Congenital Bilateral Hearing Research Articles

6415 Resistance to Thyroid Hormone -A Challenge to Manage

Abstract Disclosure: A. Altaf: None. F. Iqbal: None. E. Hamoudeh: None. C. Coyne: None. K. Anne: None. L. Buckley: None. Background: Resistance to thyroid hormone (RTH) or Refetoff syndrome was first introduced in 1967. It is an autosomal dominant or recessive genetic disease with a mutation in the thyroid hormone receptorβ (THR-β) gene or the thyroid hormone receptorα (THR-α) gene. The distinguishing biochemical feature of RTHβ is an elevated level of circulating free thyroid hormones with normal or high TSH concentration and decreased peripheral tissue response to thyroid hormone. Common signs and symptoms in patients with RTHβ are short stature, attention deficit disorder, and resting tachycardia and many patients might be asymptomatic. Case: We report a case of a 36-year-old patient with past medical history of congenital bilateral hearing loss, atrial fibrillation, CHF, and slow learning/comprehending who presented to the ER with shortness of breath and atrial fibrillation with tachycardia. Admission labs revealed elevated TSH 3.9, elevated fT4 3.28, and elevated TT3 205. He reported that for the past year, he has been on levothyroxine 50mcg for abnormal TSH. Levothyroxine was stopped and the patient was discharged on methimazole 10mg daily. Further workup revealed negative thyroglobulin and thyroid peroxidase antibodies. Thyroid ultrasound with Doppler demonstrated a mildly hypervascular thyroid gland without evidence of nodules. Brain MRI was negative for any pituitary abnormalities. HAMA testing continued to show elevated TSH. Patient was followed by cardiology and due to continued atrial fibrillation, had multiple cardioversions and was managed on a beta blocker. Due to his atrial fibrillation, endocrinology service continued his methimazole till his genetic testing came positive for an autosomal dominant heterozygous pathogenic mutation in THRB c.1373 T>C (p. Val458Ala). His thyroid hormones and TSH continue to be elevated. Currently, he is not on thyroid medication and getting monitored. The need for multiple cardioversions for atrial fibrillation in this patient makes resistance to thyroid hormone management challenging. Discussion: Hyperthyroidism is commonly mistaken for RTH. However, the lack of TSH suppression should be further investigated. Most patients with RTHβ are adequately compensated by the increased endogenous supply of thyroid hormone showing increased serum fT3 and fT4 levels and normal or near normal TSH levels. Beta Blockers like atenolol cannot inhibit the conversion of T4 to T3 and can be used for RTHβ with tachycardia. Triiodothyroaceticacid (TRIAC) or dextrothyroxine (DT4) have also been used to treat thyrotoxicosis. In summary, treatment for RTHβ remains a challenge for clinicians, especially in patients with atrial fibrillation and many patients are misdiagnosed and managed as hyperthyroidism. Presentation: 6/3/2024

Dynamic functional network connectivity in children with profound bilateral congenital sensorineural hearing loss.

Functional magnetic resonance imaging (fMRI) studies have revealed extensive functional reorganization in patients with sensorineural hearing loss (SNHL). However, almost no study focuses on the dynamic functional connectivity after hearing loss. This study aimed to investigate dynamic functional connectivity changes in children with profound bilateral congenital SNHL under the age of 3years. Thirty-two children with profound bilateral congenital SNHL and 24 children with normal hearing were recruited for the present study. Independent component analysis identified 18 independent components composing five resting-state networks. A sliding window approach was used to acquire dynamic functional matrices. Three states were identified using the k-means algorithm. Then, the differences in temporal properties and the variance of network efficiency between groups were compared. The children with SNHL showed longer mean dwell time and decreased functional connectivity between the auditory network and sensorimotor network in state 3 (P < 0.05), which was characterized by relatively stronger functional connectivity between high-order resting-state networks and motion and perception networks. There was no difference in the variance of network efficiency. These results indicated the functional reorganization due to hearing loss. This study also provided new perspectives for understanding the state-dependent connectivity patterns in children with SNHL.

