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Treatment for chronic inflammatory conditions in children should take into account the specific pathophysiological and clinical processes underlying these disorders. These guidelines provide a framework for both the medical and surgical treatment of chronic inflammatory diseases such as otitis media, allergic rhinitis and chronic rhinosinusitis, chronic inflammation of tonsils and adenoids, and laryngitis. In addition, the role of vaccinations and immunomodulatory therapies is discussed. Whenever possible, the evidence levels for specific treatments comply with the Oxford Levels of Evidence.

Item does not contain fulltext, Mutations inactivating the potassium channel KCNQ4 (K(v)7.4) lead to deafness in humans and mice. In addition to its expression in mechanosensitive hair cells of the inner ear, KCNQ4 is found in the auditory pathway and in trigeminal nuclei that convey somatosensory information. We have now detected KCNQ4 in the peripheral nerve endings of cutaneous rapidly adapting hair follicle and Meissner corpuscle mechanoreceptors from mice and humans. Electrophysiological recordings from single afferents from Kcnq4(-/-) mice and mice carrying a KCNQ4 mutation found in DFNA2-type monogenic dominant human hearing loss showed elevated mechanosensitivity and altered frequency response of rapidly adapting, but not of slowly adapting nor of D-hair, mechanoreceptor neurons. Human subjects from independent DFNA2 pedigrees outperformed age-matched control subjects when tested for vibrotactile acuity at low frequencies. This work describes a gene mutation that modulates touch sensitivity in mice and humans and establishes KCNQ4 as a specific molecular marker for rapidly adapting Meissner and a subset of hair follicle afferents.

Contains fulltext : 51041.pdf (publisher's version ) (Closed access), OBJECTIVE: To report the audiometric and radiologic findings in the first otosclerosis family linked to OTSC5. STUDY DESIGN: A clinical investigation of a family linked to OTSC5, including analyses of audiometric data and of high-resolution computed tomography (CT) images of the temporal bones from genetically affected family members. SETTING: Tertiary referral center. PATIENTS: Family members from a four-generation pedigree with otosclerosis segregating as an autosomal dominant trait. MAIN OUTCOME MEASURE(S): Pre-surgery pure tone audiometric data. Classification of otosclerotic foci on high-resolution spiral CT images of the temporal bones of genetically affected individuals. RESULTS: Audiometric data showed a considerable degree of phenotypic variability. Cross-sectional regression analysis did not disclose any clear age dependence of threshold-related data. Systematic differences between mean parameter values relating to the thresholds in the best or the worst ear were found. High-resolution CT images revealed a fenestral otosclerotic focus in seven of nine (78%) clinically affected individuals and cochlear foci in one of these seven patients. CONCLUSION: The phenotype of OTSC5 seems to be variable. Additional long-term audiometric data are needed to construct age-related typical audiograms, which may also facilitate the comparison between phenotypes of the different otosclerosis loci. The detection rate of otospongiotic foci in our study group is similar or lower compared with previous reports on CT data in consecutive otosclerosis patients who had stapes replacing surgery.

Contains fulltext : 47623.pdf (publisher's version ) (Closed access), OBJECTIVES: To perform genetic analysis and to analyze cochleovestibular impairment features in a newly identified Dutch family with nonsyndromic autosomal dominant hearing impairment (DFNA9). STUDY DESIGN: Genetic analysis was performed using microsatellite markers and single nucleotide polymorphisms. Audiometric data were collected and analyzed longitudinally. Results were compared with those obtained in previously identified P51S COCH mutation carriers (n = 74). Special attention was also given to a comparison of age-related features such as progressive hearing loss and vestibular impairment. SETTING: Tertiary referral center. PATIENTS: G88E COCH mutation carriers from a Dutch family. MAIN OUTCOME MEASURES: The study of clinical features of a DFNA9 family carrying a G88E COCH mutation and to compare this to the symptoms of those carrying a P51S/COCH mutation. RESULTS: Pure-tone thresholds, phoneme recognition scores, and vestibular responses of the G88E mutation carriers were essentially similar to those previously established in the P51S mutation carriers. Hearing started to deteriorate in G88E mutation carriers from age 46 to 49 years and onward, whereas deterioration of vestibular function started from approximately age 46 years. In the P51S mutation carriers, vestibular impairment started earlier, at approximately age 34 years. However, the difference in age of onset with the G88E mutation carriers was not significant. Remarkably, the proportion of patients who developed complete vestibular areflexia within the age range of 40 to 56 years was significantly lower for the G88E mutation carriers than for the P51S mutation carriers. CONCLUSION: Apart from a significantly lower frequency of vestibular areflexia between the ages of 40 and 56 years, there are no phenotypic differences between carriers of the G88E and P51S mutations in the COCH gene.

