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OBJECTIVES: This is a report of the audiological and vestibular characteristics of a Dutch DFNA9 family with a novel mutation, I109T, in the LCCL domain of COCH. METHODS: From the family with the novel I109T COCH mutation, audiometric data were collected and analyzed longitudinally. Results were compared to those obtained in previously identified P51 S, G88E, and G87W COCH mutation carriers. Special attention was also given to a comparison of age-related features such as progressive hearing loss and vestibular impairment. RESULTS: A novel mutation (I109T) in COCH segregates with hearing impairment and vestibular dysfunction in the present family. Pure tone thresholds, phoneme recognition scores, and vestibular responses of the I109T mutation carriers were essentially similar to those previously established in P51S, G87W, and G88E mutation carriers. Deterioration of hearing in the I109T mutation carriers started at 43 years of age, and vestibular function deteriorated at least 7 years later. CONCLUSIONS: The phenotype associated with the novel COCH (I109T) mutation is largely similar to that associated with P51S and G88E mutation carriers. However, subtle differences in terms of onset age and rate of progression seem to exist. [ABSTRACT FROM AUTHOR]

Objective: Non-syndromic sensorineural hearing impairment is inherited in an autosomal recessive fashion in 75-85% of cases. To date, 61 genes with this type of inheritance have been identified as related to hearing impairment, and the genetic heterogeneity is accompanied by a large variety of clinical characteristics. Adequate counselling on a patient's hearing prognosis and rehabilitation is part of the diagnosis on the genetic cause of hearing impairment and, in addition, is important for the psychological well-being of the patient., Type of Review: Traditional literature review., Data Source: All articles describing clinical characteristics of the audiovestibular phenotypes of identified genes and related loci have been reviewed., Conclusion: This review aims to serve as a summary and a reference for counselling purposes when a causative gene has been identified in a patient with a non-syndromic autosomal recessively inherited sensorineural hearing impairment., (© 2015 John Wiley & Sons Ltd.)

Objectives: Usher syndrome is an inherited disorder that is characterized by hearing impairment (HI), retinitis pigmentosa, and in some cases vestibular dysfunction. Usher syndrome type IIa is caused by mutations in USH2A. HI in these patients is highly heterogeneous and the present study evaluates the effects of different types of USH2A mutations on the audiometric phenotype. Data from two large centres of expertise on Usher Syndrome in the Netherlands and Sweden were combined in order to create a large combined sample of patients to identify possible genotype-phenotype correlations., Design: A retrospective study on HI in 110 patients (65 Dutch and 45 Swedish) genetically diagnosed with Usher syndrome type IIa. We used methods especially designed for characterizing and testing differences in audiological phenotype between patient subgroups. These methods included Age Related Typical Audiograms (ARTA) and a method to evaluate the difference in the degree of HI developed throughout life between subgroups., Results: Cross-sectional linear regression analysis of last-visit audiograms for the best hearing ear demonstrated a gradual decline of hearing over decades. The congenital level of HI was in the range of 16-33 dB at 0.25-0.5 kHz, and in the range of 51-60 dB at 1-8 kHz. The annual threshold deterioration was in the range of 0.4-0.5 dB/year at 0.25-2 kHz and in the range of 0.7-0.8 dB/year at 4-8 kHz. Patients with two truncating mutations, including homozygotes for the common c.2299delG mutation, developed significantly more severe HI throughout life than patients with one truncating mutation combined with one nontruncating mutation, and patients with two nontruncating mutations., Conclusions: The results have direct implications for patient counselling in terms of prognosis of hearing and may serve as baseline measures for future (genetic) therapeutic interventions., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To present audiometric data in 3 dimensions by considering age as an addition dimension., Methods: Audioprofile surfaces (APSs) were fitted to a set of audiograms by plotting each measurement of an audiogram as an independent point in 3 dimensions with the x, y, and z axes representing frequency, hearing loss in dB, and age, respectively., Results: Using the Java-based APS viewer as a standalone application, APSs were pre-computed for 34 loci. By selecting APSs for the appropriate genetic locus, a clinician can compare this APS-generated average surface to a specific patient's audiogram., Conclusion: Audioprofile surfaces provide an easily interpreted visual representation of a person's hearing acuity relative to others with the same genetic cause of hearing loss. Audioprofile surfaces will support the generation and testing of sophisticated hypotheses to further refine our understanding of the biology of hearing., (© The Author(s) 2015.)

Objectives: MYH9-related disease (MYH9-RD) is an autosomal- dominant disorder deriving from mutations in MYH9, the gene for the nonmuscle myosin heavy chain (NMMHC)-IIA. MYH9-RD has a complex phenotype including congenital features, such as thrombocytopenia, and noncongenital manifestations, namely sensorineural hearing loss (SNHL), nephropathy, cataract, and liver abnormalities. The disease is caused by a limited number of mutations affecting different regions of the NMMHC-IIA protein. SNHL is the most frequent noncongenital manifestation of MYH9-RD. However, only scarce and anecdotal information is currently available about the clinical and audiometric features of SNHL of MYH9-RD subjects. The objective of this study was to investigate the severity and propensity for progression of SNHL in a large series of MYH9-RD patients in relation to the causative NMMHC-IIA mutations., Design: This study included the consecutive patients diagnosed with MYH9-RD between July 2007 and March 2012 at four participating institutions. A total of 115 audiograms were analyzed from 63 patients belonging to 45 unrelated families with different NMMHC-IIA mutations. Cross-sectional analyses of audiograms were performed. Regression analysis was performed, and age-related typical audiograms (ARTAs) were derived to characterize the type of SNHL associated with different mutations., Results: Severity of SNHL appeared to depend on the specific NMMHC-IIA mutation. Patients carrying substitutions at the residue R702 located in the short functional SH1 helix had the most severe degree of SNHL, whereas patients with the p.E1841K substitution in the coiled-coil region or mutations at the nonhelical tailpiece presented a mild degree of SNHL even at advanced age. The authors also disclosed the effects of different amino acid changes at the same residue: for instance, individuals with the p.R702C mutation had more severe SNHL than those with the p.R702H mutation, and the p.R1165L substitution was associated with a higher degree of hearing loss than the p.R1165C. In general, mild SNHL was associated with a fairly flat audiogram configuration, whereas severe SNHL correlated with downsloping configurations. ARTA plots showed that the most progressive type of SNHL was associated with the p.R702C, the p.R702H, and the p.R1165L substitutions, whereas the p.R1165C mutation correlated with a milder, nonprogressive type of SNHL than the p.R1165L. ARTA for the p.E1841K mutation demonstrated a mild degree of SNHL with only mild progression, whereas the ARTA for the mutations at the nonhelical tailpiece did not show any substantial progression., Conclusions: These data provide useful tools to predict the progression and the expected degree of severity of SNHL in individual MYH9-RD patients, which is especially relevant in young patients. Consequences in clinical practice are important not only for appropriate patient counseling but also for development of customized, genotype-driven clinical management. The authors recently reported that cochlear implantation has a good outcome in MYH9-RD patients; thus, stricter follow-up and earlier intervention are recommended for patients with unfavorable genotypes.

