A 4-year-old boy born to a 28-year-old mother presents with mild developmental delay (IQ 65), subtle upslanting palpebral fissures, and a single transverse palmar crease. Echocardiography shows a small ventricular septal defect. Peripheral blood karyotype counting 25 cells reveals the pattern shown in the diagram marked **A** — a mixture of normal 46,XY cells and cells with trisomy 47,XY,+21. Which of the following statements best characterizes the pathogenesis and recurrence risk of this condition?

Explanation

## Why "Post-zygotic mitotic nondisjunction in a normal zygote; recurrence risk ~1% (near baseline for maternal age)" is right Mosaic Down syndrome (the pattern marked **A** showing both normal 46,XY and trisomy 47,XY,+21 cell lines) results from post-zygotic mitotic nondisjunction occurring after fertilization of a normal zygote. The nondisjunction event during early mitosis produces one trisomic daughter cell and one monosomic cell (which is typically lost); subsequent cell divisions create a mixed population. Critically, because the zygote was initially normal, this condition is NOT associated with advanced maternal age, and the recurrence risk in future pregnancies is LOW (~1%, near baseline for the mother's age) — there is no parental chromosomal abnormality to transmit. This is the defining feature that distinguishes mosaic Down from the other 95% of Down syndrome cases caused by maternal meiotic nondisjunction (Nelson Textbook of Pediatrics 21e, Chapter 98; Robbins Basic Pathology 10e). ## Why each distractor is wrong - **Maternal meiotic nondisjunction during oogenesis; recurrence risk increases with maternal age in future pregnancies**: This describes standard (non-mosaic) trisomy 21, which accounts for ~95% of Down syndrome cases and IS associated with advanced maternal age. Mosaic Down arises from post-zygotic mitotic nondisjunction, not meiotic nondisjunction, and the zygote began normal, so maternal age is irrelevant to its origin. - **Robertsonian translocation inherited from a carrier parent; recurrence risk ~15% if mother is the carrier**: This describes translocation Down syndrome (~3% of Down cases), where a parent carries a balanced Robertsonian translocation. Recurrence risk is indeed ~15% if the mother is the carrier. Mosaic Down has no parental translocation and a much lower recurrence risk (~1%). - **Trisomic zygote with subsequent loss of extra chromosome 21 in all cells; recurrence risk ~50% due to parental germline mosaicism**: While trisomic rescue (loss of the extra chromosome in some cells of an originally trisomic zygote) is an alternative mechanism for mosaicism, it does not explain the pattern marked **A** and would not result in ~50% recurrence risk. Parental germline mosaicism is not a recognized mechanism for mosaic Down syndrome recurrence; the recurrence risk remains ~1%. **High-Yield:** Mosaic Down = ~2% of all Down syndrome, post-zygotic mitotic nondisjunction, milder phenotype, LOW recurrence risk (~1%), NOT associated with advanced maternal age. Always count ≥20 cells on karyotype to detect mosaicism. [cite: Nelson Textbook of Pediatrics 21e, Chapter 98 (Down Syndrome); Robbins Basic Pathology 10e]