Paul J. Govaerts

A genotype-phenotype correlation for GJB2 (connexin 26) deafness

Introduction: Mutations in GJB2 are the most common cause of non-syndromic autosomal recessive hearing impairment, ranging from mild to profound. Mutation analysis of this gene is widely available as a genetic diagnostic test. Objective: To assess a possible genotype-phenotype correlation for GJB2. Design: Retrospective analysis of audiometric data from people with hearing impairment, segregating two GJB2 mutations. Subjects: Two hundred and seventy seven unrelated patients with hearing impairment who were seen at the ENT departments of local and university hospitals from Italy, Belgium, Spain, and the United States, and who harboured bi-allelic GJB2 mutations. Results: We found that 35delG homozygotes have significantly more hearing impairment, compared with 35delG/non-35delG compound heterozygotes. People with two non-35delG mutations have even less hearing impairment. We observed a similar gradient of hearing impairment when we categorised mutations as inactivating (that is, stop mutations or frame shifts) or non-inactivating (that is, missense mutations). We demonstrated that certain mutation combinations (including the combination of 35delG with the missense mutations L90P, V37I, or the splice-site mutation IVS1+1G>A, and the V37I/V37I genotype) are associated with significantly less hearing impairment compared with 35delG homozygous genotypes. Conclusions: This study is the first large systematic analysis indicating that the GJB2 genotype has a major impact on the degree of hearing impairment, and identifying mild genotypes. Furthermore, this study shows that it will be possible to refine this correlation and extend it to additional genotypes. These data will be useful in evaluating habilitation options for people with GJB2 related deafness.

Outcome of cochlear implantation at different ages from 0 to 6 years.

Objective To evaluate the outcome of cochlear implantation in young children in relation to the age at implantation. Study Design A retrospective longitudinal and cross-sectional analysis of pediatric cochlear implant patients. Patients All children with congenital deafness who underwent implantation before the age of 6 years (n = 48 for the longitudinal analysis and n = 70 for the cross-sectional analysis) Interventions All children received a multichannel cochlear implant. Main Outcome Measures Categories of Auditory Performance (CAP) score and integration into the mainstream school system. Results For all children, the CAP score increased after implantation. Implantation beyond the age of 4 years hardly ever resulted in normal CAP scores or in integration into the mainstream primary school (20 to 30% of cases). Implantation between the age of 2 and 4 years always resulted in normal CAP scores after 3 years with a 66% probability of integration into the primary school. Implantation before the age of 2 years always resulted in immediate normalization of the CAP scores, with a 90% probability of integration into the mainstream kindergarten, well before entrance into the primary school. Conclusion All children with congenital deafness who underwent implantation before the age of 6 years appeared to benefit from the implant. However, these data add evidence to the importance of early implantation (before the age of 2 years). Intervention before the age of 4 years seemed to be critical to avoid irreversible auditory performance losses, and intervention before the age of 2 years seemed to be critical to achieve optimal results.

Factors Affecting Auditory Performance of Postlinguistically Deaf Adults Using Cochlear Implants: An Update with 2251 Patients

Objective: To update a 15-year-old study of 800 postlinguistically deaf adult patients showing how duration of severe to profound hearing loss, age at cochlear implantation (CI), age at onset of severe to profound hearing loss, etiology and CI experience affected CI outcome. Study Design: Retrospective multicenter study. Methods: Data from 2251 adult patients implanted since 2003 in 15 international centers were collected and speech scores in quiet were converted to percentile ranks to remove differences between centers. Results: The negative effect of long duration of severe to profound hearing loss was less important in the new data than in 1996; the effects of age at CI and age at onset of severe to profound hearing loss were delayed until older ages; etiology had a smaller effect, and the effect of CI experience was greater with a steeper learning curve. Patients with longer durations of severe to profound hearing loss were less likely to improve with CI experience than patients with shorter duration of severe to profound hearing loss. Conclusions: The factors that were relevant in 1996 were still relevant in 2011, although their relative importance had changed. Relaxed patient selection criteria, improved clinical management of hearing loss, modifications of surgical practice, and improved devices may explain the differences.