Objectives: Mutations in EYA4 can cause nonsyndromic autosomal dominant sensorineural hearing impairment (DFNA10) or a syndromic variant with hearing impairment and dilated cardiomyopathy. A mutation in EYA4 was found in a Dutch family, causing DFNA10. This study is focused on characterizing the hearing impairment in this family., Design: Whole exome sequencing was performed in the proband. In addition, peripheral blood samples were collected from 23 family members, and segregation analyses were performed. All participants underwent otorhinolaryngological examinations and pure-tone audiometry, and 12 participants underwent speech audiometry. In addition, an extended set of audiometric measurements was performed in five family members to evaluate the functional status of the cochlea. Vestibular testing was performed in three family members. Two individuals underwent echocardiography to evaluate the nonsyndromic phenotype., Results: The authors present a Dutch family with a truncating mutation in EYA4 causing a mid-frequency hearing impairment. This mutation (c.464del) leads to a frameshift and a premature stop codon (p.Pro155fsX). This mutation is the most N-terminal mutation in EYA4 found to date. In addition, a missense mutation, predicted to be deleterious, was found in EYA4 in two family members. Echocardiography in two family members revealed no signs of dilated cardiomyopathy. Results of caloric and velocity step tests in three family members showed no abnormalities. Hearing impairment was found to be symmetric and progressive, beginning as a mid-frequency hearing impairment in childhood and developing into a high-frequency, moderate hearing impairment later in life. Furthermore, an extended set of audiometric measurements was performed in five family members. The results were comparable to those obtained in patients with other sensory types of hearing impairments, such as patients with Usher syndrome type IIA and presbyacusis, and not to those obtained in patients with (cochlear) conductive types of hearing impairment, such as DFNA8/12 and DFNA13., Conclusions: The mid-frequency hearing impairment in the present family was found to be symmetric and progressive, with a predominantly childhood onset. The results of psychophysical measurements revealed similarities to other conditions involving a sensory type of hearing impairment, such as Usher syndrome type IIA and presbyacusis. The study results suggest that EYA4 is expressed in the sensory cells of the cochlea. This phenotypic description will facilitate counseling for hearing impairment in DFNA10 patients.

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Hereditary hearing loss is a clinically and genetically heterogeneous disorder. More than 80 genes have been implicated to date, and with the advent of targeted genomic enrichment and massively parallel sequencing (TGE+MPS) the rate of novel deafness-gene identification has accelerated. Here we report a family segregating post-lingual progressive autosomal dominant non-syndromic hearing loss (ADNSHL). After first excluding plausible variants in known deafness-causing genes using TGE+MPS, we completed whole exome sequencing in three hearing-impaired family members. Only a single variant, p.Arg185Pro in HOMER2, segregated with the hearing-loss phenotype in the extended family. This amino acid change alters a highly conserved residue in the coiled-coil domain of HOMER2 that is essential for protein multimerization and the HOMER2-CDC42 interaction. As a scaffolding protein, HOMER2 is involved in intracellular calcium homeostasis and cytoskeletal organization. Consistent with this function, we found robust expression in stereocilia of hair cells in the murine inner ear and observed that over-expression of mutant p.Pro185 HOMER2 mRNA causes anatomical changes of the inner ear and neuromasts in zebrafish embryos. Furthermore, mouse mutants homozygous for the targeted deletion of Homer2 present with early-onset rapidly progressive hearing loss. These data provide compelling evidence that HOMER2 is required for normal hearing and that its sequence alteration in humans leads to ADNSHL through a dominant-negative mode of action.

Objective: Mutations in the transient receptor potential vanilloid 4 gene (TRPV4) can induce a great diversity of neuropathies. Together with these neuropathies, hearing loss can occur. This study is focused on providing an audiometric phenotype description of a Dutch family with spinal muscular atrophy caused by a mutation in TRPV4., Methods: A neurological examination was repeated and pure tone and speech audiometry were performed., Results: A large variety in neurological symptoms as well as variation in audiometric characteristics was observed. The severity of hearing loss is mild to moderate and the audiogram configuration is highly variable. The hearing loss of these patients has a progressive nature in general. The frequencies that deteriorate significantly differ between family members. When compared to presbyacusis patients, speech recognition scores of patients with a TRPV4 mutation are not clearly different., Conclusion: The function of TRPV4 in the inner ear is still elusive but it is suggested that TRPV4 is required for maintenance of cochlear function in stress conditions, like acoustic injury. We can neither confirm nor reject this based on the results obtained in this family. Therefore, one might consider advising patients with a TRPV4 mutation to avoid exposure to environmental influences such as noise exposure., (© The Author(s) 2014.)

Objective: To evaluate karyotype-specific ear and hearing problems in young-adult patients with Turner syndrome (TS) and assess the effects of previous treatment with oxandrolone (Ox)., Study Design: Double-blind follow-up study., Setting: University hospital., Patients: Sixty-five TS patients (mean age, 24.3 yr) previously treated with growth hormone combined with placebo, Ox 0.03 mg/kg per day, or Ox 0.06 mg/kg per day from the age of 8 years and estrogen from the age of 12 years., Intervention: Ear examination was performed according to standard clinical practice. Air- and bone conduction thresholds were measured in decibel hearing level., Main Outcome Measures: We compared patients with total monosomy of the short arm of the X chromosome (Xp), monosomy 45,X and isochromosome 46,X,i(Xq), with patients with a partial monosomy Xp, mosaicism or other structural X chromosomal anomalies. We assessed the effect of previous Ox treatment., Results: Sixty-six percent of the patients had a history of recurrent otitis media. We found hearing loss in 66% of the ears, including pure sensorineural hearing loss in 32%. Hearing thresholds in patients with a complete monosomy Xp were about 10 dB worse compared with those in patients with a partial monosomy Xp. Air- and bone conduction thresholds were not different between the placebo and Ox treatment groups., Conclusion: Young-adult TS individuals frequently have structural ear pathology, and many suffer from hearing loss. This indicates that careful follow-up to detect ear and hearing problems is necessary, especially for those with a monosomy 45,X or isochromosome 46,X,i(Xq). Ox does not seem to have an effect on hearing.

