Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures.

The inner ear contains the sensory organs for hearing and balance. Both hearing and balance are commonly affected in individuals with CHARGE syndrome (CS), an autosomal dominant condition caused by heterozygous pathogenic variants in the CHD7 gene. Semicircular canal dysplasia or aplasia is the single most prevalent feature in individuals with CHARGE leading to deficient gross motor skills and ambulation. Identification of CHD7 as the major gene affected in CHARGE has enabled acceleration of research in this field. Great progress has been made in understanding the role of CHD7 in the development and function of the inner ear, as well as in related organs such as the middle ear and auditory and vestibular neural pathways. The goals of current research on CHD7 and CS are to (a) improve our understanding of the pathology caused by CHD7 pathogenic variants and (b) to provide better tools for prognosis and treatment. Current studies utilize cells and whole animals, from flies to mammals. The mouse is an excellent model for exploring mechanisms of Chd7 function in the ear, given the evolutionary conservation of ear structure, function, Chd7 expression, and similarity of mutant phenotypes between mice and humans. Newly recognized developmental functions for mouse Chd7 are shedding light on how abnormalities in CHD7 might lead to CS symptoms in humans. Here we review known human inner ear phenotypes associated with CHD7 pathogenic variants and CS, summarize progress toward diagnosis and treatment of inner ear-related pathologies, and explore new avenues for treatment based on basic science discoveries.

An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.

Exome sequencing coupled with homozygosity mapping was used to identify a transition mutation (c.794T>C; p.Leu265Ser) in ELMOD3 at the DFNB88 locus that is associated with nonsyndromic deafness in a large Pakistani family, PKDF468. The affected individuals of this family exhibited pre-lingual, severe-to-profound degrees of mixed hearing loss. ELMOD3 belongs to the engulfment and cell motility (ELMO) family, which consists of six paralogs in mammals. Several members of the ELMO family have been shown to regulate a subset of GTPases within the Ras superfamily. However, ELMOD3 is a largely uncharacterized protein that has no previously known biochemical activities. We found that in rodents, within the sensory epithelia of the inner ear, ELMOD3 appears most pronounced in the stereocilia of cochlear hair cells. Fluorescently tagged ELMOD3 co-localized with the actin cytoskeleton in MDCK cells and actin-based microvilli of LLC-PK1-CL4 epithelial cells. The p.Leu265Ser mutation in the ELMO domain impaired each of these activities. Super-resolution imaging revealed instances of close association of ELMOD3 with actin at the plasma membrane of MDCK cells. Furthermore, recombinant human GST-ELMOD3 exhibited GTPase activating protein (GAP) activity against the Arl2 GTPase, which was completely abolished by the p.Leu265Ser mutation. Collectively, our data provide the first insights into the expression and biochemical properties of ELMOD3 and highlight its functional links to sound perception and actin cytoskeleton.

Molecular and clinical studies of X-linked deafness among Pakistani families.

There are 68 sex-linked syndromes that include hearing loss as one feature and five sex-linked nonsyndromic deafness loci listed in the OMIM database. The possibility of additional such sex-linked loci was explored by ascertaining three unrelated Pakistani families (PKDF536, PKDF1132 and PKDF740) segregating X-linked recessive deafness. Sequence analysis of POU3F4 (DFN3) in affected members of families PKDF536 and PKDF1132 revealed two novel nonsense mutations, p.Q136X and p.W114X, respectively. Family PKDF740 is segregating congenital blindness, mild-to-profound progressive hearing loss that is characteristic of Norrie disease (MIM#310600). Sequence analysis of NDP among affected members of this family revealed a novel single nucleotide deletion c.49delG causing a frameshift and premature truncation (p.V17fsX1) of the encoded protein. These mutations were not found in 150 normal DNA samples. Identification of pathogenic alleles causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling and molecular epidemiology of hearing loss among Pakistanis.

Congenital cytomegalovirus (CMV) for the pediatric otolaryngologist.

Cytomegalovirus (CMV) is a double-stranded DNA virus and a member of the herpesvirus family. It is the most common congenital viral infection. For symptomatic infections, symptoms can vary widely but tends to have a predilection for the central nervous system and for the reticuloendothelial system. Sensorineural hearing loss (SNHL) is by far the most common sequelae of congenital CMV infection. For this reason, it is imperative to understand the screening, diagnosis, and possible treatment options for congenital CMV induced SNHL. This literature review explores the association of CMV with hearing loss, screening for congenital CMV infections, possible treatments options, and the development of a possible vaccine.

