eMedicine Specialties > Pediatrics: General Medicine > Oncology

Li-Fraumeni Syndrome

Kavita Patel, MD, Clinical Postdoctoral Fellow in Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine
Kathleen M Sakamoto, MD, PhD, Professor and Chief, Division of Hematology-Oncology, Vice-Chair of Research, Mattel Children's Hospital at UCLA; Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA and California Nanosystems Institute and Molecular Biology, UCLA; Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories

Updated: Dec 1, 2008

Introduction

Background

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant syndrome in which patients are predisposed to cancer. Li-Fraumeni syndrome is characterized by the wide variety of cancer types seen in affected individuals, a young age at onset of malignancies, and the potential for multiple primary sites of cancer during the lifetime of affected individuals. The following 3 criteria must be met for a diagnosis of Li-Fraumeni syndrome:

1. A proband diagnosed with sarcoma when younger than 45 years
2. A first-degree relative with any cancer diagnosed when younger than 45 years
3. Another first-degree or second-degree relative of the same genetic lineage with any cancer diagnosed when younger than 45 years or sarcoma diagnosed at any age

Most hereditary family cancer syndromes involve 1 or 2 specific tumor types, whereas members of Li-Fraumeni syndrome kindreds are at risk for a wide range of malignancies, with particularly high occurrences of breast cancer, brain tumors, acute leukemia, soft tissue sarcomas, bone sarcomas, and adrenal cortical carcinoma. Several other cancers have been seen at lower rates in Li-Fraumeni syndrome kindreds. Although osteosarcoma and chondrosarcomas occur frequently, no evidence suggests increased occurrence of Ewing sarcoma in association with Li-Fraumeni syndrome. Since Li-Fraumeni syndrome was first characterized in 1969, more than 100 Li-Fraumeni syndrome kindreds have been described.

Pathophysiology

Li-Fraumeni syndrome has been linked to germline mutations of the tumor suppressor gene p53 (TP53). Mutations can be inherited or can arise de novo early in embryogenesis or in one of the parent's germ cells.¹ Subsequent studies analyzing the coding and noncoding portions of TP53 have shown that approximately 70% of Li-Fraumeni syndrome kindreds have constitutional (germline) mutations of 1 of the 2 copies of the TP53 tumor suppressor gene; the second copy is normal.² TP53, which is located on chromosome band 17p13, codes for a 53-kd nuclear protein transcription factor that has important regulatory control over cell proliferation and homeostasis, specifically the cell cycle, DNA repair processes, and apoptosis.

Somatic (nongermline) TP53 tumor suppressor gene mutations are common in sporadic human cancers, suggesting that TP53 alterations play an important role in the development of cancer. Moreover, a broad range of cell line and transgenic animal experiments show direct involvement of TP53 mutations in malignant transformation. Alterations of p53 function are the result of either loss of function of wild type p53, increased or aberrant protein function, or dominant negative effects of the mutated protein. This impairment in p53 function is thought to lead to loss of protection against the accumulation of genetic alterations.

These laboratory data support the hypothesis of constitutional mutations as the etiology of Li-Fraumeni syndrome. Although inactivation of TP53 confers a predisposition to cancer, this alone is not sufficient because not all families with classic Li-Fraumeni syndrome have detectable alterations of TP53. This could be a result of how TP53 alterations are assessed. Previous analyses only measured certain portions of the gene. In addition, the p53 protein may undergo posttranslational alterations. Finally, Li-Fraumeni syndrome can result from defects in other genes that participate in the cell cycle regulatory pathway.

Specifics of the inherited TP53 mutation may have a significant effect on the cancer phenotype in the affected family. Most Li-Fraumeni syndrome–associated TP53 defects involve missense point mutations occurring in a hot-spot region of exons 5-8, a portion of the gene that codes for the core DNA-binding domain of the protein. Missense mutations lead to a stable but inactive protein, which accumulates in the nucleus of tumor cells. Frameshift, nonsense, and splice site mutations can also be present; these do not lead to accumulation of p53 protein.

Kindreds with constitutional mutations in the hot spot region display more aggressive cancer phenotypes than patients with other TP53 mutations and those patients that appear to lack any heritable defect. Families with mutations in the hot spot region include those with younger probands at the time of cancer diagnosis. Mutations in exons 5-8 are also associated with a higher overall incidence in family members with breast cancer and CNS tumors diagnosed when patients are younger than 45 years, suggesting a higher rate of penetrance of the cancer phenotype in families with these types of inherited TP53 defects. Other proposed genetic modifiers that predispose Li-Fraumeni syndrome carriers to develop cancers include the MDM2-SNP309 polymorphism, shorter telomere length and increased genomic DNA copy number variation.^3,4  

A significant portion of Li-Fraumeni syndrome and, particularly, Li-Fraumeni–like (LFL) kindreds do not have demonstrable constitutional TP53 mutations. This suggests that other mechanisms disrupting normal function or defects in other genes may also be involved in familial predisposition to various cancer types.