Objectives: Recently, OTOG and OTOGL were identified as human deafness genes. Currently, only four families are known to have autosomal recessive hearing loss based on mutations in these genes. Because the two genes code for proteins (otogelin and otogelin-like) that are strikingly similar in structure and localization in the inner ear, this study is focused on characterizing and comparing the hearing loss caused by mutations in these genes., Design: To evaluate this type of hearing, an extensive set of audiometric and vestibular examinations was performed in the 13 patients from four families., Results: All families show a flat to downsloping configuration of the audiogram with mild to moderate sensorineural hearing loss. Speech recognition scores remain good (>90%). Hearing loss is not significantly different in the four families and the psychophysical test results also do not differ among the families. Vestibular examinations show evidence for vestibular hyporeflexia., Conclusion: Because otogelin and otogelin-like are localized in the tectorial membrane, one could expect a cochlear conductive hearing loss, as was previously shown in DFNA13 (COL11A2) and DFNA8/12 (TECTA) patients. Results of psychophysical examinations, however, do not support this. Furthermore, the authors conclude that there are no phenotypic differences between hearing loss based on mutations in OTOG or OTOGL. This phenotype description will facilitate counseling of hearing loss caused by defects in either of these two genes.

We present the case of a Dutch family with a new mutation (c523_528dup) in GATA3 causing HDR syndrome. HDR syndrome is characterised by hypoparathyroidism, deafness and renal defects. In this study, we describe the audiometric characteristics of 5 patients from this family. Their hearing impairment was congenital, bilateral and symmetric. Audiograms showed mild-to-moderate hearing impairment with a flat audiogram configuration. Higher frequencies tended to be affected more strongly. Cross-sectional analyses showed no progression, and a mean audiogram was established. Psychophysical measurements in 3 HDR patients - including speech reception in noise, loudness scaling, gap detection and difference limen for frequency - were obtained to assess hearing function in greater detail. Overall, the results of the psychophysical measurements indicated characteristics of outer hair cell loss. CT scanning showed no anomalies in 3 of the HDR patients. Although 2 patients displayed vestibular symptoms, no anomalies in the vestibular system were found by vestibulo-ocular examination. Our results are in agreement with the theory that outer hair cell malfunctioning can play a major role in HDR syndrome.

Objective: To investigate the familial correlations and intraclass correlation of age-related hearing impairment (ARHI) in specific frequencies. In addition, heritability estimates were calculated., Study Design: Multicenter survey in 8 European centers., Subjects: One hundred ninety-eight families consisting of 952 family members, screened by otologic examination and structured interviews. Subjects with general conditions, known to affect hearing thresholds or known otologic cause were excluded from the study., Results: We detected familial correlation coefficients of 0.36, 0.37, 0.36, and 0.30 for 0.25, 0.5, 1, and 2 kHz, respectively, and correlation coefficients of 0.20 and 0.18 for 4 and 8 kHz, respectively. Variance components analyses showed that the proportion of the total variance attributable to family differences was between 0.32 and 0.40 for 0.25, 0.5, 1, and 2 kHz and below 0.20 for 4 and 8 kHz. When testing for homogeneity between sib pair types, we observed a larger familial correlation between female than male subjects. Heritability estimates ranged between 0.79 and 0.36 across the frequencies., Discussion: Our results indicate that there is a substantial shared familial effect in ARHI. We found that familial aggregation of ARHI is markedly higher in the low frequencies and that there is a trend toward higher familial aggregation in female compared with male subjects.

A total of 64 loci for autosomal dominant non-syndromic hearing impairment have been described, and the causative genes have been identified for 24 of these. The present study reports on the clinical characteristics of an autosomal dominantly inherited hearing impairment that is linked to a region within the DFNA60 locus located on chromosome 2 in q22.1-24.1. A pedigree spanning four generations was established with 13 affected individuals. Linkage analysis demonstrated that the locus extended over a 2.96 Mb region flanked by markers D2S2335 and D2S2275. The audiograms mainly showed a distinctive U-shaped configuration. Deterioration of hearing started at a wide age range, from 12 to 40 years. Cross-sectional analysis showed rapid progression of hearing impairment from mild to severe, between the ages of 40 and 60 years, a phenomenon that is also observed in DFNA9 patients. The results of the individual longitudinal analyses were generally in line with those obtained by the cross-sectional analysis. Speech recognition scores related to the level of hearing impairment (PTA1,2,4 kHz) appeared to be fairly similar to those of presbyacusis patients. It is speculated that hearing impairment starting in mid-life, as shown by DFNA60 patients, could play a role in the development of presbyacusis. Furthermore, speech recognition did not deteriorate appreciably before the sixth decade of life. We conclude that DFNA60 should be considered in hearing impaired patients who undergo a rapid progression in middle age and are negative for DFNA9. Furthermore, cochlear implantation resulted in good rehabilitation in two DFNA60 patients., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Since deafness is the most common sensorineural disorder in humans, better understanding of the underlying causes is necessary to improve counseling and rehabilitation. A Dutch family with autosomal dominantly inherited sensorineural hearing loss was clinically and genetically assessed. The MYO6 gene was selected to be sequenced because of similarities with other, previously described DFNA22 phenotypes and a pathogenic c.3610C > T (p.R1204W) mutation was found to co-segregate with the disease. This missense mutation results in a flat configured audiogram with a mild hearing loss, which becomes severe to profound and gently to steeply downsloping later in life. The age-related typical audiograms (ARTA) constructed for this family resemble presbyacusis. Speech audiometry and results of loudness scaling support the hypothesis that the phenotype of this specific MYO6 mutation mimics presbyacusis., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a common and often progressive sensory deficit. ADNSHL displays a high degree of genetic heterogeneity and varying rates of progression. Accurate, comprehensive, and cost-effective genetic testing facilitates genetic counseling and provides valuable prognostic information to affected individuals. In this article, we describe the algorithm underlying AudioGene, a software system employing machine-learning techniques that utilizes phenotypic information derived from audiograms to predict the genetic cause of hearing loss in persons segregating ADNSHL. Our data show that AudioGene has an accuracy of 68% in predicting the causative gene within its top three predictions, as compared with 44% for a majority classifier. We also show that AudioGene remains effective for audiograms with high levels of clinical measurement noise. We identify audiometric outliers for each genetic locus and hypothesize that outliers may reflect modifying genetic effects. As personalized genomic medicine becomes more common, AudioGene will be increasingly useful as a phenotypic filter to assess pathogenicity of variants identified by massively parallel sequencing., (© 2012 Wiley Periodicals, Inc.)

