Makindo Medical Notes

Related Subjects: | Autosomal Recessive | X Linked Recessive | Autosomal Dominant | Li Fraumeni syndrome | Genetic Linkage | Cell Cycle | DNA replication | Adrenal Cancer

📖 About

• Li-Fraumeni Syndrome (LFS) is a rare inherited condition with markedly increased lifetime risk of diverse cancers, often occurring at young ages. 🧬
• Cancers include soft tissue sarcomas, osteosarcomas, early-onset breast cancer, brain tumours, and adrenocortical carcinoma.
• LFS is responsible for ~1% of all paediatric cancers and has major implications for families due to early onset and multiple primaries.

🧬 Aetiology

• Inheritance: Autosomal dominant pattern with high penetrance.
• Mutation: Germline mutations in the TP53 tumour suppressor gene on chromosome 17p13.1.
• Mechanism: TP53 encodes p53 protein (“guardian of the genome”), regulating DNA repair, apoptosis, and cell-cycle arrest. Loss of function → unchecked proliferation → malignancy.

🩺 Clinical Features & Malignancy Spectrum

• Leukaemia: Presents with pancytopenia, fevers, bruising, bone pain.
• Sarcomas: Soft tissue or bone tumours (osteosarcoma, rhabdomyosarcoma) — often limb or trunk masses.
• Breast Cancer: Very common in women with LFS; onset often <35 yrs. Regular MRI-based screening advised. 🎗️
• Brain tumours: Gliomas, medulloblastomas — seizures, headaches, neurological deficits.
• Adrenocortical carcinoma: May present with virilisation (hirsutism, deep voice), hypertension, or abdominal mass.
• Multiple primaries: Patients often develop >1 distinct cancer during their lifetime.

🧾 Diagnostic Criteria (Classic LFS)

• Proband with a sarcoma <45 years, AND
• A first-degree relative with any cancer <45 years, AND
• Another first/second-degree relative with any cancer <45 years or sarcoma at any age.

🔑 Modified “Chompret criteria” are often used clinically to broaden inclusion.

⚖️ Differential Diagnoses

• Hereditary Breast & Ovarian Cancer (BRCA1/2) – also early breast cancer but lacks sarcoma/brain tumour association.
• Familial Adenomatous Polyposis (FAP) – colorectal polyposis and GI malignancy predominance.
• Ataxia-telangiectasia – recessive, immunodeficiency + ataxia + malignancy risk.

🔍 Investigations

• Genetic testing: Germline TP53 mutation analysis (gold standard).
• Family studies: Testing of at-risk relatives, genetic counselling essential.
• Cancer-specific investigations: Imaging (MRI, CT), biopsy depending on tumour type.

💊 Management & Surveillance

• Surveillance (“Toronto protocol”):
  • Annual whole-body MRI + brain MRI.
  • Breast MRI (not mammogram, due to radiation risk) from age 20 or earlier.
  • Abdominal/pelvic ultrasound every 3–4 months in children to detect adrenal tumours early.
• Treatment of cancers: Standard (surgery, chemo), but ⚠️ radiotherapy avoided/minimised as patients are radiation-sensitive.
• Preventive surgery: Some women consider prophylactic mastectomy due to extreme early breast cancer risk.
• Genetic counselling: Essential for family planning & cascade testing.

📚 References

• National Cancer Institute – Li-Fraumeni Syndrome
• Genetics Home Reference – LFS
• Villani A et al. "Biochemical and imaging surveillance in germline TP53 mutation carriers with LFS." Lancet Oncol 2011.

🧾 Clinical Case Example – Li-Fraumeni Syndrome

A 16-year-old girl presents with a rapidly enlarging, painless lump in her thigh. MRI shows a soft tissue sarcoma. Family history reveals her mother had premenopausal breast cancer at 32, and her maternal grandfather died of a brain tumour in his 40s. Genetic testing confirms a pathogenic mutation in the TP53 tumour suppressor gene. 👉 Diagnosis: Li-Fraumeni syndrome (hereditary cancer predisposition). 👉 Management: Genetic counselling, lifelong surveillance (annual whole-body MRI, breast screening from adolescence), and family testing. Avoid unnecessary radiotherapy due to risk of secondary malignancies.