Comparison of Depth of Mastoid Antrum on High Resolution Computed Tomography and Per Operatively in Cases Undergoing Mastoidectomy.

To compare the depth of mastoid antrum on High Resolution Computed Tomography and per operatively in cases undergoing mastoidectomy. This prospective observational study was done in a tertiary care Army Hospital with 35 patients meriting cortical mastoidectomy surgery. The patients underwent HRCT of temporal bone as a routine pre-operative work up, where depth of mastoid antrum was measured from dome of lateral semicircular canal to outer cortex of temporal bone. Depth was also recorded per-operatively with the help of measuring scale. Measurements were correlated and data was analysed statistically. There were 12 male patients and 23 females. 6 patients were < 3years of age and 29 above. Study included 29 cases of Chronic Otitis Media and 6 of Bilateral Congenital Sensorineural Hearing Loss. Mean depth of mastoid antrum was 1.625cm ± 0.228 on HRCT, and 1.651cm ± 0.245 per-operatively. Depths of mastoid antrum on HRCT and per operatively amongst paediatrics as well as adult cases were comparable, but were more than the standard depth of 1cm in 5 (82.3%) paediatrics cases and ˃1.5cm in 24 (82.9%) adult patients. In absence of Koerner's Septum, mean HRCT depth was 1.60cm ± SD 0.23 and per operatively was 1.63cm ± SD 0.21; whereas in its presence mean HRCT depth was 1.84cm ± SD 0.069 and per-operatively was 1.85cm ± SD 0.42. Significant difference in depth was noted between adults and children, and between the cases with or without Koerner's Septum. However, difference in depth was not significant when compared between different genders, laterality of disease or disease pathology.

Early-stage use of hearing aids preserves auditory cortical structure in children with sensorineural hearing loss.

Hearing is critical to spoken language, cognitive, and social development. Little is known about how early auditory experiences impact the brain structure of children with bilateral sensorineural hearing loss. This study examined the influence of hearing aid use and residual hearing on the auditory cortex of children with severe to profound congenital sensorineural hearing loss. We evaluated cortical preservation in 103 young pediatric cochlear implant candidates (55 females and 48 males) by comparing their multivoxel pattern similarity of auditory cortical structure with that of 78 age-matched children with typical hearing. The results demonstrated that early-stage hearing aid use preserved the auditory cortex of children with bilateral congenital sensorineural hearing loss. Children with less residual hearing experienced a more pronounced advantage from hearing aid use. However, this beneficial effect gradually diminished after 17months of hearing aid use. These findings support timely fitting of hearing aids in conjunction with early implantation to take advantage of neural preservation to maximize auditory and spoken language development.

Management of Bilateral Congenital Sensorineural Hearing Loss with Cochlear Implant Surgery in a child with Developmental Delay: A Case Report

Background : Most people have congenital hearing loss. This type of hearing loss happens during pregnancy. The causes are Prematurity, maternal hyperglycemia, anoxia before birth, genetics, and infectious disorders like rubella transmitted from mother to baby in utero. Early diagnosis of hearing loss in some neonates allows for timely treatment with cochlear implants or hearing aid treatment to support language development. Cochlear implants may enable better speech comprehension in both quiet and noisy situations with the aid of therapy. Case Presentation : We discuss Bilateral Congenital Profound Sensorineural Hearing Loss with Developmental Delay and Cochlear Implant Surgery. This 2.5-year-old female child registered in the ENT department, with the chief complaint of inability to hear by both ears and inability to speak. The child was aged 2.5 years and responded only to loud sounds. An examination and evaluation of a doctor confirmed the diagnosis of bilateral severe hearing loss with developmental delays. Therapeutic Management : Medication was given to a child as per the doctor’s order, Ivf DNS 400ml +Inj. KCL 4ml 8 Hourly, Inj. Cefuroxime 700 Mg Bd, Inj Pan 15mg Od, Inj. Emeset 1.5 Mg Tds, Inj. Neomol 20ml Tds, Inj. Dexa 2 Mg Bd, SypIbugesic Plus 7ml Tds ,Syp. Taxol Dx 3.5 ml Tds Syp. Sinarest 1 Tsp, N/D Otrivin (P) 2 Drops Tds. Child was treated with cochlear implant surgery. After treatment child’s condition improved. Conclusion : Timely intervention can be beneficial to improve the hearing sense and ultimately development of child with Sensorineural hearing loss.

