The phenotype of DFNA13/COL11A2: nonsyndromic autosomal dominant mid-frequency and high-frequency sensorineural hearing impairment

OBJECTIVE: To study nonsyndromic progressive sensorineural hearing impairment in patients with a COL11A2 mutation (DFNA13) in a Dutch kindred. STUDY DESIGN: Survey. SETTING: Department of otorhinolaryngology of a university hospital. PATIENTS: Twenty-one living members of a Dutch family (150 relatives in 5 generations; 49 were studied) with autosomal dominant nonsyndromic sensorineural hearing impairment showed linkage to the DFNA13 locus. Mutation analysis revealed a missense mutation in the COL11A2 gene. METHODS: History was taken, hearing threshold levels were measured in all affected persons, and penetrance was evaluated. Longitudinal analysis (using linear regression analysis of threshold-on-age data) was possible in only 1 case. Cross-sectional analysis comprised the comparison of threshold levels between different generations of the family. Also, hearing thresholds were corrected for median presbyacusis to find out whether the hearing impairment characteristic of this trait is stationary or progressive. Vestibular functions were evaluated with electronystagmography, by use of rotatory and caloric tests. RESULTS: Most of the affected persons dated their first hearing impairment symptoms to the second to third decade of life. A possibly reduced penetrance was found. Anamnestically, 4 affected persons had hearing impairment symptoms from early childhood onward. Longitudinal analysis in the proband (IV26) revealed the exceptional combination of congenital offset and substantial early progression. Most of the threshold levels differed significantly between the frequencies within each age group and, at the high frequencies (2-8 kHz), between the two age groups covered by generations IV and III (ages 30-38 years and 58-74 years, respectively); the latter could be attributed to presbyacusis. Various caloric abnormalities, including areflexia, were found in about half (8/17) of the tested subjects with sensorineural hearing impairment. CONCLUSIONS: Correction for age, hearing impairment-presumably present and stationary from an early age onward-showed the worst or second-worst threshold usually at 1, 2, and 6 kHz (3540 dB) or 8 kHz (50 dB), whereas the best or second-best threshold was found at 0.25 to 0.5 and 4 kHz (25 dB). Presbyacusis, presumably from the fourth decade of life onward, caused a change of the typically shaped audiogram described as midfrequency hearing impairment with additional high-frequency impairment.