RESUMEN
Due to development of molecular techniques at hand, the number of genomic sequence variants detected in patient investigations is rising constantly. The number of potentially involved genes in hereditary hearing loss is rising simultaneously.In this overview, current methods for diagnostic workup on a molecular and functional level for variants of the SLC26A4 gene are described. Based on the description of the physiological function of the resulting protein Pendrin, molecular investigations for interpretation of the function are explained. Based on these investigations, the potential clinical consequences of a variant may be predicted more precisely and simplify routine reporting of a proven genotype and a phenotype, at hand. Finally, subsequent clinical investigations necessary, such as perchlorate discharge test, as well as therapeutic options are discussed.
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Pérdida Auditiva Sensorineural , Acueducto Vestibular , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , Humanos , Proteínas de Transporte de Membrana/genética , Mutación , Transportadores de Sulfato/genéticaRESUMEN
The prevalence and spectrum of sequence alterations in the SLC26A4 gene, which codes for the anion exchanger pendrin, are population-specific and account for at least 50% of cases of non-syndromic hearing loss associated with an enlarged vestibular aqueduct. A cohort of nineteen patients from Austria with hearing loss and a radiological alteration of the vestibular aqueduct underwent Sanger sequencing of SLC26A4 and GJB2, coding for connexin 26. The pathogenicity of sequence alterations detected was assessed by determining ion transport and molecular features of the corresponding SLC26A4 protein variants. In this group, four uncharacterized sequence alterations within the SLC26A4 coding region were found. Three of these lead to protein variants with abnormal functional and molecular features, while one should be considered with no pathogenic potential. Pathogenic SLC26A4 sequence alterations were only found in 12% of patients. SLC26A4 sequence alterations commonly found in other Caucasian populations were not detected. This survey represents the first study on the prevalence and spectrum of SLC26A4 sequence alterations in an Austrian cohort and further suggests that genetic testing should always be integrated with functional characterization and determination of the molecular features of protein variants in order to unequivocally identify or exclude a causal link between genotype and phenotype.
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Pérdida Auditiva Sensorineural/patología , Proteínas de Transporte de Membrana/genética , Acueducto Vestibular/anomalías , Población Blanca/genética , Adolescente , Adulto , Anciano , Alelos , Austria , Niño , Conexina 26/genética , Retículo Endoplásmico/metabolismo , Femenino , Genotipo , Células HEK293 , Pérdida Auditiva Sensorineural/genética , Humanos , Masculino , Proteínas de Transporte de Membrana/metabolismo , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Transportadores de Sulfato , Acueducto Vestibular/patología , Adulto JovenRESUMEN
'Elastometry' is a novel technique that allows for the quantitative assessment of elastic properties of the nasal tissues, providing valuable insights into the dynamic behavior of the external, soft lateral nasal wall. This study aimed to explore the application of 'elastometry' in understanding the biomechanics of the lateral nasal wall and its implications for nasal function in 'elastometry' measurements. After validation of safety and reliability of this method, we investigated mechanical properties of the lateral nasal wall by 'elastometry' using specifically developed measurement forceps with end pieces including sensors applied on 30 healthy volunteers, aged 18 to 82 without a history of severe trauma or surgery. By measuring normal stress and path length between the end pieces the modulus of elasticity was calculated. Among 360 measurements, the mean value determined for healthy female volunteers was E = 0.135 [N/mm2] and for healthy males E = 0.169 [N/mm2], fitting the range reported in the literature. A tendency of an age-related degree of elastic behavior of the lateral nasal wall was observed, whereby a decrease in elasticity with age in female and a slight increase in elasticity with age in male was detected. Our research showed that 'elastometry' is a cost and time-efficient method to calculate the modulus of elasticity, and could be used in conjunction with 4-phase rhinomanometry (4 PR) to extend diagnostic yield.
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Nariz , Humanos , Masculino , Femenino , Reproducibilidad de los Resultados , Nariz/cirugía , Elasticidad , Fenómenos BiomecánicosRESUMEN
BACKGROUND: Sensorineural hearing loss (SNHL) in newborns is estimated with an incidence around 1:10,000 per year and is divided into syndromic and non-syndromic forms. In case of present retrocochlear function' cochlear implantation allows speech and cognitive development in affected children, comparable to that of normal hearing children. Pathogenesis of SNHL remains unclear in many cases. Imaging of the temporal bone, such as computed tomography (CT) and magnetic resonance imaging (MRI), can reveal conspicuous findings, e.g. enlarged vestibular aqueduct (EVA) and Mondini malformation (MM) of the cochlea. These malformations can be a clinical sign for Pendred syndrome. METHODS: We screened CT scans of 75 cochlear implant patients for EVA and MM. RESULTS: Six patients were observed to have either EVA alone (n=3), or MM alone (n=2), or a combination of both (n=1). Further malformations of the temporal bone could be found within the whole group, as well. CONCLUSION: Our results confirm the general opinion on EVA and MM, being commonly found in patients with SNHL. A possible association with Pendred syndrome needs to be confirmed by genetic investigations with search for mutations in the SLC26A4 gene and further clinical tests, such as Perchlorate test for surveillance of thyroid function.
