The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis.

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

Hearing loss and history of otolaryngological conditions in adults with microdeletion 22q11.2.

Previous studies have shown that the 22q11.2 microdeletion, associated with 22q11.2 deletion syndrome (22q11.2DS), conveys an increased risk of chronic otitis media, and hearing loss at young age. This study reports on hearing loss and history of otolaryngological conditions in adults with 22q11.2DS. We conducted a retrospective study of 60 adults with 22q11.2DS (41.7% male) at median age 25 (range 16-74) years who had visited an otolaryngologist and audiologist for routine assessment at a 22q11.2 expert center. Demographic, genetic, audiometric, and otolaryngological data were systematically extracted from the medical files. Regression analysis was used to evaluate the effect of age, sex, full-scale intelligence quotient, and history of chronic otitis media on the severity of hearing loss. Hearing loss, mostly high-frequency sensorineural, was found in 78.3% of adults. Higher age and history of chronic otitis media were associated with more severe hearing loss. Otolaryngological conditions with possible treatment implications included chronic otitis media (56.7%), globus pharyngeus (18.3%), balance problems (16.7%), and obstructive sleep apnea (8.3%). The results suggest that  in 22q11.2DS, high-frequency hearing loss appears to be common from a young adult age, and often unrecognized. Therefore, we recommend periodic audiometric screening in all adults, including high-frequency ranges.

Vestibular assessment in children with sensorineural hearing loss: diagnostic accuracy and proposal for a diagnostic algorithm.

Introduction: Vestibular assessment in children with sensorineural hearing loss (SNHL) is critical for early vestibular rehabilitation therapy to promote (motor) development or guide decision making towards cochlear implantation (timing of surgery and laterality). It can be challenging from a clinical viewpoint to decide which vestibular tests should be performed for a pediatric patient. The aim of this study was to evaluate the diagnostic accuracy of several clinically available vestibular tests in children with SNHL, and to provide recommendations for the implementation of vestibular testing of children in clinical practice, to screen for vestibular hypofunction (VH). Methods: A two-center retrospective chart review was conducted. Eighty-six patients between the age of 0 and 18 years were included in this study with SNHL. Vestibular tests included video headimpulse test (VHIT), caloric test (performed at the age of four or higher), rotatory chair and cervical vestibular evoked myogenic potential (cVEMP). A combination of the clinical assessment and (combinations of) vestibular test outcomes determined the diagnosis. The diagnostic quality of tests and combination of tests was assessed by diagnostic accuracy, sensitivity and specificity. Results: VH was diagnosed in 44% of the patients. The VHIT and caloric test showed the highest diagnostic accuracy compared to the rotatory chair and cVEMP. All combinations of VHIT, caloric test and cVEMP showed improvement of the diagnostic accuracy compared to the respective tests when performed singularly. All combinations of tests showed a relatively similar diagnostic accuracy, with the VHIT combined with the caloric test scoring the highest. Adding a third test did not substantially improve the diagnostic accuracy. Discussion: Vestibular testing is feasible and VH is highly prevalent in children with SNHL. A proposed diagnostic algorithm recommends starting with VHIT, followed by cVEMP for children under the age of four, and caloric testing for older children if VH is not confirmed with the first test. Performing a third test is redundant as the diagnostic accuracy does not improve substantially. However, challenges remain, including the lack of a gold standard and the subjective nature of the diagnosis, highlighting the need for standardized testing and increased understanding of VH in this population.

The DizzyQuest Combined with Accelerometry: Daily Physical Activities and Limitations among Patients with Bilateral Vestibulopathy Due to DFNA9.

