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Objective: To understand the audiologic and vestibular toxicities associated with adoptive cell immunotherapy (ACI) targeting pigment-pathway antigens on melanoma and to investigate the use of intratympanic steroid injections in the treatment of these toxicities.Study Design: Prospective nonrandomized study.Setting: Tertiary clinical research center.Methods: Thirty-two patients with progressive metastatic melanoma who failed conventional therapy underwent ACI with T cells genetically modified to target MART-1 (n = 18) or gp100 (n = 14). All patients received serial audiometric testing. Vestibular testing was performed on patients with vestibular complaints. Patients with significant deficits received intratympanic steroid injections.Results: Of 32 patients, 15 had no hearing change, 9 had mild hearing loss, and 8 had moderate hearing loss following treatment. Ten patients received intratympanic steroid injections for mild (n = 2) or moderate (n = 7) hearing loss or for significant imbalance (n = 1). Of those with mild hearing loss (n = 9), all but 1 recovered to pretreatment hearing levels. Four of 8 patients with moderate hearing loss recovered to baseline hearing levels, and 4 had partial recovery. All 7 patients with posttreatment vestibular complaints had demonstrable vestibular dysfunction. Three of these patients demonstrated recovery to normal vestibular function. The number of modified T cells infused for therapy correlated with the degree of audiovestibular deficit.Conclusion: Adoptive cell immunotherapy targeting pigment-pathway cell proteins, a novel therapy for melanoma, can induce hearing loss and vestibular dysfunction. The presumed mechanism of autoimmune attack on normal melanocytes in the cochlear stria vascularis and in the vestibular organs demonstrates the importance of melanocytes in normal inner ear function. [ABSTRACT FROM AUTHOR]

Fabry disease, OMIM 301500, is a progressive multisystem storage disorder due to the deficiency of alpha-galactosidase A (GALA). Neurological and vascular manifestations of this disorder with regard to hearing loss have not been analysed quantitatively in large cohorts. We conducted a retrospective cross sectional analysis of hearing loss in 109 male and female patients with Fabry disease who were referred to and seen at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA on natural history and enzyme replacement study protocols. There were 85 males aged 6-58 years (mean 31 years, SD 13) and 24 females aged 22-72 years (mean 42 years, SD 12). All patients underwent a comprehensive audiological evaluation. In addition, cerebral white matter lesions, peripheral neuropathy, and kidney function were quantitatively assessed. HL(95), defined as a hearing threshold above the 95th percentile for age and gender matched normal controls, was present in 56% [95% CI (42.2-67.2)] of the males. Prevalence of HL(95) was lower in the group of patients with residual GALA enzyme activity compared with those without detectable activity (33% versus 63%) HL(95) was present in the low-, mid- and high-frequency ranges for all ages. Male patients with HL(95) had a higher microvascular cerebral white matter lesion load [1.4, interquartile range (IQR) 0-30.1 +/- versus 0, IQR 0-0], more pronounced cold perception deficit [19.4 +/- 5.5 versus 13.5 +/- 5.5 of just noticeable difference (JND) units] and lower kidney function [creatinine: 1.6 +/- 1.2 versus 0.77 +/- 0.2 mg/dl; blood urea nitrogen (BUN): 20.1 +/- 14.1 versus 10.3 +/- 3.28 mg/dl] than those without HL(95) (P < 0.001). Of the females, 38% had HL(95). There was no significant association with cold perception deficit, creatinine or BUN in the females. Word recognition and acoustic reflexes analyses suggested a predominant cochlear involvement. We conclude that hearing loss involving all frequency regions significantly contributes to morbidity in patients with Fabry disease. Our quantitative analysis suggests a correlation of neuropathic and vascular damage with hearing loss in the males. Residual GALA activity appears to have a protective effect against hearing loss. [ABSTRACT FROM AUTHOR]

Importance: US government personnel stationed internationally have reported anomalous health incidents (AHIs), with some individuals experiencing persistent debilitating symptoms., Objective: To assess the potential presence of magnetic resonance imaging (MRI)-detectable brain lesions in participants with AHIs, with respect to a well-matched control group., Design, Setting, and Participants: This exploratory study was conducted at the National Institutes of Health (NIH) Clinical Center and the NIH MRI Research Facility between June 2018 and November 2022. Eighty-one participants with AHIs and 48 age- and sex-matched control participants, 29 of whom had similar employment as the AHI group, were assessed with clinical, volumetric, and functional MRI. A high-quality diffusion MRI scan and a second volumetric scan were also acquired during a different session. The structural MRI acquisition protocol was optimized to achieve high reproducibility. Forty-nine participants with AHIs had at least 1 additional imaging session approximately 6 to 12 months from the first visit., Exposure: AHIs., Main Outcomes and Measures: Group-level quantitative metrics obtained from multiple modalities: (1) volumetric measurement, voxel-wise and region of interest (ROI)-wise; (2) diffusion MRI-derived metrics, voxel-wise and ROI-wise; and (3) ROI-wise within-network resting-state functional connectivity using functional MRI. Exploratory data analyses used both standard, nonparametric tests and bayesian multilevel modeling., Results: Among the 81 participants with AHIs, the mean (SD) age was 42 (9) years and 49% were female; among the 48 control participants, the mean (SD) age was 43 (11) years and 42% were female. Imaging scans were performed as early as 14 days after experiencing AHIs with a median delay period of 80 (IQR, 36-544) days. After adjustment for multiple comparisons, no significant differences between participants with AHIs and control participants were found for any MRI modality. At an unadjusted threshold (P < .05), compared with control participants, participants with AHIs had lower intranetwork connectivity in the salience networks, a larger corpus callosum, and diffusion MRI differences in the corpus callosum, superior longitudinal fasciculus, cingulum, inferior cerebellar peduncle, and amygdala. The structural MRI measurements were highly reproducible (median coefficient of variation <1% across all global volumetric ROIs and <1.5% for all white matter ROIs for diffusion metrics). Even individuals with large differences from control participants exhibited stable longitudinal results (typically, <±1% across visits), suggesting the absence of evolving lesions. The relationships between the imaging and clinical variables were weak (median Spearman ρ = 0.10). The study did not replicate the results of a previously published investigation of AHIs., Conclusions and Relevance: In this exploratory neuroimaging study, there were no significant differences in imaging measures of brain structure or function between individuals reporting AHIs and matched control participants after adjustment for multiple comparisons.

