A 2-month-old male infant born to unaffected parents of average stature presents with rhizomelic short limbs, macrocephaly with frontal bossing, and a depressed nasal bridge. The father is 52 years old. Genetic testing confirms achondroplasia. The inheritance pattern marked **B** in the diagram — autosomal dominant with paternal age effect — is the mechanism underlying this case. Which of the following best explains why new mutations in achondroplasia show a strong paternal age effect?
A. Accumulation of mitochondrial mutations in the female germline affecting embryonic development
B. Increased maternal X-chromosome inactivation with advancing maternal age
C. Accumulated replication errors in spermatogonial stem cells during prolonged male gametogenesis
D. Progressive decline in oocyte meiotic checkpoint control in older mothers
Explanation
Why "Accumulated replication errors in spermatogonial stem cells during prolonged male gametogenesis" is right
The strong paternal age effect in achondroplasia (~80% of cases are de novo mutations) is directly explained by the continuous proliferation of spermatogonial stem cells throughout male life. Each cell division introduces opportunity for replication errors; with advancing paternal age, the cumulative number of cell divisions increases dramatically, raising the mutation rate in sperm. This is the textbook mechanism for paternal age-related de novo mutations in achondroplasia (Nelson Pediatrics 21e; GeneReviews Achondroplasia). The mutation typically occurs in the paternal germline during spermatogenesis, not in the oocyte.
Why each distractor is wrong
Increased maternal X-chromosome inactivation with advancing maternal age: Achondroplasia is autosomal dominant (chromosome 4p16 FGFR3 mutation), not X-linked. X-inactivation is irrelevant to this condition and does not explain the paternal age effect.
Progressive decline in oocyte meiotic checkpoint control in older mothers: This describes maternal age effect (seen in Down syndrome and other aneuploidies), not paternal age effect. Achondroplasia shows a paternal, not maternal, age effect because the mutation arises in the male germline.
Accumulation of mitochondrial mutations in the female germline affecting embryonic development: Mitochondrial mutations are maternally inherited and would show a maternal, not paternal, age effect. This is not the mechanism of achondroplasia.
High-YieldNEET PG
Paternal age effect = spermatogonial replication errors; maternal age effect = oocyte meiotic errors. Achondroplasia is paternal.
Nelson Pediatrics 21e; GeneReviews Achondroplasia
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