Li-Fraumeni syndrome presenting with de novo TP53 mutation, severe phenotype and advanced paternal age: a case report

Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome caused by pathogenic variants in the gene TP53. This gene codes for the P53 protein, a crucial player in genomic stability, which functions as a tumor suppressor gene. Individuals with LFS frequently develop multiple primary tumors at a young age, such as soft tissue sarcomas, breast cancer, and brain tumors.

A 38 years-old female with a history of femur osteosarcoma, ductal carcinoma of the breast, high-grade breast sarcoma, pleomorphic sarcoma of the left upper limb, infiltrating lobular carcinoma of the breast, gastric adenocarcinoma, leiomyosarcoma of the right upper limb, and high-grade pleomorphic renal sarcoma. Complete molecular sequencing of the TP53 gene showed c.586 C > T (p.R196X) in exon 6, which is a nonsense mutation that produces a shorter and malfunctioning P53. Family history includes advanced father's age at the time of conception (75 years), which has been associated with an increased risk of de novo germline mutations. The patient had seven paternal half-siblings with no cancer history. The patient received multiple treatments including surgery, systemic therapy, and radiotherapy, but died at the age of 38.

Advanced paternal age is a risk factor to consider when hereditary cancer syndrome is suspected. Early detection of hereditary cancer syndromes and their multi-disciplinary surveillance and treatment is important to improve clinical outcomes for these patients. Further investigation of the relationship between the pathogenic variant of TP53 and its phenotype may guide the stratification of surveillance and treatment.