Isabelle Schatteman

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.

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.

Hearing impairment and neurological dysfunction associated with a mutation in the mitochondrial tRNA^{Ser(UCN)} gene

We studied a large Dutch family with maternally inherited, progressive, sensorineural hearing loss in 27 patients. Only in a single family member was the hearing loss accompanied by neurological symptoms including ataxia and dysarthria. DNA analysis of the mitochondrial genome revealed the insertion of a C at nucleotide position 7472 in the tRNASer(UCN) gene (7472insC mutation). We determined the percentage of mutant DNA (heteroplasmy) in blood from all family members, and found no correlation between hearing loss and leucocyte heteroplasmy. The 7472insC mutation was previously identified in a smaller family from Sicily with sensorineural hearing loss in 9 family members, six of them also presenting neurologically with ataxia and myoclonus. The presence of the 7472insC mutation in two different pedigrees strongly supports its pathogenicity. However, the interfamilial difference in penetrance of the neurologic abnormalities is most likely to be strongly influenced by secondary factors different from the 7472insC mutation, as heteroplasmy or age of the patients were similar in both families. This mutation should therefore be analysed in families with maternally inherited hearing loss, irrespective of whether the hearing loss is non-syndromic or accompanied by neurologic abnormalities.

Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations

Abstract. Hereditary hearing impairment is an extremely heterogeneous trait, with more than 70 identified loci. Only two of these loci are associated with an auditory phenotype that predominantly affects the low frequencies (DFNA1 and DFNA6/14). In this study, we have completed mutation screening of the WFS1 gene in eight autosomal dominant families and twelve sporadic cases in which affected persons have low-frequency sensorineural hearing impairment (LFSNHI). Mutations in this gene are known to be responsible for Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), which is an autosomal recessive trait. We have identified seven missense mutations and a single amino acid deletion affecting conserved amino acids in six families and one sporadic case, indicating that mutations in WFS1 are a major cause of inherited but not sporadic low-frequency hearing impairment. Among the ten WFS1 mutations reported in LFSNHI, none is expected to lead to premature protein truncation, and nine cluster in the C-terminal protein domain. In contrast, 64% of the Wolfram syndrome mutations are inactivating. Our results indicate that only non-inactivating mutations in WFS1 are responsible for non-syndromic low-frequency hearing impairment.

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.

A Moroccan family with autosomal recessive sensorineural hearing loss caused by a mutation in the gap junction protein gene connexin 26 (GJB2).

We report a mutation in the connexin 26 gene (Cx26) in a consanguineous Moroccan family linked to the DFNA3/DFNB1 locus on human chromosome 13q11-q12. Affected subjects display congenital, bilateral, sensorineural hearing loss. We have previously identified Cx26 mutations in consanguineous Pakistani families. This current finding indicates that Cx26 mutations are not restricted to ethnically and geographically distinct populations. This is an important observation since it will help to determine the overall contribution of connexin 26 mutations to autosomal deafness in different populations.