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Cóclea/patología , Bocio Nodular/patología , Pérdida Auditiva Sensorineural/patología , Proteínas de Transporte de Membrana/genética , Acueducto Vestibular/anomalías , Niño , Preescolar , Cóclea/diagnóstico por imagen , Implantes Cocleares , Femenino , Bocio Nodular/diagnóstico por imagen , Bocio Nodular/genética , Pérdida Auditiva Sensorineural/diagnóstico por imagen , Pérdida Auditiva Sensorineural/genética , Humanos , Recién Nacido , Masculino , Mutación , Tomografía Computarizada por Rayos X , Acueducto Vestibular/diagnóstico por imagen , Acueducto Vestibular/patologíaRESUMEN
BACKGROUND: Patients with nonallergic rhinitis with eosinophilia syndrome (NARES) show typical symptoms of persistent allergic rhinitis (PAR). The aim of the present study was to compare nasal cytokine patterns between NARES and PAR. METHODS: Nasal secretions of 31 patients suffering from NARES, 20 patients with PAR to house dust mite and 21 healthy controls were collected using the cotton wool method and analyzed for interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1ß (MIP-1ß) by Bio-Plex Cytokine Assay as well as eosinophil cationic protein (ECP) and tryptase by UniCAP-FEIA. RESULTS: NARES and PAR presented elevated levels of tryptase, while ECP was markedly increased solely in NARES compared to both the controls and PAR. Elevated levels of IL-1ß, IL-17, IFN-γ, TNF-α and MCP-1 were found in NARES compared to the controls as well as PAR. MIP-1ß was elevated in NARES and PAR, while IL-4, IL-6 and G-CSF showed increased levels in NARES, and IL- 5 was elevated in PAR only. CONCLUSIONS: In patients with NARES and PAR, eosinophils and mast cells appear to be the pivotal cells of inflammation, reflected by high levels of tryptase and ECP as well as IL-5 and GM-CSF as factors for eosinophil migration and survival. The elevated levels of proinflammatory cytokines in NARES may indicate the chronic, self-perpetuating process of inflammation in NARES which seems to be more pronounced than in PAR. IL-17 might be a factor for neutrophilic infiltration or be responsible for remodeling processes in NARES.
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Citocinas/metabolismo , Eosinofilia/complicaciones , Eosinofilia/inmunología , Mediadores de Inflamación/metabolismo , Rinitis Alérgica Perenne/inmunología , Rinitis/complicaciones , Rinitis/inmunología , Adolescente , Adulto , Anciano , Animales , Estudios de Casos y Controles , Dermatophagoides pteronyssinus/inmunología , Eosinófilos/inmunología , Femenino , Humanos , Masculino , Mastocitos/inmunología , Persona de Mediana Edad , Mucosa Nasal/inmunología , Síndrome , Adulto JovenRESUMEN
Hearing loss (HL) is the most common sensory defect and affects 450 million people worldwide in a disabling form. Pathogenic sequence alterations in the POU3F4 gene, which encodes a transcription factor, are causative of the most common type of X-linked deafness (X-linked deafness type 3, DFN3, DFNX2). POU3F4-related deafness is characterized by a typical inner ear malformation, namely an incomplete partition of the cochlea type 3 (IP3), with or without an enlargement of the vestibular aqueduct (EVA). The pathomechanism underlying POU3F4-related deafness and the corresponding transcriptional targets are largely uncharacterized. Two male patients belonging to a Caucasian cohort with HL and EVA who presented with an IP3 were submitted to genetic analysis. Two novel sequence variants in POU3F4 were identified by Sanger sequencing. In cell-based assays, the corresponding protein variants (p.S74Afs*8 and p.C327*) showed an aberrant expression and subcellular distribution and lack of transcriptional activity. These two protein variants failed to upregulate the transcript levels of the amino acid transporter gene SLC6A20, which was identified as a novel transcriptional target of POU3F4 by RNA sequencing and RT-qPCR. Accordingly, POU3F4 silencing by siRNA resulted in downregulation of SLC6A20 in mouse embryonic fibroblasts. Moreover, we showed for the first time that SLC6A20 is expressed in the mouse cochlea, and co-localized with POU3F4 in the spiral ligament. The findings presented here point to a novel role of amino acid transporters in the inner ear and pave the way for mechanistic studies of POU3F4-related HL.