Objective: To evaluate hearing impairment and cochlear function in non-ocular Stickler syndrome., Study Design: Multifamily study., Patients & Methods: Ten patients from two different families with non-ocular Stickler syndrome (Stickler syndrome type 3) were included. Six members of the first family and four members of the second family participated in this study. Otorhinolaryngologic examinations were performed. Pure-tone and speech audiograms were obtained. Longitudinal analysis was performed. Psychophysical measurements, including loudness scaling, gap detection, difference limen for frequency and speech perception in noise were administered to assess cochlear function at a deeper level., Results: Affected individuals in the first family were carriers of a heterozygous splice donor mutation in the COL11A2 gene. Affected individuals in the second family were carriers of a novel heterozygous missense mutation in COL11A2. Both families showed bilateral, non-progressive hearing impairment with childhood onset. The severity of the hearing impairment exhibited inter- and intrafamilial variability and was mostly mild to moderate. The results of the psychophysical measurements were similar to those previously published for DFNA8/12 (TECTA) and DFNA13 (COL11A2) patients and thus consistent with an intra-cochlear conductive hearing impairment. This is in line with the theory that mutations in COL11A2 affect tectorial membrane function., Conclusion: Hearing impairment in non-ocular Stickler syndrome is characterized by non-progressive hearing loss, present since childhood, and mostly mild to moderate in severity. Psychophysical measurements in non-ocular Stickler patients were suggestive of intra-cochlear conductive hearing impairment., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The Nathalie syndrome (OMIM 255990) comprises a combination of features that do not resemble any other known syndrome and is as such an independent, rare entity. It is characterized by sensorineural hearing impairment, juvenile cataract, spinal muscular atrophy, skeletal abnormalities, retardation of growth, underdeveloped secondary gender characteristics and cardiomyopathy. Worldwide, only one family with this syndrome is known. An update of the clinical follow-up in this family and the results of autopsy are given. Audiometry showed a downsloping configuration that corresponded to the findings at histopathological examination of the cochlea: a diffuse atrophy of the organ of Corti, severe and diffuse atrophy of the stria vascularis and moderate loss of cochlear neurons in all turns. Another new striking feature is that individuals with the Nathalie syndrome have a shortened life expectancy with a risk of sudden death or death from heart failure resulting from (dilated) cardiomyopathy., (Copyright © 2012 S. Karger AG, Basel.)

Description of the audiometric and vestibular characteristics of a Dutch family with Muckle-Wells syndrome (MWS). Examination of all family members consisted of pure tone audiometry, otoscopy and genetic analysis. In addition, a selected group underwent speech audiometry, vestibulo-ocular examination, acoustic reflex testing and tests assessing loudness scaling, gap detection, difference limen for frequency and speech perception in noise. Linear regression analyses were performed on the audiometric data. Six clinically affected family members participated in this study and all were carriers of a p.Tyr859His mutation in the NLPR3 gene. Most affected family members reported bilateral, slowly progressive hearing impairment since childhood. Hearing impairment started at the high frequencies and the low- and mid-frequency threshold values deteriorated with advancing age. Annual threshold deterioration (ATD) ranged from 1.3 to 1.9 dB/year with the highest values at the lower frequencies. Longitudinal linear regression analysis demonstrated significant progression for a number of frequencies in five individuals. Speech recognition scores were clearly affected. However, these individuals tended to have higher speech recognition scores than presbyacusis patients at similar PTA(1,2,4 kHz) levels. The loudness growth curves were steeper than those found in individuals with normal hearing, except for one family member (individual IV:6). Suprathreshold measurements, such as difference limen for frequency (DL(f)), gap detection and particularly speech perception in noise were within the normal range or at least close to data obtained in two groups of patients with a so-called conductive type of hearing loss, situated in the cochlea. Hearing impairment in MWS is variable and shows resemblance to previously described intra-cochlear conductive hearing impairment. This could be helpful in elucidating the pathogenesis of hearing impairment in MWS. Other associated symptoms of MWS were mild and nonspecific in the present family. Therefore, even without any obvious syndromic features, MWS can be the cause of sensorineural hearing impairment, especially when combined with (mild) skin rash and musculoskeletal symptoms. An early diagnosis of MWS is essential to prevent irreversible damage from amyloidosis. The effect of IL-1β inhibitors on hearing impairment is more controversial, but an early start of treatment seems to be essential. Therefore, our results are of importance in patient care and counselling., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: Investigation of the audiometric characteristics of a large Dutch DFNX4 family with a p.Glu72X mutation in the SMPX gene., Patients and Methods: Sixty family members participated in this study and examination consisted of medical history, otoscopy, pure tone and speech audiometry. Linkage and mutation analysis revealed a pathogenic mutation in the SMPX gene., Results: All 25 mutation carriers exhibited hearing impairment, except one woman aged 25 years. The men (n = 10) showed more severe hearing impairment than the women (n = 14) and already at a younger age. The age of onset according to history was 2-10 years (mean: 3.3 years) in men and 3-48 years (mean: 26.4 years) in women. In the men, severe threshold deterioration mainly occurred during the first two decades of life, especially at the higher frequencies. The women showed milder threshold deterioration and more pronounced across-subjects and individual inter-aural variation, especially at 2-8 kHz. Longitudinal linear regression analysis demonstrated significant progression of at least two frequencies in five individuals (3 men and 2 women). The speech recognition scores of the mutation carriers with hearing impairment were decreased at relatively young ages compared to a reference group of patients with only presbycusis, especially in men. However, all these patients tended to have better speech recognition scores than the presbycusis patients at matching PTA(1,2,4 kHz) levels., Conclusion: This study demonstrates the phenotypic heterogeneity in this large family with an X-linked pattern of inherited sensorineural hearing impairment. The men showed more severe hearing impairment at a younger age with more pronounced progression during the first two decades of life, while women demonstrated less severe hearing impairment with more gradual progression and a wider variation in age of onset, degree of hearing impairment and inter-aural asymmetry in thresholds., (Copyright © 2011 Elsevier B.V. All rights reserved.)