International Pediatric Otolaryngology Group (IPOG) Consensus Recommendations: Congenital Cholesteatoma.

OBJECTIVE: To provide recommendations to otolaryngologists and allied physicians for the comprehensive management of children who present with signs and symptoms of congenital cholesteatoma. METHODS: A two-iterative Delphi method questionnaire was used to establish expert recommendations by the members of the International Pediatric Otolaryngology Group, on the preoperative work-up, the perioperative considerations, and follow-up. RESULTS: Twenty-two members completed the survey, in 14 tertiary-care center departments representing 5 countries. The main consensual recommendations were: a precise otoscopic description of the quadrants involved, extensive audiological workup (bilateral tonal, vocal audiometry, and BERA), and a CT scan are required. Facial nerve monitoring and a combination of microscope and telescope are recommended for surgical removal. Clinical and audiological follow-up should be pursued yearly for at least 5 years. First MRI follow-up should be done at 18 months postoperatively if the removal violated the matrix. MRI follow-up duration depends on the initial extent of the cholesteatoma. CONCLUSION: The goal of preoperative and follow-up consensus from International Pediatric Otolaryngology Group participants is to help manage infants and children with congenital cholesteatoma. The operative techniques may vary, and experienced surgeons must perform these procedures.

Advanced practice providers and children's hospital-based pediatric otolarynology practices.

INTRODUCTION: Advanced practice providers (APPs), including nurse practitioners and physician assistants, have been deployed in children's hospital-based academic pediatric otolaryngology practices for many years. However, this relationship in terms of prevalence, roles, financial consequences and satisfaction has not been examined. The objective of this study is to explore how APPs impact healthcare delivery in this setting. METHODS: Pediatric otolaryngology chiefs of all academic children's hospitals in the US were electronically surveyed about the ways APPs intersected clinically and financially in their respective practice. RESULTS: A total of 29 of 36 children's hospital-based pediatric otolaryngology practices completed the survey, of which 26 practices (90%) utilized APP. There were large variances within the APP practice cohort in faculty size (mean/median/range = 9.4/8.5/3-29); annual patient visits (mean/median = 18,373/17,600); number of practice site (mean/median/range = 4.3/4/2-9) and number of outpatient APP (mean/median/range = 6.3/5/1-30). No factors (faculty size, annual visits and number of practice sites) differentiated between the APP and non-APP practices. Among APP practices, significant correlation (p<.00001) was observed between size of APP cohort to faculty size and annual visits. 69% of the practices did not differentiate job functions of nurse practitioners and physician assistants. 85% of the practices utilized APPs in all practice sites and 19% utilized APPs in the operating room. 77% of APPs billed independently and 46% had on-site supervision. The most prevalent APP salary bracket based on 0-5, 6-10 and > 11 years of tenure were $76-100K (65%), $100-150K (77%) and $100-150K (86%), respectively. In 46% of the practices, APPs were able to generate enough revenue to cover more than 75% of their salary and 23% of practices generated a profit. 81% of the chiefs ranked the effectiveness of APPs as high (4 and 5) on a 5-point Likert scale. DISCUSSION: The majority of academic pediatric otolaryngology practices employed APPs. Despite the diversity seen in practice complexity, APP functionality and financial impact, most found the APP model to be beneficial in improving patient care, patient access and faculty productivity.

Surgical management of otologic disease in pediatric patients with Turner syndrome.