A Novel Biallelic Variant in CDH23 Gene in a Family with Atypical USH1D Manifestation: A Literature Review and Investigation of Genotype-Phenotype Correlation

Introduction: Usher syndrome (USH) is an autosomal recessive disorder that predominantly affects hearing, vision, and, in some cases, vestibular function. USH, according to the onset age, severity, and progression of symptoms, is categorized into four main types. In addition, there are a significant number of reports that patients’ manifestations deviate from canonical phenotypic criteria of main types of USH, which are named atypical USH. CDH23 is the second most common USH gene in which its defects result in USH1D, non-syndromic autosomal recessive deafness-12 (DFNB12), and in a few cases, atypical USH1D. While some studies have suggested that missense and truncating damaging variants in the CDH23 gene cause DFNB12 and USH1D, respectively, no genotype-phenotype correlation for atypical USH1D has been established. Methods: Using whole-exome sequencing, we studied an Iranian family with two affected siblings who manifested congenital bilateral hearing loss, late-onset nyctalopia, retinitis pigmentosa, and normal vestibular function, indicating that their clinical symptoms are consistent with USH2. Results: Whole-exome data analysis revealed a novel bi-allelic nonsense variant (c.6562G>T; p.Glu2188Ter) in the CDH23 gene, which was confirmed by Sanger sequencing. Surprisingly, CDH23 is a member of the USH1 genes; therefore, our patients suffered from atypical USH1D. Also, by conducting a literature review, we provided a clinical and mutational profile of all reported patients with atypical manifestations or those who refuted the claimed genotype-phenotype correlation. Conclusion: By reporting a novel damaging variant, we expand the mutational spectrum of the CDH23 gene that leads to atypical USH1D. Also, reviewing the literature shows that, contrary to previous claims, different genotypes occur in the CDH23 gene allelic disorders, and there is no clear-cut genotype-phenotype correlation.

The Extent of Hearing Input Affects the Plasticity of the Auditory Cortex in Children With Hearing Loss: A Preliminary Study.

This study investigated to what extent residual hearing and rehabilitation options (e.g., hearing aids [HAs]) affect the auditory cortex in children with hearing loss. Twenty-one children with bilateral congenital sensorineural hearing loss who were candidates for cochlear implantation were recruited. Voxel-based morphometry analysis was conducted to assess the gray matter (GM) volume in the auditory cortex. Children's residual hearing was measured by pure-tone audiometry at different frequencies. Multiple linear regression models were conducted to examine the effects of residual hearing and the use of HAs on GM volume in the auditory cortex with the control of age and gender. Children with more residual hearing at high frequencies had larger GM volume ratio (corrected by total intracranial volume) in the left Heschl's gyrus (r = -.545, p = .013). An interaction effect between residual hearing and the use of HAs suggested that the effect of residual hearing on GM ratio was moderated by the use of HAs (β = -.791, p = .020). Compared with children with less residual hearing, children who had more residual hearing benefited more from longer use of HAs in terms of a larger GM ratio. Our preliminary findings highlight the impact of residual hearing on the neuroanatomy of the auditory cortex in children with hearing loss. Moreover, our results call for more auditory input via HAs for children with more residual hearing to preserve the auditory cortex before cochlear implantation. For children with less residual hearing who might receive limited benefit from HAs, an early cochlear implant would be necessary.