BACKGROUND: DFNA9 is a genetic disease of the inner ear, causing progressive bilateral sensorineural deafness and bilateral vestibulopathy (BV). In this study, DizzyQuest, a mobile vestibular diary, and the MOX accelerometer were combined to assess the daily life functional limitations and physical activity of patients with DFNA9 suffering from BV. These parameters might be appropriate as potential candidacy criteria and outcome measures for new therapeutic interventions for BV. METHODS: Fifteen DFNA9 patients with BV and twelve age-matched healthy controls were included. The DizzyQuest was applied for six consecutive days, which assessed the participants' extent of functional limitations, tiredness, types of activities performed during the day, and type of activity during which the participant felt most limited. The MOX accelerometer was worn during the same six days of DizzyQuest use, measuring the participants intensity and type of physical activity. Mixed-effects linear and logistic regression analyses were performed to compare the DFNA9 patients and control group. RESULTS: DFNA9 patients with BV felt significantly more limited in activities during the day compared to the age-matched controls, especially in social participation (p < 0.005). However, these reported limitations did not cause adjustment in the types of activities and did not reduce the intensity or type of physical activity measured with accelerometry. In addition, no relationships were found between self-reported functional limitations and physical activity. CONCLUSIONS: This study demonstrated that self-reported functional limitations are significantly higher among DFNA9 patients with BV. As a result, these limitations might be considered as part of the candidacy criteria or outcome measures for therapeutic interventions. In addition, the intensity or type of physical activity performed during the day need to be addressed more specifically in future research.

Effect of cochlear implantation on vestibular function in children: A scoping review.

Objective: To provide a scoping review of the available literature for determining objectively the effect of cochlear implantation on vestibular function in children. Methods: A literature search was performed and the following criteria were applied: vestibular tests that were performed on subjects within the range of 0-18 years old before and after cochlear implantation. The papers conducted at least one of the following tests: (video) head impulse test, caloric test, cervical and ocular vestibular evoked myogenic potentials or rotatory chair test. Included papers underwent quality assessment and this was graded by risk of bias and directness of evidence. Results: Fourteen articles met the selection criteria. The included studies showed that cochlear implantation leads to a decrease in vestibular function in a proportion of the patient population. This loss of vestibular function can be permanent, but (partial) restoration over the course of months to years is possible. The pooling of data determined that the articles varied on multiple factors, such as time of testing pre- and post-operatively, age of implantation, etiologies of hearing loss, used surgical techniques, type of implants and the applied protocols to determine altered responses within vestibular tests. The overall quality of the included literature was deemed as high risk of bias and medium to low level of directness of evidence. Therefore, the data was considered not feasible for systematic analysis. Conclusion: This review implicates that vestibular function is either unaffected or shows short-term or permanent deterioration after cochlear implantation in children. However, the heterogeneity of the available literature indicates the importance of standardized testing to improve our knowledge of the effect of cochlear implantation on the vestibular function and subsequent developmental consequences for the concerned children.

Bilateral vestibulopathy decreases self-motion perception.

OBJECTIVE: Current diagnostic criteria for bilateral vestibulopathy (BV) primarily involve measurements of vestibular reflexes. Perceptual self-motion thresholds however, are not routinely measured and their clinical value in this specific population is not yet fully determined. Objectives of this study were (1) to compare perceptual self-motion thresholds between BV patients and control subjects, and (2) to explore patterns of self-motion perception performance and vestibular function in BV patients. METHODS: Thirty-seven BV patients and 34 control subjects were included in this study. Perceptual self-motion thresholds were measured in both groups using a CAREN platform (Motek Medical BV, Amsterdam, The Netherlands). Vestibular function was evaluated (only in BV patients) by the caloric test, torsion swing test, video head impulse test of all semicircular canals, and cervical- and ocular vestibular-evoked myogenic potentials. Differences in thresholds between both groups were analyzed. Hierarchical cluster analysis was performed to visualize patterns between self-motion perception and vestibular function within the group of BV patients. RESULTS: Perceptual self-motion thresholds were significantly higher in BV patients compared to control subjects, regarding nearly all rotations and translations (depending on the age group) (p ≤ 0.001). Cluster analysis showed that within the group of BV patients, higher perceptual self-motion thresholds were generally associated with lower vestibular test results (significant for yaw rotation, caloric test, torsion swing test, and video head impulse test (p ≤ 0.001)). CONCLUSION: Self-motion perception is significantly decreased in BV patients compared to control subjects regarding nearly all rotations and translations. Furthermore, decreased self-motion perception is generally associated with lower residual vestibular function in BV patients. TRIAL REGISTRATION: Trial registration number NL52768.068.15/METC.