Pre-, Per- and Postoperative Factors Affecting Performance of Postlinguistically Deaf Adults Using Cochlear Implants: A New Conceptual Model over Time

Objective To test the influence of multiple factors on cochlear implant (CI) speech performance in quiet and in noise for postlinguistically deaf adults, and to design a model of predicted auditory performance with a CI as a function of the significant factors. Study Design Retrospective multi-centre study. Methods Data from 2251 patients implanted since 2003 in 15 international centres were collected. Speech scores in quiet and in noise were converted into percentile ranks to remove differences between centres. The influence of 15 pre-, per- and postoperative factors, such as the duration of moderate hearing loss (mHL), the surgical approach (cochleostomy or round window approach), the angle of insertion, the percentage of active electrodes, and the brand of device were tested. The usual factors, duration of profound HL (pHL), age, etiology, duration of CI experience, that are already known to have an influence, were included in the statistical analyses. Results The significant factors were: the pure tone average threshold of the better ear, the brand of device, the percentage of active electrodes, the use of hearing aids (HAs) during the period of pHL, and the duration of mHL. Conclusions A new model was designed showing a decrease of performance that started during the period of mHL, and became faster during the period of pHL. The use of bilateral HAs slowed down the related central reorganization that is the likely cause of the decreased performance.

Cochlear implantation between 5 and 20 months of age: the onset of babbling and the audiologic outcome.

Objective: The objective of this study was to investigate the onset of prelexical babbling and the audiologic outcome of 10 deaf children who received a cochlear implant (CI) before the age of 20 months. Study Design: A prospective longitudinal observation and analysis. Patients: Ten congenitally deaf infants implanted at an age between 6 and 18 months. Intervention: All children received a Nucleus-24 multichannel cochlear implant. Main Outcome Measures: 1) The onset of babbling defined as a) the first appearance of multiple articulatory movements and b) a canonical babbling ratio of .2 or higher; 2) the babbling spurt defined as a sudden increase of babbled utterances; 3) the audiologic outcome defined by the CAP score (Categories of Auditory Performance) and the results of the A§E (Auditory Speech Sound Evaluation). Results: All children started babbling after a short interval of 1 to 4 months after activation of the device so that the onset of babbling in the youngest subjects occurred at a chronologic age comparable to that of normally hearing infants. The outcomes of the different babbling measures correlated significantly with the age of implantation: the earlier the implantation, the closer the results approached the outcomes of normally hearing infants. The children implanted in their first year of life showed a normal CAP development as early as 3 months after implantation. All CI children were able to discriminate phoneme pairs of the A§E immediately after the fitting of the device. Conclusions: The earlier the implantation took place, the smaller the delay was in comparison with normally hearing children with regard to the onset of prelexical babbling and with regard to auditory performance as measured by CAP.

A Second Gene for Otosclerosis, OTSC2, Maps to Chromosome 7q34-36

Otosclerosis due to abnormal bone homeostasis of the otic capsule is a frequent cause of hearing loss in adults. Usually, the hearing loss is conductive, resulting from fixation of the stapedial footplate, which prevents normal ossicular vibration in response to sound. An additional type of sensorineural hearing loss may be caused by otosclerotic damage to the cochlea. The etiology of the disease is unknown, and both environmental and genetic factors have been implicated. Autosomal dominant inheritance with reduced penetrance has been proposed, but large families are extremely rare. To elucidate the pathogenesis of the disease, identification of the responsible genes is essential. In this study, we completed linkage analysis in a Belgian family in which otosclerosis segregates as an autosomal dominant disease. After excluding linkage to a known locus on chromosome 15 (OTSC1), we found linkage on chromosome 7q, with a multipoint LOD score of 3.54. Analysis of key recombinant individuals maps this otosclerosis locus (OTSC2) to a 16-cM interval on chromosome 7q34-36 between markers D7S495 and D7S2426.