In the present study, genotype-phenotype correlations in eight Dutch DFNB8/10 families with compound heterozygous mutations in TMPRSS3 were addressed. We compared the phenotypes of the families by focusing on the mutation data. The compound heterozygous variants in the TMPRSS3 gene in the present families included one novel variant, p.Val199Met, and four previously described pathogenic variants, p.Ala306Thr, p.Thr70fs, p.Ala138Glu, and p.Cys107Xfs. In addition, the p.Ala426Thr variant, which had previously been reported as a possible polymorphism, was found in one family. All affected family members reported progressive bilateral hearing impairment, with variable onset ages and progression rates. In general, the hearing impairment affected the high frequencies first, and sooner or later, depending on the mutation, the low frequencies started to deteriorate, which eventually resulted in a flat audiogram configuration. The ski-slope audiogram configuration is suggestive for the involvement of TMPRSS3. Our data suggest that not only the protein truncating mutation p.T70fs has a severe effect but also the amino acid substitutions p.Ala306Thr and p.Val199Met. A combination of two of these three mutations causes prelingual profound hearing impairment. However, in combination with the p.Ala426Thr or p.Ala138Glu mutations, a milder phenotype with postlingual onset of the hearing impairment is seen. Therefore, the latter mutations are likely to be less detrimental for protein function. Further studies are needed to distinguish possible phenotypic differences between different TMPRSS3 mutations. Evaluation of performance of patients with a cochlear implant indicated that this is a good treatment option for patients with TMPRSS3 mutations as satisfactory speech reception was reached after implantation.

The prevalence of DFNA8/DFNA12 (DFNA8/12), a type of autosomal dominant nonsyndromic hearing loss (ADNSHL), is unknown as comprehensive population-based genetic screening has not been conducted. We therefore completed unbiased screening for TECTA mutations in a Spanish cohort of 372 probands from ADNSHL families. Three additional families (Spanish, Belgian, and English) known to be linked to DFNA8/12 were also included in the screening. In an additional cohort of 835 American ADNSHL families, we preselected 73 probands for TECTA screening based on audiometric data. In aggregate, we identified 23 TECTA mutations in this process. Remarkably, 20 of these mutations are novel, more than doubling the number of reported TECTA ADNSHL mutations from 13 to 33. Mutations lie in all domains of the α-tectorin protein, including those for the first time identified in the entactin domain, as well as the vWFD1, vWFD2, and vWFD3 repeats, and the D1-D2 and TIL2 connectors. Although the majority are private mutations, four of them-p.Cys1036Tyr, p.Cys1837Gly, p.Thr1866Met, and p.Arg1890Cys-were observed in more than one unrelated family. For two of these mutations founder effects were also confirmed. Our data validate previously observed genotype-phenotype correlations in DFNA8/12 and introduce new correlations. Specifically, mutations in the N-terminal region of α-tectorin (entactin domain, vWFD1, and vWFD2) lead to mid-frequency NSHL, a phenotype previously associated only with mutations in the ZP domain. Collectively, our results indicate that DFNA8/12 hearing loss is a frequent type of ADNSHL., (© 2011 Wiley-Liss, Inc.)

Objectives: We studied the clinical characteristics of an Australian family with an autosomal dominant sensorineural hearing impairment (DFNA9) caused by an I109N mutation in COCH., Methods: Retrospective analyses of audiometric data from 8 mutation carriers of an Australian DFNA9 family with the I109N COCH mutation were performed. Cross-sectional hearing levels related to age, age-related typical audiograms, and speech recognition scores related to age and to the level of hearing impairment were investigated. Data were compared to those obtained in previously identified DFNA9 families with P51S, V66G, G87W, G88E, I109T, and C542F COCH mutations., Results: Deterioration of hearing in the I109N mutation carriers started before the age of 40 years. The audiometric characteristics of the I109N mutation carriers are essentially similar to those previously established in I109T mutation carriers and, to a lesser extent, in P51S, G87W, and G88E mutation carriers., Conclusions: The phenotype associated with the I109N COCH mutation is largely similar to that associated with the I109T, P51S, G87W, and G88E mutation carriers. However, subtle differences seem to exist in terms of age of onset and rate of progression.