Bilateral vestibulopathy patients' perspectives on vestibular implant treatment: a qualitative study.

OBJECTIVES: The aim of this study was to explore expectations of patients with bilateral vestibulopathy regarding vestibular implant treatment. This could advance the definition of recommendations for future core outcome sets of vestibular implantation and help to determine on which characteristics of bilateral vestibulopathy future vestibular implant research should focus. METHODS: Semi-structured interviews were conducted with 50 patients diagnosed with bilateral vestibulopathy at Maastricht UMC + . Interviews followed a semi-structured interview guide and were recorded and transcribed. Transcripts were analyzed thematically by two independent researchers. A consensus meeting took place to produce a joint interpretation for greater dimensionality and to confirm key themes. RESULTS: Overall, patient expectations centralized around three key themes: (physical) symptom reduction, functions and activities, and quality of life. These themes appeared to be interrelated. Patient expectations focused on the activity walking (in a straight line), reducing the symptom oscillopsia and being able to live the life they had before bilateral vestibulopathy developed. In general, patients indicated to be satisfied with small improvements. CONCLUSION: This study demonstrated that patient expectations regarding a vestibular implant focus on three key themes: symptom reduction, functions and activities, and quality of life. These themes closely match the functional improvements shown in recent vestibular implantation research. The results of this study provide a clear guideline from the patient perspective on which characteristics of bilateral vestibulopathy, future vestibular implant research should focus. TRIAL REGISTRATION: NL52768.068.15/METC.

Development and Content Validity of the Bilateral Vestibulopathy Questionnaire.

Background: To date, the burden and severity of the full spectrum of bilateral vestibulopathy (BVP) symptoms has not yet been measured in a standardized manner. Since therapeutic interventions aiming to improve BVP symptoms are emerging, the need for a new standardized assessment tool that encompasses the specific aspects of BVP arises. Therefore, the aim of this study was to develop a multi-item Patient Reported Outcome Measure (PROM) that captures the clinically important symptoms of BVP and assesses its impact on daily life. Methods: The development of the Bilateral Vestibulopathy Questionnaire (BVQ) consisted of two phases: (I) initial item generation and (II) face and content validity testing. Items were derived from a literature review and individual semi-structured interviews focusing on the full spectrum of reported BVP symptoms (I). Subsequently (IIa), individual patient interviews were conducted using "thinking aloud" and concurrent verbal probing techniques to assess the comprehensibility of the instructions, questions and response options, and the relevance, missing domains, or missing items. Interviews continued until saturation of input was reached. Finally, international experts with experience in the field of the physical, emotional, and cognitive symptoms of BVP participated in an online focus group to assess the relevance and comprehensiveness of the BVQ (IIb). Results: The BVQ consisted of two sections. The first section included 50 items scored on a six-point Likert scale arranged into seven constructs (i.e., imbalance, oscillopsia, other physical symptoms, cognitive symptoms, emotional symptoms, limitations and behavioral changes and social life). The second section consisted of four items, scored on a visual analog scale from 0 to 100, to inquire about limitations in daily life, perceived health and expectations regarding future recovery. Interviews with BVP patients [n = 8, 50% female, mean age 56 years (range 24-88 years)] and the expert meeting confirmed face and content validity of the developed BVQ. Conclusion: The BVQ, which was developed to assess the spectrum of BVP symptoms and its impact on daily life, proved to have good face and content validity. It can be used to characterize current self-reported symptoms and disability and to evaluate symptom burden before and after therapeutic interventions in future research and clinical practice.

Patterns of Vestibular Impairment in Bilateral Vestibulopathy and Its Relation to Etiology.