SLC26A4 Phenotypic Variability Influences Intra- and Inter-Familial Diagnosis and Management.

SLC26A4 is one of the most common genes causing autosomal recessive non-syndromic sensorineural hearing loss (SNHL). It has been reported to cause Pendred Syndrome (PDS) and DFNB4 which is deafness with enlarged vestibular aqueduct (EVA). However, mutated SLC26A4 is not conclusive for having either DFNB4 or PDS. Three unrelated Jordanian families consisting of eight affected individuals with congenital bilateral hearing loss (HL) participated in this study. Whole-exome and Sanger sequencing were performed to investigate the underlying molecular etiology of HL. Further clinical investigations, including laboratory blood workup for the thyroid gland, CT scan for the temporal bone, and thyroid ultrasound were performed. Three disease-causing variants were identified in SLC26A4 in the three families, two of which were novel. Two families had a novel pathogenic homozygous splice-site accepter variant (c.165-1G&gt;C), while the third family had compound heterozygous pathogenic variants (c.1446G&gt;A; p.Trp482* and c.304G&gt;A; p.Gly102Arg). Our approach helped in redirecting the diagnosis of several affected members of three different families from non-syndromic HL to syndromic HL. Two of the affected individuals had typical PDS, one had DFNB4, while the rest had atypical PDS. Our work emphasized the intra- and inter-familial variability of SLC26A4-related phenotypes. In addition, we highlighted the variable phenotypic impact of SLC26A4 on tailoring a personalized healthcare management.

Follow-up on children with suspected bilateral congenital hearing loss identified through universal newborn hearing screening program in Taiwan: A national-based population study

ObjectiveThis investigation was to ascertain the performance of the UNHS in Taiwan. MethodsThe predefined questionnaire was delivered on the phone in 2016. The descriptive analysis was applied to the research data. 941 neonates in birth cohorts 2013–2014 who were documented as a bilateral referral in the national UNHS tracking system were targeted. The respondents were either caregivers or family members. Results40.3% of 941 children were lost to follow-up, and 66.24% of 363 children were diagnosed with SNHL. 45.15% of 163 children used hearing amplification device(s). 77.46% of hearing amplification device users and 7.51% of non-users participated in the auditory training courses. By six months of age, 38.51% and 22.58% of children diagnosed with bilateral SNHL commenced the hearing amplification device fitting and the auditory training courses, respectively. ConclusionsMore efforts are needed to enhance the performance of the UNHS to achieve national goals stated in the 2014 Taiwan UNHS Revised Guidelines and the well-known benchmarks set by the JCIH in 2007. The development of an electronic tracking system for storing and sharing information on the follow-up on children with congenital hearing loss was as significant as the improvements in the understanding of early hearing detection and intervention of the public and stakeholders.

Three novel variants in SOX10 gene: Waardenburg and PCWH syndromes

BackgroundWaardenburg syndrome (WS) is a rare genetic disorder characterized by musculoskeletal abnormalities, deafness and hypopigmentation of hair and skin. This article’s aim is to investigate clinical and genetic characteristics of WS in three unrelated Caucasian individuals.Case presentationThe first patient was a 25-year-old female with congenital bilateral hearing loss, bright-blue-eyes, hypopigmentation of hair and skin, megacolon, language retardation, tenosynovitis and neuromas. The second case was an infant symptomatic from birth, with dysphagia, Hirschsprung disease and neurological abnormalities. The third patient was a 14-year-old boy with congenital bilateral hearing loss and ileocolic Hirschsprung disease. In order to identify variants in potentially causal genes of the patients’ phenotype, genetical testing was conducted: targeted clinical exome, targeted exome and trio exome, respectively. We identified three novel variants spread throughout the coding sequence of SOX10. The c.395C>G variant identified de novo in patient 1 was a single nucleotide substitution in exon 2. The c.850G>T variant identified as heterozygous in patient 2 was a loss-of-function variant that generated a premature stop codon. The c.966dupT variant identified in patient 3 was a duplication that generated a premature stop codon. It had been identified in his father, arising a possible germinal mosaicism. According to in silico predictors the variant identified in patient 1 was considered as pathogenic, whereas the other two were classified as likely pathogenic.ConclusionsAn exact description of the mutations responsible for WS provides useful information to explain clinical features of WS and contributes to better genetic counselling of WS patients.