Frequency

United States

Li-Fraumeni syndrome incidence in the general population is not well identified, but this condition is considered rare. Each year, approximately 5-10 cases of soft tissue sarcoma occur per 1 million children younger than 15 years. Of children with soft tissue sarcomas, 5-10% have family histories of malignancies consistent with Li-Fraumeni syndrome or other syndromes with an autosomal dominant inheritance pattern.

Mortality/Morbidity

The cancers that occur most commonly in members of Li-Fraumeni syndrome kindreds are breast cancer, brain tumors, acute leukemia, soft tissue sarcomas, osteosarcoma, and adrenal cortical carcinoma. Individuals with Li-Fraumeni syndrome have a lifetime cancer risk as high as 85%, with more than half of all tumors occurring before age 30 years.⁵ A significant proportion of affected patients, particularly children, can be successfully treated for the initial cancer but are at significant risk of subsequent development of a second primary malignancy.

Race

No evidence suggests either an ethnic predisposition for Li-Fraumeni syndrome or an increased or decreased frequency based on nationality.

Sex

Li-Fraumeni syndrome has an autosomal dominant inheritance pattern; therefore, the genetic predisposition for cancer equally affects males and females. Females affected by Li-Fraumeni syndrome have almost a 100% lifetime risk of developing cancer compared with 73% for affected males. This discrepancy may be due to the increased incidence of breast cancer in affected females. Almost 90% of affected females develop breast cancer by age 60 years with a majority occurring before age 45 years.⁶ Significantly increased occurrence of breast cancer in males of Li-Fraumeni syndrome kindreds is not reported.

Age

Although approximately 10% of cancers occur in individuals younger than 45 years in the general population, more than one half of the cancers occur in Li-Fraumeni syndrome family members younger than 45 years, even when members who meet clinical criteria for Li-Fraumeni syndrome are excluded.

Clinical

History

• Because of the significantly increased risk of cancer associated with Li-Fraumeni syndrome (LFS), obtaining a thorough family cancer history is very important. The history should screen for all tumor types, with particular attention to soft tissue sarcomas, osteosarcoma, and adrenal cortical carcinoma. Occasionally, family history only becomes positive after several years; therefore, updating the family cancer history in patients with Li-Fraumeni syndrome is important.
• Early age of onset, positive family history, and multiple primary malignancies suggest a hereditary cancer syndrome.
• Birch and colleagues found that the probands in families with significant cancer history are more likely to be males younger than 24 months at time of diagnosis and are more likely have tumors with embryonic histologic findings when compared with other children (not affected by Li-Fraumeni syndrome) diagnosed with soft tissue sarcomas.⁷
• Birch et al showed that mothers of children with soft tissue sarcomas and osteosarcomas have a 3-fold increased risk of developing breast cancer at young ages.⁸

Physical

• No specific physical findings are attributed to individuals affected by Li-Fraumeni syndrome other than the findings related to the presentation of specific cancers, which are summarized as follows:
  • Breast lump (breast cancer)
  • Neurologic changes including seizures, headaches, vomiting, and gait abnormalities (brain cancers)
  • Formation of a soft tissue mass (soft tissue sarcoma) or a bone-related mass (bone sarcoma)
  • Findings of pancytopenia, including pallor, bruising, or bleeding
  • Fever (acute leukemia)
  • Signs of virilization including prepubertal genital hair, clitoromegaly or increased penile size, and acne associated with an abdominal mass (adrenal cortical carcinoma)
• Annual physical examination as part of well child care should be performed. Additional exams may be performed if symptoms arise.
• In patients with an identified p53 mutation, when a tumor may arise is unknown, thus, having a physician with whom one has an established relationship may assist in noting changes in the physical examination.

Causes

• Inheritance of a germline mutation of the TP53 tumor suppressor gene is a predisposing genetic factor in Li-Fraumeni syndrome family members.
• A germline mutation of the checkpoint kinase gene CHK2 may be a predisposing factor in some kindred that do not have TP53 mutations.
• Other risk factors that may significantly contribute to cancer formation have not been identified.