Objective: This study aimed to investigate (1) the patterns of vestibular impairment in bilateral vestibulopathy (BVP) and subsequently, the implications regarding patient eligibility for vestibular implantation, and (2) whether this pattern and severity of vestibular impairment is etiology dependent. Methods: A total of one hundred and seventy-three subjects from three tertiary referral centers in Europe were diagnosed with BVP according to the Bárány Society diagnostic criteria. The subjects underwent vestibular testing such as the caloric test, torsion swing test, video Head Impulse Test (vHIT) in horizontal and vertical planes, and cervical and/or ocular vestibular evoked myogenic potentials (c- and oVEMPs). The etiologies were split into idiopathic, genetic, ototoxicity, infectious, Menière's Disease, (head)trauma, auto-immune, neurodegenerative, congenital, and mixed etiology. Results: The caloric test and horizontal vHIT more often indicated horizontal semicircular canal impairment than the torsion swing test. The vHIT results showed significantly higher gains for both anterior canals compared with the horizontal and posterior canals (p < 0.001). The rates of bilaterally absent oVEMP responses were higher compared to the bilaterally absent cVEMP responses (p = 0.010). A total of fifty-four percent of the patients diagnosed with BVP without missing data met all three Bárány Society diagnostic test criteria, whereas 76% of the patients were eligible for implantation according to the vestibular implantation criteria. Regarding etiology, only horizontal vHIT results were significantly lower for trauma, neurodegenerative, and genetic disorders, whereas the horizontal vHIT results were significantly higher for Menière's Disease, infectious and idiopathic BVP. The exploration with hierarchical cluster analysis showed no significant association between etiology and patterns of vestibular impairment. Conclusion: This study showed that caloric testing and vHIT seem to be more sensitive for measuring vestibular impairment, whereas the torsion swing test is more suited for measuring residual vestibular function. In addition, no striking patterns of vestibular impairment in relation to etiology were found. Nevertheless, it was demonstrated that although the implantation criteria are stricter compared with the Bárány Society diagnostic criteria, still, 76% of patients with BVP were eligible for implantation based on the vestibular test criteria. It is advised to carefully examine every patient for their overall pattern of vestibular impairment in order to make well-informed and personalized therapeutic decisions.

Vestibular Migraine of Childhood and Recurrent Vertigo of Childhood: Diagnostic criteria Consensus document of the Committee for the Classification of Vestibular Disorders of the Bárány Society and the International Headache Society.

This paper describes the diagnostic criteria for "Vestibular Migraine of Childhood", "probable Vestibular Migraine of Childhood" and "Recurrent Vertigo of Childhood" as put forth by the Committee for the Classification of Vestibular Disorders of the Bárány Society (ICVD) and the Migraine Classification subgroup of the International Headache Society. Migraine plays an important role in some subgroups of children with recurrent vertigo. In this classification paper a spectrum of three disorders is described in which the migraine component varies from definite to possibly absent. These three disorders are: Vestibular Migraine of Childhood, probable Vestibular Migraine of Childhood and Recurrent Vertigo of Childhood. The criteria for Vestibular Migraine of Childhood (VMC) include (A) at least five episodes with vestibular symptoms of moderate or severe intensity, lasting between five minutes and 72 hours, (B) a current or past history of migraine with or without aura, and (C) at least half of episodes are associated with at least one migraine feature. Probable Vestibular Migraine of Childhood (probable VMC) is considered when at least three episodes with vestibular symptoms of moderate or severe intensity, lasting between five minutes and 72 hours, are accompanied by at least criterion B or C from the VMC criteria. Recurrent Vertigo of Childhood (RVC) is diagnosed in case of at least three episodes with vestibular symptoms of moderate or severe intensity, lasting between 1 minute and 72 hours, and none of the criteria B and C for VMC are applicable. For all disorders, the age of the individual needs to be below 18 years old. It is recommended that future research should particularly focus on RVC, in order to investigate and identify possible subtypes and its links or its absence thereof with migraine.

Challenges in evaluating the oculomotor function in individuals with Rett syndrome using electronystagmography.

