Random Dermatology MCQ - Li-Fraumeni Syndrome

A 28-year-old woman is diagnosed with a high-grade pleomorphic sarcoma of the thigh. Her medical history is notable for being treated for breast cancer at age 25. Her father died of a brain tumor at age 40, and her 5-year-old son was recently treated for an adrenocortical carcinoma. What is the most likely underlying genetic defect and the recommended first-line surveillance tool for detecting associated malignancies in this family?

A. Germline mutation in the TP53 tumor suppressor gene; annual whole-body MRI and breast MRI.
B. Germline mutation in the BRCA1 gene; annual breast MRI and mammography.
C. Germline mutation in the RB1 gene; regular ophthalmologic exams.
D. Germline mutation in the APC gene; annual colonoscopy.
E. Germline mutation in the MSH2 gene; annual colonoscopy and endometrial biopsy.

Correct Answer: A. Germline mutation in the TP53 tumor suppressor gene; annual whole-body MRI and breast MRI.

Answer and Explanation

The correct answer is A. This question describes a classic family history meeting the Li-Fraumeni syndrome (LFS) criteria: a proband with a sarcoma before age 45, a first-degree relative with breast cancer before age 50, and another first-degree relative with adrenocortical carcinoma before age 18. LFS is caused by a germline mutation in the TP53 tumor suppressor gene, the "guardian of the genome." Due to the extremely broad tumor spectrum and early age of onset, surveillance is aggressive. The current international consensus recommends annual whole-body MRI (WB-MRI) and annual breast MRI (starting at age 20-25) as the cornerstone of surveillance, as these modalities can detect a wide range of cancers without exposing patients to ionizing radiation.

Why the Other Options are Incorrect:

• B. Germline mutation in the BRCA1 gene: While this causes hereditary breast and ovarian cancer, the tumor spectrum does not typically include childhood adrenocortical carcinoma, sarcomas, or brain tumors at the young ages described.

• C. Germline mutation in the RB1 gene: This causes hereditary retinoblastoma, with a high risk of secondary cancers (osteosarcoma, melanoma), but not the specific constellation of breast cancer, adrenocortical carcinoma, and sarcoma in close relatives.

• D. Germline mutation in the APC gene: This causes Familial Adenomatous Polyposis (FAP), leading to colorectal cancer and other GI tumors, not the spectrum seen here.

• E. Germline mutation in the MSH2 gene: This causes Lynch syndrome, associated with colorectal, endometrial, and other GI/gu cancers, but not childhood adrenocortical carcinoma or sarcomas.

Additional High-Yield Information for Exams:

• Classic Li-Fraumeni Syndrome Criteria:

  • A proband with a sarcoma diagnosed before age 45.

  • A first-degree relative with any cancer before age 45.

  • Another first- or second-degree relative with any cancer before age 45 OR a sarcoma at any age.

• Tumor Spectrum ("The 5 Core Cancers"): The most common LFS-associated malignancies are:

  1. Soft tissue and bone sarcomas

  2. Pre-menopausal breast cancer

  3. Brain tumors (especially choroid plexus carcinoma, glioblastoma)

  4. Adrenocortical carcinoma (ACC) – a hallmark, especially in children.

  5. Acute leukemia

  • Also: Lung adenocarcinoma, gastric cancer, melanoma, and others.

• Genetics: Autosomal dominant inheritance with very high penetrance (~90% by age 60). TP53 mutations are often missense, leading to a dominant-negative effect.

• Differential Diagnosis: Other hereditary cancer syndromes with a broad tumor spectrum (e.g., hereditary retinoblastoma due to RB1, Constitutional Mismatch Repair Deficiency due to biallelic MMR mutations) but the specific combination of sarcoma, young breast cancer, and pediatric ACC is pathognomonic for LFS.

• Prognosis: Extremely high lifetime risk of multiple primary cancers. Prognosis depends on the types and stages of cancers that develop. Early detection through surveillance is paramount.

• Management & Rationale:

  • Rationale: The goal is early cancer detection in a population at risk for a wide array of malignancies, many of which are treatable if caught early. Avoidance of ionizing radiation is a key principle, as it is mutagenic in TP53-deficient cells.

  • First-line Surveillance Protocol (Toronto Protocol or similar):

    • Annual Whole-Body MRI (WB-MRI): From birth or time of diagnosis. To screen for sarcomas, brain tumors, ACC, etc.

    • Annual Breast MRI: For women, starting at age 20-25.

    • Annual Brain MRI: Often included separately or as part of WB-MRI.

    • Annual Abdominal Ultrasound: For children, to screen for ACC.

    • Annual Dermatologic Exam: For melanoma screening.

  • Avoidance: Minimize exposure to ionizing radiation (CT scans, radiographic surveillance) and DNA-damaging agents where possible.

  • Genetic Counseling & Testing: Offered to all at-risk family members.