Li-Fraumeni Syndrome Clinical Presentation

  • Author: Kavita Patel, MD; Chief Editor: Max J Coppes, MD, PhD, MBA   more...
 
Updated: Apr 27, 2011
 

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.[8]
  • 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.[9]
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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.
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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.
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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; Co-Associate Program Director of the Signal Transduction Program Area, Jonsson Comprehensive Cancer Center, California Nanosystems Institute and Molecular Biology Institute, University of California, Los Angeles, David Geffen School of Medicine

Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, International Society for Experimental Hematology, 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.

Specialty Editor Board

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 School of Medicine

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.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

Timothy P Cripe, MD, PhD  Professor of Pediatrics, Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center; Clinical Director, Musculoskeletal Tumor Program, Co-Medical Director, Office for Clinical and Translational Research, Cincinnati Children's Hospital Medical Center; Director of Pilot and Collaborative Clinical and Translational Studies Core, Center for Clinical and Translational Science and Training, University of Cincinnati College of Medicine

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.

Samuel Gross, MD  Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; 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  Senior Vice President, Center for Cancer and Blood Disorders, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University School of Medicine; Clinical Professor of Pediatrics, George Washington University School of Medicine and Health Sciences

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.

References

  1. Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. Nov 30 1990;250(4985):1233-8. [Medline].

  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].

  3. Wu H, Pomeroy SL, Ferreira M, Teider N, Mariani J, Nakayama KI, et al. UBE4B promotes Hdm2-mediated degradation of the tumor suppressor p53. Nat Med. Mar 2011;17(3):347-55. [Medline].

  4. Tabori U, Nanda S, Druker H, Lees J, Malkin D. Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer Res. Feb 15 2007;67(4):1415-8. [Medline].

  5. 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].

  6. 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].

  7. Allain DC. Genetic counseling and testing for common hereditary breast cancer syndromes: a paper from the 2007 William Beaumont hospital symposium on molecular pathology. J Mol Diagn. Sep 2008;10(5):383-95. [Medline].

  8. Birch JM, Blair V, Kelsey AM, et al. Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. Oncogene. Sep 3 1998;17(9):1061-8. [Medline].

  9. Birch JM, Hartley AL, Marsden HB, et al. Excess risk of breast cancer in the mothers of children with soft tissue sarcomas. Br J Cancer. Mar 1984;49(3):325-31. [Medline].

  10. Boyle JM, Mitchell EL, Greaves MJ, et al. Chromosome instability is a predominant trait of fibroblasts from Li-Fraumeni families. Br J Cancer. Jun 1998;77(12):2181-92. [Medline].

  11. Cohen RJ, Curtis RE, Inskip PD, Fraumeni JF Jr. The risk of developing second cancers among survivors of childhood soft tissue sarcoma. Cancer. Jun 1 2005;103(11):2391-6. [Medline].

  12. Culler D, Grimes SJ, Acheson LS, Wiesner GL. Cancer genetics in primary care. Prim Care. Sep 2004;31(3):649-83, xi. [Medline].

  13. Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol. Jan 10 2005;23(2):276-92. [Medline].

  14. Hartley AL, Birch JM, Marsden HB, Harris M. Breast cancer risk in mothers of children with osteosarcoma and chondrosarcoma. Br J Cancer. Nov 1986;54(5):819-23. [Medline].

  15. Heyn R, Haeberlen V, Newton WA, et al. Second malignant neoplasms in children treated for rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee. J Clin Oncol. Feb 1993;11(2):262-70. [Medline].

  16. Hisada M, Garber JE, Fung CY, et al. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst. Apr 15 1998;90(8):606-11. [Medline].

  17. Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?. Ann Intern Med. Oct 1969;71(4):747-52. [Medline].

  18. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. Sep 15 1988;48(18):5358-62. [Medline].

  19. Li FP, Garber JE, Friend SH, et al. Recommendations on predictive testing for germ line p53 mutations among cancer-prone individuals. J Natl Cancer Inst. Aug 5 1992;84(15):1156-60. [Medline].

  20. Olivier M, Goldgar DE, Sodha N, et al. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. Oct 15 2003;63(20):6643-50. [Medline].

  21. Peterson SK, Pentz RD, Blanco AM, et al. Evaluation of a decision aid for families considering p53 genetic counseling and testing. Genet Med. Apr 2006;8(4):226-33. [Medline].

  22. Soussi T, Beroud C. Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer. Dec 2001;1(3):233-40. [Medline].

  23. Tsutsui T, Tanaka Y, Matsudo Y, et al. Extended lifespan and immortalization of human fibroblasts induced by X- ray irradiation. Mol Carcinog. Jan 1997;18(1):7-18. [Medline].

 
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