BACKGROUND: Rett syndrome (RTT) is a neurological disorder characterized by a broad spectrum of symptoms. Communication is a major area of difficulty. Use of eye tracking technology offers a potentially effective method of communication when underpinned by intact oculomotor function. In this study, oculomotor function was assessed using electronystagmography (ENG). However, challenges were encountered when examining individuals with RTT. PURPOSE: To improve oculomotor examination in individuals with RTT by evaluating the challenges encountered during ENG examination. MATERIAL AND METHODS: Oculomotor function was examined in 17 girls and young women with RTT and 16 typically developing (TD) individuals using ENG. Observational analysis of both performance and results indicated that challenges in examination were mainly related to quality of attention and quality of signals. Subsequently these outcome values were explored quantitatively according to percentage looking time for attention and drift for signal quality. RESULTS: A significantly reduced level of attention and suboptimal electrode signals were evident in the RTT group when compared with the TD group for all tests except torsion swing. CONCLUSION: The challenges in testing confirm that regular oculomotor examination should be adjusted to meet the needs of individuals with RTT. It is hypothesized that the RTT group's higher quality of attention on the torsion swing can be explained by the more forceful vestibular rather than visual-ocular stimulus operating in this test. Suggested adaptations include reducing the number of electrodes, changing the picture stimuli and bringing them closer, performing observational assessments rather than ENG, and using virtual reality goggles.

Bi-allelic inactivating variants in the COCH gene cause autosomal recessive prelingual hearing impairment.

Pathogenic variant in COCH are a known cause of DFNA9 autosomal dominant progressive hearing loss and vestibular dysfunction with adult onset. Hitherto, only dominant nonsynonymous variants and in-frame deletions with a presumed dominant negative or gain-of-function effect have been described. Here, we describe two brothers with congenital prelingual deafness and a homozygous nonsense c.292C>T(p.Arg98*) COCH variant, suggesting a loss-of-function effect. Vestibular dysfunction starting in the first decade was observed in the older patient. The heterozygous parents and sibling have normal hearing and vestibular function, except for the mother, who shows vestibular hyporeflexia and abnormal smooth pursuit tests, most likely due to concomitant disease. This is the first report of autosomal recessive inheritance of cochlea-vestibular dysfunction caused by a pathogenic variant in the COCH gene. An earlier onset of hearing impairment and vestibular dysfunction compared to the dominant hearing loss causing COCH variants is observed.

Oculomotor Function in Individuals With Rett Syndrome.

BACKGROUND: Individuals with Rett syndrome (RTT) are notoriously reliant on the use of eye gaze as a primary means of communication. Underlying an ability to communicate successfully via eye gaze is a complex matrix of requirements, with an intact oculomotor system being just one element. To date, the underlying neural and motor pathways associated with eye gaze are relatively under-researched in RTT. PURPOSE: This study was undertaken to plug this gap in knowledge and to further the understanding of RTT in one specific area of development and function, namely oculomotor function. MATERIAL AND METHODS: The eye movements of 18 girls and young women with RTT were assessed by electronystagmography (ENG). This tested their horizontal saccadic and smooth pursuit eye movements as well as optokinetic nystagmus and vestibulo-ocular reflex. Their results were compared with normative data collected from 16 typically developing children and teenagers. RESULTS: Overall, the individuals with RTT demonstrated a range of eye movements on a par with their typically developing peers. However, there were a number of difficulties in executing the ENG testing with the RTT cohort which made quantitative analysis tricky, such as reduced motivation and attention to test materials and low-quality electrode signals. CONCLUSIONS: This study suggests that individuals with RTT have an intact oculomotor system. However, modifications should be made to the ENG assessment procedure to combat problems in testing and add strength to the results. Further investigation into these testing difficulties is warranted in order to inform such modifications.

A candidate gene approach to identify modifiers of the palatal phenotype in 22q11.2 deletion syndrome patients.