Importance: Since 2015, US government and related personnel have reported dizziness, pain, visual problems, and cognitive dysfunction after experiencing intrusive sounds and head pressure. The US government has labeled these anomalous health incidents (AHIs)., Objective: To assess whether participants with AHIs differ significantly from US government control participants with respect to clinical, research, and biomarker assessments., Design, Setting, and Participants: Exploratory study conducted between June 2018 and July 2022 at the National Institutes of Health Clinical Center, involving 86 US government staff and family members with AHIs from Cuba, Austria, China, and other locations as well as 30 US government control participants., Exposures: AHIs., Main Outcomes and Measures: Participants were assessed with extensive clinical, auditory, vestibular, balance, visual, neuropsychological, and blood biomarkers (glial fibrillary acidic protein and neurofilament light) testing. The patients were analyzed based on the risk characteristics of the AHI identifying concerning cases as well as geographic location., Results: Eighty-six participants with AHIs (42 women and 44 men; mean [SD] age, 42.1 [9.1] years) and 30 vocationally matched government control participants (11 women and 19 men; mean [SD] age, 43.8 [10.1] years) were included in the analyses. Participants with AHIs were evaluated a median of 76 days (IQR, 30-537) from the most recent incident. In general, there were no significant differences between participants with AHIs and control participants in most tests of auditory, vestibular, cognitive, or visual function as well as levels of the blood biomarkers. Participants with AHIs had significantly increased fatigue, depression, posttraumatic stress, imbalance, and neurobehavioral symptoms compared with the control participants. There were no differences in these findings based on the risk characteristics of the incident or geographic location of the AHIs. Twenty-four patients (28%) with AHI presented with functional neurological disorders., Conclusions and Relevance: In this exploratory study, there were no significant differences between individuals reporting AHIs and matched control participants with respect to most clinical, research, and biomarker measures, except for objective and self-reported measures of imbalance and symptoms of fatigue, posttraumatic stress, and depression. This study did not replicate the findings of previous studies, although differences in the populations included and the timing of assessments limit direct comparisons.

Chiari Malformation Type I (CM1) is a neurological condition in which the cerebellar tonsils extend past the foramen magnum. While many studies have reported dizziness symptoms in patients with CM1, the prevalence of peripheral labyrinthine lesions is largely unknown. This study aimed to comprehensively describe the audiovestibular phenotype in a cohort of patients with CM1 expressly referred for dizziness. Twenty-four patients with CM1 and a complaint of dizziness/vertigo were evaluated. Hearing and auditory brainstem tract function were essentially normal. While vestibular abnormalities were most prevalent during rotational testing (33%), abnormal functional balance was the most common finding (40%). Patients with CM1 had a greater likelihood of exhibiting an abnormal sensory organization test (SOT) postural stability score for fixed platform conditions, and for the somatosensory analysis score. While no significant associations were identified between tonsillar ectopia extent and any vestibular/balance outcome measure, a significant negative association was identified between neck pain and the somatosensory sensory analysis score. Abnormal functional balance in the somatosensory domain was remarkable, with poorer scores associated with neck pain. An isolated peripheral vestibulopathy was present in only 8% of patients. Despite the low prevalence of vestibulopathy, vestibular/balance assessment is warranted to identify patients who may benefit from referral to specialized medical disciplines.

Background and Importance: Hearing loss (HL) has been sporadically described, but not well characterized, in Generalized Arterial Calcification of Infancy (GACI), a rare disease in which pathological calcification typically presents in infancy., Objectives: This study aims to describe the clinical audiologic and otologic features and potential etiology of hearing impairment in GACI and gain pathophysiological insight from a murine model of GACI., Design: Cross-sectional cohort study of individuals with GACI. Murine ossicle micromorphology of the ENPP1 asj/asj mutant compared to wild-type., Setting: Clinical research hospital; basic science laboratory., Participants: Nineteen individuals with GACI who met clinical, biochemical, and genetic criteria for diagnosis., Main Outcomes and Measures: Clinical, biochemical, and radiologic features associated with hearing status., Results: Pure-tone thresholds could be established in 15 (n = 30 ears) of the 19 patients who underwent audiological assessments. The prevalence of HL was 50% (15/30) of ears, with conductive HL in 80% and sensorineural HL in 20%. In terms of patients with HL (n = 8), seven patients had bilateral HL and one patient had unilateral HL. Degree of HL was mild to moderate for 87% of the 15 ears with hearing loss. Of those patients with sufficient pure-tone and middle ear function data, 80% (8/10) had audiometric configurations suggestive of ossicular chain dysfunction (OCD). Recurrent episodes of otitis media (ROM) requiring pressure-equalizing tube placement were common. In patients who underwent cranial CT, 54.5% (6/11) had auricular calcification. Quantitative backscattered electron imaging (qBEI) of murine ossicles supports an OCD component of auditory dysfunction in GACI, suggesting loss of ossicular osteocytes without initiation of bone remodeling., Conclusions and Relevance: Hearing loss is common in GACI; it is most often conductive, and mild to moderate in severity. The etiology of HL is likely multifactorial, involving dysfunction of the ossicular chain and/or recurrent otitis media. Clinically, this study highlights the importance of early audiologic and otologic evaluation in persons with GACI. Novel findings of high rates of OCD and ROM may inform management, and in cases of unclear HL etiology, dedicated temporal bone imaging should be considered., (© 2022. The Author(s).)

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital malformation and intellectual disability syndrome resulting from variants in DHCR7. Auditory characteristics of persons with SLOS have been described in limited case reports but have not been systematically evaluated. The objective of this study is to describe the auditory phenotype in SLOS. Age- and ability-appropriate hearing evaluations were conducted on 32 patients with SLOS. A subset of 21 had auditory brainstem response testing, from which an auditory neural phenotype is described. Peripheral or retrocochlear auditory dysfunction was observed in at least one ear of 65.6% (21) of the patients in our SLOS cohort. The audiometric phenotype was heterogeneous and included conductive, mixed, and sensorineural hearing loss. The most common presentation was a slight to mild conductive hearing loss, although profound sensorineural hearing loss was also observed. Abnormal auditory brainstem responses indicative of retrocochlear dysfunction were identified in 21.9% of the patients. Many were difficult to test behaviorally and required objective assessment methods to estimate hearing sensitivity. Individuals with SLOS are likely to have hearing loss that may impact communication, including speech and language development. Routine audiologic surveillance should be conducted to ensure prompt management of hearing loss., (© 2021 Wiley Periodicals LLC.)

Usher syndrome has classically been described as a combination of hearing loss and rod-cone dystrophy; vestibular dysfunction is present in many patients. Three distinct clinical subtypes were documented in the late 1970s. Genotyping efforts have led to the identification of several genes associated with the disease. Recent literature has seen multiple publications referring to "atypical" Usher syndrome presentations. This manuscript reviews the molecular etiology of Usher syndrome, highlighting rare presentations and molecular causes. Reports of "atypical" disease are summarized noting the wide discrepancy in the spectrum of phenotypic deviations from the classical presentation. Guidelines for establishing a clear nomenclature system are suggested.

