A 10-month-old female infant presents with seizures that began at 8 months of age, severe developmental delay, and characteristic facial features including a broad beaked nose continuous with a high forehead, widely spaced eyes, and a short philtrum. Karyotype analysis reveals the abnormality marked **A** in the diagram. Which of the following is the MOST appropriate next step in confirming the diagnosis and providing accurate recurrence counseling for the parents?

Explanation

## Why "Obtain chromosomal microarray (CMA) to define exact breakpoints and detect cryptic deletions" is right The clinical presentation—Greek warrior helmet facies (broad beaked nose, hypertelorism, short philtrum), seizures onset 6–12 months, severe intellectual disability, and growth failure—is pathognomonic for Wolf-Hirschhorn syndrome (WHS / 4p- deletion). The abnormality marked **A** is the deletion of the short arm of chromosome 4 (4p-), specifically affecting the WHS critical region (WHSCR-1/WHSCR-2 containing WHSC1/NSD2 and LETM1 genes). While high-resolution karyotype detects ~60% of deletions, **chromosomal microarray (CMA) is the test of choice** because it detects all deletions including cryptic submicroscopic ones and defines exact breakpoints—essential for accurate recurrence risk counseling. Nelson Textbook of Pediatrics 21e and Smith's Recognizable Patterns of Human Malformation 8e both emphasize CMA as the diagnostic gold standard for unexplained intellectual disability with dysmorphism. ## Why each distractor is wrong - **Perform high-resolution karyotype on both parents to exclude balanced translocation**: While parental karyotype is mandatory for recurrence counseling (to detect balanced translocations in ~15% of cases), this step comes AFTER confirming the diagnosis with CMA. CMA is superior because it detects all deletions, including cryptic ones that standard karyotype may miss. The question asks for the next diagnostic step, not the counseling step. - **Perform FISH with WHSCR probe to confirm the classic deletion pattern**: FISH with WHSCR probe is confirmatory for classic deletions but is less comprehensive than CMA. FISH does not detect cryptic submicroscopic deletions and does not define exact breakpoints. CMA provides both confirmation and detailed molecular characterization in a single test. - **Initiate valproate therapy and arrange neurology follow-up without further genetic testing**: While valproate is first-line for seizure control in WHS (seizures respond well to it), this option skips genetic confirmation and parental counseling. Diagnosis must be confirmed before management, and recurrence counseling requires knowledge of the deletion mechanism (de novo vs. inherited translocation). **High-Yield:** CMA is the diagnostic test of choice for any unexplained intellectual disability + dysmorphism; it detects all 4p- deletions and defines breakpoints for accurate recurrence counseling. Parental karyotype is mandatory to exclude balanced translocation (15% of WHS cases). [cite: Nelson Textbook of Pediatrics 21e, Chapter 98; Smith's Recognizable Patterns of Human Malformation 8e]