Fanconi anemia is characterized by short stature, cafe au lait spots, thumb/radial defects, and increased risk of tumors; which underlying mechanism is involved?

• A. Bloom syndrome
• B. Li-Fraumeni syndrome
• C. Noonan syndrome
• D. Fanconi anemia

Answer: (D)

Defective DNA repair in the Fanconi anemia pathway explains the findings. Fanconi anemia results from mutations in FANC genes that impair repair of DNA interstrand crosslinks. When these crosslinks occur, cells can’t fix them properly, leading to chromosomal breaks and genomic instability. This instability underlies the congenital abnormalities (such as thumb/radial defects and short stature) and the markedly increased risk of bone marrow failure and malignancy. Diagnostic testing shows heightened chromosomal breakage after exposure to cross-linking agents, highlighting the repair defect. Most cases are autosomal recessive. Other conditions involve different mechanisms—Bloom syndrome from a helicase defect causing high sister chromatid exchange, Li-Fraumeni from TP53 tumor-suppressor mutation, and Noonan from RAS/MAPK pathway mutations—so the defective DNA repair pathway best fits the scenario described.