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Li-Fraumeni Syndrome


Li-Fraumeni syndrome is a rare autosomal dominant genetic ailment that represents a predisposition toward several malignant diseases. Mutations in the tumor protein (TP) 53 tumor suppressor gene are the underlying cause of this syndrome. It is clinically recognized when an individual develops a sarcoma before 45 years of age and has a first-degree relative with any kind of malignancy before 45 years of age. To make a definite diagnosis, molecular genetic studies that confirm TP53 mutations are necessary.


Li-Fraumeni syndrome is rarely encountered in clinical practice, with approximately 500 families described in the medical literature so far [1]. Because of the identified mutations of the TP53 gene (missense, nonsense, frameshift, and splice mutations have all been described), the main component of the presentation is the appearance of one or more malignant tumors before the age of 45 years [2] [3] [4] [5]. Specifically, sarcomas are the predominant tumor type encountered in this patient population [6]. Osteosarcoma is the most common subtype seen in Li-Fraumeni syndrome, followed by rhabdomyosarcoma (embryonal type), which possesses a very low incidence rate (1 in 2.6 million cases) and is predominantly diagnosed in younger children and adolescents [6]. Additional tumors that are regarded as "hallmarks" of Li-Fraumeni syndrome arise from the breast, the brain, the kidneys (adrenal cortical carcinoma, or ACC), and the hematopoietic system (leukemias) [7] [8] [9]. However, studies in the past years have recognized a range of other cancers that develop in Li-Fraumeni syndrome, including those of the gastrointestinal tract (the colon and the stomach), the breast, lungs, prostate, ovaries, pancreas, kidneys (Wilms tumor), but also the skin (melanoma), lymphomas and choroid plexus carcinoma, mainly because of their very young onset in these cases compared to the general population [1] [2].

Cervical Lymphadenopathy
  • On physical examination, a poorly defined, firm mass was noted in the medial upper portion of her right breast, measuring approximately 3 cm, and no axillary or cervical lymphadenopathy was detected.[doi.org]
  • In a Turkish family with the diagnosis of Li-Fraumeni syndrome, we analyzed the mutation pattern of TP53, P57KIP2, P15INK4B, and P16INK4A in the peripheral blood, and loss of heterozygosity (homo/hemizygous deletion) pattern of TP53 and P15INK4B/P16INK4A[ncbi.nlm.nih.gov]
  • Zeynep Karakas, Deniz Tugcu, Aysegul Unuvar, Didem Atay, Arzu Akcay, Hakan Gedik, Hulya Kayserili, Oner Dogan, Sema Anak and Omer Devecioglu, LI-FRAUMENI SYNDROME IN A TURKISH FAMILY, Pediatric Hematology and Oncology, 27, 4, (297), (2010).[doi.org]
  • On physical examination, a poorly defined, firm mass was noted in the medial upper portion of her right breast, measuring approximately 3 cm, and no axillary or cervical lymphadenopathy was detected.[doi.org]
  • The clinical, cytogenetic, and molecular diagnostic data and bone marrow aspirate smears and biopsies on all patients were reviewed. Immunohistochemical staining with antibody to p53 was also performed.[ncbi.nlm.nih.gov]
  • In the analyses of tumor tissues from the propositus and his daughter, a P16INK4A codon 94 missense point mutation (GCG-- GAG; Ala-- Glu) was observed with the hereditary TP53 mutation.[ncbi.nlm.nih.gov]
Neck Mass
  • A 21-year-old woman presented with a left maxillary mucosal lesion and a left neck mass. Biopsies revealed metastatic mucosal melanoma, which is a pathology previously unreported in LFS families.[ncbi.nlm.nih.gov]
  • A 7-year-old boy experiencing a convulsive attack was brought to our institute. He underwent surgical tumor resection, and magnetic resonance imaging of the head revealed a tumor-like lesion in the right parietal lobe.[ncbi.nlm.nih.gov]
  • […] atrophy with contractures, see Spinal muscular atrophy with lower extremity predominance Autosomal dominant congenital stationary night blindness autosomal dominant craniometaphyseal dysplasia, see Craniometaphyseal dysplasia autosomal dominant familial hematuria[ghr.nlm.nih.gov]