OBJECTIVES: Previous reports suggest that patients with Turner syndrome have a predisposition for acute and chronic otitis media. However, the role of early or aggressive surgical management of otologic disease has not been explored in the pediatric population. With respect to otitis media in pediatric Turner syndrome patients, we examined (1) the impact of timing and (2) the type of surgical intervention in the treatment of disease. METHODS: Retrospective 10-year review of patients with Turner syndrome and chronic otitis and its surgical management at a single pediatric tertiary institution. RESULTS: One hundred and seventy-eight patients with Turner syndrome were evaluated at our institution from 1997 to 2007. Thirty-two (18.0%) were diagnosed with middle ear disease. Eighteen (10.1%) were referred to otolaryngology for evaluation. Average age at presentation was 4.7 years (range: 1 month to 12 years). The 18 patients referred to otolaryngology required a mean of 16 clinic visits each for otologic symptoms. A mean of 6.7 pressure equalization tubes (PET) were required per patient (range: 0-25). Middle ear effusions (n=14, 78%) along with tympanic membrane retractions and/or perforations (n=10, 55.6%) were the most common otoscopic findings. Patients with tympanic membrane retractions (8/18) required a higher average number of PET (9.1) and cumulatively underwent a total of five tympanoplasty-type procedures. Six ears had evidence of cholesteatoma. Two patients underwent myringoplasty, 6 patients underwent tympanoplasty (33.3%, mean age 11.6 years), and 3 patients (16.7%, mean age 9.4 years) underwent tympanomastoidectomy. Revision procedures were common. Older age at first PET placement was significantly correlated with the need for later tympanoplasty and/or tympanomastoidectomy operations (p<0.036). Tympanoplasty or tympanomastoidectomy patients had their first PET placed on average at 5.2 years as compared to 2.6 years in those not requiring tympanoplasty or tympanomastoidectomy operations. CONCLUSIONS: Recurrent and chronic otitis media is common in patients with Turner syndrome. Once established, disease is recalcitrant and leads to multiple surgical procedures. Early PET insertion is advocated to offset the future necessity of more extensive tympanic procedures.

Relative Preservation of Superior Semicircular Canal Architecture in CHARGE Syndrome.

OBJECTIVES: (1) Describe common patterns of semicircular canal (SCC) anomalies in CHARGE syndrome (CS) and (2) recognize that in CS, the architecture of the superior SCC may be relatively preserved. STUDY DESIGN: This is a retrospective review of temporal bone imaging studies. SETTING: Quaternary care center. SUBJECTS AND METHODS: A sample of 37 patients with CS. All subjects met clinical diagnostic criteria for CS. The presence/absence of anomalies of the middle ear, mastoid, temporal bone venous anatomy, inner ear, and internal auditory canal was recorded. Anomalies of each SCC were considered separately and by severity (normal, dysplasia, aplasia). RESULTS: Thirty-seven subjects (74 temporal bones) were reviewed. Thirty-four (92.0%) patients demonstrated bilateral SCC anomalies. Three (8.0%) had normal SCCs. In patients with SCC anomalies, all canals demonstrated bilateral abnormalities. Thirty-two (86.5%) patients had bilateral horizontal SCC aplasia. These 32 patients also demonstrated posterior SCC aplasia in at least 1 ear. Of 74 temporal bones, 37 (50.0%) had superior SCC dysplasia. All dysplastic superior SCCs showed preservation of the anterior limb. Complete superior SCC aplasia was found in 28 (37.8%) temporal bones. CONCLUSION: SCC anomalies occur with high frequency in CS. Complete absence of the horizontal and posterior canals is typical and usually bilateral. By contrast, the superior SCC often demonstrates relative preservation of the anterior limb.

Pediatric hearing impairment caregiver experience: impact of duration of hearing loss on parental stress.

OBJECTIVES: Caregivers of children who are deaf/hard of hearing have been reported to have greater stress than caregivers of children with normal hearing. The time of diagnosis is a particularly stressful time and stress levels may change over time based on varying needs at different life events. Thus, we hypothesized that stress experienced by caregivers evolves over time and is impacted by the duration since the diagnosis of hearing loss. METHODS: The 68-item pediatric hearing impairment caregiver experience (PHICE) is a validated questionnaire used to measure stress. The PHICE was administered to 152 caregivers of children with permanent hearing loss. Domain scores were converted into z-scores for analysis of trends of stress over time. RESULTS: Parents of children whose hearing loss was identified more than 60 months ago reported higher stress levels regarding educational aspects of their child's needs as compared to parents of children with less than 24 months or 24-60 months duration since diagnosis. Parents of children diagnosed with hearing loss within the preceding 24 months reported higher stress levels in the area of healthcare than parents of children diagnosed greater than 24 months ago. CONCLUSIONS: Parental stressors change over time with respect to the time of diagnosis of hearing impairment. This phenomenon was observed irrespective of the age of diagnosis of hearing loss. As professionals serving families of children with hearing loss, we should be aware of changing stressors over time and identify the appropriate support services for families to meet those changing needs. By addressing those evolving stressors, the families' ability to support and improve the outcomes for their children who are deaf or hard of hearing may be enhanced.