In a Dutch family with an X-linked postlingual progressive hearing impairment, a critical linkage interval was determined to span a region of 12.9 Mb flanked by the markers DXS7108 and DXS7110. This interval overlaps with the previously described DFNX4 locus and contains 75 annotated genes. Subsequent next-generation sequencing (NGS) detected one variant within the linkage interval, a nonsense mutation in SMPX. SMPX encodes the small muscle protein, X-linked (SMPX). Further screening was performed on 26 index patients from small families for which X-linked inheritance of nonsyndromic hearing impairment (NSHI) was not excluded. We detected a frameshift mutation in SMPX in one of the patients. Segregation analysis of both mutations in the families in whom they were found revealed that the mutations cosegregated with hearing impairment. Although we show that SMPX is expressed in many different organs, including the human inner ear, no obvious symptoms other than hearing impairment were observed in the patients. SMPX had previously been demonstrated to be specifically expressed in striated muscle and, therefore, seemed an unlikely candidate gene for hearing impairment. We hypothesize that SMPX functions in inner ear development and/or maintenance in the IGF-1 pathway, the integrin pathway through Rac1, or both., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The aim of the study was to report otologic and audiologic characteristics in a group of children with Turner syndrome (TS) and correlate these findings to karyotype. Additionally, we give recommendations for the otologic care of these children. Sixty children (age 1.7-21.2 years) were included in this retrospective study. Medical history and karyotypes were recorded and otologic and audiologic evaluation was performed. A history of recurrent otitis media was reported in 41/60 (68%) children and 3/60 (5%) had suffered from cholesteatoma. Audiometric data in 56 children revealed that normal hearing was only present in 33/112 (29%) ears. All other ears 79/112 (71%) were classified in five different audiometric categories for hearing loss. Hearing thresholds in general appeared to be about 10-11 dB worse in children with a monosomy 45,X or isochromosome (both have a total deletion of the short (p) arm of the X-chromosome) compared to those having a mosaicism or structural anomaly (partial deletion, or total deletion in only a few cells). Our findings support the hypothesis that hearing can be affected by loss of the p-arm of the X-chromosome. It is for the first time that a relation between hearing problems and karyotype is statistically confirmed in a large group of children with TS., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objectives: To report on the audiometric findings in the first otosclerosis family linked to OTSC10., Study Design: Retrospective cohort study., Methods: A family study in a large otosclerosis family was performed, and a pedigree was constructed. Examination of all family members consisted of medical history guided by a questionnaire, pure-tone audiometry, otoscopy, and collection of blood samples for genetic linkage analysis. In addition, a selected group underwent stapedial reflex measurements and tympanometry. Cross-sectional as well as longitudinal analyses of audiometric data were performed., Results: Eleven family members were identified as clinically affected and were all carriers of the disease haplotype. Twelve clinically unaffected family members carried the disease haplotype as well. Cross-sectional analyses of clinically affected family members showed no significant progression of air conduction (AC) thresholds, bone conduction (BC) thresholds, and air-bone gap (ABG) levels with increasing age. Longitudinal regression analyses in one family member revealed significant deterioration of AC thresholds at all frequencies. The BC thresholds showed a significant increase with advancing age at 0.5 kHz, 2 kHz, and 4 kHz. A significant progression of ABG was seen at 8 kHz., Conclusions: The intersubject variation, in terms of age of onset, level of progression, and audiogram configuration, was remarkable, probably due to reduced penetrance and variable expression of the disease. Long-term audiometric data in one patient, however, were useful to demonstrate progression of hearing impairment., (Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.)

Objectives: We undertook to show that in a family with nonsyndromic autosomal dominant sensorineural hearing loss, genetic analysis can be successful when there is a match with a specific DFNA audioprofile. We also provide an update of relevant DFNA2/KCNQ4 audioprofiles and report the results of automatic audioprofile analysis using the Internet program AudioGene., Methods: Audiometric data and blood samples were obtained from the family W08-0384. Based on the audiograms of the affected participants, mutation analysis of KCNQ4 was started. Original audiometric threshold data were collected for all identified KCNQ4-related DFNA2 families. The Internet computer program AudioGene, recently developed for automatic audioprofile analysis, was accessed., Results: The family's audioprofile and the program AudioGene predicted the DFNA2/KCNQ4 locus. Mutation analysis of KCNQ4 revealed a c.821T>A (p.Leu274His) mutation of the KCNQ4 gene. This mutation has been previously identified in a Dutch family. Genetic analysis revealed a common haplotype in these two families over a region including the KCNQ4 gene., Conclusions: Familiarity with the audioprofiles of DFNA traits may lead to successful mutation analysis of the gene involved, even in a small family in which genetic linkage analysis is not an option. Alternatively, the specially developed program AudioGene can be accessed on the Internet to perform automatic audioprofile analysis of a family's (audiological) phenotype.

Objectives: We describe the phenotype of 2 Dutch DFNA3 families with mutations in the GJB2 gene., Methods: Two patients from family 1 and one isolated patient from family 2 were studied. The audiometric examination consisted of pure tone and speech audiometry. Two patients underwent vestibular testing and high-resolution computed tomographic scanning of the temporal bone. Mutation analysis of GJB2 and GJB6 was performed., Results: All 3 patients had severe to profound sensorineural hearing impairment. Cochlear implantation was performed in 2 patients, and their phoneme recognition scores were good. Mutation analyses revealed a p.Arg184Gln mutation in GJB2 in family 1 and a p.Arg75Trp mutation in GJB2 in family 2. No mutations in GJB6 were identified. Vestibular function tests and computed tomographic scans yielded normal findings in the examined subjects., Conclusions: Severe to profound sensorineural hearing impairment was found in these DFNA3 patients, and was well rehabilitated with cochlear implantation. A thorough genotype-phenotype correlation is difficult because of the small number of affected patients and the limited clinical data of these patients. More clinical data on DFNA3 families need to be published in order to create a reliable and precise phenotype characterization.

In a Dutch family with autosomal recessive hearing loss, genome-wide single-nucleotide polymorphism analysis mapped the genetic defect to the DFNB7/11 locus. A novel homozygous A-to-G change in the TMC1 gene was detected near the splice donor site of intron 19 (c.1763+3A→G) segregating with the hearing loss in this family. One of the 6 transmembrane domains and the actual TMC channel domain are predicted to be absent in the mutant protein. The sensorineural hearing impairment in this DFNB7/11 family has a postlingual onset. Audiometric analysis initially showed a steeply downward-sloping threshold configuration. The progressive phenotype in this family resembles the phenotype previously described for families with dominant TMC1 mutations (DFNA36) rather than that of families with recessive TMC1 mutations (DFNB7/11) which invariably cause severe-to-profound prelingual hearing impairment., (Copyright © 2010 S. Karger AG, Basel.)

Optokinetic nystagmus (OKN) responses (stimuli 40°/s and 60°/s) were evaluated in 121 patients with vestibular areflexia (VA) and were compared with a control group of 99 control subjects matched by age. The mean response levels were significantly higher in the VA group than in the control group: 1.7°/s at 40°/s stimulation, and 4.4°/s at 60°/s. The VA group showed a significantly wider scattering and greater variances and, as a group, they exhibited higher OKN gains than the control subjects. We suggest that the higher gain of OKN responses in VA patients can be attributed to an increased efficiency in signal processing by the cortical optokinetic system. This enhancement may be similar to the enhancement which, in healthy subjects, is produced by "optokinetic training".