Contains fulltext : 57152.pdf (publisher's version ) (Closed access), A novel DFNA5 mutation was found in a Dutch family, of which 37 members were examined. A nucleotide substitution was identified in the splice acceptor site of intron 7, leading to skipping of exon 8 in part of the transcripts. The mutation was found in 18 individuals. Sensorineural hearing impairment was non-syndromic and symmetric. In early life, presumably congenitally, hearing impairment amounted to 30 dB in the high frequencies. Progression was most pronounced at 1 kHz (1.8 dB/year). Speech recognition was relatively good with a phoneme score of about 50% at the age of 70. Onset age was 37 years, and recognition deteriorated by 1.3% per year. The recognition score deteriorated by 1.0% per decibel threshold increase from a mean pure-tone average (PTA at 1, 2 and 4 kHz) of 63 dB onwards. Vestibular function was generally normal. The second mutation identified in the DFNA5 gene results in hearing impairment, similar to that in the original DFNA5 family in terms of pure-tone thresholds, but with more favourable speech recognition.

Contains fulltext : 57284.pdf (publisher's version ) (Closed access)

Contains fulltext : 58020.pdf (publisher's version ) (Closed access), OBJECTIVE: To report a successful stapedectomy for stapedial fixation in a patient with Stickler syndrome type I (COL2A1). SETTING: University Hospital Department for Otology, Pathology, Ophthalmology and Clinical Genetics. STUDY DESIGN: A clinical and genetic evaluation of a mother and daughter focusing mainly on the otological, ophthalmological, histological and genetical aspects. INTERVENTION: A stapedectomy was performed successfully. RESULTS: Hearing impairment improved after stapedectomy. Postoperatively a shift in high-frequency threshold wa seen related to the stapedectomy. A new mutation in COL2A1 gene was dectected. CONCLUSION: Stapedial fixation can be the cause of hearing impairment in Stickler syndrome type I (COL2A1). The hearing impairment can be improved by stapes surgery.

Contains fulltext : 57357.pdf (publisher's version ) (Closed access), OBJECTIVES: To perform linkage analysis and to outline hearing loss characteristics in a family exhibiting a nonsyndromic, autosomal dominant type of progressive sensorineural hearing loss. DESIGN: Genetic analysis was performed using microsatellite markers. Audiometric data were collected and analyzed longitudinally. Sigmoidal dose-response curves enabled us to perform nonlinear regression analysis per frequency and on phoneme recognition scores. Speech recognition scores were compared with those of DFNA2, DFNA5, DFNA9, and presbyacusis subjects. SUBJECTS: Affected family members of a Dutch family (W99-060). RESULTS: We revealed linkage of hearing loss to the DFNA20/26 locus (maximum logarithm of odds score, 3.1 at theta=0.04) and reduced the critical region from 12 to 9.5 centimorgans. Patients younger than 15 years already showed gently downsloping audiograms. At ages 15 to 20 and 25 to 40 years, hearing loss was profound at 8 kHz and 1 to 4 kHz, respectively. The 0.25- to 0.5-kHz thresholds showed more gradual progression by about 1.5 to 2 dB/y. From about age 40 years onward, hearing was residual. Hearing impairment took a more severe course than in a known DFNA20 family. Score recognition in DFNA20/26 subjects was better than in DFNA9 subjects at any pure-tone average (1-4 kHz) threshold. Compared with subjects having DFNA2 and DFNA5, speech recognition in those with DFNA20/26 scored better at threshold levels below 85 dB hearing level, but worse at levels above 90 dB. Compared with presbyacusis subjects, those with DFNA20/26 scored better in speech recognition at levels below 100 dB and worse at levels above 100 dB. CONCLUSIONS: Autosomal dominant hearing loss is linked to the DFNA20/26 locus in this Dutch family. The critical region is reduced from 12 to 9.5 centimorgans. Phenotypically, patients are more severely affected than those of a known DFNA20 family.