Language Underperformance in Young Children Who Are Deaf or Hard-of-Hearing: Are the Expectations Too Low?

OBJECTIVE: (1) To examine language performance in the context of cognitive abilities in young children who are deaf or hard-of-hearing and (2) to identify factors associated with having a language underperformance, defined as a gap between the language standard score and the nonverbal IQ (NVIQ) standard score. METHODS: Children 6 to 82 months of age with bilateral hearing loss were enrolled. Language performance was defined as a ratio of language skills relative to cognitive abilities with language underperformance defined as a ratio of language scores to NVIQ <0.85. RESULTS: Among 149 children, approximately half had hearing loss that was clinically classified as mild or moderate, and over one-third received a cochlear implant. Participants had a mean NVIQ in the average range (95.4 [20.3]). Receptive language scores were significantly lower than their NVIQ by 10.6 points (p < .0001). Among children with NVIQs 80 to 100, 62.5% had receptive scores <85 and 50% had a language underperformance (ratio <0.85). Among children with NIVQs >100, 21.1% had receptive scores <85 with 42% having a language underperformance. Children with language underperformance (n = 61, 41.5%) were more likely to have more severe levels of hearing loss, lower socioeconomic status, and be nonwhite. CONCLUSION: Many children early identified with hearing loss continue to demonstrate language underperformance, defined using their cognitive potential. Language deficits have a cascading effect on social functioning in children who are deaf or hard-of-hearing. This study highlights the need to understand a child's cognitive potential to adequately address language needs in existing intervention models.

Pediatric acute mastoiditis in the era of pneumococcal vaccination.

OBJECTIVES/HYPOTHESIS: The objective was to describe trends in the annual prevalence of hospitalization for pediatric acute mastoiditis since introduction of the 7-valent pneumococcal vaccine in 2000 and the 13-valent vaccine in 2010. STUDY DESIGN: Cross-sectional retrospective data analysis. METHODS: The Kids' Inpatient Database from years 2000 to 2012 was analyzed. To determine the annual prevalence of hospitalization for acute mastoiditis, nationally weighted frequencies of hospitalization for children <21 years with acute mastoiditis diagnoses were collected. Trend analysis of hospitalization rates from 2000 to -2012 was performed. RESULTS: From 2000 to 2012, there was no significant trend in hospitalization rates for acute mastoiditis overall (1.38 and 1.43 per 100,000 persons in 2000 and 2012, respectively; P = .86) or by age group. When comparing hospitalization rates at time points 2000 and 2012, children <1 year (4.65 and 3.27 per 100,000 persons, P = .0023) and 1 to 2 years of age (3.95 and 3.18 per 100,000 persons, respectively; P = .0107) demonstrated declines in hospitalization over time. Between 2009 and 2012, hospitalization rates also significantly declined for children aged <1 year (4.50 to 3.27 per 100,000 persons, P = .0056) and 1 to 2 years (4.30 to 3.18 per 100,000 persons, P = .0002) but increased for children 5 to 9 years (1.10 to 1.81 per 100,000 persons, P < .0001) and 10 to 20 years of age (0.41 to 0.72 per 100,000 persons, P < .0001). CONCLUSIONS: Despite introduction of two pneumococcal vaccines, rates of hospitalization for pediatric acute mastoiditis did not decline between 2000 and 2012. Between 2009 and 2012, however, children 0 to 2 years of age showed declining hospitalization rates, possibly reflecting the protective benefit of the 13-valent pneumococcal vaccine. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1480-1485, 2018.

Controversies in aural atresia repair.

PURPOSE OF REVIEW: To discuss recent controversies regarding the management of aural atresia. RECENT FINDINGS: Management of unilateral atresia is less controversial. Candidacy for successful repair is based on high-resolution computed tomography findings and atresia grading. The bone-anchored hearing aid is a viable alternative strategy for hearing improvement. Stability of hearing results following atresia repair improves with the number of atresiaplasties performed. Development of image-guided surgery may provide benefit in atresia surgery. New unrecognized rare complications of aural atresia and atresia repair including salivary fistula and middle ear cholesteatoma are now being recognized and are manageable. SUMMARY: Management of aural atresia continues to be difficult and surrounded by controversy. New studies and cases series may shed light on these management issues.