Altered Functional Network in Infants With Profound Bilateral Congenital Sensorineural Hearing Loss: A Graph Theory Analysis.

Functional magnetic resonance imaging (fMRI) studies have suggested that there is a functional reorganization of brain areas in patients with sensorineural hearing loss (SNHL). Recently, graph theory analysis has brought a new understanding of the functional connectome and topological features in central neural system diseases. However, little is known about the functional network topology changes in SNHL patients, especially in infants. In this study, 34 infants with profound bilateral congenital SNHL and 28 infants with normal hearing aged 11–36 months were recruited. No difference was found in small-world parameters and network efficiency parameters. Differences in global and nodal topologic organization, hub distribution, and whole-brain functional connectivity were explored using graph theory analysis. Both normal-hearing infants and SNHL infants exhibited small-world topology. Furthermore, the SNHL group showed a decreased nodal degree in the bilateral thalamus. Six hubs in the SNHL group and seven hubs in the normal-hearing group were identified. The left middle temporal gyrus was a hub only in the SNHL group, while the right parahippocampal gyrus and bilateral temporal pole were hubs only in the normal-hearing group. Functional connectivity between auditory regions and motor regions, between auditory regions and default-mode-network (DMN) regions, and within DMN regions was found to be decreased in the SNHL group. These results indicate a functional reorganization of brain functional networks as a result of hearing loss. This study provides evidence that functional reorganization occurs in the early stage of life in infants with profound bilateral congenital SNHL from the perspective of complex networks.

A Study of Middle Ear Diseases in Children with Congenital Bilateral Severe to Profound Sensorineural Hearing Loss.

(1) To find the presence of middle ear diseases present in the patients with congenital bilateral severe to profound SNHL (2) If it poses as a threat to rehabilitative efforts for the existing severe to profound SNHL. Study setting: Department of ENT, C U Shah medical college and hospital. Study design: Prospective study Study population: Patients attending ENT department with complaints of congenital bilateral severe to profound sensorineural hearing loss. A total of 50 cases were studied during the study period. Methods of data collection: The Proforma was designed based on objective of the study. Detailed history was taken followed by thorough ENT and systemic examinations. Otoscopy and otoendoscopy were carried out and all patients were subjected to hearing tests consisting of Pure Tone Audiometry (PTA), Impedance Audiometry (IA), Brainstem Evoked Response Audiometry (BERA) and Oto Acoustic Emissions (OAE). HRCT and MRI scanning of temporal bones of all the patients was included as a part of the routine workup. Out of the 50 children with bilateral congenital hearing loss studied in this study, 13(26%) children were observed to have concurrent middle ear pathologies. 2 patients had bilateral retracted drum with tympanosclerosis; 3 had bilateral retraction pocketswith mastoiditis; 1 had bilateral SOM; 1 had right SOM and left retracted drum; 2 had bilateral PSQ cholesteatoma; 1 had left SOM and right sided tympanic membrane perforation, 3 had right sided tympanic membrane perforation with left sided normal ears. Children with congenital bilateral severe to profound hearing loss should be examined for middle ear pathologies, which can most often be overlooked otherwise, hence rendering the patient unfit for definitive management of the severe to profound SNHL in the form of Hearing Aid trial or Cochlear Implantation, further delaying the development of speech. Hence, all children with congenital bilateral severe to profound hearing loss should undergo regular screening for assessment of middle ear pathologies with prompt treatment when any middle ear pathology is encountered, therefore rendering the patient fit for fitting of cochlear implantation at the earliest possible to decrease permanent impairment of speech.