The diagnosis of Li-Fraumeni syndrome may be difficult to attain without clinical suspicion. For this reason, the physician must obtain a detailed history that focuses on the age of malignancy onset and if more than one neoplastic disorder is present [4] [5]. A family history is perhaps the crucial component of the patient interview, as the diagnostic criteria mandate the presence of a first-degree relative with any form of malignancy before the age of 45 years and a first or second-degree relative with a malignant disease diagnosed before 45 years of age or a sarcoma recognized at any age [2] [3] [4] [5]. Some authors have established criteria for a "Li-Fraumeni-like" syndrome, which comprise a patient having a childhood cancer (for example, a brain tumor, sarcoma, or adrenocortical carcinoma), a first- or second-degree relative with any of the malignancies that are typical for Li-Fraumeni syndrome, and a first- or second-degree relative with any kind of cancer developing before 60 years of age [7] [10] [11]. When clinical criteria are met and when appropriate histopathological studies confirm the tumor types [7], a more detailed investigation should be employed. To make a definite diagnosis, it is necessary to perform molecular genetic studies that evaluate the TP53 gene and associated mutations [4] [12]. However, only 70% of cases exhibit severe TP53 mutations that are known to cause the disease [4].


  • During AML treatment, detection of LOH of 17p was used as a marker for clonality and treatment control. The mutation was found to be inherited from the proband's mother, who was diagnosed with breast cancer at the age of 48 years.[ncbi.nlm.nih.gov]


  • Prognosis Prognosis depends on the type and severity of cancers developed. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • Patients with LFS may develop MDS, which is most likely therapy-related and is associated with cytogenetic markers of poor prognosis.[ncbi.nlm.nih.gov]
  • The cancers associated with LFS each have a different prognosis and so, an individual's prognosis is highly dependent upon the type of cancer he/she has developed. In some cases, prognosis is associated with how early the cancer has been found.[encyclopedia.com]
  • When that person’s short-term prognosis is poor, or their health is unstable, urgent storage of a blood sample may be prudent. The goal of storing a blood sample is to allow for the possibility of hereditary cancer genetic testing in a family.[bccancer.bc.ca]


  • The deletion in chromosome 12p12 with hereditary p53 mutation should have a critical role in chronic myeloid leukemia-like syndrome etiology in our case.[ncbi.nlm.nih.gov]
  • Etiology LFS is caused by mutations in the tumor suppressor gene TP53 (17p13.1) in about 80% of families with classic LFS.[orpha.net]
  • Questionnaires are administered to gather etiologic risk factor data. Participants are offered the option of undergoing a screening protocol and are followed prospectively.[clinicaltrials.gov]
  • Genetic etiology Li-Fraumeni Syndrome is caused by mutations in p53, a tumor suppressor gene. Sufferers inherit one defective copy of the p53 gene retaining one normal copy.[wikidoc.org]


  • New Jersey, Ewing, NJ, USA. 3 Clinical Genetics Branch (CGB), Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), NIH, DHHS, Rockville, MD, USA.[ncbi.nlm.nih.gov]
Sex distribution
Age distribution


  • Pathophysiology Li-Fraumeni syndrome has been linked to germline mutations of the tumor suppressor gene TP53.[emedicine.com]


  • In addition, there may be a significant psychosocial burden to intensive cancer surveillance and some prevention modalities.[ncbi.nlm.nih.gov]



  1. Malkin D. Li-Fraumeni Syndrome. Levine AJ, ed. Genes Cancer. 2011;2(4):475-484.
  2. Nichols KE, Malkin D, Garber JE, Fraumeni JF Jr, Li FP. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev. 2001;10:83-87.
  3. Olivier M, Goldgar DE, Sodha N, et al. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003;63:6643-6650.
  4. Sorrell AD, Espenschied CR, Culver JO, Weitzel JN. TP53 Testing and Li-Fraumeni Syndrome: Current Status of Clinical Applications and Future Directions. Mol Diagn Ther. 2013;17(1):31-47.
  5. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988;48(18):5358–5362.
  6. Correa H. Li–Fraumeni Syndrome. J Pediatr Genet. 2016;5(2):84-88.
  7. Mai PL, Malkin D, Garber JE, et al. Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet. 2012;205(10):479-487.
  8. Hwang SJ, Lozano G, Amos CI, et al. Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet. 2003;72:975–983.
  9. Garber JE, Goldstein AM, Kantor AF, et al. Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res. 1991;51:6094–6097.
  10. Birch JM, Hartley AL, Tricker KJ, et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994;54:1298–130.
  11. Eeles RA. Germline mutations in the TP53 gene. Cancer Surv. 1995;25:101–124.
  12. Upton B, Chu Q, Li BD. Li-Fraumeni syndrome: the genetics and treatment considerations for the sarcoma and associated neoplasms. Surg Oncol Clin N Am. 2009;18(1):145-56, ix.

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Last updated: 2019-07-11 21:05