Audiological findings in large vestibular aqueduct syndrome

An enlarged vestibular aqueduct is a congenital disorder causing early onset and progressive hearing loss in children. This paper presents the audiological findings at first presentation and the audiological evolution in 10 consecutive cases presenting with hearing loss and showing a large vestibular aqueduct on imaging. The reported onset of the hearing loss is within the first few years of life. Most of the cases (80%) showed bilateral involvement. The sex ratio was 1. Patients presented on average at age 5 with a median hearing loss of 62 dB at the speech frequencies. The hearing loss was essentially asymmetrical with an interaural difference, of 33 dB and it was a mixed type of hearing loss in 90% of the cases. The authors claim that the conductive component of this hearing loss is a pure cochlear conductive loss which may be pathognomonic for the disease. The presence of a conductive component in a child is easily misinterpreted as a middle ear ventilation problem or in case of good ventilation as an ossicular problem (type otosclerosis). In addition and in contrast to most literature data, the authors did not find evidence for stabilization of the hearing loss but they found a steady decrease of the hearing at an average rate of 4 dB/year.

Statistical Analysis of Otosclerosis Surgery Performed by Jean Marquet

The early and long-term hearing results of 1,681 primary otosclerosis operations performed by the same surgeon, Jean Marquet, were reviewed retrospectively and analyzed with very strict statistical standards. Significantly better short- and long-term results were achieved with the stapedotomy technique compared to total stapedectomy, mainly at the higher frequencies (4 and 8 kHz) important for speech discrimination. Whatever technique was used to open the footplate (micropick, microdrill, or laser), no statistical audiometric difference could be found. The results were equal whether or not the stapedial tendon was preserved. Perioperative problems like pronounced oozing, difficult anatomic relationships, and accidental perilymph aspiration could affect hearing at higher frequencies. The calibrated hole technique was equally as good as conventional oval window sealing in sealing of the fenestra to prevent fistula. The stapedotomy technique was found the safest, having fewer complications.

Cochlear implants in aplasia and hypoplasia of the cochleovestibular nerve

Objective To report on the outcome of four patients with aplasia or hypoplasia of the cochleovestibular nerve who have received a cochlear implant. Study Design Retrospective case review. Setting Tertiary referral center. Patients Four patients with: 1) type I aplasia; 2) type IIa aplasia; 3) type IIa hypoplasia; and 4) type IIb aplasia received a cochlear implant. All patients had corner audiograms even with hearing aids. Intervention Three patients received a LAURA multichannel implant, and one patient received a Nucleus 24 implant. Main Outcome Measure Auditory performance, educational setting. Results The patients with type I and type IIb aplasia did not have auditive perception with their implant and became non-users. Both are now in a total communication educational setting. The patients with type IIa aplasia and hypoplasia had moderate audiological results with the implant with audiometrical thresholds of approximately 40–60 dB HL (pure tone average), moderate phoneme discrimination, and poor word discrimination. One child is in a total communication educational setting and the other in an oral educational setting, but the preferred mode of communication remains total communication for both. Both appear to benefit from the implant nonetheless. Conclusion Patients with aplasia/hypoplasia of the cochleovestibular nerve should be counseled with caution with respect to cochlear implantation, but particular circumstances may justify the intervention. At present these circumstances seem to be a type IIa aplasia or hypoplasia in which the end organ (cochlea or common cavity) still connects to a neural structure on MRI.

Otosclerosis: a genetically heterogeneous disease involving at least three different genes

Otosclerosis is caused by abnormal bone homeostasis of the otic capsule, resulting in hearing impairment in 0.3%-0.4% of the white population. The etiology of the disease remains unclear and environmental as well as genetic factors have been implicated. We localized the first autosomal-dominant locus to chromosome 15 in 1998 (OTSC1) in an Indian family and, recently, we reported the localization of a second gene for otosclerosis to a 16 cM interval on chromosome 7q (OTSC2). In this study, we recruited and analyzed nine additional families (seven Belgian and two Dutch families with 53 affected and 20 unaffected subjects) to investigate the importance of these loci in autosomal-dominant otosclerosis. We completed linkage analysis with three microsatellite markers of chromosome 15 (D15S652, D15S1004, D15S657) and five microsatellite markers of chromosome 7 (D7S495, D7S2560, D7S684, D7S2513, D7S2426). In two families, results compatible with linkage to OTSC2 were found, but in the seven remaining families OTSC1 and OTSC2 were excluded. Heterogeneity testing provided significant evidence for genetic heterogeneity, with an estimated 25% of families linked to OTSC2. These results indicate that, besides OTSC1 and OTSC2, there must be at least one additional otosclerosis locus.