Auditory and speech performance after unilateral cochlear implantation for cochlear nerve canal stenosis.

To explore the correlation between the width of the bony cochlear nerve canal (CNC) and long-term auditory rehabilitation after unilateral cochlear implantation (CI) in pediatric patients with congenital deafness and bilateral cochlear nerve canal stenosis (CNCS). A retrospective review was performed on 10 patients with bilateral CNCS and bilateral congenital profound hearing loss who each underwent unilateral cochlear implantation. The width of the CNC was determined on computed tomography (CT) imaging and following CI, auditory and speech performance following CI were graded using categories of auditory performance (CAP), speech intelligibility rating (SIR), and the meaningful auditory integration scale (MAIS) at 24 months following implantation. No correlation was noted between CAP score and CNCS at 24 months post CI (P > .05). A positive correlation was noted between SIR score and CNC width (ρ = .81, P < .05). Similarly, a positive correlation was noted between MAIS and CNC width (ρ = .71, P < .05). The width of the CNC in patients with CNCS is positively correlated with some long-term auditory and speech outcomes after CI.

Mild matters: parental insights into the conundrums of managing mild congenital hearing loss

Objective To explore and describe parental experiences related to the management of mild bilateral congenital hearing loss in children. Design Using qualitative methods, we conducted semi-structured interviews with parents/caregivers until saturation of themes was achieved. We analysed transcripts using inductive content analysis. Study sample Caregivers of children under 3-years-old with mild bilateral sensorineural hearing loss. Results We interviewed 12 parents. Parental perception of advice regarding hearing aid fitting was varied; almost all children were offered hearing aids. Perceived positives related to hearing aids: feeling empowered that action has been taken; improvements in the child’s hearing perception and; facilitation of behavioural management. Perceived negatives of hearing aid use: difficulties with compliance resulting in parental frustration and guilt, damage/loss of equipment, discomfort, parental discord, altered quality of natural sound and potential bullying/stigma. Some parents were ambivalent about the effect of the hearing aids. Where hearing aids were offered and not fitted, there was significant ongoing uncertainty, and the family carried the burden of their decision. Conclusions There was a wide variation in perceived advice regarding early hearing aid fitting in children with mild bilateral hearing loss. We identified parental perceptions of positive/negative impacts of hearing aid fitting and potential perceived harms from not fitting.

Evaluation of a Screening Program: Challenges of Data Collection Using the Example of the Newborn Hearing Screening

The aim of the newborn hearing screening (NHS) is to identify and treat children with bilateral hearing disorders early. The NHS is regulated in Germany by the Pediatric Directive, which recommends an evaluation after 5 years. This evaluation was performed for the first time nationwide for children born between 2011 and 2012 regarding structural, process and result quality. Challenges in the collection of appropriate data as basis for evaluation are described and possible improvements are suggested. All maternity and neonatology wards performing the NHS were identified and their documentations of the NHS analysed. In addition, all pediatric audiologists were identified to gather data on children with bilateral permanent congenital hearing disorder. The identification of relevant maternity and neonatology wards was very burdensome. More than half of them were not aware that NHS had to be documented. There was no documentation on more than 15% of the children that were to be screened. Furthermore, data concerning bilateral congenital hearing disorders was only accessible for 60% of the expected number of affected children. Data required for the evaluation of the NHS regarding structural, process and result quality were incomplete and missing. The database for evaluations should be defined precisely and structures needed to obtain meaningful results have to be established in advance. Nevertheless, the evaluation of the NHS provides meaningful results concerning the screening process in Germany.

Cochlear Implants: Evaluation of Effects of Various Parameters on Outcomes in Pediatric Patients at a Tertiary Care Centre for Unilateral Ear Implantation.

