A 6-year-old child from rural India presents with bilateral profound sensorineural hearing loss detected at age 2 years. Audiometry shows the pattern marked **A** in the diagram. High-resolution temporal bone CT reveals an enlarged vestibular aqueduct (≥1.5 mm) with incomplete partition of the cochlea. Thyroid examination reveals a firm, diffuse goiter. Which of the following genetic and molecular defects best explains this clinical presentation?
A. Biallelic mutations in SLC26A4 encoding pendrin, a chloride/iodide/bicarbonate anion exchanger
B. Biallelic mutations in TECTA encoding α-tectorin, a structural protein of the tectorial membrane
C. Heterozygous mutation in MITOCHONDRIAL 12S rRNA, causing maternal inheritance of hearing loss
Monoallelic mutation in GJB2 encoding connexin 26, a gap junction protein
D.
Explanation
Why biallelic mutations in SLC26A4 encoding pendrin is correct
Pendred syndrome is the most common syndromic cause of congenital sensorineural hearing loss, accounting for up to 10% of hereditary hearing loss. It is autosomal recessive, caused by biallelic mutations in SLC26A4 on chromosome 7q22.3. Pendrin is a multifunctional anion exchanger expressed in the inner ear (maintaining endocochlear potential and endolymph ionic composition), thyroid follicular cells (coupling iodide efflux for thyroid hormone synthesis), and kidney. The classic triad—bilateral profound SNHL (often prelingual), inner ear malformations (enlarged vestibular aqueduct and Mondini dysplasia), and thyroid dysfunction (goiter with organification defect)—is pathognomonic for pendrin deficiency. The patient's presentation of pattern A (bilateral profound SNHL) with EVA and goiter directly reflects pendrin deficiency (Cummings Otolaryngology 7e, Ch 196).
Why each distractor is wrong
Monoallelic mutation in GJB2: GJB2 mutations cause nonsyndromic hearing loss (DFNB1/DFNA3); they do not produce thyroid goiter or inner ear malformations like EVA. Monoallelic variants are typically associated with dominant inheritance, not the recessive pattern with syndromic features seen here.
Biallelic mutations in TECTA: TECTA mutations cause nonsyndromic hearing loss (DFNA8/12); they do not cause thyroid dysfunction, goiter, or the characteristic inner ear malformations (EVA and Mondini dysplasia) seen in this patient.
Heterozygous mitochondrial 12S rRNA mutation: Mitochondrial mutations show maternal inheritance, not autosomal recessive inheritance. Mitochondrial hearing loss is not associated with thyroid goiter or EVA. The family history pattern would be maternal, not consistent with autosomal recessive Pendred syndrome.
High-YieldNEET PG
Pendred syndrome = bilateral SNHL + EVA/Mondini + goiter + SLC26A4 mutations (autosomal recessive); the perchlorate discharge test is classically positive, confirming iodide organification defect.
Cummings Otolaryngology 7e, Ch 196
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