A 4-year-old boy born to a consanguineous family presents with congenital bilateral leukocoria and grayish-yellow retrolental masses. Genetic testing confirms Norrie disease (NDP gene mutation at Xp11.4). At age 16 years, he develops progressive high-frequency hearing loss that progresses to bilateral profound sensorineural hearing loss as shown by the audiogram marked **B**. Which of the following best explains the mechanism of hearing loss in this patient?
A. Ototoxicity from prolonged use of aminoglycosides for recurrent ear infections
B. Loss of Norrin-FZD4-LRP5 signaling causing cochlear vascular compromise and stria vascularis dysfunction
C. Conductive ossicular fixation secondary to chronic otitis media with effusion
Mutation in GJB2 gene leading to connexin-26 deficiency in the cochlear epithelium
D.
Explanation
Why "Loss of Norrin-FZD4-LRP5 signaling causing cochlear vascular compromise and stria vascularis dysfunction" is right
Norrie disease is caused by loss-of-function mutations in the NDP gene encoding Norrin, a secreted cysteine-knot growth factor and high-affinity ligand for Frizzled-4 (FZD4) receptor. Norrin-FZD4-LRP5 signaling activates the canonical Wnt/β-catenin pathway, which is essential for retinal and inner ear vascular development. The bilateral profound sensorineural hearing loss marked B in this patient develops in the 2nd–3rd decade due to defective Norrin signaling in the cochlear stria vascularis, leading to vascular compromise and progressive high-frequency hearing loss that advances to profound loss. This is a hallmark feature of Norrie disease affecting 30–50% of patients (GeneReviews — NDP-Related Retinopathies; Nelson Pediatrics 22e).
Why each distractor is wrong
Mutation in GJB2 gene leading to connexin-26 deficiency: GJB2 mutations cause non-syndromic autosomal recessive deafness (DFNB1), not the X-linked syndromic hearing loss seen in Norrie disease. The patient's genetic testing already confirmed NDP mutation, not GJB2.
Ototoxicity from aminoglycosides: While aminoglycosides can cause ototoxicity, there is no clinical history suggesting chronic infection requiring aminoglycoside therapy in this Norrie disease patient. The hearing loss mechanism is vascular, not drug-induced.
Conductive ossicular fixation from chronic otitis media: The audiogram marked B shows bilateral profound sensorineural loss, not conductive loss. Ossicular fixation would produce conductive or mixed hearing loss, not pure sensorineural loss.
High-YieldNEET PG
Norrie disease = X-linked NDP mutation → Norrin-FZD4-LRP5 pathway defect → bilateral congenital blindness + progressive SNHL (30–50% of patients) from cochlear vascular compromise in 2nd–3rd decade.
GeneReviews — NDP-Related Retinopathies (Norrie Disease); Nelson Pediatrics 22e
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