To determine whether variables such as Age, Gender, Demographic background of the patient and Pre-operative usage of hearing aids affect the outcomes of pediatric cochlear implant surgery when modified; in terms of speech and hearing gain. A hospital based retrospective-prospective type of cohort study was conducted over a period of 5years at a Tertiary care Teaching hospital and referral centre covering a population of about 68.9 million. Candidates selected were 1-5years of age with bilateral congenital severe-profound sensori-neural hearing loss. 50 patients were selected and were operated using VERIA technique of Cochlear Implant Surgery. Intraoperative testing of electrode functioning was done in all patients using NRT technique. The switching on of implant was done after 1month, following which patients underwent 100 sessions of auditory verbal therapy and training. Outcomes were evaluated in terms of hearing and speech gain by using Revised CAP scores, ITMAIS scores and PEACH scores in the loco-regional language. Those implanted at a younger age and with at least 3months of hearing aid usage pre-operatively had better outcomes measures. There was no effect on outcomes when the gender and demographic origin of the patient were compared. Candidates implanted before 3years age give better results and they should be encouraged to use hearing aid regularly and continuously before the surgery and should be advised trial and fitting as soon as CI planning begins. Also, gender and demographic background should not be considered when planning CI as these have no significant effect on outcomes.

Bilateral congenital semicircular canal malformation and hearing loss - case report

The main aims of this observational study were to describe a poorly characterized malformation of the inner ear termed bilateral congenital semicircular canal malformation; determine if the degree and pattern of semicircular canal dysmorphology and the presence or absence of a well-formed cochlea predict audiological outcomes, type, and severity of congenital hearing loss; and investigate its relationship with known syndromic forms of hearing loss. Review of eight cases of hearing loss with radiographic evidence of congenital semicircular canal malformation was performed. Information was collected on clinical history, physical examination, computed tomography study and serial audiograms for all patients. Analyzed features included other syndrome-characteristic phenotypic dysmorphologies, audiometric configuration, severity and type of hearing loss, type of audiological rehabilitation, and presence of associated inner ear abnormalities besides those in the vestibular system. Among the eight cases included in the study, six patients had recognized syndromes/chromosomal abnormalities. Hearing loss was moderate to profound in all cases. All patients had bilateral semicircular canal deformities, with usually identical anatomical pattern on each side. Of the eight cases, six had normal cochlear development; malformations in the tympanic membrane and external auditory canal were only found in one; changes in ossicular chain were found in three patients; vestibules and vestibular aqueduct were normal in most cases; and abnormalities of oval window development and hypoplasia were found in two cases. The present study shows that a correlation between the severity and type of hearing loss and radiographic abnormalities is difficult to establish. Hearing loss associated with semicircular canal dysplasia is more likely due to anomalous membranous labyrinth development, which is not radiologically detectable by computerized tomography scan.

Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies

Biallelic variants in TOR1AIP1, encoding the integral nuclear membrane protein LAP1 (lamina-associated polypeptide 1) with two functional isoforms LAP1B and LAP1C, have initially been linked to muscular dystrophies with variable cardiac and neurological impairment. Furthermore, a recurrent homozygous nonsense alteration, resulting in loss of both LAP1 isoforms, was identified in seven likely related individuals affected by multisystem anomalies with progeroid-like appearance and lethality within the 1st decade of life. Here, we have identified compound heterozygosity in TOR1AIP1 affecting both LAP1 isoforms in two unrelated individuals affected by congenital bilateral hearing loss, ventricular septal defect, bilateral cataracts, mild to moderate developmental delay, microcephaly, mandibular hypoplasia, short stature, progressive muscular atrophy, joint contractures and severe chronic heart failure, with much longer survival. Cellular characterization of primary fibroblasts of one affected individual revealed absence of both LAP1B and LAP1C, constitutively low lamin A/C levels, aberrant nuclear morphology including nuclear cytoplasmic channels, and premature senescence, comparable to findings in other progeroid forms of nuclear envelopathies. We additionally observed an abnormal activation of the extracellular signal-regulated kinase 1/2 (ERK 1/2). Ectopic expression of wild-type TOR1AIP1 mitigated these cellular phenotypes, providing further evidence for the causal role of identified genetic variants. Altogether, we thus further expand the TOR1AIP1-associated phenotype by identifying individuals with biallelic loss-of-function variants who survived beyond the 1st decade of life and reveal novel molecular consequences underlying the TOR1AIP1-associated disorders.

