development of different tumours in a child. It is caused by a mutation in the TP53 gene. If a parent carries a mutated copy of this gene, each of their children has a 50% chance of inheriting it.²

LFS may be a rare condition, but that doesn't mean it does not require attention. As a parent, you will be worried if your child is at an increased risk of developing this disease. In this article, we will provide you with all the necessary information about LFS and how to manage it if your child is affected by it.

What is Li-Fraumeni Syndrome (LFS)?

LFS is also called SBLA (sarcoma, breast, leukemia, adrenal gland) disease. It is an autosomal dominant disease, meaning it can still develop if only one parent is affected by the condition.

LFS was first discovered by Li and Fraumeni. In LFS, the affected child inherits a faulty or mutated TP53 gene.. This gene is a tumour suppressor gene (a gene that regulates cell division and prevents uncontrolled cell growth), and its mutation causes an abnormal growth of cancerous cells in the body. Your child may have one of the three variants.

The three variants are LFS1, LFS2, and LFS-L.  LFS1 has a mutated TP53 gene. In LFS2, the mutations develop in another tumour suppressor gene called CHEK2 (checkpoint kinase 2). LFS-L are people who do not have detectable TP53 mutations, but they do suffer from the condition.³

What Causes Li-Fraumeni Syndrome?

TP53 is a tumour suppressor gene present on chromosome 17. This gene has anti-cancer functions in the body. It causes apoptosis (programmed cell death) and inhibits the abnormal division of blood vessels and different cells of the body.³

How can a child develop Li-Fraumeni syndrome?

A child always inherits a pair of genes from their parents.In Li-Fraumeni syndrome, the mutated gene from the affected parent is dominant (only one defective copy is needed), and the other gene gets deleted or also mutated But in the case of Li-Fraumeni, the abnormal gene of the affected parent is dominant (one faulty copy is enough), and the other gene gets deleted or also mutated.

These mutations cause decreased functioning of the TP53 gene and increase the chance of cancerous growth in a child. Children suffering from adrenal gland tumours have the highest chances of having TP53 mutations present.

If an LFS-affected child survives childhood cancers, they still need close monitoring because cancer chances increase as they age.³

How does Li-Fraumeni syndrome affect children?

Children suffering from Li-Fraumeni syndrome are at risk of developing multiple tumours at a young age. The core cancers are:⁴

• Osteosarcoma (bone cancer)
• Soft tissue sarcoma (tumours that develop in muscles and fat in the arms, legs, chest, and belly)
• Breast cancer
• Brain and central nervous system (CNS) tumours such as choroid plexus carcinoma, glioma, and SHH subtype medulloblastoma
• Rhabdomyosarcoma 
• Adrenal gland carcinoma (adrenocortical carcinoma)
• Acute leukemia

Other tumours that may develop are:⁴

• Gastrointestinal  tumours (GIT) (colon and pancreas)
• Lung adenocarcinoma
• Melanoma
• Ovarian and testicular tumours
• Kidney tumors
• Thyroid tumors

According to Cancer Research UK, 1 in 5 children born with Li-Fraumeni syndrome is likely to develop a tumour before their 5th birthday. Children with LFS have a 2 in 5 chance of developing LFS-related tumours before they reach 18 years of age. However, with proper diagnosis and early treatment, we can control the risk of cancer development.⁵

Signs and Symptoms of Li-Fraumeni Syndrome

The child with LFS usually shows symptoms of the cancer they are suffering from. 

Common signs of Li-Fraumeni syndrome in children:³ 

• Brain tumour symptoms—seizures, headaches, and changes in manner of walking
• A breast lump in females with breast cancer
• Soft tissue sarcoma—a soft tissue mass or lump present in muscles or bones
• Acute leukaemia symptoms— pancytopenia (reduced number of all three types of blood cells), fatigue, fever, weight loss, loss of appetite, swollen lymph nodes, and bleeding gums
• Adrenal gland cancer signs—prepubertal hair growth, increased size of penis, enlarged clitoris and deep voice associated with a lump present

How is Li-Fraumeni syndrome diagnosed?

A complete family history of multiple generations is required for a child who has Li-Fraumeni syndrome. It involves thoroughly investigating the cancer history and the types of cancers present in the families to better diagnose the condition. Multiple cancers at a young age are mostly inherited, and a strong family history suggests Li-Fraumeni syndrome.³

A child should be screened for sarcomas, breast, adrenal gland, blood, and brain tumours to better diagnose the condition.³

Genetic counselling and testing for the LFS-affected child

Genetic testing plays a vital role in identifying mutations in the TP53 gene.

With this test, parents can know if a child has a mutated TP53 before the signs of LFS appear. If a mutated TP53 gene appears, then genetic counselling and testing are offered to all the families at risk of developing LFS.³ 

Parents of the affected child are counselled for genetic testing to explain the procedures and also the long-term screening processes of LFS-related cancers that need to be carried out to diagnose the tumours early.³

Diagnostic criteria for Li-Fraumeni Syndrome

Whether to perform genetic testing for TP53 mutations and counselling depends on the following criteria.

