A 18-month-old boy presents with severe developmental delay, profound hypotonia, and seizures since 6 months of age. On examination, he has microbrachycephaly, straight eyebrows, deep-set eyes, midfacial hypoplasia, and a large anterior fontanelle. Echocardiography reveals left ventricular noncompaction. The structure marked **A** in the diagram is suspected based on this clinical presentation. Which of the following is the MOST COMMON TERMINAL DELETION SYNDROME in humans and the FIRST-LINE diagnostic test to confirm this diagnosis?
A. 4p16.3 deletion (Wolf-Hirschhorn syndrome); conventional karyotype is the first-line test for detecting terminal deletions
B. 5p15.2 deletion (Cri-du-chat syndrome); fluorescence in situ hybridization (FISH) with subtelomeric probes is the first-line diagnostic test
C. 15q11-q13 deletion (Prader-Willi syndrome); chromosomal microarray is used only after karyotype has ruled out other conditions
D. 1p36 deletion syndrome; chromosomal microarray (CMA) is the first-line test that delineates deletion size and gene content with high resolution
Explanation
Why option 1 is right
The clinical presentation—severe intellectual disability with speech impairment, profound hypotonia, seizures (often infantile spasms), distinctive craniofacial features (microbrachycephaly, straight eyebrows, deep-set eyes, midfacial hypoplasia, large anterior fontanelle), and congenital heart defects including left ventricular noncompaction or dilated cardiomyopathy—is pathognomonic for 1p36 deletion syndrome (monosomy 1p36). This is the most common terminal deletion syndrome in humans, with an incidence of 1 in 5,000–10,000 live births, arising de novo in ~95% of cases. The deletion results from loss of contiguous genes including MMP23B and PRDM16 (cardiomyopathy), GABRD and KCNAB2 (seizures), and SKI (clefting and developmental delay). Chromosomal microarray (CMA) is the first-line diagnostic test for unexplained intellectual disability and delineates deletion size and gene content with high resolution, replacing conventional karyotype which detects only larger deletions. FISH with subtelomeric 1p probes is confirmatory but is no longer the primary diagnostic modality. Management includes serial echocardiography for cardiac surveillance, antiepileptic drugs, and multidisciplinary developmental support (Nelson Pediatrics 22e, Ch 100).
Why each distractor is wrong
Option 2 (4p16.3 deletion / Wolf-Hirschhorn syndrome): While Wolf-Hirschhorn syndrome is a well-recognized terminal deletion, it is NOT the most common terminal deletion syndrome. Its incidence is approximately 1 in 50,000 live births—much lower than 1p36 deletion. Additionally, conventional karyotype is not the first-line test; CMA is preferred for diagnostic accuracy.
Option 3 (5p15.2 deletion / Cri-du-chat syndrome): Cri-du-chat syndrome presents with a characteristic cat-like cry, severe intellectual disability, and microcephaly, but the incidence (~1 in 20,000–50,000) is lower than 1p36 deletion. Left ventricular noncompaction is not a cardinal feature. FISH is not the first-line test; CMA is standard.
Option 4 (15q11-q13 deletion / Prader-Willi syndrome): Prader-Willi syndrome (PWS) presents with hypotonia, developmental delay, and hyperphagia, but the distinctive features include short stature, hypogonadism, and characteristic behavioral phenotype (food-seeking behavior, skin-picking). Left ventricular noncompaction is not typical. The statement that CMA is used "only after karyotype has ruled out other conditions" is incorrect; CMA is the first-line test for intellectual disability.
High-YieldNEET PG
1p36 deletion syndrome is the most common terminal deletion syndrome; CMA is the first-line diagnostic test for any unexplained intellectual disability, and cardiac surveillance (especially for cardiomyopathy) is essential for long-term management.
Nelson Pediatrics 22e, Ch 100
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