A 6-year-old girl presents with progressive reticulated hyperpigmentation and hypopigmentation with telangiectasia affecting the face, buttocks, and extensor surfaces. She has short stature, sparse eyebrows and eyelashes, and a history of juvenile cataracts. Genetic testing confirms biallelic loss-of-function mutations in the gene located at the locus marked **A** in the diagram. Which of the following best explains the pathophysiologic basis for her increased susceptibility to osteosarcoma and cutaneous squamous cell carcinoma?
A. Impaired telomerase activity leading to progressive telomere shortening and replicative senescence
B. Defective DNA helicase function leading to impaired double-strand break repair and chromosomal instability
C. Defective nucleotide excision repair pathway resulting in inability to remove UV-induced thymine dimers
D. Loss of tumor suppressor protein function with inability to arrest cell cycle at G1/S checkpoint
Explanation
Why "Defective DNA helicase function leading to impaired double-strand break repair and chromosomal instability" is right
The RECQL4 gene at chromosome 8q24.3 (marked A) encodes a member of the RecQ family of DNA helicases. Loss-of-function mutations in RECQL4 result in defective DNA helicase activity, which impairs the resolution of stalled replication forks, double-strand break repair, and DNA replication fidelity. This leads to chromosomal instability and accumulation of genomic damage, predisposing to malignancy—particularly osteosarcoma (≈30% lifetime risk) and cutaneous squamous cell carcinoma. This is the direct mechanistic link between RECQL4 deficiency and cancer risk in Rothmund-Thomson syndrome (Robbins 10e Ch 7; Fitzpatrick Dermatology 9e).
Why each distractor is wrong
Loss of tumor suppressor protein function with inability to arrest cell cycle at G1/S checkpoint: This describes TP53 mutations (chromosome 17p13, marked D), which cause Li-Fraumeni syndrome, not Rothmund-Thomson syndrome. While both predispose to osteosarcoma, the mechanism is distinct—TP53 loss impairs apoptosis and cell cycle arrest, whereas RECQL4 loss impairs DNA repair.
Defective nucleotide excision repair pathway resulting in inability to remove UV-induced thymine dimers: This describes xeroderma pigmentosum (XP), caused by mutations in nucleotide excision repair genes. While XP also presents with photosensitivity and cutaneous malignancy, it does not cause the characteristic poikiloderma, skeletal dysplasia, or osteosarcoma risk of RTS.
Impaired telomerase activity leading to progressive telomere shortening and replicative senescence: This describes dyskeratosis congenita, which is caused by mutations in telomerase and related genes. Although dyskeratosis congenita shares some features with RTS (poikiloderma, malignancy risk), the primary mechanism is telomere dysfunction, not DNA helicase deficiency.
High-YieldNEET PG
RECQL4 (RTS) = RecQ helicase → DNA repair defect → chromosomal instability → osteosarcoma + SCC; distinguish from TP53 (Li-Fraumeni), XP (nucleotide excision repair), and dyskeratosis congenita (telomerase).
Robbins 10e Ch 7; Fitzpatrick Dermatology 9e
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