A 6-month-old boy with microcephaly, anteverted nares, 2-3 toe syndactyly, and hypospadias is referred for audiological assessment. The audiogram shows the pattern marked **A** in the diagram. Genetic testing reveals mutations in DHCR7 on chromosome 11q13.4. Which of the following best explains the hearing loss pattern in this patient?
A. Mutation in GJB2 (connexin 26) causing sensorineural hearing loss from cochlear hair cell dysfunction
B. Deficiency of mitochondrial cytochrome c oxidase causing progressive sensorineural hearing loss and lactic acidosis
C. Mutation in SLC26A4 (pendrin) causing sensorineural hearing loss with thyroid dyshormonogenesis
D. Deficiency of 7-dehydrocholesterol reductase causing impaired cholesterol biosynthesis and craniofacial anomalies leading to conductive or mixed hearing loss
Explanation
Why option 1 is correct
Smith-Lemli-Opitz syndrome (SLOS) is caused by mutations in DHCR7, which encodes 7-dehydrocholesterol reductase — the enzyme catalyzing the final step of cholesterol biosynthesis. Deficiency of this enzyme results in elevated 7-dehydrocholesterol and reduced cholesterol, disrupting the Hedgehog signaling pathway critical for craniofacial development. The resulting craniofacial anomalies (cleft palate, micrognathia, narrow bifrontal diameter) and middle ear effusions from these structural defects lead to conductive or mixed hearing loss, which is the pattern marked A in the diagram. This is a cardinal feature of SLOS and directly reflects the biochemical defect and its developmental consequences (Nelson Pediatrics 22e, Ch 107).
Why each distractor is wrong
Option 2 (GJB2/connexin 26): Mutations in GJB2 cause non-syndromic sensorineural hearing loss through cochlear hair cell dysfunction, not conductive/mixed loss. This patient's hearing loss is secondary to craniofacial anomalies from SLOS, not primary cochlear pathology. The clinical presentation (syndactyly, hypospadias, microcephaly) is pathognomonic for SLOS, not GJB2-related deafness.
Option 3 (Cytochrome c oxidase deficiency): Mitochondrial disorders cause progressive sensorineural hearing loss and systemic features like lactic acidosis and developmental regression. This patient's hearing loss is conductive/mixed (not sensorineural), and the biochemical defect is in cholesterol synthesis, not mitochondrial respiration.
Option 4 (SLC26A4/pendrin): Pendrin mutations cause sensorineural hearing loss with thyroid dyshormonogenesis (Pendred syndrome). This patient has conductive/mixed loss from craniofacial anomalies, not sensorineural loss, and no thyroid involvement is mentioned in the SLOS phenotype.
High-YieldNEET PG
SLOS hearing loss is conductive/mixed (from cleft palate and middle ear effusions), not sensorineural — a key distinguishing feature from other genetic syndromes causing deafness.
Nelson Pediatrics 22e, Ch 107
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