Li-Fraumeni syndrome
LFS · SBLA syndrome (sarcoma, breast, leukaemia, adrenocortical)
Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition syndrome caused by germline TP53 mutations. It carries an extremely high lifetime cancer risk and an unusually broad tumour spectrum — soft-tissue and bone sarcomas, premenopausal breast cancer, brain tumours, adrenocortical carcinoma, leukaemias and a clearly increased melanoma and skin-cancer risk. Recognition matters for melanoma surveillance, radiotherapy decisions and family-cascade testing.
Genetics
- Autosomal dominant. Germline TP53 on chromosome 17p13.1.
- Lifetime cancer risk ≥70% in men and ≥90-100% in women.
- ~7-20% of cases are de novo.
- LFS-like phenotype occurs with CHEK2 or other DNA-damage-response mutations.
Core tumour spectrum
- Soft-tissue sarcoma (any age).
- Osteosarcoma (childhood / adolescence).
- Premenopausal breast cancer (often before age 30).
- Brain tumours — astrocytoma, glioblastoma, choroid plexus carcinoma, medulloblastoma.
- Adrenocortical carcinoma (childhood); a hallmark for prompting TP53 testing.
- Leukaemia — particularly hypodiploid ALL.
- Increased melanoma, colorectal, gastric and lung cancer risk.
Diagnostic criteria
Classic Li-Fraumeni criteria (Li & Fraumeni, 1988) — all three:
- Proband with a sarcoma before age 45,
- First-degree relative with any cancer before age 45,
- Second additional first- or second-degree relative with any cancer before age 45 or sarcoma at any age.
Chompret criteria (revised 2015) — any one triggers TP53 testing:
- Proband with an LFS-spectrum tumour (sarcoma, premenopausal breast, brain, adrenocortical) before age 46 + ≥1 first/second-degree relative with LFS-spectrum tumour (other than breast if the proband has breast cancer) before age 56 or with multiple primary tumours.
- Proband with multiple primary tumours, at least 2 of which are LFS-spectrum, with the first before age 46.
- Adrenocortical carcinoma, choroid plexus tumour or anaplastic rhabdomyosarcoma at any age.
- Premenopausal breast cancer before age 31 (with negative BRCA testing).
Surveillance
The Toronto protocol (Villani et al., extended 2016) is widely adopted in NHS clinical genetics services. Typical components:
- Whole-body MRI annually from diagnosis (children and adults).
- Brain MRI annually from diagnosis.
- Annual abdominal / pelvic ultrasound or MRI.
- Annual physical and full skin examination — including ENT and dermatologic.
- Annual blood count and biochemistry.
- From age 20-25: breast MRI annually, mammography from age 30; consider risk-reducing mastectomy.
- Annual colonoscopy from age 25.
Practical points
- Avoid radiotherapy where possible — induces second primaries in LFS; surgery preferred over RT for early breast cancer.
- Limit cumulative diagnostic radiation — use ultrasound and MRI in preference to CT.
- Counsel against intense UV exposure; total-body photography / digital dermoscopy if melanoma history.
- Document family history meticulously. Pedigree is the diagnostic instrument.
- Pre-test counselling is essential — implications for siblings and children are profound.
References
- Li FP, Fraumeni JF. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med. 1969;71:747-752.
- Bougeard G et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 2015;33:2345-2352.
- Villani A et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016;17:1295-1305.
- Frebourg T et al. Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet. 2020;28:1379-1386.
- Kratz CP et al. Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin Cancer Res. 2017;23:e38-e45.
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