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OBJECTIVES: Hearing loss is a clinical symptom, frequently mentioned in the context of mitochondrial disease. With no cure available for mitochondrial disease, supportive treatment of clinical symptoms like hearing loss is of the utmost importance. The aim of this study was to summarize current knowledge on hearing loss in genetically proven mitochondrial disease in children and deduce possible and necessary consequences in patient care. METHODS: Systematic literature review, including Medline, Embase, and Cochrane library. Review protocol was established and registered prior to conduction (International prospective register of systematic reviews-PROSPERO: CRD42020165356). Conduction of this review was done in accordance with MOOSE criteria. RESULTS: A total of 23 articles, meeting predefined criteria and providing sufficient information on 75 individuals with childhood onset hearing loss was included for analysis. Both cochlear and retro-cochlear origin of hearing loss can be identified among different types of mitochondrial disease. Analysis was hindered by inhomogeneous reporting and methodical limitations. CONCLUSION: Overall, the findings do not allow for a general statement on hearing loss in children with mitochondrial disease. Retro-cochlear hearing loss seems to be found more often than expected. A common feature appears to be progression of hearing loss over time. However, hearing loss in these patients shows manifold characteristics. Therefore, awareness of mitochondrial disease as a possible causative background is important for otolaryngologists. Future attempts rely on standardized reporting and long-term follow-up. LEVEL OF EVIDENCE: NA Laryngoscope, 132:2459-2472, 2022.
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Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva , Enfermedades Mitocondriales , Humanos , Pérdida Auditiva/diagnóstico , Enfermedades Mitocondriales/complicacionesRESUMEN
Hearing loss is the most common sensorial deficit in humans and one of the most common birth defects. In developed countries, at least 60% of cases of hearing loss are of genetic origin and may arise from pathogenic sequence alterations in one of more than 300 genes known to be involved in the hearing function. Hearing loss of genetic origin is frequently associated with inner ear malformations; of these, the most commonly detected is the enlarged vestibular aqueduct (EVA). EVA may be associated to other cochleovestibular malformations, such as cochlear incomplete partitions, and can be found in syndromic as well as non-syndromic forms of hearing loss. Genes that have been linked to non-syndromic EVA are SLC26A4, GJB2, FOXI1, KCNJ10, and POU3F4. SLC26A4 and FOXI1 are also involved in determining syndromic forms of hearing loss with EVA, which are Pendred syndrome and distal renal tubular acidosis with deafness, respectively. In Caucasian cohorts, approximately 50% of cases of non-syndromic EVA are linked to SLC26A4 and a large fraction of patients remain undiagnosed, thus providing a strong imperative to further explore the etiology of this condition.
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OBJECTIVE: Clinical report on feasibility and outcome of a surgical procedure. PATIENT: Nine-year-old child, supplied with a transcutaneous bone conduction hearing implant, requiring magnetic resonance imaging of the head to exclude a tumor of the pituitary gland. INTERVENTION: Temporal removal and subsequent reimplantation of the implant in a single surgical procedure. MAIN OUTCOME MEASURE: Postoperative audiometric results. CONCLUSION: Under specific clinical circumstances, temporary removal of the transcutaneous bone conduction implant described, is technically accomplishable.
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Remoción de Dispositivos/métodos , Audífonos , Imagen por Resonancia Magnética/métodos , Hipófisis/diagnóstico por imagen , Conducción Ósea , Niño , Femenino , HumanosRESUMEN
BACKGROUND: Tumour heterogeneity and clonal evolution within a cancer patient are deemed responsible for relapse in malignancies and present challenges to the principles of targeted therapy, for which treatment modality is often decided based on the molecular pathology of the primary tumour. Nevertheless, the clonal architecture in distant relapse of head and neck cancer is fairly unknown. PATIENTS AND METHODS: For this project, we analysed a cohort of 386 patients within the Austrian Registry of head and neck cancer. We identified 26 patients with material from the primary tumour, the distant metastasis after curative first-line treatment and a germline sample for analysis of clonal evolution. After pathological analyses, these samples were analysed using a targeted massively parallel sequencing (MPS) panel of 257 genes known to be recurrently mutated in head and neck cancer plus a genome-wide SNP-set. RESULTS: Despite histological diagnosis of distant metastasis, no corresponding mutation in the supposed metastases was found in two of 23 (8.6%) evaluable patients suggesting a primary tumour of the lung instead of a distant metastasis of head and neck cancer. We observed a branched pattern of evolution in 31.6% of the analysed patients. This pattern was associated with a shorter time to distant metastasis, compared with a pattern of punctuated evolution. Structural genomic changes over time were also present in 7 of 12 (60%) evaluable patients with metachronous metastases. CONCLUSION: Targeted MPS demonstrated substantial heterogeneity at the time of diagnosis and a complex pattern of evolution during disease progression in head and neck cancer. Copy number analyses revealed additional changes that were not detected by mutational analyses. Mutational and structural changes contribute to tumour heterogeneity at diagnosis and progression.
