A 7-year-old boy presents with bilateral profound sensorineural hearing loss detected on neonatal screening. Temporal bone MRI shows bilateral enlarged vestibular aqueducts (EVA) with incomplete cochlear partition (Mondini malformation). The structure marked **A** in the diagram demonstrates this classic imaging finding. At age 12, the child develops a palpable neck swelling. Thyroid function tests show normal TSH and fT4, but thyroid ultrasound confirms a diffuse goiter. Which of the following genetic and molecular defects best explains this clinical presentation?
A. X-linked recessive mutation in PCDH15 gene encoding cadherin-related protein causing Usher syndrome with progressive hearing loss and retinitis pigmentosa
B. Autosomal recessive mutation in SLC26A4 gene encoding pendrin, a transmembrane anion exchanger (Cl−/I−/HCO3−) causing defective iodide organification in thyroid and abnormal inner ear development
C. Autosomal recessive mutation in FOXI1 gene causing branchio-oto-renal (BOR) syndrome with hearing loss, preauricular pits, and renal anomalies but normal thyroid function
D. Autosomal dominant mutation in GJB2 gene encoding connexin-26, resulting in profound prelingual hearing loss with normal inner ear anatomy and no thyroid involvement
Explanation
Why option 1 is correct
The clinical triad of bilateral congenital sensorineural hearing loss, enlarged vestibular aqueduct (EVA) with Mondini malformation, and euthyroid goiter developing in late childhood is pathognomonic for Pendred syndrome. This autosomal recessive disorder results from mutations in the SLC26A4 gene (chromosome 7q22.3) encoding pendrin, a transmembrane anion exchanger responsible for chloride, iodide, and bicarbonate transport. In the inner ear, pendrin is expressed in the endolymphatic sac and cochlea; defective pendrin leads to abnormal inner ear fluid homeostasis and structural malformations (EVA, Mondini). In the thyroid, pendrin mediates apical membrane iodide efflux into the colloid; mutations impair iodide organification, causing TSH-driven goiter despite euthyroid status. Pendred syndrome accounts for 7–8% of childhood deafness and is the most common syndromic form of genetic hearing loss. The imaging finding marked A (bilateral SNHL with EVA) is the most consistent diagnostic hallmark.
Why each distractor is wrong
Option 2 (Connexin-26/GJB2): Connexin-26 mutations cause nonsyndromic profound prelingual hearing loss (Connexin-26 accounts for ~50% of autosomal recessive nonsyndromic SNHL). Crucially, GJB2 mutations do NOT produce EVA or thyroid involvement; inner ear anatomy is normal. This distractor tests whether students confuse syndromic vs. nonsyndromic genetic hearing loss.
Option 3 (FOXI1/BOR syndrome): Branchio-oto-renal (BOR) syndrome presents with hearing loss, preauricular pits/sinuses, branchial cysts, and renal anomalies. While BOR can have EVA, it does NOT cause thyroid goiter. Additionally, FOXI1 mutations are associated with digenic inheritance patterns in some Pendred cases, but monoallelic FOXI1 mutations alone do not produce the full Pendred phenotype. This distractor tests confusion between syndromic forms of genetic deafness.
Option 4 (PCDH15/Usher syndrome): Usher syndrome is X-linked or autosomal recessive (PCDH15 mutations) and presents with progressive hearing loss and retinitis pigmentosa (progressive vision loss). There is no EVA, no goiter, and no inner ear malformation. This distractor tests whether students recognize that Usher syndrome is a syndromic form of hearing loss but with a completely different phenotype (ocular involvement, not thyroid).
High-YieldNEET PG
Pendred syndrome = bilateral SNHL + EVA (Mondini) + euthyroid goiter + SLC26A4 mutation; it is the most common syndromic genetic hearing loss in childhood and requires lifelong thyroid monitoring and hearing rehabilitation (cochlear implants often needed).
Cummings Otolaryngology 7e; Smith RJH GeneReviews — Pendred Syndrome 2023
Practice similar questions
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.
