A 6-year-old boy of Ashkenazi Jewish descent presents with severe short stature (height 100 cm), photosensitive malar telangiectatic erythema, and recurrent sinopulmonary infections. Cytogenetic analysis reveals the abnormality marked **B** in the diagram — quadriradial chromosomal configurations with a 10-fold increase in sister chromatid exchanges. Which of the following molecular defects best explains this cytogenetic finding?
A. Deficiency of FANC proteins involved in nucleotide excision repair and interstrand crosslink resolution
B. Mutation in ATM kinase, leading to impaired checkpoint control and double-strand break sensing
C. Loss of BLM helicase activity, a RECQ-family DNA helicase required for resolving Holliday junctions and replication intermediates
D. Loss of XPA protein function, preventing recognition and removal of UV-induced thymine dimers
Explanation
Why "Loss of BLM helicase activity, a RECQ-family DNA helicase required for resolving Holliday junctions and replication intermediates" is right
Bloom syndrome is caused by biallelic mutations in the BLM gene at 15q26.1, encoding a RECQ-family DNA helicase. Loss of BLM helicase activity prevents proper resolution of Holliday junctions and replication intermediates, directly causing the pathognomonic cytogenetic hallmark shown at B: a 10-fold increase in sister chromatid exchanges (SCE) and quadriradial chromosomal configurations. The clinical presentation—short stature, photosensitive malar telangiectasia, immunodeficiency, and cancer predisposition—is characteristic of Bloom syndrome. Sister chromatid exchange assay (>10 SCE/metaphase vs. normal 5–7) is the gold standard diagnostic test (Nelson 21e Ch. 99).
Why each distractor is wrong
Deficiency of FANC proteins involved in nucleotide excision repair and interstrand crosslink resolution: This describes Fanconi anemia, a different chromosomal instability syndrome. While Fanconi anemia also presents with short stature and cancer predisposition, the cytogenetic hallmark is chromosomal breakage and radial formation (not quadriradials with SCE), and the molecular defect is in the FA/BRCA pathway, not BLM helicase.
Mutation in ATM kinase, leading to impaired checkpoint control and double-strand break sensing: This is the pathophysiology of ataxia-telangiectasia (A-T). Although A-T shares immunodeficiency and cancer predisposition with Bloom syndrome, the hallmark features are cerebellar ataxia, oculomotor apraxia, and telangiectasia of conjunctiva and ears (not malar). The cytogenetic finding in A-T is not SCE/quadriradials but rather chromosomal translocations, particularly involving T-cell receptor and immunoglobulin loci.
Loss of XPA protein function, preventing recognition and removal of UV-induced thymine dimers: This describes xeroderma pigmentosum (XP), a nucleotide excision repair defect. XP presents with severe photosensitivity and skin cancer but lacks the characteristic short stature, immunodeficiency, and SCE/quadriradial cytogenetics of Bloom syndrome. The cytogenetic abnormality is not the hallmark finding in XP.
High-YieldNEET PG
Bloom syndrome = BLM helicase defect + 10-fold increase in SCE + quadriradials on karyotype + malar telangiectasia + short stature + cancer predisposition (median onset age ~25).
Nelson Textbook of Pediatrics 21e, Ch. 99; German Bloom Syndrome Registry 2018
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