Differential Diagnoses

Other Problems to Be Considered

Families with Li-Fraumeni-like (LFL) syndrome have (1) a proband younger than 45 years with childhood cancer or sarcoma, brain tumor, or adrenal cortical carcinoma; (2) first-degree or second-degree relative with a typical LFL cancer occurring at any age; and (3) another first-degree or second-degree relative in the lineage younger than 60 years diagnosed with any cancer. Only approximately 20% of LFL kindreds have demonstrable germline TP53 mutations. Much less stringent criteria for LFL familial cancer predisposition include 2 first-degree or second-degree relatives with Li-Fraumeni (LFS)-related malignancies (sarcoma, breast cancer, malignant brain tumor, adrenal cortical carcinoma, acute leukemia) at any age.

Breast and ovarian cancer family syndrome with genetic mutations of BRCA1 or BRCA2 may be in the differential diagnosis.

Workup

Laboratory Studies

Evaluation for constitutional TP53 mutation in patients with cancer and a family history or presentation suggestive of potential Li-Fraumeni syndrome (LFS) cancer predisposition is warranted to aid in predicting future risk of other primary malignancies for the patient and other family members.

Although most reported Li-Fraumeni syndrome–related TP53 mutations occur in exons 5-8, optimal DNA analysis should include evaluation of the entire coding and noncoding portions of the gene (exons 1-11) by automated sequencing methods. Because TP53 mutations are constitutional (ie, germline), DNA derived from any clinical source can potentially be evaluated. Peripheral blood leukocytes are the most easily obtained source and are typically collected in citrate or heparin anticoagulant tubes.

Imaging Studies

Mammography screening of females in Li-Fraumeni syndrome kindreds is advocated by some but remains controversial. To be most effective, serial mammograms are initiated at an early age (late teens to early twenties). Some debate surrounds the accuracy of mammographic findings in identifying small masses in the breasts of young women due to increased tissue density. Breast MRI screening beginning at age 20-25 years has also been advocated.

Experimental evidence suggests potential increased cancer risk due to increased adverse effects of ionizing radiation on Li-Fraumeni syndrome cells with TP53 defects.

Treatment

Medical Care

No clear evidence suggests that individuals with Li-Fraumeni syndrome (LFS) diagnosed with cancers should be treated differently than other patients with cancer through the modalities of chemotherapy, radiation, or surgery. However, many studies are being conducted regarding specific mutations, in regards to prognosis and response to therapy. Specifics of therapy are related to the type of cancer.

Based on expert opinions and limited evidence, the National Comprehensive Cancer Network has provided an algorithm for the testing and management of Li-Fraumeni syndrome in adults.

Surgical Care

Prophylactic mastectomy is controversial in the Li-Fraumeni syndrome population, although it may be considered on a case-by-case basis depending on the degree of risk and reconstructive options available.

Consultations

Strongly consider genetic counseling for families with Li-Fraumeni syndrome to ensure appropriate understanding of potential risk and possible evaluation of genetic predisposition markers.

Follow-up

Further Outpatient Care

• Improvements in the treatment of childhood cancers, including acute lymphocytic leukemia, soft tissue sarcomas, and osteosarcomas, have led to long-term survival in most children diagnosed with these cancers. Potential late effects for the survivors include second primary malignancies. These may occur in part because of carcinogenic effects of chemotherapy and radiation therapy; however, they may also be due to genetic predispositions such as constitutional TP53 mutations.
• Clinical evaluation of family members who are potentially affected by Li-Fraumeni syndrome (LFS) is controversial. Although some sources have recommended yearly CBC counts and abdominal ultrasonography in children in Li-Fraumeni syndrome kindreds, no evidence has been established that these or other screening tests significantly improve the ability to diagnose cancer or increase survival rates.
  • Factors that complicate the counseling of patients regarding tumor risk and preventative measures include the wide variety of cancer types that can occur, the lifetime cancer risk, and an incomplete understanding of the variability of penetrance.
  • Prediction of cancer risk is feasible via carrier testing in Li-Fraumeni syndrome kindreds in whom specific constitutional TP53 mutations are documented. Due to ethical considerations, some medical genetics laboratories do not perform testing for TP53 mutations nor do they report TP53 mutations in clinically unaffected minors in families with Li-Fraumeni syndrome. Closely monitor known carriers of TP53 mutations.
  • Individuals who are known to be affected, either because of a history of a previous cancer consistent with Li-Fraumeni syndrome or because they carry a TP53 mutation, should be advised regarding the following: (1) the potential risk of the wide variety of related cancers, (2) the importance of having an established physician or other health care professional who is cognizant of the syndrome involved in ongoing care, and (3) the potential for genetic testing to evaluate potential risk for family members.
  • Individuals who are at risk based on Li-Fraumeni syndrome family history but who have not had cancer and for whom no TP53 mutation information is available should be closely monitored, similar to those with known predilection.

