Li-Fraumeni syndrome C80.-

Li-Fraumeni syndrome (LFS) is a rare tumor predisposition syndrome with an increased risk of various tumors that occur in childhood and young adulthood. This diagnosis should be considered in the following clinical constellations:

• premenopausal breast carcinoma, soft tissue sarcoma, osteosarcoma, brain tumor, adrenocortical carcinoma, leukemia, bronchoalveolar lung carcinoma, skin carcinomas before age 46, and at least one first- or second-degree relative with an LFS tumor before age 56 or with multiple tumor diseases (except breast carcinoma if the index patient also has breast carcinoma)
• Multiple tumor disease, two of which are on the LFS tumor spectrum and the first of which occurred prior to 46 LY (excluding metastatic/synchronous breast carcinoma)
• Adrenocortical carcinoma, regardless of family history (FA).
• Choroid plexus carcinoma, regardless of FA
• Rhabdomyosarcoma of embryonal anaplastic subtype, independent of FA
• Breast carcinoma before 31 years of age, regardless of FA

The estimated prevalence is 1:5000-1:20,000.

The cause is mutations in the gene TP53 on chromosome 17p13.1. The protein p53 is significantly involved in the regulation of the cell cycle. P53 plays a role in the arrest (growth arrest) of cell division in the case of radiation-induced DNA damage, for example. If the protein p53 is activated by DNA damage, either programmed cell death(apoptosis) or growth arrest of the cell in the G1 phase occurs. This cell cycle arrest gives the cell the opportunity to repair defective DNA.

In addition, mutations in the CHEK2 gene have also been described in individual families with LFS. However, for this mutation, the causal relationship is not certain.

The pathogenic sequence variants of TP53 include missense mutations (approximately 73%, mostly localized in the DNA-binding domain), nonsense mutations (approximately 9%), splice mutations (approximately 8%), frameshift mutations (6%), deletions, duplications, and other chromosomal rearrangements (Valdez JM et al. 2017).

Already in childhood, autosomal-dominant inherited Li-Fraumeni syndrome (LFS) is characterized by sarcomas, adrenocortical carcinomas and hematological tumors (especially "low hypodiploid" ALL in childhood, AML, MDS, less frequently lymphomas) as well as CNS tumors (astrocytomas, glioblastomas, medulloblastomas, choroid plexus carcinomas).

The late-manifest form of LFS includes soft tissue sarcomas, osteosarcomas, premenopausal breast carcinomas, CNS tumors, melanomas, lung carcinomas, gastrointestinal tumors, thyroid carcinomas, and urogenital carcinomas.

The risk of developing skin cancer in patients with LFS is approximately 14% at a median age of 41 (25-65).

The cumulative risk for skin cancer is 10.4% at age 40, 25.2% at age 60, and 44.6% at age 70. The cumulative risks for melanoma and basal cell carcinoma at age 70 years were significantly increased in a Dutch collective compared with the general population (Nieuwenburg SA et al. 2020).

In therapy, radiotherapy or certain chemotherapeutic agents, especially genotoxic substances such as alkylating agents, lead to a significantly increased risk of secondary diseases (secondary tumors in the radiation field, therapy-associated leukemia/MDS (Petry V et al. 2020). This must be taken into account in the choice of therapy regimen as well as early detection measures.

Early detection examinations in childhood:

• Ultrasound examination of abdomen and pelvis every 3-4 months.
• Laboratory examinations (blood count, ESR, LDH, 17-OH-progesterone, total testosterone, dehydroepiandrosterone sulfate, androstenedione, if possible cortisol determination in 24 h-collection urine) every 3-4 months
• Annual whole body MRI and cranial MRI
• Physical examination with growth parameters,
• Pubertal developmental and neurological examination every 3-4 months
• Dermatological full body examination 1x per year

From adulthood additionally:

• Monthly breast self-examination, clinical palpation examination every six months (from the age of 20-25 years or 5-10 years before the earliest breast cancer in the family)
• Annual MRI examinations of the breast and annual mammography
• Ultrasound examination of abdomen and pelvis every 3-4 months
• Colonoscopy every 2 years (starting at age 25 or 10 years before the earliest age of onset of disease in the family)
• Annual dermatological full body examination

1. Bougeard G et al (2015) RevisitingLi-Fraumeni syndromefromTP53 mutation carriers. J Clin Oncol 33:2345-2352.
2. Giavedoni P et al. (2017) Familial Melanoma Associated with Li-Fraumeni Syndrome and Atypical Mole Syndrome: Total-body Digital Photography, Dermoscopy and Confocal Microscopy. Acta Derm Venereol 97:720-723.
3. May PL et al. (2016) Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer 122:3673-3681.
4. Nieuwenburg SA et al (2020) Cumulative risk of skin cancer in patients with Li-Fraumeni syndrome. Fam Cancer 19:347-351.
5. Petry V et al (2020) Radiotherapy-induced malignancies in breast cancer patients with TP53 pathogenic germline variants (Li-Fraumeni syndrome). Fam Cancer 19:47-53.
6. Valdez JM et al. (2017) Li-Fraumenisyndrome: aparadigmfor theun derstanding of hereditary cancer predisposition. Br JHaematol 176:539-552.