Middle and inner ear malformations in velocardiofacial syndrome

Cunningham et al. [2003] recently described a patient with the velocardiofacial syndrome (VCF) and a unilateral congenital conductive hearing loss due to a malformation of the stapes. We want to report our experience with two children with a deletion in chromosome 22q11.2 and hearing loss due to congenital ear malformations. Patient 1 is a girl of 6 years. At a gestational age of 38 weeks, she weighted 3,230 g (50th centile), length was 50.5 cm (50– 75th centile), and head circumference measured 33.5 cm (3rd– 10th centile). Polyhydramnios was noted during the last 4 months of pregnancy. She presented a congenital heart malformation (perimembranous ventricular septal defect (VSD), right aortic arch, bicuspid aortic valve, and a cranial origin of a mildly hypoplastic left pulmonary artery). The heart defect lead to the diagnosis of a microdeletion in chromosome 22q11.2 in the neonatal period. The VSD was surgically corrected at the age of 4 months. Motor developmental milestones were mildly delayed, whereas she had a more pronounced speech and language delay. At the age of 3 years, full scale IQ (determined by means of the SON-R) was 73. She experienced recurrent middle ear infections during infancy, for which ventilation tubes were placed. Bilateral mixed hearing loss was noted, with a Fletcher-index of 33 dB (right side) and 61 dB (left side). CT and MRI of the petrosal bones revealed a Mondini-type cochlea malformation bilaterally (broad basal turn and abnormally short 2nd and apical turns). The vestibular aqueduct was normal on both sides. On the right side, there was an abnormal shape of the ossicles, with fusion of the malleus with the incus and a monopodal stapes. She started wearing hearing aids from age 4 years on the left ear and bilaterally from 5 years of age. Patient 2 is a girl of 11 years. She was born at 40 weeks gestational age after an uneventful pregnancy. She is the oldest of two children of healthy, unrelated parents. Birth weight at term was 3,300 g (50th centile), length 49.5 cm (50the centile), and head circumference 35 cm (50th centile). The diagnosis of a de novo deletion in chromosome 22q11.2 was made during an evaluation for developmental delay at the age of 3 years 8 months. Intelligence testing (Dutch version of Mc Carthy developmental scales) demonstrated a global mental retardation (<50 ( 3 SD), verbal performance 2.9 SD, performal performance 2.7 SD, quantitative performance 2.3 SD, motor performance 2.5 SD) [Van der Meulen and Smrkovsky, 1985]. She had more pronounced speech and language delay. Audiological investigation showed bilaterally absent transient evoked oto-acoustic emissions at a stimulus level of about 90 dB (peak). Click-evoked brainstem auditory responses indicated an overall hearing sensitivity of approximately 30 dB nHL bilaterally. Admittance at 226 Hz revealed a normal tympanometric shape and pressure for both ears though ipsilateral accoustic reflexes at maximum stimulation intensity were absent. Standard threshold audiometry at the age of 4 indicated a bilateral conductive hearing loss with a pure-tone average of 32 and 25 dB HL for left and right ears, respectively. Otoscopy was normal. CT findings of the temporal bones at 5 years of age revealed a congenital middle ear malformation with fixation of the malleus on the left annulus tympanicus. A common cavity was bilaterally present between the vestibule and the lateral semicircular canal (Fig. 1). This entity is sometimes referred to as ‘‘common lateral semicircular canal-utriculosaccular cavity.’’ The left ear was fitted with a hearing aid. She had pronounced velopharyngeal insufficiency treated with a pharyngoplasty at the age of 7.5 years. Full scale IQ (determined by means of the WISC-R) at the age of 8 years was 70 (verbal IQ 84, PIQ 60). Hearing loss is a common manifestation in children with a del22q11.2. In most instances this mild and fluctuating hearing loss is related to recurrent middle ear infections due to velopharyngeal insufficiency. As clearly demonstrated in both cases reported, there are however, instances in which congenital middle and inner ear malformations are found. Whenever unexpectedly major hearing loss is found or a conductive loss appears in the absence of middle ear effusion, imaging is mandatory. In both patients middle ear anomalies were associated with inner ear malformations. This is of interest, since absence of TBX1 expression (causing the major malformations in the del22q11.2 syndrome) in mice also leads to severe defects in both cochlea and vestibulum [Vitelli et al., 2003].

Involvement of T-cell receptor-\beta alterations in the development of otosclerosis linked to **OTSC2**

Otosclerosis is a common form of hearing loss, characterized by disordered bone remodeling in the otic capsule. Within the otosclerotic foci, several immunocompetent cells and immune-modulating factors can be found. Different etiological theories involving the immune system have been suggested. However, a genetic component is clearly present. In large otosclerosis families, seven autosomal-dominant loci have been found, but none of the disease-causing genes has been identified. This study focused on the exploration of the second otosclerosis locus on chromosome 7q34-36 (OTSC2), holding the T-cell receptor beta locus (TRB locus). A significantly lower T-cell receptor-β (TCR-β) mRNA expression and percentage of blood circulating TCR-αβ+ T cells was detected in OTSC2 patients compared with controls and patients with the complex form of the disease. Further analysis illustrated more significant disturbances in specific T-cell subsets, including an increased CD28null cell population, suggesting a disturbed T-cell development and ageing in OTSC2 patients. These disturbances could be associated with otosclerotic bone remodeling, given the known effects of immunocompetent cells on bone physiology. These data implicate the TRB locus as the causative gene in the OTSC2 region and represent an important finding in the elucidation of the disease pathology.

The Use of Malleus Allografts in Ossiculoplasty

Objective To assess the functional performance of remodeled malleus allografts in a malleus‐footplate assembly in terms of hearing results and mid long‐term stability.

Transient Depression of Inner Ear Function after Stapedotomy: Skeeter versus CO2 Laser Technique

Performing stapes surgery for otosclerosis is known to be potentially irreversibly harmful to the inner ear function in about 1% of the cases. An early postoperative transient depression of the bone conduction thresholds is frequently detected after stapes surgery. The purpose of this study was to compare the evolution of bone conduction thresholds after primary stapedotomy with two different techniques: skeeter versus CO(2) laser stapedotomy. Audiological data of 336 otosclerosis operations performed by 2 surgeons between 1997 and 2003 were subjected to analysis. The calibrated hole in the footplate was performed randomly either with the skeeter drill or with the CO(2) laser. Preoperative bone conduction thresholds were compared with the postoperative levels (day 2-3, week 2, week 6 and month 6) in all patients. Evolution of the bone conduction was compared for the two studied subgroups (laser versus skeeter).