Li-Fraumeni syndrome (germline TP53)

Described by Li and Fraumeni (1969); germline TP53 mutations identified 1990 (Malkin). Core cancers: soft-tissue and bone sarcoma, premenopausal breast cancer, brain tumours (choroid plexus carcinoma, medulloblastoma SHH, glioma), adrenocortical carcinoma (~50-80% of childhood ACC carry germline TP53; R337H founder mutation in southern Brazil with 0.3% carrier frequency), leukaemia (hypodiploid ALL), and radiation-induced second cancers (radiotherapy avoided where possible). The 'Toronto protocol' (Villani, Lancet Oncol 2011, 2016) of annual whole-body MRI, brain MRI, breast MRI, ultrasound and biochemical screening detected tumours early and improved survival; now standard (NCCN, AACR 2017 consensus). Risk-reducing mastectomy is offered. Chompret criteria guide testing; ~1 in 5,000-20,000 prevalence; mosaic and low-penetrance variants complicate counselling; clonal haematopoiesis can mimic germline TP53 on blood testing.