A 6-month-old boy from a consanguineous family in North India presents with bilateral profound sensorineural hearing loss detected on universal newborn hearing screening. Audiometry shows bilateral symmetric hearing thresholds >90 dB across all frequencies. Tympanometry is normal (type A), and MRI of the temporal bones shows normal cochlear anatomy with intact cochlear nerves. Vestibular testing is normal. The clinical and genetic findings are consistent with the condition marked **A** in the diagram — DFNB3 due to MYO15A mutations. Which of the following best describes the primary pathophysiological mechanism underlying this form of hearing loss?
A. Failure of stereocilia elongation and disorganization of the staircase pattern due to defective myosin XVa-mediated trafficking of whirlin and actin polymerization machinery to stereocilia tips
B. Abnormal potassium recycling through the cochlear lateral wall due to connexin-26 gap junction dysfunction
C. Defective hair cell apoptosis and excessive proliferation leading to cochlear epithelial dysplasia and loss of tonotopic organization
D. Abnormal endolymphatic sac development with enlarged vestibular aqueduct causing mechanical compression of the cochlear duct
Explanation
Why option 1 is correct
MYO15A encodes myosin XVa, an unconventional myosin motor protein essential for trafficking whirlin and other cargo proteins to the stereocilia tips of cochlear and vestibular hair cells. This trafficking is critical for organizing actin polymerization and establishing the characteristic staircase pattern of stereocilia (graded heights from short to tall) required for proper mechanotransduction. Biallelic loss-of-function mutations in MYO15A result in short, disorganized stereocilia in both inner and outer hair cells, leading to failure of mechanotransduction and profound congenital deafness. This is the defining molecular pathology of DFNB3 (Cummings Otolaryngology 7e; Smith RJH GeneReviews — DFNB3 MYO15A 2024).
Why each distractor is wrong
Option 2: This describes the pathophysiology of GJB2-related non-syndromic hearing loss (DFNB1), not MYO15A. Connexin-26 mutations impair K+ recycling through gap junctions in the lateral wall, not stereocilia structure. GJB2 is the most common cause of autosomal recessive SNHL, but the normal tympanometry and imaging here, combined with the genetic anchor, point to MYO15A.
Option 3: This describes Pendred syndrome (SLC26A4 mutations) with enlarged vestibular aqueduct (EVA), marked as B in the diagram. The normal MRI temporal bone anatomy and normal vestibular testing explicitly exclude EVA and syndromic features.
Option 4: Abnormal hair cell apoptosis and proliferation are not the primary mechanism in MYO15A-related hearing loss. The stereocilia structural defect, not epithelial dysplasia, is the hallmark. This distractor conflates developmental anomalies with myosin motor protein dysfunction.
High-YieldNEET PG
MYO15A (DFNB3) is the second most common cause of autosomal recessive non-syndromic SNHL in consanguineous populations (after GJB2) — always suspect it when bilateral profound prelingual SNHL is present with normal temporal bone anatomy and intact vestibular function.
Cummings Otolaryngology 7e; Smith RJH GeneReviews — DFNB3 MYO15A 2024
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