The role of CMV inflammatory genes in hearing loss.

HYPOTHESIS: The purpose of this study is to test the hypothesis that virally encoded immunomodulatory genes play a role in cytomegalovirus (CMV)-related hearing loss. OBJECTIVE: Cytomegalovirus is the leading cause of infectious-related congenital sensorineural hearing loss worldwide. Unfortunately, little is known about the pathophysiology of CMV-related injury to the developing ear. METHODS: Viral mutagenesis techniques were developed that allow the deletion of a specific viral immunomodulatory gene, macrophage inflammatory protein (MIP) 1alpha homolog. We assessed the extent to which this gene product contributed to auditory pathologic findings in the guinea pig (GP) model. Eighteen weanling GPs (250-350 g) were used under an Institutional Animal Control and Use Committee-approved protocol. We analyzed preinoculation hearing using auditory brainstem response recordings. Intracochlear inoculations were performed on one group of six GPs with sterile viral media, 6 GPs with wild-type (WT) CMV virus, and 6 GPs with mutant "knockout" (KO) virus (with deleted MIP-1alpha homolog). Auditory brainstem responses were then obtained on postinoculation Days 7, 14, 21, and 28. RESULTS: There was a significant difference in hearing between the KO group and the WT group, with significantly better hearing in the KO group. A comparison of the KO group to the sham group revealed no significant hearing differences between the groups. The WT group had significant threshold shifts by dose at all frequencies meeting our criteria of hearing loss (>30 dB). There were no statistical differences in the sham or KO group. CONCLUSION: Virally encoded immunomodulatory genes such as MIP-1alpha seem to play a significant role in CMV-related hearing loss. This study is the first demonstration of the role of specific viral immune modulation genes in the in vivo pathogenesis of CMV-induced hearing loss in a relevant animal model.

Macrophage inflammatory proteins in cytomegalovirus-related inner ear injury.

OBJECTIVE: Inner ear inflammation triggered by CMV infection may play a role in CMV-related auditory pathogenesis. The purpose of the study was to determine if a virally encoded macrophage inflammatory protein played a role in CMV-related hearing loss. DESIGN: Mutagenesis was performed with deletion of a guinea pig CMV macrophage inflammatory protein. Intracochlear inoculations were performed on three groups of animals (n = 18). Group 1 received sterile viral media, Group 2 received wild-type CMV virus, and Group 3 received "knockout" (KO) virus with a deleted immunomodulation gene. Baseline and postinoculation ABRs were obtained. ELISA and PCR were performed and temporal bones examined. SUBJECTS: Eighteen guinea pigs. RESULTS: The KO group had significantly better hearing than the WT group. There were no significant differences between the KO and sham groups. The WT group had significant hearing loss at all frequencies. Inflammation and fibrosis were noted in the WT temporal bones only. CONCLUSIONS: Virally encoded macrophage inflammatory proteins appear to play a significant role in CMV-related hearing loss.

The utility of early developmental assessments on understanding later nonverbal IQ in children who are deaf or hard of hearing.

OBJECTIVE: In children who are deaf or hard of hearing (DHH), it is helpful to have meaningful early measures of development in order to provide effective interventions and offer benchmarks that help recognize varied developmental trajectories. The main objective of this study was to compare results of an early developmental assessment prior to 3 years of age to later nonverbal IQ assessed between 3 and 6 years of age in children who are DHH. METHODS: This study included children 3-6 years of age with bilateral permanent hearing who were enrolled in a prospective cohort study on developmental outcomes. As part of the study, children received the Leiter International Performance Scale-Revised, which provided a nonverbal Brief IQ, as well as standardized language assessment and behavioral checklists. Children were included in this analysis if they had received an early developmental assessment with the Gesell Developmental Schedules-Revised as part of a clinical visit with a developmental pediatrician. Correlation coefficients and multiple regression analysis were used to associate the scores on the Gesell (using a developmental quotient) with scores on the Leiter-R Brief IQ. RESULTS: Forty-five participants who enrolled in the observational study had available evaluation results from the Gesell and complete Brief IQ results from the Leiter-R. The adaptive domain of the Gesell had good correlation (r = 0.61, p < 0.0001) with the Brief IQ on the Leiter-R. Children who had stable developmental or intelligence classifications based on scores (<70, 70 to <85, 85 to <100, ≥100) over time were older (>24 months) at the early Gesell assessment. Degree of hearing loss or maternal education did not appear to confound the relationship between the Gesell and the Leiter-R. CONCLUSIONS: The adaptive domain of the Gesell Developmental Schedules - Revised administered in early childhood (under 3 years of age) has good correlation with the nonverbal Brief IQ on the Leiter International Performance Scale-R. Because children who are DHH have a higher likelihood of having a developmental disability compared to the general population, early developmental assessments are often important. Although early developmental assessments have their limitations, our results indicate that they are fairly robust indicators of later development. Such early indicators can be extremely useful in the clinical and educational management of children who are DHH.

