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 characterized by a significantly increased risk of developing various types of cancer at a young age.
• It is associated with a wide spectrum of malignancies, including sarcomas, breast cancer, brain tumours, and adrenocortical carcinoma.
• The syndrome accounts for approximately 1% of all pediatric cancers and significantly impacts affected families.

Aetiology

• Li-Fraumeni Syndrome follows an autosomal dominant inheritance pattern.
• It is primarily caused by mutations in the TP53 gene, a tumour suppressor gene located on chromosome 17 (band 17p13.1).
• The TP53 gene encodes the p53 protein, which plays a critical role in regulating the cell cycle and preventing tumour development. A loss of p53 function leads to unchecked cell proliferation and cancer formation.

Clinical Features – Regular Screening

• Leukemias: Common symptoms include fevers, pancytopenia, fatigue, pallor, bruising, bleeding, and bone pain.
• Sarcomas: Present as a soft tissue mass, typically in the limbs or torso.
• Breast Cancer: A common malignancy in females with LFS. Regular breast self-exams and screening for lumps are recommended.
• Brain malignancies: May present with seizures, headaches, vomiting, and neurological deficits (weakness, sensory loss).
• Adrenal cortical carcinoma: This rare cancer may cause symptoms such as virilization (development of male characteristics in females), deep voice, acne, and abdominal masses.

Diagnostic Criteria

• A proband diagnosed with a sarcoma before age 45 years and
• A first-degree relative with any cancer diagnosed before age 45 years and
• Another first- or second-degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age.

Differential Diagnoses

• Other hereditary cancer syndromes such as Hereditary Breast and Ovarian Cancer Syndrome (BRCA1/BRCA2 mutations) and Familial Adenomatous Polyposis (FAP).
• Ataxia-telangiectasia: Another autosomal recessive condition associated with an increased risk of malignancies.

Investigations

• Specific diagnostic tests are conducted based on the suspected malignancy, such as imaging studies (MRI, CT scans) or biopsies.
• Genetic studies: Testing for mutations in the TP53 gene is used to confirm a diagnosis of Li-Fraumeni Syndrome. Genetic counseling is recommended for affected families.

Management

• Screening Programs: Regular screening programs are essential for early cancer detection in individuals with Li-Fraumeni Syndrome. These may include regular MRI scans for soft tissue sarcomas, brain tumours, and breast cancer screening from an early age.
• Treatment of Malignancies: Identified malignancies are treated based on the cancer type, using surgery, chemotherapy, or radiation therapy.
• Genetic Counseling: Important for families affected by LFS to discuss inheritance patterns and screening options for at-risk relatives.

References

• National Cancer Institute - Li-Fraumeni Syndrome
• Genetics Home Reference - Li-Fraumeni Syndrome