A 6-month-old girl is referred from the newborn hearing screening programme after failing the auditory brainstem response (ABR) test. Audiometry shows bilateral symmetric moderate-profound sensorineural hearing loss (SNHL) as marked **A** in the diagram. The child has no associated syndromic features, normal vestibular function, and normal otoscopy. Genetic testing confirms a homozygous GJB2 mutation (Connexin-26). Which of the following best explains the pathophysiology of hearing loss in this child?

Explanation

## Why "Loss of gap-junction protein function in the cochlear lateral wall leading to impaired potassium recycling and outer hair cell death" is right GJB2 encodes Connexin-26, a transmembrane gap-junction protein expressed in non-sensory cells of the cochlear lateral wall (stria vascularis and supporting cells). Connexin-26 forms hexameric connexons that are essential for potassium recycling from hair cells back to the endolymph after mechanotransduction. Loss of function due to mutation results in potassium accumulation (potassium toxicity) in the perilymphatic space surrounding outer hair cells, leading to their death and bilateral symmetric SNHL. This is the established pathophysiological mechanism of GJB2-related hearing loss (Dhingra 7e, Ch 17; Nelson Pediatrics 22e, Ch 663). ## Why each distractor is wrong - **Mutation in the gene encoding myosin VIIA causing disruption of stereocilia structure and hair cell apoptosis**: This describes MYO7A mutations, which cause Usher syndrome (syndromic SNHL with retinitis pigmentosa). The clinical presentation here explicitly excludes syndromic features and normal vestibular function, ruling out Usher syndrome. - **Defective iodine organification in the thyroid gland with secondary endolymphatic hydrops and cochlear collapse**: This describes Pendred syndrome (SLC26A4 mutations), which presents with bilateral SNHL + thyroid goiter + hypothyroidism. The absence of thyroid disease and syndromic features excludes Pendred syndrome. - **Abnormal development of the stria vascularis with primary melanocyte dysfunction and progressive endolymphatic acidosis**: This describes Jervell-Lange-Nielsen syndrome (KCNQ1/KCNE1 mutations), which presents with congenital bilateral SNHL + prolonged QT interval + cardiac arrhythmia risk. The absence of cardiac involvement and syndromic features excludes this diagnosis. **High-Yield:** GJB2 mutations → bilateral symmetric congenital SNHL + no syndromic features + normal vestibular function = test GJB2 first; pathophysiology is potassium recycling failure, not structural malformation or metabolic defect. [cite: Dhingra Diseases of Ear Nose & Throat 7e Ch 17; Nelson Pediatrics 22e Ch 663]