A 6-month-old infant with Apert syndrome undergoes audiological assessment. The audiogram shows the pattern marked **A** in the diagram. Which of the following genetic mutations is MOST likely responsible for this hearing phenotype in this patient?
A. Gain-of-function missense mutation in FGFR2 (p.Ser252Trp or p.Pro253Arg) causing constitutive receptor activation and ossicular fixation with chronic otitis media with effusion
B. Loss-of-function mutation in GJB2 (connexin 26) causing non-syndromic sensorineural hearing loss
C. Haploinsufficiency of SOX9 causing campomelic dysplasia with conductive hearing loss from cartilage abnormalities
D. Mutation in MITOCHONDRIAL DNA causing maternal inheritance pattern with progressive sensorineural hearing loss
Explanation
Why Option 1 is correct
The pattern marked A represents bilateral conductive hearing loss, which is the hallmark audiological finding in Apert syndrome, occurring in approximately 80% of affected individuals. This conductive loss arises from the constitutive FGFR2 activation caused by gain-of-function missense mutations (p.Ser252Trp in 66% and p.Pro253Arg in 33% of cases) that dysregulate skeletal development. The mutations specifically affect the linker region between the IgII and IgIII immunoglobulin-like domains of FGFR2, leading to chronic otitis media with effusion, ossicular fixation (particularly stapes footplate ankylosis), and narrow ear canals—all hallmarks of the conductive pathology in Apert syndrome. This is the defining genetic basis of Apert syndrome as an autosomal dominant craniosynostosis.
Why each distractor is wrong
Option 2: GJB2 mutations cause non-syndromic sensorineural hearing loss (DFNB1/DFNA3), not conductive loss. These mutations do not produce the craniofacial, limb, or skeletal features of Apert syndrome and would result in a sensorineural rather than conductive audiogram pattern.
Option 3: SOX9 mutations cause campomelic dysplasia, a distinct skeletal dysplasia with different phenotypic features (sex reversal, limb bowing, micrognathia) and conductive loss from cartilage abnormalities—not the ossicular fixation and OME pathophysiology of Apert syndrome.
Option 4: Mitochondrial DNA mutations produce maternal inheritance and progressive sensorineural hearing loss, not the bilateral conductive loss pattern seen in Apert syndrome. Apert syndrome is autosomal dominant with FGFR2 nuclear mutations.
High-YieldNEET PG
Apert syndrome = FGFR2 gain-of-function (p.Ser252Trp or p.Pro253Arg) → conductive hearing loss from ossicular fixation and OME in 80% of cases; pure SNHL is rare in Apert.
Cummings Otolaryngology 7e, Ch 197
Practice similar questions
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.