Classic Li-Fraumeni Syndrome

The condition is diagnosed when an individual meets all three diagnostic criteria:³

• A sarcoma presents when they are young, before 45
• A parent, child, sibling, or any first-degree relative suffers from a tumour before turning 45
• A sarcoma found at any age in a close family member, like a grandparent, aunt, uncle, or grandchild,  or the onset of cancer, regardless of kind, prior to the age of forty-five 

Chompret criteria

Genetic testing for TP53 mutations is recommended for any affected individual who has a family history that meets at least one of the three specified criteria.

Criteria 1 

• A person affected with LFS tumours before they turn 46. LFS-related tumours include:
  • Soft tissue sarcomas, brain tumours (medulloblastoma, choroid plexus carcinoma), adrenal gland tumour, pre-menopausal breast cancer, osteosarcoma, blood cancer (leukaemia), and lung cancer
• A person with any first-degree (immediate family members) or second-degree relatives (uncle/aunt, niece, etc.) with LFS-related tumours. Except for breast cancer, if the person has it before 56 or with multiple tumours

Criteria 2

• A person with multiple tumours, of which 2 are LFS tumours, and one occurs before they turn 46. Except for multiple breast tumours

Criteria 3 

• A person diagnosed with adrenal gland cancer or brain cancer in the choroid plexus (a membrane that surrounds the brain), whether they have a family history or not⁶

LFL-1, Birch Definition

• A person with any of the 4 LFS tumours (brain tumour, adrenal gland cancer, sarcoma, breast cancer) before the age of 45 
• LFS cancer in a first- or second-degree relative at any age 
• Any cancer in a first- or second-degree relative, before they turn 60³

LFL-2, ELES Criteria

If two close family members have had a type of cancer linked to Li-Fraumeni Syndrome at any age, this may be a sign of the condition. 

It includes:³

• Even if no TP53 gene mutation has been found in the family, people who meet the classical or Chompret guidelines for LFS could still be at risk.  These people may still have LFS even if their test results are negative
• Women with breast cancer without a detectable breast cancer gene (BRCA 1 and BRCA 2) mutation before they turn 31. They tend to develop LFS if there is a positive family history of LFS-related tumours
• Testing should be done on anybody with a family history of TP53 mutations. While a confirmed negative result may lower the likelihood, those who haven't had genetic testing should still be managed as if they have LFS, at least until they reach the age of 50

No matter the age of the kid, if there is a positive family history of these tumours, testing for the TP53 mutation should be done.

• Rhabdomyosarcoma at three years of age
• Osteosarcoma before they are 10
• Sarcoma in childhood, except Ewing's Sarcoma (Yoo-ing sarcoma) 

Prenatal genetic testing should be performed for at-risk pregnancies if a mutated TP53 gene is present.³

Management of children with Li-Fraumeni Syndrome

Management of children with Li-Fraumeni is done by taking a complete family history and performing regular screening for the development of potential LFS tumours.

Cancer screening protocols for children with LFS (birth to 18 years)

General physical exam

• Complete physical exam of the child every 3 to 4 months
• Immediate treatment for any illness by their primary physician

Adrenal gland cancer (adrenocortical carcinoma) management

• Ultrasound of the abdomen and pelvis of the child every 3 to 4 months
• If the ultrasound is not satisfactory, go for blood tests every 3 to 4 months

Brain tumour management

Brain MRI every year (first MRI with contrast and then without contrast if the previous MRI is normal and no new abnormality is seen)

Leukemia 

CBC (Complete blood count) with differential from birth every 3 to 4 months.

Melanoma 

Annual dermatological exam.

Soft tissue or bone cancer management

Whole body MRI without contrast annually.⁷

Treatment of children with Li-Fraumeni Syndrome

Children with LFS cancers are treated for those specific cancers because no standard treatment for LFS is currently available. Radiation therapy is not done by doctors because it can trigger LFS-related cancers. That’s why CT scans and other ionising radiation options are also limited in use due to radiation risk. But if the benefits are more from the radiation therapy, then it can be performed.⁷

Treatment of LFS in a child includes early screening and lifelong prevention. Parents should use sunscreen when outside and apply preventive measures in their child’s daily routine. Having an emotional support system from their family will help the child navigate their illness with positivity. Parents may join other networks of families with LFS support programmes and help each other. The research is ongoing for LFS treatment, and hope is always present.⁷

Summary

Li-Fraumeni syndrome’s other name is SBLA (sarcoma, breast, leukaemia, and adrenal gland cancer) syndrome. It arises when a child's TP53 gene is mutated, leading to abnormal cell proliferation throughout the body. A child can be affected by Li-Fraumeni syndrome if one of their parents suffers from the condition. This syndrome increases the chances of multiple tumours in a child’s body, and regular screening is recommended to treat those cancers.

To date, no specific treatment is available for LFS, but research is ongoing. Treatment is based on the type of cancer the child is suffering from. Regular screening and lifelong prevention are the only solutions. With the help of support from LFS programmes, parents can navigate this situation for their children and help them live a fulfilling life.