Background: Recessive mutations of coding regions and splice sites of the SLC26A4 gene cause hearing loss with enlargement of the vestibular aqueduct (EVA). Some patients also have a thyroid iodination defect that can lead to multinodular goiter as part of Pendred syndrome. A haplotype of variants upstream of SLC26A4, called CEVA, acts as a pathogenic recessive allele in trans to mutations affecting the coding regions or splice sites of SLC26A4. Our first hypothesis is that CEVA, acting as a pathogenic recessive allele, is correlated with a less severe phenotype than mutations affecting the coding regions and splice sites of SLC26A4. Our second hypothesis is that CEVA acts as a modifier of the phenotype in patients with EVA caused by mutations affecting the coding regions or splice sites of both alleles of SLC26A4 or EVA caused by other factors., Methods: This was a prospective cohort study of 114 individuals and 202 ears with EVA. To test our first hypothesis, we compared the thyroid and auditory phenotypes of subjects with mutations affecting coding regions of both alleles of SLC26A4 with those of subjects carrying CEVA in trans to mutations affecting the coding regions. To test our second hypothesis, we compared the phenotypes associated with the presence versus absence of CEVA among subjects with no coding region mutations, as well as among subjects with mutations affecting coding regions of both alleles., Results: Subjects carrying CEVA in trans to a mutation of SLC26A4 have a normal thyroid phenotype and less severe hearing loss in comparison to individuals with mutations affecting coding regions of both alleles of SLC26A4. In subjects with no mutant alleles of SLC26A4, hearing loss was more severe in subjects who carry the CEVA haplotype in comparison to non-carriers. There was no correlation of CEVA with the phenotype of subjects with mutations affecting coding regions of both alleles., Conclusions: CEVA, acting as a likely pathogenic recessive allele, is associated with a less severe phenotype than alleles with a mutation affecting the coding regions or splice sites of SLC26A4. CEVA may act as a genetic modifier in patients with EVA caused by other factors.

Background: Previous functional magnetic resonance imaging (fMRI) sleep studies have been hampered by the difficulty of obtaining extended amounts of sleep in the sleep-adverse environment of the scanner and often have resorted to manipulations such as sleep depriving subjects before scanning. These manipulations limit the generalizability of the results., New Method: The current study is a methodological validation of procedures aimed at obtaining all-night fMRI data in sleeping subjects with minimal exposure to experimentally induced sleep deprivation. Specifically, subjects slept in the scanner on two consecutive nights, allowing the first night to serve as an adaptation night., Results/comparison With Existing Method(s): Sleep scoring results from simultaneously acquired electroencephalography data on Night 2 indicate that subjects (n = 12) reached the full spectrum of sleep stages including slow-wave (M = 52.1 min, SD = 26.5 min) and rapid eye movement (REM, M = 45.2 min, SD = 27.9 min) sleep and exhibited a mean of 2.1 (SD = 1.1) nonREM-REM sleep cycles., Conclusions: It was found that by diligently applying fundamental principles and methodologies of sleep and neuroimaging science, performing all-night fMRI sleep studies is feasible. However, because the two nights of the study were performed consecutively, some sleep deprivation from Night 1 as a cause of the Night 2 results is likely, so consideration should be given to replicating the current study with a washout period. It is envisioned that other laboratories can adopt the core features of this protocol to obtain similar results., (Published by Elsevier B.V.)

Objectives: Significant advancements have been made toward the clinical assessment of utricular function through ocular vestibular-evoked myogenic potentials (oVEMP) and unilateral centrifugation (UCF) testing. To date, no study has examined intrasubject relationships between these measures. The study hypothesis was that intrasubject responses from oVEMP and UCF testing would be correlated inasmuch as both tests have been reported to assess utricular function., Design: UCF rotations and oVEMP testing were performed on healthy volunteers, aged 18 to 62 years. A within-subject study design compared and correlated UCF outcome measures of ocular counterroll, subjective visual vertical, and ocular counterroll-gravitational inertial acceleration slope against peak to peak oVEMP N1-P1 amplitude., Results: Correlational analyses failed to reveal any significant relationships between oVEMP amplitude and UCF responses suggesting that these tests may be inciting different response properties within the utricular system., Conclusions: Various anatomical and physiological differences within the utricle, in addition to the fundamental differences in stimulus properties between the oVEMP and UCF tests, could explain the lack of significant correlations between these measures and suggest that oVEMP and UCF testing may be complimentary in their evaluation of the utricular system. These data reinforce the complexities of the utricular system and provide further insight into the difficulties encountered in its clinical assessment.

Objective: To characterize the audiometric natural progression in patient-ears with small volume (<1,000 mm), treatment-naïve cochleovestibular schwannomas (CVSs) in Neurofibromatosis Type 2 (NF2)., Study Design: Prospective, longitudinal cohort study., Setting: Quaternary medical research institute., Patients: One hundred eleven ears in 71 NF2 patients with small, treatment-naïve CVSs observed from July 2006 to July 2016., Intervention: Serial audiometric testing, including pure tone audiometry, speech audiometry, and magnetic resonance imaging (MRI)., Outcome Measures: Four-frequency pure tone average (4f-PTA) of 0.5, 1, 2, and 4 kHz and word recognition score (WRS) were recorded. Their changes were compared with MRI changes in CVS volume over time. Times to significant hearing loss (10 dB loss in 4f-PTA) and WRS based on 95% critical difference were measured., Results: Linear regression analysis showed a significant correlation with baseline hearing level (4f-PTA) and internal auditory canal (IAC) tumor volume to annual hearing decrease rate (AHDR) (p = 0.003, p = 0.0004). Hearing level at baseline and tumor volume correlate with AHDR while tumor volume growth rate does not. Two-way analysis of variance found significant differences in AHDR, risk of significant hearing loss, and risk of critical difference in WRS based on baseline hearing level (abnormal or normal) and IAC tumor volume (greater or less than 200 mm)., Conclusion: Subjects with normal baseline hearing and small IAC tumor component had a low AHDR and low risk of significant hearing loss and may warrant conservative management while the presence of baseline hearing loss and large IAC volume resulted in higher ADHR and greater risk for further hearing loss and may benefit from early treatment interventions.

Importance: Fibrous dysplasia (FD) and McCune-Albright syndrome (MAS) are rare bone and endocrine disorders in which expansile fibro-osseous lesions result in deformity, pain, and functional impairment. The effect of FD on hearing and otologic function has not been established., Objectives: To characterize audiologic and otologic manifestations in a large cohort of individuals with FD/MAS and to investigate potential mechanisms of hearing loss., Design, Setting, and Participants: In this natural history study, individuals with craniofacial FD seen at a clinical research center underwent clinical, biochemical, computed tomographic, audiologic, and otolaryngologic evaluations., Main Outcomes and Measures: Clinical and radiologic features associated with hearing loss and otologic disease were evaluated. Conductive hearing loss was hypothesized to be associated with narrowing of the external auditory canal (EAC), FD involving the epitympanum, and FD crowding the ossicular chain. Sensorineural hearing loss was hypothesized to be associated with FD affecting the internal auditory canal (IAC) and otic capsule., Results: Of the 130 study participants with craniofacial FD who were evaluated, 116 (89.2%) had FD that involved the temporal bone (median age, 19.6 years; range, 4.6-80.3 years; 64 female [55.2%]), whereas 14 (10.8%) had craniofacial FD that did not involve the temporal bone. Of the 183 ears with temporal bone FD, hearing loss was identified in 41 ears (22.4%) and was conductive in 27 (65.9%), sensorineural in 12 (29.3%), and mixed in 2 (4.9%). Hearing loss was mild and nonprogressive in most participants. Whereas EACs were narrower in ears with FD (mean difference [MD], 0.33 mm; 95% CI, 0.11-0.55 mm), this finding was associated with conductive hearing loss in only 4 participants. Fibrous dysplasia crowding of the ossicles was associated with conductive hearing loss (odds ratio [OR], 5.0; 95% CI, 2.1-11.6). The IAC length was not different between ears with and without FD (MD, -0.37; 95% CI, -0.95 to 0.211); however, canals were elongated in ears with sensorineural hearing loss (MD, -1.33; 95% CI, -2.60 to -0.07). Otic capsule involvement was noted in only 4 participants, 2 of whom had sensorineural hearing loss. Both MAS-associated growth hormone excess (OR, 3.1; 95% CI, 1.3-7.5) and neonatal hypercortisolism (OR, 11; 95% CI, 2.5-55) were associated with an increased risk of hearing loss ., Conclusions and Relevance: Hearing loss in craniofacial FD is common and mild to moderate in most individuals. It typically arises from FD crowding of the ossicular chain and elongation of the IAC, whereas EAC stenosis and otic capsule invasion are less common causes. Individuals with craniofacial FD should undergo otolaryngologic evaluation and monitoring, including assessment to identify those with high-risk features.

