Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis

S Usami,N Suzuki,Y Sakurai,S Nishio,T Tono,H Kojima,S Abe

doi:10.1111/j.1399-0004.2011.01831.x

S Usami, N Suzuki + Show 5 more

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https://doi.org/10.1111/j.1399-0004.2011.01831.x

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Abstract

Human noggin (NOG) is a responsible gene for multiple synostosis syndrome (SYNS1) and proximal symphalangism (SYM1), two conditions that are recently known to be within a wider range of clinical manifestations of stapes ankylosis with symphalangism. This study was performed to determine the range of phenotype caused by NOG mutations, using Japanese patients with various phenotypes including sporadic inherited SYM1, dominantly inherited SYM1, stapes ankylosis with broad thumb and toes (Teunissen and Cremer syndrome). In addition, 33 patients with typical otosclerosis (without symphalangism) were studied. Direct sequencing analysis disclosed three novel mutations of the NOG gene in three SYM1 families. None of the otosclerosis patients without symphalangism had NOG mutations, indicating that NOG mutations may be restrictively found within patients with various skeletal abnormalities. These results together with the literature review indicated that there are no clear genotype–phenotype correlations for NOG mutations. With regard to surgical outcome, most of the patients in these three families with NOG mutations showed remarkable air–bone gap recovery after stapes surgery. Molecular genetic testing is useful to differentiate syndromic stapes ankylosis from otosclerosis, and even mild skeletal anomalies can be a diagnostic indicator of NOG-associated disease.

Highlights

Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis
We thought this may be true because (i) within SYM1, NOG mutations were found in patients with minor skeletal anomalies without symphalangism [3], and (ii) stapes ankylosis is an important phenotype of the animal model for
We ascertained three Japanese families to be associated with conductive hearing loss and symphalangism, including an autosomal dominant SYM1 family, a sporadic SYM1 case with normal parents, and an autosomal dominant stapes ankylosis with broad thumb and toes (Teunissen and Cremer syndrome) family

Summary

Conflict of interest

The most common clinical features are the immobility of the proximal interphalangia (PIP) joints of the hands and toes, and congenital conductive hearing loss due to stapes ankylosis. Typical otosclerosis was included in this study because it is an interesting question as to whether some of the typical otosclerosis is a continuum of a category of disease caused by NOG mutations. We thought this may be true because (i) within SYM1, NOG mutations were found in patients with minor skeletal anomalies without symphalangism [3], and (ii) stapes ankylosis is an important phenotype of the animal model for. Previously reported NOG mutations were reviewed to determine their spectrum as well as whether there are any particular genotype–phenotype correlations caused by NOG mutations

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