Elastometry - The biomechanical analysis of the lateral nasal wall.

'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.

Novel POU3F4 variants identified in patients with inner ear malformations exhibit aberrant cellular distribution and lack of SLC6A20 transcriptional upregulation.

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.

Mitochondrial Disease and Hearing Loss in Children: A Systematic Review.

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.

Genetic Determinants of Non-Syndromic Enlarged Vestibular Aqueduct: A Review.

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.

[Molecular and functional testing in case of hereditary hearing loss associated with the SLC26A4 gene]. / Molekulare und funktionale Abklärung hereditärer Schwerhörigkeiten am Beispiel des SLC26A4-Gens.

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.

Temporary Explant of a Transcutaneous Bone Conduction Hearing Implant for Imaging of the Pituitary Gland.

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.

Clonal evolution and heterogeneity in metastatic head and neck cancer-An analysis of the Austrian Study Group of Medical Tumour Therapy study group.

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.

Functional Testing of SLC26A4 Variants-Clinical and Molecular Analysis of a Cohort with Enlarged Vestibular Aqueduct from Austria.

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.

The role of fissula ante fenestram in unilateral sudden hearing loss.

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.

A common language to assess allergic rhinitis control: results from a survey conducted during EAACI 2013 Congress.

BACKGROUND: The concept of control is gaining importance in the field of allergic rhinitis (AR), with a visual analogue scale (VAS) score being a validated, easy and attractive tool to evaluate AR symptom control. The doctors' perception of a VAS score as a good tool for evaluating AR symptom control is unknown, as is the level of AR control perceived by physicians who treat patients. METHODS: 307 voluntarily selected physicians attending the annual (2013) European Academy of Allergy and Clinical Immunology (EAACI) meeting completed a digital survey. Delegates were asked to (1) estimate how many AR patients/week they saw during the season, (2) estimate the proportion of patients they considered to have well-, partly- and un-controlled AR, (3) communicate how they gauged this control and (4) assess how useful they would find a VAS as a method of gauging control. 257 questionnaires were filled out completely and analysed. RESULTS: EAACI delegates reported seeing 46.8 [standard deviation (SD) 68.5] AR patients/week during the season. They estimated that 38.7 % (SD 24.0), 34.2 % (SD 20.2) and 20.0 % (SD 16.34) of their AR patients had well-controlled (no AR symptoms), partly-controlled (some AR symptoms), or un-controlled-(moderate/severe AR symptoms) disease despite taking medication [remainder unknown (7.1 %)]. However, AR control was assessed in many ways, including symptom severity (74 %), frequency of day- and night-time symptoms (67 %), activity impairment (57 %), respiratory function monitoring (nasal and/or lung function; 40 %) and incidence of AR exacerbations (50 %). 91 % of delegates felt a simple VAS would be a useful tool to gauge AR symptom control. CONCLUSIONS: A substantial portion of patients with AR are perceived as having uncontrolled or partly controlled disease even when treated. A simple VAS score is considered a useful tool to monitor AR control.

Ectopic apocrine glands as a predisposing factor for postinflammatory medial meatal fibrosis: a clinicopathologic study.

OBJECTIVE: To illuminate pathophysiologic processes in postinflammatory medial meatal fibrosis (PMMF), a rare otologic disease of unknown etiology, which is defined by a progressive, obliterating fibrosis that affects the osseous part of the external auditory canal (EAC) exclusively. STUDY DESIGN: Retrospective clinical and histopathologic study. SETTING: Tertiary referral center. PATIENTS: Eleven patients (4 female and 7 male subjects) who underwent surgery of the bony EAC due to PMMF (13 ears operated). METHODS: Histologic and immunohistochemical assessment of tissue specimens obtained during surgical excision. MAIN OUTCOME MEASURE: Detection of ectopic apocrine glands and concomitant inflammatory infiltrate within tissue harvested from the osseous EAC. RESULTS: Additionally to expected histologic findings, such as excessive fibrosis and a chronic inflammatory infiltrate, ectopic spread of apocrine glands was consistently detected in all of our patients. CONCLUSION: Based on our findings, we suggest that an ectopic occurrence of adnexal structures within the bony EAC may predispose susceptible individuals to the development of PMMF. To avoid postoperative recurrence due to iatrogenic spread of cutaneous adnexal structures during surgery, the split-thickness skin graft should not exceed a thickness of 0.4 mm.

Anatomic parameters of the long process of incus for stapes surgery.

HYPOTHESIS: The purpose of this study is to offer new anatomic data about the long process of incus (LPI) for stapes surgery. BACKGROUND: Anatomic study of 50 human macerated incudes to measure different parameters of cross sections of the LPI. METHODS: Step-by-step cutting of the LPI perpendicular to its axis starting from its free end next to the lenticular process. The layer thickness was 0.5 mm. The cutting surfaces were documented with Canon EOS 20D camera, and a standard software tool (MATLAB) was used for automated statistical analysis. RESULTS: The LPI had a maximum diameter of 1.15 mm and a minimum diameter of 0.52 mm at the level of 1.5 mm far from the tip of the long process, which is the most common site for stapes prosthesis attachment. Concerning each cross section, having a long and a short diameter, the average long diameter is 0.9011 mm, and the short diameter is 0.6507 mm. CONCLUSION: Our anatomic study revealed wide variations of diameters and shape of the LPI. Best possible crimping of stapes prosthesis depends not only on the shape and diameters of the LPI but also on the vertical surface of the LPI as well. To prevent incus necrosis due to compression of the feeding blood vessels, the maximum contact surface of the loop of stapes prosthesis should be about 1.9 mm in length.

Congenital granular cell tumor with uncommon clinical behavior.

OBJECTIVES/HYPOTHESIS: Congenital granular cell tumor (CGCT), also known as congenital epulis, is a rare benign mesenchymal tumor of the oral cavity. We report of a 3 years and 7 months old female patient undergoing surgical excision of an oral tumor. Subsequent histological and immunohistological investigations within the clinical course led to the diagnosis of CGCT. However, clinical findings in this case, such as primary onset and an untypical location within the oral cavity, clearly stand in contrast to those usually found in CGCT, resulting in an exceptional case not previously described in the literature.