Objectives/hypothesis: To characterize the severity and natural history of hearing loss, and the prevalence of having a cochlear implant in a maturing cohort of individuals with enlarged vestibular aqueduct (EVA) and zero or one mutant allele of SLC26A4., Study Design: Prospective cohort study of subjects ascertained between 1998 and 2015 at the National Institutes of Health Clinical Center., Methods: Study subjects were 127 individuals (median age, 8 years; range, 0-59 years) with EVA in at least one ear., Results: Ears with EVA and zero or one mutant allele of SLC26A4 had mean 0.5/1/2/4-kHz pure-tone averages of 62.6 and 52.9 dB HL, respectively, in contrast to EVA ears with two mutant alleles of SLC26A4 (88.1 dB HL; P < .01). This association was independent of age, sex, or side of EVA (P < .001). Natural history of hearing loss was not associated with number of mutant alleles (P = .94). The prevalence of having a cochlear implant was nine (12%) of 76, two (13%) of 15, and 12 (38%) of 32 subjects with zero, one, and two mutant alleles, respectively (P = .00833). This association was not independent (P = .534) but reflected underlying correlations with age at time of first audiogram (P = .003) or severity of hearing loss (P = .000)., Conclusions: Ears with EVA and zero or one mutant allele of SLC26A4 have less severe hearing loss, no difference in prevalence of fluctuation, and a lower prevalence of cochlear implantation in comparison to ears with two mutant alleles of SLC26A4., Level of Evidence: NA Laryngoscope, 127:E238-E243, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: The purpose of this study was to describe the auditory phenotype of a large cohort with Smith-Magenis syndrome (SMS), a rare disorder including physical anomalies, cognitive deficits, sleep disturbances, and a distinct behavioral phenotype., Method: Hearing-related data were collected for 133 individuals with SMS aged 1-49 years. Audiogram data (97 participants) were used for cross-sectional and longitudinal analyses. Caregivers completed a sound sensitivity survey for 98 individuals with SMS and a control group of 24 unaffected siblings., Results: Nearly 80% of participants with interpretable audiograms (n = 76) had hearing loss, which was typically slight to mild in degree. When hearing loss type could be determined (40 participants), sensorineural hearing loss (48.1%) occurred most often in participants aged 11-49 years. Conductive hearing loss (35.2%) was typically observed in children aged 1-10 years. A pattern of fluctuating and progressive hearing decline was documented. Hyperacusis was reported in 73.5% of participants with SMS compared with 12.5% of unaffected siblings., Conclusions: This study offers the most comprehensive characterization of the auditory phenotype of SMS to date. The auditory profile in SMS is multifaceted and can include a previously unreported manifestation of hyperacusis. Routine audiologic surveillance is recommended as part of standard clinical care.

Background: The inherited bone marrow failure syndromes (IBMFSs) are diverse disorders with syndrome-specific features; their otologic and audiologic manifestations have not been well described. Our objective was to characterize these in patients with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS), and to determine the association between physical findings and hearing loss., Methods: Patients with an IBMFS underwent comprehensive clinical and laboratory evaluations and testing for syndrome-specific gene mutations. Hearing loss was measured by pure tone audiometry and otologic abnormalities by otomicroscopy., Results: Patients included 33 with FA, 37 with DC, 32 with DBA, and nine with SDS. Hearing loss was most frequent in patients with FA (45%) and DBA (14%). The most common type of hearing loss in FA was conductive (65%). Absent or hypoplastic radius, noted in 21% of the patients with FA, was associated with hearing loss in all cases. Otomicroscopy was abnormal in 66% of patients with FA. Characteristic ear abnormalities included small tympanic membrane (66%), malformed malleus (57%), aberrant tympanic bony island (48%), narrow external auditory canal (EAC) (32%), and abnormal course of chorda tympani (34%). Ear malformations were almost always associated with hearing loss. Hearing loss was rare in patients with DC and SDS., Conclusions: FA is the major IBMFS with associated hearing loss, which is most commonly conductive. Radial hypoplasia or aplasia and characteristic congenital ear malformations are associated with hearing loss in patients with FA. Recognition of these syndrome-specific abnormalities should lead to earlier management of hearing loss., (© 2016 Wiley Periodicals, Inc.)

Recent insight into the genetic bases for autism spectrum disorder, dyslexia, stuttering, and language disorders suggest that neurogenetic approaches may also reveal at least one etiology of auditory processing disorder (APD). A person with an APD typically has difficulty understanding speech in background noise despite having normal pure-tone hearing sensitivity. The estimated prevalence of APD may be as high as 10% in the pediatric population, yet the causes are unknown and have not been explored by molecular or genetic approaches. The aim of our study was to determine the heritability of frequency and temporal resolution for auditory signals and speech recognition in noise in 96 identical or fraternal twin pairs, aged 6-11 years. Measures of auditory processing (AP) of non-speech sounds included backward masking (temporal resolution), notched noise masking (spectral resolution), pure-tone frequency discrimination (temporal fine structure sensitivity), and nonsense syllable recognition in noise. We provide evidence of significant heritability, ranging from 0.32 to 0.74, for individual measures of these non-speech-based AP skills that are crucial for understanding spoken language. Identification of specific heritable AP traits such as these serve as a basis to pursue the genetic underpinnings of APD by identifying genetic variants associated with common AP disorders in children and adults.