Contains fulltext : 58578.pdf (publisher's version ) (Open Access), Members of a Dutch DFNA13/COL11A2 family were evaluated with pure tone audiometry, stapedial reflexes, otoacoustic emissions, loudness scaling, difference limen for frequency, gap detection, and speech perception in quiet and noise. The tone audiometry showed a predominant loss for the low and middle frequencies, with only a few otoacoustic emissions at thresholds better than 25 dB hearing level. The stapedial reflexes appeared elevated, and loudness growth curves were shifted parallel to those for normal-hearing subjects, indicating a shift of the dynamic range toward higher presentation levels. The data for the difference limen for frequency, gap detection, and speech perception in noise fell within the (near-)normal range. Despite elevated thresholds, all suprathreshold functions showed fairly normal properties, suggesting an attenuation of signal energy in the cochlea with limited degradation of the cochlea's signal analyzing capabilities. The effect of DFNA13/COL11A2 may thus be characterized as a cochlear conductive loss.

Item does not contain fulltext, Linkage analysis in a multigenerational family with autosomal dominant hearing loss yielded a chromosomal localisation of the underlying genetic defect in the DFNA20/26 locus at 17q25-qter. The 6-cM critical region harboured the gamma-1-actin (ACTG1) gene, which was considered an attractive candidate gene because actins are important structural elements of the inner ear hair cells. In this study, a Thr278Ile mutation was identified in helix 9 of the modelled protein structure. The alteration of residue Thr278 is predicted to have a small but significant effect on the gamma 1 actin structure owing to its close proximity to a methionine residue at position 313 in helix 11. Met313 has no space in the structure to move away. Moreover, the Thr278 residue is highly conserved throughout eukaryotic evolution. Using a known actin structure the mutation could be predicted to impair actin polymerisation. These findings strongly suggest that the Thr278Ile mutation in ACTG1 represents the first disease causing germline mutation in a cytoplasmic actin isoform.

Item does not contain fulltext, Conductive hearing loss was detected in a boy with a previous diagnosis of dyschondrosteosis. Dyschondrosteosis is a rare inherited condition characterized by mesomelic dwarfism and Madelung's deformity. The syndrome can be caused by mutations in the SHOX gene, and in that case, the pattern of inheritance is pseudoautosomal dominant. Indeed, SHOX mutation analysis in our patient revealed a deletion. The combination of dyschondrosteosis and conductive hearing loss has been reported in 2 previous cases. In our patient, exploratory tympanotomy revealed ankylosis of the stapes and a malformed incus. A substantial gain in hearing threshold was obtained by a stapedectomy in combination with a malleovestibulopexy.

Item does not contain fulltext, Several different mutations in the KCNQ4 K+ channel gene are responsible for autosomal dominant nonsyndromic hearing impairment (DFNA2). Here we describe two additional families originating from Europe and Japan with a KCNQ4 missense mutation (W276S) that was previously found in one European family. We compared the disease-associated haplotype of the three W276S-bearing families using closely linked microsatellite markers and intragenic single nucleotide polymorphisms. Differences between the haplotypes were found, excluding a single founder mutation for the families. Therefore, the W276S mutation has occurred three times independently, and most likely represents a hot spot for mutation in the KCNQ4 gene.

Item does not contain fulltext, We analyzed hearing thresholds, speech recognition scores, and vestibular responses in 32 affected persons in a large family with DFNA2/KCNQ4-related hearing impairment caused by a W276S missense mutation. Linear regression analysis of individual longitudinal data revealed significant threshold progression (1 dB/y) and offset (at age zero). The mean offset thresholds were 5, 21, 40, 39, 31, and 51 dB hearing level (HL) at 0.25, 0.5, 1, 2, 4, and 8 kHz, respectively. Cross-sectional analysis of last-visit thresholds against age produced less-steep slopes and higher offset thresholds. Nonlinear regression analysis of last-visit phoneme recognition scores against age in 25 cases showed that speech recognition did not deteriorate before the third decade. A hyperactive vestibuloocular reflex was found in 3 of 11 cases: 2 persons were especially susceptible to motion sickness. Persons with this KCNQ4 mutation showed congenital, progressive high-frequency impairment without substantial loss of speech recognition during the first decades of life.