Objectives: We investigated the cause of autosomal recessive nonsyndromic hearing loss (ARNSHL) that segregated in 2 consanguineous Iranian families., Methods: Otologic and audiometric examinations were performed on affected members of each family. Genome-wide parametric multipoint linkage mapping using a recessive model was performed with Affymetrix 50K GeneChips or short tandem repeat polymorphisms. Direct sequencing was used to confirm the causative mutation in each family., Results: In 2 Iranian families, L-1651 and L-8600606, with ARNSHL that mapped to the DFNB7/11 locus, homozygosity for a reported splice site mutation (c.776+1G>A), and a novel deletion (c.1589_1590delCT; p.S530*) were identified in the TMC1 gene, respectively., Conclusions: Consistent with the previously reported phenotype in DFNB7/11 families, the 2 Iranian families had segregated congenital, profound hearing impairment. However, in family L-1651, one affected family member (IV:3) has milder hearing impairment than expected, suggesting a potential genetic modifier effect. These results indicate that DFNB7/11 is a common form of genetic hearing loss in Iran, because this population is the source of 6 of the 29 TMC1 mutations reported worldwide.

High resolution sonography is a relatively new diagnostic technique in diagnosing carpal tunnel syndrome (CTS). Normal values in different studies, however, vary and this makes their practical use difficult. The aim of this study was to establish normal values for the median nerve cross-sectional area (CSA) and to investigate the value of measuring additional parameters. Ninety-eight wrists of 29 women and 25 men without signs or symptoms of CTS were included. Width and circumference of the wrist were measured. The CSA of the median nerve at the level of the pisiform bone was measured using ultrasonography. We found a significant correlation between the CSA of the median nerve at the wrist and wrist circumference. Measuring wrist circumference will establish the upper level of normal more accurately compared to predictions solely based upon gender. This has important implications in diagnosing CTS with ultrasonography.

Objectives/hypothesis: To determine the cause of autosomal dominant hearing loss segregating in an American family., Study Design: Family study., Methods: Otologic and audiometric examination was performed on affected family members. Genome wide parametric multipoint linkage mapping using a dominant model was performed with Affymetrix 50K GeneChip data. Direct sequencing was used to confirm the causative mutation., Results: In American family 467, segregating autosomal dominant nonsyndromic hearing loss, a novel heterozygous missense mutation (c.362T>C; p.F121S) was identified in the COCH gene. This mutation was also associated with vestibular dysfunction typical of other DFNA9 families. However, affected family members also exhibited memory loss and night blindness., Conclusions: The novel COCH mutation affects the functionally important limulus factor C, Coch-5b2 and Lgl1 domain where most DFNA9 mutations have been localized. The onset of the hearing loss, in the 2nd or 3rd decade of life, is earlier than in most DFNA9 families. The progression of hearing loss and vestibular dysfunction in the American family is typical of other DFNA9 families with mutations in this domain. Memory loss and night blindness have not been previously reported in DFNA9 families.

We identified overlapping homozygous regions within the DFNB84 locus in a nonconsanguineous Dutch family and a consanguineous Moroccan family with sensorineural autosomal-recessive nonsyndromic hearing impairment (arNSHI). The critical region of 3.17 Mb harbored the PTPRQ gene and mouse models with homozygous mutations in the orthologous gene display severe hearing loss. We show that the human PTPRQ gene was not completely annotated and that additional, alternatively spliced exons are present at the 5' end of the gene. Different PTPRQ isoforms are encoded with a varying number of fibronectin type 3 (FN3) domains, a transmembrane domain, and a phosphatase domain. Sequence analysis of the PTPRQ gene in members of the families revealed a nonsense mutation in the Dutch family and a missense mutation in the Moroccan family. The missense mutation is located in one of the FN3 domains. The nonsense mutation results in a truncated protein with only a small number of FN3 domains and no transmembrane or phosphatase domain. Hearing loss in the patients with PTPRQ mutations is likely to be congenital and moderate to profound and most severe in the family with the nonsense mutation. Progression of the hearing loss was observed in both families. The hearing loss is accompanied by vestibular dysfunction in all affected individuals. Although we show that PTPRQ is expressed in many tissues, no symptoms other than deafness were observed in the patients., ((c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

We identified overlapping homozygous regions within the DFNB25 locus in two Dutch and ten Pakistani families with sensorineural autosomal-recessive nonsyndromic hearing impairment (arNSHI). Only one of the families, W98-053, was not consanguineous, and its sibship pointed toward a reduced critical region of 0.9 Mb. This region contained the GRXCR1 gene, and the orthologous mouse gene was described to be mutated in the pirouette (pi) mutant with resulting hearing loss and circling behavior. Sequence analysis of the GRXCR1 gene in hearing-impaired family members revealed splice-site mutations in two Dutch families and a missense and nonsense mutation, respectively, in two Pakistani families. The splice-site mutations are predicted to cause frameshifts and premature stop codons. In family W98-053, this could be confirmed by cDNA analysis. GRXCR1 is predicted to contain a GRX-like domain. GRX domains are involved in reversible S-glutathionylation of proteins and thereby in the modulation of activity and/or localization of these proteins. The missense mutation is located in this domain, whereas the nonsense and splice-site mutations may result in complete or partial absence of the GRX-like domain or of the complete protein. Hearing loss in patients with GRXCR1 mutations is congenital and is moderate to profound. Progression of the hearing loss was observed in family W98-053. Vestibular dysfunction was observed in some but not all affected individuals. Quantitative analysis of GRXCR1 transcripts in fetal and adult human tissues revealed a preferential expression of the gene in fetal cochlea, which may explain the nonsyndromic nature of the hearing impairment., (Copyright (c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objectives: We analyzed the phenotype in a 5-generation DFNA20/26 family with a novel missense mutation in the ACTG1 gene (c.151G>A) and compared the findings to previous reports on DFNA20/26 families., Methods: Audiometric data were collected from the family members of a Dutch kindred with the novel ACTG1 mutation. Cross-sectional and/or longitudinal analyses were performed on pure tone and speech audiometry data of the mutation carriers. Age-related typical audiograms were constructed. Vestibular examination was performed in all mutation carriers., Results: Overall, high-frequency hearing impairment, most prominent at ages over 30 years, was observed with a progression rate of 1.1 to 2.1 dB/y, increasing with frequency. It ultimately resulted in residual hearing. Speech recognition scores remained good at given pure tone average (1, 2, and 4 kHz) levels, but were slightly poorer than those at similar levels in a group of patients with presbycusis. Vestibular examination did not reveal any consistent, statistically significant abnormalities., Conclusions: The audiometric phenotype of the Dutch DFNA20/26 family with a novel mutation in ACTG1 was largely consistent with previous reports on DFNA20/26. Considerable variations were found in audiogram configurations within the family. This is the first known DFNA20/26 family that has experienced tinnitus.