Objectives/hypothesis: Hearing loss and enlarged vestibular aqueduct (EVA) can be inherited as an autosomal recessive trait caused by mutant alleles of the SLC26A4 gene. In some other families, EVA does not segregate in a typical autosomal recessive pattern. The goal of this study was to characterize the SLC26A4 genotypes and phenotypes of extended families with atypical segregation of EVA., Study Design: Prospective study of cohort of families ascertained between 1998 and 2014 at the National Institutes of Health Clinical Center., Methods: Study subjects were members of eight families segregating EVA in at least two members who were not related as siblings. Evaluations included pure-tone audiometry, temporal bone imaging, SLC26A4 nucleotide sequence analysis, SLC26A4-linked marker genotype and haplotype analysis, and pedigree analysis., Results: One family had members with EVA caused by different etiologies, and two families had pseudodominant inheritance of recessive mutations of SLC26A4. In five families, the etiology remained unknown and could include inheritance of mutant alleles at another genetic locus, nongenetic influences, or a combination of these factors., Conclusions: Familial EVA can demonstrate a variety of atypical segregation patterns. Pseudodominant inheritance of SLC26A4 mutations or recessive alleles of other hearing loss genes may be more likely to occur in families in which deaf individuals have intermarried. The etiologic basis of atypical segregation of EVA without detectable SLC26A4 mutations remains unknown. Future studies of these families may reveal novel genes for EVA., Level of Evidence: NA Laryngoscope, 126:E240-E247, 2016., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Laminins are heterotrimeric complexes, consisting of α, β and γ subunits that form a major component of basement membranes and extracellular matrix. Laminin complexes have different, but often overlapping, distributions and functions., Methods: Under our clinical protocol, NCT00068224, we have performed extensive clinical and neuropsychiatric phenotyping, neuroimaging and molecular analysis in patients with laminin α1 (LAMA1)-associated lamininopathy. We investigated the consequence of mutations in LAMA1 using patient-derived fibroblasts and neuronal cells derived from neuronal stem cells., Results: In this paper we describe individuals with biallelic mutations in LAMA1, all of whom had the cerebellar dysplasia, myopia and retinal dystrophy, in addition to obsessive compulsive traits, tics and anxiety. Patient-derived fibroblasts have impaired adhesion, reduced migration, abnormal morphology and increased apoptosis due to impaired activation of Cdc42, a member of the Rho family of GTPases that is involved in cytoskeletal dynamics. LAMA1 knockdown in human neuronal cells also showed abnormal morphology and filopodia formation, supporting the importance of LAMA1 in neuronal migration, and marking these cells potentially useful tools for disease modelling and therapeutic target discovery., Conclusion: This paper broadens the phenotypes associated with LAMA1 mutations. We demonstrate that LAMA1 deficiency can lead to alteration in cytoskeletal dynamics, which may invariably lead to alteration in dendrite growth and axonal formation. Estimation of disease prevalence based on population studies in LAMA1 reveals a prevalence of 1-20 in 1 000 000., Trial Registration Number: NCT00068224., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Enlarged vestibular aqueduct (EVA) is the most common inner ear malformation. While a strong correlative relationship between EVA and hearing loss is well established, its association with vestibular dysfunction is less well understood. In this study, we examine the effects of EVA on the vestibular system in patients with EVA., Study Design: Prospective, cross-sectional study of a cohort ascertained between 1999 and 2013., Setting: National Institutes of Health Clinical Center, a federal biomedical research facility., Subjects and Methods: In total, 106 patients with unilateral or bilateral EVA, defined as a midpoint diameter greater than 1.5 mm, were referred or self-referred to participate in a study of the clinical and molecular aspects of EVA. Clinical history was ascertained with respect to the presence or absence of various vestibular signs and symptoms and history of head trauma. Videonystagmography (VNG), cervical vestibular evoked myogenic potential (cVEMP), and rotational vestibular testing (RVT) were performed to assess the vestibular function., Results: Of the patients with EVA, 45% had vestibular signs and symptoms, and 44% of tested patients had abnormal VNG test results. An increased number of vestibular signs and symptoms was correlated with the presence of bilateral EVA (P = .008) and a history of head injury (P < .001). Abnormal VNG results also correlated with a history of head injury (P = .018)., Conclusion: Vestibular dysfunction is common in patients with EVA. However, not all patients with vestibular signs and symptoms have abnormal vestibular test results. Clinicians should be aware of the high prevalence of vestibular dysfunction in patients with EVA., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

Aging affects every sensory system in the body, including the vestibular system. Although its impact is often difficult to quantify, the deleterious impact of aging on the vestibular system is serious both medically and economically. The deterioration of the vestibular sensory end organs has been known since the 1970s; however, the measurable impact from these anatomical changes remains elusive. Tests of vestibular function either fall short in their ability to quantify such anatomical deterioration, or they are insensitive to the associated physiologic decline and/or central compensatory mechanisms that accompany the vestibular aging process. When compared with healthy younger individuals, a paucity of subtle differences in test results has been reported in the healthy older population, and those differences are often observed only in response to nontraditional and/or more robust stimuli. In addition, the reported differences are often clinically insignificant insomuch that the recorded physiologic responses from the elderly often fall within the wide normative response ranges identified for normal healthy adults. The damaging economic impact of such vestibular sensory decline manifests itself in an exponential increase in geriatric dizziness and a subsequent higher prevalence of injurious falls. An estimated $10 to $20 billion dollar annual cost has been reported to be associated with falls-related injuries and is the sixth leading cause of death in the elderly population, with a 20% mortality rate. With an estimated 115% increase in the geriatric population over 65 years of age by the year 2050, the number of balanced-disordered patients with a declining vestibular system is certain to reach near epidemic proportions. An understanding of the effects of age on the vestibular system is imperative if clinicians are to better manage elderly patients with balance disorders, dizziness, and vestibular disease.