Pediatric Acute Otitis Media in the Era of Pneumococcal Vaccination.

Objectives (1) Describe longitudinal trends in annual prevalence of hospital admission for pediatric acute otitis media (AOM) and complications of AOM (CAOM) since introduction of pneumococcal vaccination in 2000 and (2) describe the longitudinal trend of prevalence of hospital admission for pneumococcal meningitis in children with AOM-related diagnoses in the postvaccination era. Study Design Retrospective analysis of Kids' Inpatient Database from 2000 to 2012. Setting Community, nonrehabilitation hospitals. Subjects and Methods To determine annual prevalence of admission for AOM/CAOM, nationally weighted frequencies of children aged <21 years with acute suppurative otitis media, acute mastoiditis, suppurative labyrinthitis, and/or acute petrositis were collected. The frequency of coexisting pneumococcal meningitis diagnoses among these patients was also collected. Trend analysis of prevalences of admission for AOM/CAOM and for pneumococcal meningitis occurring in the setting of AOM/CAOM from 2000 to 2012 was performed. Results Between 2000 and 2012, annual prevalence of admission for AOM/CAOM decreased from 3.956 to 2.618 per 100,000 persons ( P < .0001) (relative risk reduction 34%). Declines in admission prevalence were most pronounced in children <1 year of age (from 22.647 to 8.715 per 100,000 persons between 2000 and 2012, P < .0001) and 1 to 2 years of age (from 13.652 to 5.554 per 100,000 persons between 2000 and 2012, P < .0001). For all ages, the admission prevalence for pneumococcal meningitis and concomitant AOM/CAOM decreased (from 1.760 to 0.717 per 1,000,000 persons, P < .0001) over the study period. Conclusions The prevalence of hospital admission for pediatric AOM/CAOM has declined since the advent of pneumococcal vaccination. Admission rates for pneumococcal meningitis with AOM/CAOM have similarly declined.

A Targeted Approach for Congenital Cytomegalovirus Screening Within Newborn Hearing Screening.

BACKGROUND AND OBJECTIVE: Congenital cytomegalovirus (cCMV) infection remains a leading cause of childhood hearing loss. Currently universal CMV screening at birth does not exist in the United States. An alternative approach could be testing infants who do not pass their newborn hearing screening (NHS) for cCMV. This study was undertaken to evaluate whether a targeted approach will identify infants with CMV-related sensorineural hearing loss (SNHL). METHODS: Infants born at 7 US medical centers received NHS and were also screened for cCMV while in the newborn nursery. Infants who tested positive for CMV received further diagnostic audiologic evaluations to identify or confirm hearing loss. RESULTS: Between 2007 and 2012, 99 945 newborns were screened for both hearing impairment and cCMV. Overall, 7.0% of CMV-positive infants did not pass NHS compared with 0.9% of CMV-negative infants (P < .0001). Among the cCMV infants who failed NHS, diagnostic testing confirmed that 65% had SNHL. In addition, 3.6% of CMV-infected infants who passed their NHS had SNHL confirmed by further evaluation during early infancy. NHS in this cohort identified 57% of all CMV-related SNHL that occurred in the neonatal period. CONCLUSIONS: A targeted CMV approach that tests newborns who fail their NHS identified the majority of infants with CMV-related SNHL at birth. However, 43% of the infants with CMV-related SNHL in the neonatal period and cCMV infants who are at risk for late onset SNHL were not identified by NHS.

The effect of cidofovir on cytomegalovirus-induced hearing loss in a Guinea pig model.