Deterrence/Prevention

• Prophylactic mastectomy decreases the risk of only one type of cancer in women at high risk for several other potentially deadly malignancies.

Prognosis

• Children in families with Li-Fraumeni syndrome who survive an initial cancer have a relative risk of developing a second cancer that is 83 times greater than that of the general population. Patients with Li-Fraumeni syndrome have a predilection for developing subsequent primary tumors (especially sarcomas) in prior radiation fields.
• Cumulative probability of a person affected by Li-Fraumeni syndrome developing a second cancer is 57% at 30 years after developing the first cancer.

Patient Education

• Genetic counseling for at-risk individuals in families with Li-Fraumeni syndrome is important to provide the necessary information to allow decision making regarding TP53 testing, if it is feasible, and to discuss the need for close medical follow-up care.
• Individuals affected by Li-Fraumeni syndrome who are successfully treated for cancer must understand the significant risk of developing further primary malignancies and the need for close medical follow-up care.

Miscellaneous

Medicolegal Pitfalls

• Obtaining a thorough family history with particular emphasis on cancer can be tedious but is an important part of the evaluation of every child diagnosed with a malignancy. Families in which predisposition for cancers is evident should have access to genetic counseling to help provide them with appropriate assessment of risk, delineation of possible interventions or behaviors that can affect risk, and assistance in dealing with the emotional stress associated with the potential of developing cancer.
• Testing for germline TP53 mutations is available, but considerations should be made regarding its use. Use of this test a general screening evaluation in patients with cancer is very limited; however, patients and families with histories consistent with Li-Fraumeni syndrome (LFS) or with presentations of cancer suggestive of a possible germline TP53 mutation should be counseled regarding the accessibility of testing.
  • Initially, testing should be limited to an affected individual (ie, in whom cancer has been diagnosed) to determine if a TP53 mutation is present. Then, subsequent testing of at-risk family members can be limited to the specific mutation previously documented. Most clinical laboratories do not test family members who are minors if they do not have cancer.
  • Prior to testing, ensure that the significance of either a positive or negative result is clear to all patients and relatives. Explain that no simple screening or intervention exists that can eliminate the potential of developing cancer for those who carry the mutation.
• Family members whose test results are negative for the TP53 mutation but for whom the mutation was previously established in an affected relative can be reasonably reassured of a low risk of developing cancer at an early age. However, they should understand that this does not mean they are immune to developing a malignancy at some point. Generally, cancer is a multifactorial condition, and risk may depend on health-related behaviors (eg, cigarette smoking, diet) and other potential genetic factors.
• Patients in families with Li-Fraumeni syndrome who are treated for cancer must be counseled regarding the significant risk of developing other primary malignancies and appropriate follow-up monitoring.

References

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2. Varley JM, McGown G, Thorncroft M, Santibanez-Koref MF, Kelsey AM, Tricker KJ. Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. Cancer Res. Aug 1 1997;57(15):3245-52. [Medline].

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4. Shlien A, Tabori U, Marshall CR, et al. Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome. Proc Natl Acad Sci U S A. Aug 12 2008;105(32):11264-9. [Medline].

5. Le Bihan C, Moutou C, Brugieres L, Feunteun J, Bonaiti-Pellie C. ARCAD: a method for estimating age-dependent disease risk associated with mutation carrier status from family data. Genet Epidemiol. 1995;12(1):13-25. [Medline].

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Keywords

Li-Fraumeni syndrome, LFS, LFL kindred, p53 mutation, Li-Fraumeni–like kindred, germline mutation, p53 tumor suppressor gene mutation, TP53, TP53 tumor suppressor gene mutation, breast cancer, brain tumor, acute leukemia, soft tissue sarcoma, osteosarcoma, adrenal cortical carcinoma, sarcoma, Ewing sarcoma

Contributor Information and Disclosures

Author

Kavita Patel, MD, Clinical Postdoctoral Fellow in Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine
Kavita Patel, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, Phi Beta Kappa, and Texas Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Kathleen M Sakamoto, MD, PhD, Professor and Chief, Division of Hematology-Oncology, Vice-Chair of Research, Mattel Children's Hospital at UCLA; Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA and California Nanosystems Institute and Molecular Biology, UCLA
Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, Society for Pediatric Research, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories
Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Stephan A Grupp, MD, PhD, Director, Stem Cell Biology Program, Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia; Associate Professor of Pediatrics, University of Pennsylvania
Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Timothy P Cripe, MD, PhD, Professor of Pediatric Hematology/Oncology, University of Cincinnati; Director, Translational Research Trials Office, Department of Pediatrics, Cincinnati Children's Hospital Medical Center
Timothy P Cripe, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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