A 5-year-old boy presents with bilateral preauricular pits and a history of recurrent drainage from a small opening anterior to the left sternocleidomastoid. Audiometry reveals the pattern marked **A** in the diagram. CT temporal bone shows Mondini dysplasia with enlarged vestibular aqueduct. His father has mild hearing loss and a preauricular pit but no renal disease. Which of the following genetic mutations is most likely responsible for this autosomal dominant syndrome?

Explanation

## Why EYA1 is correct The clinical presentation—bilateral preauricular pits, branchial cleft fistula (anterior to sternocleidomastoid), mixed hearing loss with Mondini dysplasia on imaging, and autosomal dominant inheritance with variable expressivity (father mildly affected, son more severely affected)—is pathognomonic for Branchio-Oto-Renal (BOR) syndrome. The pattern marked **A** (mixed hearing loss with air-bone gap and reduced bone conduction) reflects the combination of conductive loss from ossicular malformations and sensorineural loss from cochlear dysplasia. EYA1 mutations account for ~40% of BOR cases and are the most common genetic cause, encoding a transcription factor critical for second branchial arch, otic placode, and metanephric mesenchyme development. The autosomal dominant inheritance with variable expressivity (50% recurrence, different severity between parent and child) is characteristic of EYA1-mediated BOR (Dhingra ENT 7e, Nelson Pediatrics 21e). ## Why each distractor is wrong - **CFTR**: CFTR mutations cause cystic fibrosis, an autosomal recessive disorder affecting the respiratory and gastrointestinal systems. CF does not present with preauricular pits, branchial cleft anomalies, or the characteristic Mondini dysplasia seen in BOR. Hearing loss in CF is rare and not mixed. - **GJB2**: GJB2 mutations cause non-syndromic sensorineural hearing loss (DFNB1/DFNA3), typically pure SNHL without conductive components, branchial anomalies, or renal involvement. The audiometric pattern would be pure sensorineural loss, not the mixed loss marked **A**. - **Mitochondrial DNA mutations**: Mitochondrial disorders cause progressive sensorineural hearing loss and multisystem involvement (muscle, CNS, cardiac), but not branchial cleft anomalies, preauricular pits, or the characteristic renal malformations of BOR. Inheritance is maternal, not autosomal dominant. **High-Yield:** BOR syndrome = preauricular pits + branchial fistula + mixed hearing loss (Mondini dysplasia) + renal anomalies → EYA1 mutation in ~40% → autosomal dominant with variable expressivity → always screen renal function and imaging. [cite: Dhingra ENT 7e Ch 18; Nelson Pediatrics 21e Ch 656]