OBJECTIVE: To evaluate the utility of therapy with the cyclic cogener of the anti-cytomegalovirus (CMV) agent cidofovir against CMV-induced hearing loss in a guinea pig model. DESIGN: Thirty-six guinea pigs were randomly divided into 4 groups of 9. All groups underwent auditory brainstem response testing on days 0, 4, 7, 14, 21, and 28. Group 1 received no intervention. Group 2 underwent sham surgery consisting of unilateral round window injection of 25 microL of sterile viral media on day 0. Groups 3 and 4 underwent round window injection of 1.7 x 10(5) plaque-forming units of guinea pig CMV on day 0. Group 4 received antiviral treatment with intraperitoneal injection of cidofovir (20 mg/kg) on days 1 and 5 after inoculation. SETTING: An animal research facility. SUBJECTS: Thirty-six weanling Hartley guinea pigs. RESULTS: Of the animals who received guinea pig CMV and no cidofovir treatment, 4 of 9 (day 4) and 5 of 9 (days 7 and 28) demonstrated a hearing loss of at least 30 dB. In contrast, none of the animals in the untreated, sham surgery, or cidofovir-treated groups had a hearing loss of greater than 20 dB. This difference was statistically significant for day 4 (P = .04, 1-tailed Fisher exact test), day 7 (P = .01), and day 28 (P = .01). Histologic evaluation of hearing-impaired animals revealed inflammatory infiltrates, particularly in the scala tympani. Fibrosis of the basal turn of the cochlea was observed in 7 of 9 untreated animals and 1 of 9 treated animals. CONCLUSION: Cidofovir therapy prevents CMV-induced hearing loss and associated histologic changes in guinea pigs.

Combination therapies using an intratympanic polymer gel delivery system in the guinea pig animal model: A safety study.

OBJECTIVES: High dose antivirals have been shown to cause hearing loss when applied via the intratympanic route. The aim of this study was to determine if a combination therapy using dexamethasone (DXA) with either Cidofovir (CDV) or Ganciclovir (GCV), in solution or in PLGA-PEG-PLGA (PPP) hydrogel, is innocuous to the inner ear. METHODS: Cytomegalovirus (CMV)-free guinea pigs were separated into four principal study groups and treated via intratympanic injection (IT) of CDV/DXA solution, CDV/DXA Hydrogel, GCV/DXA solution and GCV/DXA hydrogel. Hearing thresholds were evaluated with pretreatment ABR and post injection weekly ABRs for a total follow up of 28 days. Temporal bone tissue was harvested and stained with Hematoxylin and Eosin for histologic analysis. RESULTS: ABR analysis revealed that GCV/DXA in solution and in hydrogel led to a mild hearing loss at days 7-21 but returned to baseline by day 28 When administered via PPP hydrogel, CDV/DXA demonstrated mild persistent hearing loss at 32kHz at 28 days. An inflammatory response was identified in the cochlear specimen of the CDV/DXA/PPP hydrogel group, in concert with mild hearing loss, at days 21 and 28. CONCLUSION: Results of this study support the safe intratympanic use of higher concentrations of antivirals when combined with DXA, both in solution and when applied via PPP hydrogel.

Chd7 cooperates with Sox10 and regulates the onset of CNS myelination and remyelination.

Mutations in CHD7, encoding ATP-dependent chromodomain helicase DNA-binding protein 7, in CHARGE syndrome lead to multiple congenital anomalies, including craniofacial malformations, neurological dysfunction and growth delay. Mechanisms underlying the CNS phenotypes remain poorly understood. We found that Chd7 is a direct transcriptional target of oligodendrogenesis-promoting factors Olig2 and Smarca4/Brg1 and is required for proper onset of CNS myelination and remyelination. Genome-occupancy analyses in mice, coupled with transcriptome profiling, revealed that Chd7 interacted with Sox10 and targeted the enhancers of key myelinogenic genes. These analyses identified previously unknown Chd7 targets, including bone formation regulators Osterix (also known as Sp7) and Creb3l2, which are also critical for oligodendrocyte maturation. Thus, Chd7 coordinates with Sox10 to regulate the initiation of myelinogenesis and acts as a molecular nexus of regulatory networks that account for the development of a seemingly diverse array of lineages, including oligodendrocytes and osteoblasts, pointing to previously uncharacterized Chd7 functions in white matter pathogenesis in CHARGE syndrome.