Li–Fraumeni syndrome

Overview

Li–Fraumeni syndrome (LFS) is a rare, inherited genetic disorder that significantly increases the risk of developing several types of cancer, often at a young age. Individuals with LFS are predisposed to a broad spectrum of cancers, including breast cancer, soft tissue sarcomas, brain tumors, adrenocortical carcinoma, and leukemias. The syndrome follows an autosomal dominant inheritance pattern and is characterized by early-onset malignancies, multiple primary tumors, and a strong family history of cancer. Vigilant surveillance and early intervention are key to managing the risks associated with LFS.

Causes

Li–Fraumeni syndrome is caused by mutations in the TP53 gene, which encodes the tumor protein p53. This protein plays a crucial role in regulating the cell cycle, DNA repair, and apoptosis (programmed cell death), acting as a tumor suppressor. When TP53 is mutated, its ability to prevent abnormal cell growth is compromised, leading to an increased likelihood of tumor development. Inherited TP53 mutations account for the majority of LFS cases, though some cases may arise from de novo (new) mutations without a family history.

Symptoms

Li–Fraumeni syndrome does not cause specific physical symptoms but manifests through a pattern of early and recurrent cancers. Common clinical features include:

• Early-onset cancer – particularly before age 45

• Multiple primary cancers – occurring in the same individual over time

• Family history of diverse cancers – often affecting multiple generations

The most commonly associated cancers include:

• Breast cancer (especially premenopausal)

• Soft tissue and bone sarcomas

• Brain tumors (e.g., glioblastomas, astrocytomas)

• Adrenocortical carcinoma

• Leukemia

• Lung, colon, and pancreatic cancers (in some cases)

Diagnosis

Diagnosis of Li–Fraumeni syndrome is based on clinical criteria, family history, and genetic testing. Diagnostic steps include:

• Chompret Criteria – clinical guidelines used to identify individuals who should undergo TP53 testing

• Genetic testing – identification of a pathogenic TP53 gene mutation confirms the diagnosis

• Family history analysis – documenting patterns of cancer across generations

Testing is recommended for individuals with early-onset cancers and a suggestive family history. Genetic counseling is essential prior to testing to help interpret results and guide family planning.

Treatment

Treatment of cancers in individuals with Li–Fraumeni syndrome follows standard oncology protocols, but special considerations are taken due to increased sensitivity to radiation and risk of secondary tumors. Management strategies include:

• Standard cancer therapies – including surgery and chemotherapy, tailored to the specific tumor type

• Minimizing radiation exposure – due to higher risk of radiation-induced cancers in LFS patients

• Intensive cancer screening – including whole-body MRI, regular breast imaging (MRI over mammogram), colonoscopy, and dermatologic exams

• Risk-reducing surgeries – such as prophylactic mastectomy in high-risk individuals

• Genetic counseling and family screening – for at-risk relatives

Prognosis

The prognosis for individuals with Li–Fraumeni syndrome depends on the types and stages of cancers they develop. While LFS increases the lifetime cancer risk significantly up to 70-90% in females and 50-70% in males, early detection through proactive surveillance can improve outcomes. With modern screening protocols and personalized care plans, many individuals with LFS can manage their cancer risks effectively and maintain a good quality of life. Ongoing research and clinical trials aim to improve prevention strategies and treatment outcomes for those affected by this high-risk genetic syndrome.