Purpose: Progressive decline of psychophysical cone-mediated measures has been reported in type 1 (USH1) and type 2 (USH2) Usher syndrome. Conventional cone electroretinogram (ERG) responses in USH demonstrate poor signal-to-noise ratio. We evaluated cone signals in USH1 and USH2 by recording microvolt level cycle-by-cycle (CxC) ERG., Methods: Responses of molecularly genotyped USH1 (n = 18) and USH2 (n = 24) subjects (age range, 15-69 years) were compared with those of controls (n = 12). A subset of USH1 (n = 9) and USH2 (n = 9) subjects was examined two to four times over 2 to 8 years. Photopic CxC ERG and conventional 30-Hz flicker ERG were recorded on the same visits., Results: Usher syndrome subjects showed considerable cone flicker ERG amplitude losses and timing phase delays (P < 0.01) compared with controls. USH1 and USH2 had similar rates of progressive logarithmic ERG amplitude decline with disease duration (-0.012 log μV/y). Of interest, ERG phase delays did not progress over time. Two USH1C subjects retained normal response timing despite reduced amplitudes. The CxC ERG method provided reliable responses in all subjects, whereas conventional ERG was undetectable in 7 of 42 subjects., Conclusions: Cycle-by-cycle ERG showed progressive loss of amplitude in both USH1 and USH2 subjects, comparable to that reported with psychophysical measures. Usher subjects showed abnormal ERG response latency, but this changed less than amplitude with time. In USH syndrome, CxC ERG is more sensitive than conventional ERG and warrants consideration as an outcome measure in USH treatment trials., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Objective: Describe the relationship between cochleovestibular schwannoma (CVS) volume, audiovestibular characteristics, and magnetic resonance imaging (MRI) findings in patients with neurofibromatosis type 2 (NF2)., Study Design: Subgroup analysis of NF2 prospective natural history study from 2008 to 2011., Setting: Quaternary medical research institute., Subjects and Methods: NF2 patients with small treatment-naive CVSs (volume <1000 mm(3)) by ear; N = 49 ears (32 patients). Cross-sectional analysis of the following parameters was performed: tumor size, auditory brainstem response (ABR), 4-frequency pure-tone average (4f-PTA; 0.5, 1, 2, and 4KHz), cervical vestibular evoked myogenic potential (cVEMP), caloric testing, 240° velocity step test (VST), and MRI findings., Results: For all physiologic measures but the 4f-PTA, larger tumors correlated with abnormal responses (P < .05). For abnormal ABR, mean tumor volume was 405 vs 151 mm(3) (P = .0007) for normal ABR. Similarly, larger tumors correlated with weak caloric responses (mean 521 vs 165 mm(3); P = .0007) and weak cVEMP (mean 357 vs 192 mm(3); P = .0262). Tumor volume was not significantly correlated with 4f-PTA. Elevated intralabyrinthine protein on MRI fluid-attenuated inversion recovery sequences was correlated with larger tumor volume (mean 333 vs 55 mm(3); P = .001) and abnormal ABR and 4f-PTA (P < .05) but did not correlate with cVEMP, VST, or caloric responses., Conclusion: In our cohort, ABR, caloric response, cVEMP, and elevated intralabyrinthine protein correlated with tumor volume, but 4f-PTA did not. Abnormal ABR and 4f-PTA correlated with elevated intralabyrinthine protein. These findings may provide insight on the effect of small CVS on the inner ear and cochleovestibular nerves, which may aid in their optimal management., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.)

Rationale: Treatment of pulmonary nontuberculous mycobacteria, especially Mycobacterium abscessus, requires prolonged, multidrug regimens with high toxicity and suboptimal efficacy. Options for refractory disease are limited., Objectives: We reviewed the efficacy and toxicity of inhaled amikacin in patients with treatment-refractory nontuberculous mycobacterial lung disease., Methods: Records were queried to identify patients who had inhaled amikacin added to failing regimens. Lower airway microbiology, symptoms, and computed tomography scan changes were assessed together with reported toxicity., Measurements and Main Results: The majority (80%) of the 20 patients who met entry criteria were women; all had bronchiectasis, two had cystic fibrosis and one had primary ciliary dyskinesia. At initiation of inhaled amikacin, 15 were culture positive for M. abscessus and 5 for Mycobacterium avium complex and had received a median (range) of 60 (6, 190) months of mycobacterial treatment. Patients were followed for a median of 19 (1, 50) months. Eight (40%) patients had at least one negative culture and 5 (25%) had persistently negative cultures. A decrease in smear quantity was noted in 9 of 20 (45%) and in mycobacterial culture growth for 10 of 19 (53%). Symptom scores improved in nine (45%), were unchanged in seven (35%), and worsened in four (20%). Improvement on computed tomography scans was noted in 6 (30%), unchanged in 3 (15%), and worsened in 11 (55%). Seven (35%) stopped amikacin due to: ototoxicity in two (10%), hemoptysis in two (10%), and nephrotoxicity, persistent dysphonia, and vertigo in one each., Conclusions: In some patients with treatment-refractory pulmonary nontuberculous mycobacterial disease, the addition of inhaled amikacin was associated with microbiologic and/or symptomatic improvement; however, toxicity was common. Prospective evaluation of inhaled amikacin for mycobacterial disease is warranted.

Importance: Approximately one-half of all subjects with unilateral or bilateral hearing loss with enlargement of the vestibular aqueduct (EVA) will have SLC26A4 gene mutations. The number (0, 1, or 2) of mutant alleles of SLC26A4 detected in an individual subject with EVA is each associated with a distinct combination of diagnostic and prognostic information as well as probability of recurrence of EVA in siblings., Objective: To evaluate the results of SLC26A4 mutation testing in subjects with unilateral EVA. (The study objective was formulated before data were collected.), Design: Prospective cross-sectional study of cohort ascertained between 1998 and 2012., Setting: National Institutes of Health Clinical Center, a federal biomedical research facility., Participants: Twenty-four subjects (10 males, 14 females) with unilateral EVA, defined as a midpoint diameter greater than 1.5 mm, who were referred or self-referred to participate in a study about the clinical and molecular analysis of EVA. Twenty-one (87.5%) of 24 subjects were white. Mean age was 10.3 years (age range, 5-39 years)., Intervention: SLC26A4 mutation analysis., Main Outcomes and Measures: Audiometric results, the presence or absence of EVA, and the number of mutant alleles of SLC26A4., Results: Approximately 8.3% of the subjects with unilateral EVA had 2 mutant SLC26A4 alleles, 16.7% had 1 mutant allele, and 75.0% had 0 mutant alleles., Conclusions and Relevance: Unilateral EVA can be associated with all possible SLC26A4 genotype results. The distinct combination of prognoses and recurrence probability associated with each genotype supports the clinical use of testing for SLC26A4 mutations in subjects with unilateral EVA.

Pendred syndrome (PS) is characterized by autosomal recessive inheritance of goiter associated with a defect of iodide organification, hearing loss, enlargement of the vestibular aqueduct (EVA), and mutations of the SLC26A4 gene. However, not all EVA patients have PS or SLC26A4 mutations. Two mutant alleles of SLC26A4 are detected in ¼ of North American or European EVA populations, one mutant allele is detected in another ¼ of patient populations, and no mutations are detected in the other ½. The presence of two mutant alleles of SLC26A4 is associated with abnormal iodide organification, increased thyroid gland volume, increased severity of hearing loss, and bilateral EVA. The presence of a single mutant allele of SLC26A4 is associated with normal iodide organification, normal thyroid gland volume, less severe hearing loss and either bilateral or unilateral EVA. When other underlying correlations are accounted for, the presence of a cochlear malformation or the size of EVA does not have an effect on hearing thresholds. This is consistent with observations of an Slc26a4 mutant mouse model of EVA in which hearing loss is independent of endolymphatic hydrops or inner ear malformations. Segregation analyses of EVA in families suggest that the patients carrying one mutant allele of SLC26A4 have a second, undetected mutant allele of SLC26A4 , and the probability of a sibling having EVA is consistent with its segregation as an autosomal recessive trait. Patients without any mutations are an etiologically heterogeneous group in which siblings have a lower probability of having EVA. SLC26A4 mutation testing can provide prognostic information to guide clinical surveillance and management, as well as the probability of EVA affecting a sibling.