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Item does not contain fulltext, Speech recognition scores were analyzed in 34 carriers of a DFNA5 mutation. Cross-sectional linear regression analysis (last visit, maximum recognition score in %Correct on age or PTA1,2,4 kHz) established onset age (score 90%) at 16 years and onset PTA1,2,4 kHz level (score 90%) at 41 dB hearing level. The deterioration rate was 0.7%/y in the plot of maximum score against age, whereas the deterioration gradient was 0.4%/dB in the plot of maximum score against PTA1,2,4 kHz. Given the previously demonstrated rapid progression of hearing impairment, speech recognition was relatively good: at age 70, the score was still >50%. De Leenheer, Els M R

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Item does not contain fulltext, We present a detailed analysis of the DFNA10 phenotype based on data from 25 hearing-impaired persons coming from a large American pedigree segregating for deafness at the DFNA10 locus (chromosome 6q22.3-23.2). Cross-sectional analysis of air conduction threshold-on-age data from all available last-visit audiograms (linear regression analysis, age over 15 years) showed progression of hearing loss at a rate of 0.6 dB/y over all frequencies, with a flat to gently sloping age-corrected threshold of about 50 dB. The results were significant at 0.25, 4, and 8 kHz, but only if corrections for presbycusis were not included. Longitudinal threshold analysis performed in 1 case, covering ages 6 to 32 years, showed progression of hearing loss at a rate of 2 to 3 dB/y over 0.25 to 8 kHz. Nonlinear regression analysis was performed on phoneme discrimination scores with use of sigmoidal dose-response curves with variable slope. On the basis of these data, the hearing loss phenotype in this American DFNA10 family can be described as postlingual, initially progressive, and resulting, without the influence of presbycusis, in largely stable, flat sensorineural deafness.

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Item does not contain fulltext, OBJECTIVE: To analyze the phenotype in a 5-generation DFNA13 family with a missense mutation in the COL11A2 gene that causes autosomal dominant, presumably prelingual, nonsyndromic sensorineural hearing impairment. DESIGN: Family study. SETTING: University hospital department. PATIENTS: Twenty mutation carriers from a large American kindred. METHODS: Cross-sectional analysis using pure-tone threshold measurements at 0.25, 0.5, 1, 2, 4, and 8 kHz. The audiometric configuration was evaluated according to an existing consensus protocol. The significance of features relating to audiometric configuration was tested using 1-way analysis of variance. Progression was evaluated with linear regression analyses of threshold-on-age. RESULTS: Most individuals showed midfrequency (U-shaped) characteristics. The mean threshold in generations IV and V was 44 dB at 1, 2, and 4 kHz (midfrequencies); it was 29 dB at the other frequencies (0.25, 0.5, and 8 kHz). There was no significant progression beyond presbyacusis. CONCLUSION: The trait in this family can be characterized as autosomal dominant, nonprogressive, presumably prelingual, midfrequency sensorineural hearing impairment.

Item does not contain fulltext, OBJECTIVE: To analyze the relationship between pure-tone hearing threshold and speech recognition performance in DFNA2/KCNQ4 and DFNA9/COCH, 2 types of high-frequency nonsyndromic hearing impairment. DESIGN: Case series with cross-sectional analysis of phoneme recognition scores related to age and hearing level. SETTING: University hospital. PATIENTS: Forty-five members of 4 separate families, all carrying 1 of 3 different mutations in the KCNQ4 gene at the DFNA2 locus (1p34); 42 members of 7 separate families, all carrying the same Pro51Ser mutation in the COCH gene at the DFNA9 locus (14q12-q13). RESULTS: The deterioration of speech recognition dropped to a 90% score at a higher level of hearing impairment (pure-tone-average at 1, 2, and 4 kHz) in DFNA2-affected patients (65 dB) than in DFNA9-affected patients (46 dB). CONCLUSION: At similar levels of hearing impairment, DFNA2/KCNQ4-affected patients showed better speech recognition performance than DFNA9/COCH-affected patients.

KUN, 05 september 2001, Promotor : Cremers, C.W.R.J., Item does not contain fulltext