Genetic Testing for Congenital Bilateral Hearing Loss in the Context of Targeted Cytomegalovirus Screening.

To determine the prevalence of children with genetic hearing loss who are cytomegalovirus (CMV) positive at birth and the relative proportion of genetic and CMV etiology among children with congenital bilateral hearing loss. Database review. We performed a review of clinical test results for patients undergoing comprehensive genetic testing for all known hearing loss-associated genes from January 2012 to January 2019. This population was reviewed for reported CMV status and genetic causes of congenital bilateral hearing loss. In the OtoSCOPE database, 61/4,282 patients were found to have a documented CMV status, and 661/4282 had documented bilateral congenital hearing loss. Two patients were identified who had both a positive CMV result and a genetic cause for their hearing loss. Forty-eight percent of patients with bilateral congenital hearing loss (320/661) were found to have a genetic etiology. In 62% (198/320), the hearing loss was associated with pathogenic variants in GJB2, STRC, SLC26A4 or an Usher syndrome-associated gene. We estimate that ~2% of CMV-positive newborns with hearing loss have a known genetic variant as a cause. The subcohort of CMV-positive newborns with symmetric mild-to-moderate bilateral hearing loss will have at least a 7% chance of having pathogenic gene variants associated with hearing loss. In a CMV-positive neonate who failed their newborn hearing screen bilaterally, genetic screening needs to be considered for accurate diagnosis and possible deferment of antiviral treatment. 4 Laryngoscope, 130:2714-2718, 2020.

Outcomes of regional-based newborn hearing screening for 35,461 newborns for 5 years in Akita, Japan

ObjectivesNewborn hearing screening (NHS) has been actively performed since 2001 in Akita, Japan. The NHS coverage rate has increased yearly, and performance has been consistently >90% since 2012. The purpose of this study was to summarize NHS outcomes in the Akita prefecture of Japan and to obtain new insights for from our summarized data for the future. MethodsA total of 35,461 newborns in hospitals and clinics where hearing screening was performed in Akita from 2012 to 2016 were included. The outcome data of NHS were collected for analysis. ResultsThe overall screening coverage rate for hearing loss was 94.7%. Of the screened infants, 0.53% received a referral on the 2-stage automated auditory brainstem response (ABR), and 80.4% of referred infants had a check-up at the hospital to receive a diagnostic hearing examination. Finally, the prevalence of bilateral congenital hearing loss was 0.14%, that of bilateral moderate to profound hearing loss was 0.12%, and that of unilateral congenital hearing loss was 0.10%. Furthermore, the average consultation period in infants with risk factors was significantly later than that in infants without risk factors (p = 0.0015). Follow-up for infants diagnosed with normal hearing after diagnostic hearing examination revealed that 4.7% suffered bilateral moderate to profound hearing loss later. This percentage is significantly higher than that of the general group (p < 0.001). ConclusionThe prevalence of bilateral congenital hearing loss was 0.14% in Akita and 0.12% of infants were diagnosed with bilateral moderate to severe hearing loss. Medical personnel should be enlightened regarding the importance of performing hearing diagnostic examinations until 3 months of age. Even if infants were diagnosed with normal hearing after a diagnostic examination, we strongly suggest continuing follow-up until they are able to perform pure tone audiometry with accuracy.