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Genetic and Rare Diseases Information Center (GARD)

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Li-Fraumeni syndrome

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Other Names for this Disease
  • LFS1
  • Li Fraumeni syndrome
  • Sarcoma family syndrome of Li and Fraumeni
  • SBLA syndrome (Sarcoma, Breast, Leukemia, and Adrenal Gland)
Related Diseases
See Disclaimer regarding information on this site. Some links on this page may take you to organizations outside of the National Institutes of Health.

Your Question

How does this syndrome begin in a lineage? Is the TP53 gene mutation a sudden and spontaneous mutation at conception? Does it have environmental causes? Is it a gradual generational erosion of gene integrity finally resulting in the full mutation that causes this syndrome? Are some TP53 genes mutated worse than others? We are trying to trace this through our family tree.

Our Answer

We have identified the following information that we hope you find helpful. If you still have questions, please contact us.

How is Li-Fraumeni syndrome inherited?

Li-Fraumeni syndrome (LFS) is inherited in an autosomal dominant manner.[1] This means that a person only needs a change (mutation) in one copy of the responsible gene in each cell to have LFS. In some cases, an affected person inherits the mutation from an affected parent. Other cases may result from new (de novo) mutations in the gene; these cases occur in people with no history of the disorder in their family. A person with LFS has a 50% chance with each pregnancy of passing along the altered gene to his or her child.
Last updated: 5/4/2015

What causes Li-Fraumeni syndrome?

Approximately 80% of families with the features of Li-Fraumeni Syndrome (LFS) have an identifiable change (mutation) in the TP53 gene.[1] TP53 is a tumor suppressor gene, which means that it encodes a protein that stops cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in TP53 result in a defective protein that is unable to carry out its normal role. This contributes to the development of the many different types of tumors found in LFS.[2]
Last updated: 5/4/2015

How and when might Li-Fraumeni syndrome begin in a family?

Li-Fraumeni syndrome (LFS) is often caused by a change (mutation) inherited from an affected parent. However, some cases may result from new (de novo) mutations in the gene. De novo mutations occur due to random events during the formation of the egg or sperm, or in early fetal development.[3] Given that all mutations must originate at some point, someone is always going to be the first affected person in an affected family. Mutations that cause LFS are not thought to be the result of progressive instability of the disease-causing gene over generations, as is the case with many trinucleotide repeat disorders.
Last updated: 3/11/2015

Are some TP53 mutations worse than others?

Nearly 300 distinct changes (mutations) in the TP53 gene have been described in the literature. The majority are classified as missense mutations; however, other types of mutations have also been identified. Studies suggest that TP53 missense mutations may be associated with an earlier onset of cancer.[1]

To date, researchers have identified two types of genetic variations (not in the TP53 gene) that may modify the behavior of the TP53 gene and affect the course of the condition (referred to as genetic modifiers). One of these modifiers is the MDM2 gene. Having a certain variation in the DNA of MDM2 has been associated with the development of tumors at significantly younger ages. The other proposed modifier is the length of the telomeres (material at the ends of chromosomes that regulate chromosome replication during cell division) of the affected person's chromosomes. Shortened telomere length has also been associated with earlier tumor development in families with Li-Fraumeni syndrome.[1] To view a free article on PubMed that discusses this in detail, click here.

People interested in learning more about the genetic concepts related to Li-Fraumeni syndrome should speak with a genetics professional.
Last updated: 3/11/2015

How can I find a genetics professional in my area?

Genetics clinics are a source of information for individuals and families regarding genetic conditions, treatment, inheritance, and genetic risks to other family members. More information about genetic consultations is available from Genetics Home Reference. To find a genetics clinic, we recommend that you contact your primary healthcare provider for a referral.

The following online resources can help you find a genetics professional in your community:
Last updated: 6/5/2014

References
Other Names for this Disease
  • LFS1
  • Li Fraumeni syndrome
  • Sarcoma family syndrome of Li and Fraumeni
  • SBLA syndrome (Sarcoma, Breast, Leukemia, and Adrenal Gland)
Related Diseases
See Disclaimer regarding information on this site. Some links on this page may take you to organizations outside of the National Institutes of Health.