OBJECTIVE: Palatal anomalies are one of the identifying features of 22q11.2 deletion syndrome (22q11.2DS) affecting about one third of patients. To identify genetic variants that increase the risk of cleft or palatal anomalies in 22q11.2DS patients, we performed a candidate gene association study in 101 patients with 22q11.2DS genotyped with the Affymetrix genome-wide human SNP array 6.0. METHODS: Patients from Children's Hospital of Philadelphia, USA and Wilhelmina Children's Hospital Utrecht, The Netherlands were stratified based on palatal phenotype (overt cleft, submucosal cleft, bifid uvula). SNPs in 21 candidate genes for cleft palate were analyzed for genotype-phenotype association. In addition, TBX1 sequencing was carried out. Quality control and association analyses were conducted using the software package PLINK. RESULTS: Genotype and phenotype data of 101 unrelated patients (63 non-cleft subjects (62.4%), 38 cleft subjects (37.6%)) were analyzed. A Total of 39 SNPs on 10 genes demonstrated a p-value ≤0.05 prior to correction. The most significant SNPs were found on FGF10. However none of the SNPs remained significant after correcting for multiple testing. CONCLUSIONS: Although these results are promising, analysis of additional samples will be required to confirm that variants in these regions influence risk for cleft palate or palatal anomalies in 22q11.2DS patients.

Histology of the pharyngeal constrictor muscle in 22q11.2 deletion syndrome and non-syndromic children with velopharyngeal insufficiency.

Plastic surgeons aim to correct velopharyngeal insufficiency manifest by hypernasal speech with a velopharyngoplasty. The functional outcome has been reported to be worse in patients with 22q11.2 deletion syndrome than in patients without the syndrome. A possible explanation is the hypotonia that is often present as part of the syndrome. To confirm a myogenic component of the etiology of velopharyngeal insufficiency in children with 22q11.2 deletion syndrome, specimens of the pharyngeal constrictor muscle were taken from children with and without the syndrome. Histologic properties were compared between the groups. Specimens from the two groups did not differ regarding the presence of increased perimysial or endomysial space, fiber grouping by size or type, internalized nuclei, the percentage type I fibers, or the diameters of type I and type II fibers. In conclusion, a myogenic component of the etiology of velopharyngeal insufficiency in children with 22q11.2 deletion syndrome could not be confirmed.

Outcome of velopharyngoplasty in patients with velocardiofacial syndrome.

OBJECTIVE: To compare the outcomes of surgical correction of velopharyngeal insufficiency (VPI) in patients with velocardiofacial syndrome (VCFS) and a non-VCFS group. DESIGN: Twenty-five patients with VCFS (16 girls and 9 boys) underwent palatal lengthening for VPI between 1986 and 2001. The mean age at surgery was 6.4 years. Revision was defined as the need for secondary sphincter pharyngoplasty as determined by speech investigation, nasal endoscopy, and acoustic nasometry. A comparison was made to a control group made up of a randomized group of patients without VCFS who underwent palatal lengthening for VPI (32 patients: 10 girls and 22 boys). SETTING: Wilhelmina Children's Hospital, a tertiary referral center in Utrecht, the Netheralands. PATIENTS: A total of 57 patients who underwent palatal lengthening for VPI, 25 with VCFS and 32 without VCFS. INTERVENTIONS: Primary surgery consisted of a palatal lengthening technique. If revision was needed, a sphincter pharyngoplasty was carried out. MAIN OUTCOME MEASURES: Pharyngeal function was assessed using perceptual speech investigation, nasal endoscopy, and acoustic nasometry. RESULTS: In the VCFS group, 16% of the patients required surgical revision (4 of 25). These patients were slightly older at the time of primary surgery than those who did not require surgical revision (mean age, 6 vs 5.5 years). In the control group, no patients required revision. Preoperative speech analysis showed a more pronounced VPI in the VCFS group than in the control group. Outcomes of endoscopy and speech hypernasality improved significantly more in the control group than in the VCFS group. Improvement in the results of acoustic nasometry did not differ significantly between the 2 groups. CONCLUSIONS: Treatment of VPI using palatal lengthening in children with VCFS is both safe and effective. The discrepancy in improvement between the speech analysis and the nasal endoscopy results within the VCFS group indicates that mechanical improvement does not necessarily correspond to an improvement in speech and emphasizes the complexity of speech disorders found in VCFS.