Context: GH excess is a serious complication of McCune-Albright syndrome (MAS) and has been associated with craniofacial morbidity., Objective: The aim of the study was to determine whether early diagnosis and treatment of MAS-associated GH excess prevents optic neuropathy and hearing impairment, the major morbidities associated with GH excess., Design and Setting: A retrospective cross-sectional analysis was conducted at a clinical research center., Patients: Twenty-two subjects with MAS-associated GH excess and 21 control MAS subjects without GH excess were included in the study., Intervention: Biochemical testing included random GH, nadir GH after glucose load, nadir GH on frequent sampling, and IGF-I Z-score. Subjects underwent imaging, ophthalmological, audiological, and otolaryngological assessment. Treatment included octreotide, pegvisomant, transphenoidal surgery, and/or radiotherapy as indicated., Main Outcome Measure: Association of optic neuropathy and hearing impairment to age at GH excess diagnosis/treatment was measured., Results: Of 129 MAS subjects, 26 (20%) were diagnosed with GH excess based on elevation of two measures of GH function. Of these, 22 subjects were candidates for pharmacological intervention. Optic neuropathy was significantly correlated with intervention status, with no cases in the early intervention group (diagnosed/treated before age 18) or the control group, and four of seven (57%) in the late intervention group (diagnosed/treated after age 18) (Fisher's exact test; odds ratio, 0.027; P = 0.0058). Early diagnosis/intervention was not associated with reduction in hearing deficits (odds ratio, 1.25; P = 1.00). Mean head circumference SD score was significantly higher in the late (6.08; range, 2.70 to 22.56) than the early intervention (2.67; range, -0.65 to 6.72) or control groups (2.13; range, -2.06 to 7.79) (P = 0.003)., Conclusions: Early diagnosis/treatment of GH excess in MAS is important to prevent optic neuropathy and craniofacial expansion. The relationship between hearing deficits and GH excess remains less clear and requires further study.

Background: Recessive mutant alleles of MYO7A, USH1C, CDH23, and PCDH15 cause non-syndromic deafness or type 1 Usher syndrome (USH1) characterised by deafness, vestibular areflexia, and vision loss due to retinitis pigmentosa. For CDH23, encoding cadherin 23, non-syndromic DFNB12 deafness is associated primarily with missense mutations hypothesised to have residual function. In contrast, homozygous nonsense, frame shift, splice site, and some missense mutations of CDH23, all of which are presumably functional null alleles, cause USH1D. The phenotype of a CDH23 compound heterozygote for a DFNB12 allele in trans configuration to an USH1D allele is not known and cannot be predicted from current understanding of cadherin 23 function in the retina and vestibular labyrinth., Methods and Results: To address this issue, this study sought CDH23 compound heterozygotes by sequencing this gene in USH1 probands, and families segregating USH1D or DFNB12. Five non-syndromic deaf individuals were identified with normal retinal and vestibular phenotypes that segregate compound heterozygous mutations of CDH23, where one mutation is a known or predicted USH1 allele., Conclusions: One DFNB12 allele in trans configuration to an USH1D allele of CDH23 preserves vision and balance in deaf individuals, indicating that the DFNB12 allele is phenotypically dominant to an USH1D allele. This finding has implications for genetic counselling and the development of therapies for retinitis pigmentosa in Usher syndrome. ACCESSION NUMBERS: The cDNA and protein Genbank accession numbers for CDH23 and cadherin 23 used in this paper are AY010111.2 and AAG27034.2, respectively.

Mutations in SLC26A4 can cause deafness and goiter in Pendred syndrome (PDS) or isolated non-syndromic enlargement of the vestibular aqueduct (NSEVA). PDS is one of the most common hereditary causes of deafness. It is characterized by autosomal-recessive inheritance of sensorineural hearing loss, enlarged vestibular aqueducts (EVA), and an iodide organification defect with or without goiter. The diagnosis is confirmed by detection of two mutant alleles of SLC26A4 in a patient with EVA. The perchlorate discharge test can detect the underlying thyroid biochemical defect and is useful for the evaluation of goiter or for the clinical diagnosis of PDS in a patient with a non-diagnostic SLC26A4 genotype. SLC26A4 encodes the pendrin polypeptide, an anion exchanger that, in recombinant expression systems, transports chloride, bicarbonate, and iodide. Investigation of pendrin function in the inner ear has been facilitated by the Slc26a4(Δ) (knockout) mouse model, but the exact mechanism of its hearing loss remains unclear, as does pendrin's principal transport function in the inner ear. Treatment of PDS is focused upon rehabilitation of hearing loss, and surveillance and management of goiter and, less commonly, hypothyroidism., (Copyright © 2011 S. Karger AG, Basel.)

Enlargement of the vestibular aqueduct (EVA) is the most common inner ear anomaly detected in ears of children with sensorineural hearing loss. Pendred syndrome (PS) is an autosomal recessive disorder characterized by bilateral sensorineural hearing loss with EVA and an iodine organification defect that can lead to thyroid goiter. Pendred syndrome is caused by mutations of the SLC26A4 gene. SLC26A4 mutations may also be identified in some patients with nonsyndromic EVA (NSEVA). The presence of two mutant alleles of SLC26A4 is correlated with bilateral EVA and Pendred syndrome, whereas unilateral EVA and NSEVA are correlated with one (M1) or zero (M0) mutant alleles of SLC26A4. Thyroid gland enlargement (goiter) appears to be primarily dependent on the presence of two mutant alleles of SLC26A4 in pediatric patients, but not in older patients. In M1 families, EVA may be associated with a second, undetected SLC26A4 mutation or epigenetic modifications. In M0 families, there is probably etiologic heterogeneity that includes causes other than, or in addition to, monogenic inheritance., (Copyright © 2011 S. Karger AG, Basel.)

Objective: To identify and characterize otolaryngologic markers for the early diagnosis of Turner syndrome (TS)., Study Design: Prospective cohort survey., Setting: Clinical Center of the National Institutes of Health (NIH)., Patients: Ninety-one females, 7-61 years old (average=28.7 y), enrolled in a multidisciplinary study of karyotype-phenotype correlations in TS., Main Outcome Measures: Age at diagnosis, X chromosome karyotype, history of chronic or recurrent otitis media (OM), sensorineural hearing loss (SNHL), palate dysmorphism, pinna deformity, pterygium colli, low posterior hairline, low-set ears, and micrognathia., Results: Sixty-nine (76%) patients had a history of chronic or recurrent OM, 62 (68%) had a dysmorphic palate, 57 (63%) had SNHL, and 90 (99%) had one or more of these findings. 83 (91%; average age at diagnosis=9.4 y) had one or more external craniofacial signs: pinna abnormalities, pterygium colli, low-set ears, micrognathia or a low posterior hairline. Eight patients (average age at diagnosis=13.2 y) had no external craniofacial signs, although seven (88%) of these eight patients had a history of chronic or recurrent OM, dysmorphic palate or SNHL. The age at diagnosis was not significantly different between groups with or without external craniofacial signs (P=0.126)., Conclusions: PATIENTS with mild or incompletely penetrant TS phenotypes often present with otitis media, hearing loss, or both before the diagnosis of TS is established. Palatal dysmorphism, including ogival morphology, is another otolaryngologic marker for TS. Prompt recognition of these manifestations of TS could hasten its diagnosis and appropriate medical care.