Objectives: Cochleovestibular characteristics were investigated in a Dutch DFNA15 family with a novel POU4F3 mutation, L223P., Methods: A 4-generation pedigree was constructed of the Dutch family with the novel L223P POU4F3 mutation. Pure tone audiometric data were collected and analyzed cross-sectionally in mutation carriers. Age-related typical audiograms were derived. Vestibular examination was performed in most of the mutation carriers. The results were compared to those obtained from previously identified 884de18 and L289F POU4F3 mutation carriers., Results: A novel mutation (L223P) in POU4F3 segregated with hearing impairment in the present family. Audiometric analysis generally showed an early-adult to midlife onset of hearing impairment. High-frequency hearing impairment was observed most frequently. Age-related typical audiograms showed a down-sloping configuration at ages of more than 30 years, with the fastest rate of progression at the high frequencies. Vestibular function tests revealed hypofunction of the vestibular labyrinth in 2 mutation carriers (not statistically significant)., Conclusions: The clinical features in the present family with a POU4F3 mutation were fairly similar to those in the 2 previously described DFNA15 families, but the level of hearing impairment was milder, and there was no substantial vestibular dysfunction.

Vestibular examination (electronystagmography with rotatory chair and caloric tests) was performed on 18 carriers and 1 phenocopy carrier in a Dutch family with autosomal dominant nonsyndromic DFNA15. This is the second DFNA15 family worldwide to have a novel L289F mutation in POU4F3. Vestibular involvement appeared to be present in 2 affected individuals according to their medical history. Vestibular examination results in an extended subset of L289F POU4F3 mutation carriers varied from normal to areflexia. DFNA15 is the third cochleovestibular disorder, after DFNA9 and DFNA11, in the autosomal dominant nonsyndromic hearing impairment., (Copyright (C) 2009 S. Karger AG, Basel.)

A novel TECTA mutation (c.5331G>A) was identified affecting alpha-tectorin just N-terminally of the zona pellucida domain in a Dutch family with nonsyndromic autosomal dominant sensorineural hearing impairment. The present mutation is clearly associated with a flat-threshold type of hearing impairment. Intriguingly, our results demonstrated that the present TECTA mutation had a significant protective effect against presbyacusis. Substantial protection against presbyacusis is a novel finding in a family with autosomal dominant hearing impairment., (Copyright 2008 S. Karger AG, Basel.)

Autosomal dominant hearing loss is highly heterogeneous. Hearing impairment mainly involves the mid-frequencies (500-2000 Hz) in only a low percentage of the cases. In a Dutch family with autosomal dominant mid-frequency/flat hearing loss, genome-wide SNP analysis combined with fine mapping using microsatellite markers mapped the defect to the DFNA8/12 locus, with a maximum two-point LOD score of 3.52. All exons and intron-exon boundaries of the TECTA gene, of which mutations are causative for DFNA8/12, were sequenced. Only one heterozygous synonymous change in exon 16 (c.5331G>A; p.L1777L) was found to segregate with the hearing loss. This change was predicted to cause the loss of an exonic splice enhancer (ESE). RT-PCR using primers flanking exon 16 revealed, besides the expected PCR product from the wild-type allele, a smaller fragment only in the affected individual, representing part of an aberrant TECTA transcript lacking exon 16. The aberrant splicing is predicted to result in a deletion of 37 amino acids (p.S1758Y/G1759_N1795del) in alpha-tectorin. Subsequently, the same mutation was detected in two out of 36 individuals with a comparable phenotype. Owing to the position of the protein deletion just N-terminal of the zona pellucida (ZP) domain of alpha-tectorin, it is likely that the deletion of 37 amino acids may affect the proteolytic processing, structure and/or function of this domain, which results in a clinical phenotype comparable to that of missense mutations in the ZP domain. In addition, this is the first report of a synonymous mutation that affects an ESE and causes hereditary hearing loss.

Objectives: A retrospective analysis was performed to evaluate the clinical outcome of percutaneous bone-anchored hearing aid (BAHA) application in children with the outcome measures of fixture loss and skin reactions., Methods: An analysis was done of 93 of the 101 children 16 years of age or younger who underwent the simplified Nijmegen surgical technique between January 1994 and July 2007., Results: Twenty-one of 129 fixtures (16.3%) were lost or removed. In 12 cases, osseointegration failed. The majority of the fixture losses (86%) occurred within 1 year after surgery. No differences were found between 3 age groups or between fixture lengths (seven 3-mm implants versus fourteen 4-mm implants). The BAHA fixtures were less stable in children than in adults. In 8 cases, Holgers grade 4 skin reactions were noted at an average (+/-SD) of 5.5 +/- 4.7 months after surgery, ie, significantly sooner than the milder reactions (p = 0.001). In 28 cases (22%), skin reactions of Holgers grades 2 to 4 were observed. Revision surgery to reduce subcutaneous scar tissue was necessary in 22 implants (17%)., Conclusions: Fixture loss was more frequent in children than in adults. The age of the child and the length of the fixture did not appear to influence fixture stability. Children should undergo frequent checkups at the outpatient clinic.

A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment.

Objectives: Wolfram syndrome is a progressive neurodegenerative syndrome characterized by the features "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). We sought to study the audiometric data of genotyped Wolfram syndrome patients with sensorineural hearing impairment., Methods: Pure tone threshold data of 23 Wolfram syndrome patients were used for cross-sectional analysis in subgroups (age less than 16 years or between 19 and 25 years, gender, and origin)., Results: All subgroups, with 1 exception, showed a fairly similar type of hearing impairment with, on average, thresholds of about 25 dB (range, 0 to 65 dB) at 0.25 to 1 kHz, gently sloping downward to about 60 dB (range, 25 to 95 dB) at 8 kHz. The subgroup of Dutch women, which was excluded from the calculations of the average hearing thresholds, showed a higher degree of hearing impairment. Only the latter subgroup showed progression; however, contrary to the previous longitudinal analysis, progression was not significant in the present cross-sectional analysis, presumably because of the high degree of cross-subject variability., Conclusions: This unique collection of audiometric data from genotyped Wolfram syndrome patients shows no substantial progression in sensorineural hearing impairment with advancing age, no relation to the types of WFS1 mutations identified, and, with exclusion of the subgroup of Dutch female patients, no significant sex-related differences.