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Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/secundario , Evolución Clonal , Neoplasias de Cabeza y Cuello/patología , Recurrencia Local de Neoplasia/patología , Austria , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/terapia , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/terapia , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
OBJECTIVE: Laryngopharyngeal reflux (LPR) is generally treated with twice-daily proton-pump inhibitor (PPI) therapy. In this study, the efficacy of esomeprazole 40 mg once-daily together with lifestyle modifications was determined by repeated 24-hour pH monitoring. STUDY DESIGN AND SETTING: A prospective study. Forty-nine patients with suspected LPR underwent 24-hour pH monitoring. Twenty-seven of 49 patients with measurable abnormal proximal reflux reflected by a reflux area index (RAI)>6.3 were treated with esomeprazole 40 mg every day, and a second pH study was performed. RESULTS: In 22 of 27 patients, everyday PPI treatment reduced the RAI. Four of 5 patients with no RAI reduction reported on symptomatic relief. CONCLUSION: In a considerable number of patients with suspected LPR, pH monitoring reveals no abnormal proximal reflux. Esomeprazole 40 mg every day together with lifestyle modifications could reach adequate acid suppression in a large number of patients. Symptom improvement is also reported by patients without measurable effects of therapy.
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Inhibidores Enzimáticos/uso terapéutico , Esomeprazol/uso terapéutico , Hipofaringe , Enfermedades Faríngeas/tratamiento farmacológico , Adulto , Anciano de 80 o más Años , Femenino , Fundoplicación , Humanos , Concentración de Iones de Hidrógeno , Estilo de Vida , Masculino , Persona de Mediana Edad , Monitoreo AmbulatorioRESUMEN
The cause of unilateral sudden sensorineural hearing loss (SNHL) remains unclear in many clinical cases. Perilymphatic leakage through a fissula ante fenestram (FAF) fistula is one possible reason. We present four clinical cases with proven FAF fistula, discovered during surgical exploration. All patients experienced partial hearing recovery after surgical coverage of the fistula. We suggest FAF as a possible site for perilymphatic leakage, representing an anatomical correlate for sudden unilateral SNHL. We recommend early exploratory tympanotomy with special attention to the bony region, anterior to the oval window, in cases of severe sudden SNHL and suspected FAF.
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Enfermedades Cocleares/complicaciones , Fístula/complicaciones , Pérdida Auditiva Unilateral/etiología , Ventana Redonda/diagnóstico por imagen , Adulto , Anciano , Enfermedades Cocleares/cirugía , Fístula/diagnóstico por imagen , Fístula/cirugía , Humanos , Masculino , Persona de Mediana Edad , Perilinfa , RadiografíaRESUMEN
OBJECTIVES: To examine whether medical history and nasopharyngeal examination are useful for predicting obstructive sleep apnea syndrome (OSAS) and to compare these findings with those of the gold standard, polysomnography. DESIGN: Patients underwent polysomnography recordings for 2 nights and an otorhinolaryngologic examination, including flexible endoscopy and the Muller maneuver. Nasal and pharyngeal findings were scored in a semiquantitative way. The medical history of each patient was taken using a standardized questionnaire. Anatomic and functional findings and patient history were correlated with the mean apnea-hypopnea index (AHI). SETTING: An otorhinolaryngologic clinic. PATIENTS: A total of 101 patients presenting with a primary complaint of snoring. MAIN OUTCOME MEASURES: Differences between patients with OSAS and primary snorers were assessed using the Mann-Whitney test (anatomic findings), t test (Muller maneuver), and chi(2) test after Pearson correlation (questionnaire). P values less than .05 were considered statistically significant. RESULTS: The mean +/- SD AHI of the patients was 19.7 +/- 21.5); 52 patients had an AHI higher than 10, which confirmed the diagnosis of OSAS. These patients tended to report the occurrence of apneas more frequently than patients with an AHI of 10 or lower. The average ranks (Mann-Whitney findings) of patients with AHIs higher than 10 vs those with AHIs of 10 or lower were 52 vs 50 for septal deviation; 50 vs 52 for tonsil size; 53 vs 49 for low velum level; and 56 vs 46 for hyperplasia of the tongue base. None of these differences reached statistical significance. Mean +/- SD narrowing of the airway during the Müller maneuver was significantly (P<.05) more pronounced in patients with an AHI higher than 10 than in patients with an AHI of 10 or lower at the levels of the velum (80% +/- 20% vs 68% +/- 30%) and the tongue base (57% +/- 24% vs 44% +/- 27%). CONCLUSIONS: None of the reported medical history and/or anatomic parameters alone or in combination could be used to distinguish patients with OSAS from snoring patients. Snoring patients, therefore, should be examined at least by a nocturnal screening test for OSAS before any therapeutic decision is made.