Hearing loss with enlargement of the vestibular aqueduct (EVA) can be associated with mutations of the SLC26A4 gene encoding pendrin, a transmembrane Cl(-)/I(-)/HCO(3)(-) exchanger. Pendrin's critical transport substrates are thought to be I(-) in the thyroid gland and HCO(3)(-) in the inner ear. We previously reported that bi-allelic SLC26A4 mutations are associated with Pendred syndromic EVA whereas one or zero mutant alleles are associated with nonsyndromic EVA. One study proposed a correlation of nonsyndromic EVA with SLC26A4 alleles encoding pendrin with residual transport activity. Here we describe the phenotypes and SLC26A4 genotypes of 47 EVA patients ascertained since our first report of 39 patients. We sought to determine the pathogenic potential of each variant in our full cohort of 86 patients. We evaluated the trafficking of 11 missense pendrin products expressed in COS-7 cells. Products that targeted to the plasma membrane were expressed in Xenopus oocytes for measurement of anion exchange activity. p.F335L, p.C565Y, p.L597S, p.M775T, and p.R776C had Cl(-)/I(-) and Cl(-)/HCO(3)(-) exchange rate constants that ranged from 13 to 93% of wild type values. p.F335L, p.L597S, p.M775T and p.R776C are typically found as mono-allelic variants in nonsyndromic EVA. The high normal control carrier rate for p.L597S indicates it is a coincidentally detected nonpathogenic variant in this context. We observed moderate differential effects of hypo-functional variants upon exchange of HCO(3)(-) versus I(-) but their magnitude does not support a causal association with nonsyndromic EVA. However, these alleles could be pathogenic in trans configuration with a mutant allele in Pendred syndrome., ((c) 2009 Wiley-Liss, Inc.)

Objective: Bilateral endolymphatic sac tumors (ELSTs) are associated with von Hippel-Lindau disease and often underlie significant audiovestibular morbidity, including hearing loss., Patient: This 44-year-old female von Hippel-Lindau disease patient presented with tinnitus, vertigo, and binaural hearing loss. Magnetic resonance and computed tomography imaging demonstrated bilateral ELSTs, and audiometry confirmed bilateral hearing loss., Intervention: The patient underwent staged resection of the ELSTs (left then right). After resection of the left ELST and during the same operation, a cochlear implant was placed., Main Outcome Measures: Clinical, audiometric, and imaging data., Results: Postoperatively, the patient had resolution of tinnitus and vertigo with a significant implant-aided improvement in hearing., Conclusion: Because of their unique anatomic and biologic features, resection of bilateral tumors and cochlear implantation in deaf ELST patients is a potential option to improve hearing and quality of life.

We administered tests commonly used in the diagnosis of auditory processing disorders (APDs) to twins recruited from the general population. We observed significant correlations in test scores between co-twins. Our analyses of test score correlations among 106 MZ and 33 DZ twin pairs indicate that dichotic listening ability is a highly heritable trait. Dichotic listening is the ability to identify and distinguish different stimuli presented simultaneously to each ear. Deficits in dichotic listening skills indicate a lesion or defect in interhemispheric information processing. Such defects or lesions can be prominent in elderly listeners, language-impaired children, stroke victims, and individuals with PAX6 mutations. Our data indicates that other auditory processing abilities are influenced by shared environment. These findings should help illuminate the etiology of APDs, and help to clarify the relationships between auditory processing abilities and learning/language disorders associated with APDs.

Endolymphatic sac tumors (ELSTs) are locally invasive neoplasms that arise in the posterior petrous bone and are associated with von Hippel-Lindau (VHL) disease. These tumors cause symptoms even when microscopic in size (below the threshold for detectability on imaging studies) and can lead to symptoms such as hearing loss, tinnitus, vertigo, and facial nerve dysfunction. While the mechanisms of audiovestibular dysfunction in patients harboring ELSTs are incompletely understood, they have critical implications for management. The authors present the case of a 33-year-old man with VHL disease and a 10-year history of progressive tinnitus, vertigo, and left-sided hearing loss. Serial T1-weighted magnetic resonance (MR) imaging and computed tomography scans revealed no evidence of tumor, but fluid attenuated inversion recovery (FLAIR) MR imaging sequences obtained after hearing loss demonstrated evidence of left intralabyrinthine hemorrhage. On the basis of progressive disabling audiovestibular dysfunction (tinnitus and vertigo), FLAIR imaging findings, and VHL disease status, the patient underwent surgical exploration of the posterior petrous region, and a small (2-mm) ELST was identified and completely resected. Postoperatively, the patient had improvement of the tinnitus and vertigo. Intralabyrinthine hemorrhage may be an early and the only neuroimaging sign of an ELST in patients with VHL disease and audiovestibular dysfunction. These findings support tumor-associated hemorrhage as a mechanism underlying the audiovestibular dysfunction associated with ELSTs.

Dominant, truncating mutations of eyes absent 4 (EYA4) on chromosome 6q23 can cause either nonsyndromic hearing loss DFNA10 or hearing loss with dilated cardiomyopathy (DCM). It has been proposed that truncations of the C-terminal Eya domain cause DFNA10 whereas upstream truncations of the N-terminal variable region cause hearing loss with DCM. Here we report an extended family co-segregating autosomal dominant, postlingual-onset, progressive, sensorineural hearing loss (SNHL) with a novel frameshift mutation, 1,490insAA, of EYA4. The 1,490insAA allele is predicted to encode a truncated protein with an intact N-terminal variable region, but lacking the entire C-terminal Eya domain. Clinical studies including electrocardiography, echocardiography, and magnetic resonance imaging (MRI) of the heart in nine affected family members revealed no DCM or associated abnormalities and confirmed their nonsyndromic phenotype. These are the first definitive cardiac evaluations of DFNA10 hearing loss to support a correlation of EYA4 mutation position with the presence or absence of DCM. These results will facilitate the counseling of patients with these phenotypes and EYA4 mutations., ((c) 2007 Wiley-Liss, Inc)

Objective: To determine whether congenital cytomegalovirus (CMV) infection is an etiologic factor in the pathogenesis of enlarged vestibular aqueducts (EVA)., Design: Two different cohort studies. Subjects The study population comprised 19 subjects with a history of congenital CMV infection and sensorineural hearing loss (cohort 1); 39 subjects with nonsyndromic EVA and their unaffected mothers (cohort 2); and 16 control subjects with EVA associated with Pendred syndrome and bi-allelic mutations of the SLC26A4 gene and their unaffected mothers., Results: In cohort 1, we detected EVA in 0 of 19 subjects with congenital CMV infection and sensorineural hearing loss. In cohort 2, anti-CMV serologic profiles were consistent with possible congenital CMV infection in 10 (26%) of 39 subjects with nonsyndromic EVA and 6 (38%) of 16 control subjects with Pendred syndrome (P = .52). These seroprevalence rates are similar to those expected in the general population (40%)., Conclusion: In spite of their auditory phenotypic similarities, congenital CMV infection is not a significant factor in the etiology of EVA.