The temporal bone pathologic correlate for conductive hearing loss in this patient with a NOG mutation was circumferentially calcified cartilage bridging the stapedovestibular joint space.
We propose that the decreased binding affinity of NOG with the p.R136C mutation to HSPG leads to an excess of BMP signaling and underlies the SYM1 and conductive hearing loss phenotype of carriers.
Haploinsufficiency of NOG gene has been implicated in the development of conductive hearing loss, skeletal anomalies including symphalangism, contractures of joints, and hyperopia in our patient and may also contribute to the development of tracheo-esophageal fistula and/or esophageal atresia.
These clinical and molecular findings suggest that (1) a broader range of conductive hearing-loss phenotypes are associated with NOG mutations than had previously been recognized, (2) patients with sporadic or familial nonsyndromic otosclerosis should be evaluated for mild features of this syndrome, and (3) NOG alterations should be considered in conductive hearing loss with subtle clinical and skeletal features, even in the absence of symphalangism.