Preservation of Distortion Product Otoacoustic Emissions in OTOF -Related Hearing Impairment.

OBJECTIVES: Attenuation of otoacoustic emissions over time has been reported for many patients with hearing impairment harboring mutations in the OTOF gene. In this study, the time course of changes of distortion product otoacoustic emissions (DPOAEs) has been analyzed in a cohort of patients in the light of tympanometry results. DESIGN: The changes of DPOAEs in 16 patients with OTOF -related hearing impairment were retrospectively analyzed. RESULTS: All but one subject showed DPOAEs bilaterally at the time of diagnosis. Three patients diagnosed as adults still had DPOAEs at ages of 27, 31, and 47 years, respectively. Follow-up was available for 7 children diagnosed at the age of 1 to 3 years, who still showed preservation of DPOAEs at ages of 5 to 16 years. The responses were absent or attenuated in amplitude at some follow-up appointments in association with type B or C tympanograms. CONCLUSIONS: DPOAEs are preserved much longer than expected in a cohort of patients with OTOF -related hearing impairment. The previously reported loss of DPOAEs may have been caused in some children by increased middle ear impedance due to otitis media.

Electrocochleography in Auditory Neuropathy Related to Mutations in the OTOF or OPA1 Gene.

Auditory Neuropathy (AN) is characterized by disruption of temporal coding of acoustic signals in auditory nerve fibers resulting in alterations of auditory perceptions. Mutations in several genes have been associated to the most forms of AN. Underlying mechanisms include both pre-synaptic and post-synaptic damage involving inner hair cell (IHC) depolarization, neurotransmitter release, spike initiation in auditory nerve terminals, loss of auditory fibers and impaired conduction. In contrast, outer hair cell (OHC) activities (otoacoustic emissions [OAEs] and cochlear microphonic [CM]) are normal. Disordered synchrony of auditory nerve activity has been suggested as the basis of both the alterations of auditory brainstem responses (ABRs) and reduction of speech perception. We will review how electrocochleography (ECochG) recordings provide detailed information to help objectively define the sites of auditory neural dysfunction and their effect on receptor summating potential (SP) and neural compound action potential (CAP), the latter reflecting disorders of ribbon synapses and auditory nerve fibers.

Frequency of Usher gene mutations in non-syndromic hearing loss: higher variability of the Usher phenotype.

Non-syndromic hearing loss (NSHL) is characterized by a vast genetic heterogeneity; some syndromic forms as Usher syndrome (USH) have onset as isolated deafness and then evolve later in life. We developed an NGS targeted gene-panel containing 59 genes and a customized bioinformatic pipeline for the analysis of DNA samples from clinically highly selected subjects with sensorineural hearing loss, previously resulted negative for GJB2 mutations/GJB6 deletions. Among the 217 tested subjects, 24 (11.1%) were found to carry mutations in genes involved both in NSHL and USH. For 6 out of 24 patients a diagnosis of USH was performed. Eleven subjects out of 24 had hearing loss without vestibular or ocular dysfunction and, due to their young age, it was not possible to establish whether their phenotype could be NSHL or USH. Seven subjects were diagnosed with NSHL, due to their age and phenotype. A total of 41 likely pathogenic/pathogenic mutations were identified, among which 17 novel ones. We report a high frequency of mutations in genes involved both in NSHL and in USH in a cohort of individuals tested for seemingly isolated deafness. Our data also highlight a wider than expected phenotypic variability in the USH phenotype.

A novel mutation of the EYA4 gene associated with post-lingual hearing loss in a proband is co-segregating with a novel PAX3 mutation in two congenitally deaf family members.

OBJECTIVES: This work was aimed at establishing the molecular etiology of hearing loss in a 9-year old girl with post-lingual non-syndromic mild sensorineural hearing loss with a complex family history of clinically heterogeneous deafness. METHODS: The proband's DNA was subjected to NGS analysis of a 59-targeted gene panel, with the use of the Ion Torrent PGM platform. Conventional Sanger sequencing was used for segregation analysis in all the affected relatives. The proband and all the other hearing impaired members of the family underwent a thorough clinical and audiological evaluation. RESULTS: A new likely pathogenic mutation in the EYA4 gene (c.1154C > T; p.Ser385Leu) was identified in the proband and in her 42-year-old father with post-lingual non-syndromic profound sensorineural hearing loss. The EYA4 mutation was also found in the proband's grandfather and uncle, both showing clinical features of Waardenburg syndrome type 1. A novel pathogenic splice-site mutation (c.321+1G > A) of the PAX3 gene was found to co-segregate with the EYA4 mutation in these two subjects. CONCLUSION: The identified novel EYA4 mutation can be considered responsible of the hearing loss observed in the proband and her father, while a dual molecular diagnosis was reached in the relatives co-segregating the EYA4 and the PAX3 mutations. In these two subjects the DFNA10 phenotype was masked by Waardenburg syndrome. The use of NGS targeted gene-panel, in combination with an extensive clinical and audiological examination led us to identify the genetic cause of the hearing loss in members of a family in which different forms of autosomal dominant deafness segregate. These results provide precise and especially important prognostic and follow-up information for the future audiologic management in the youngest affected member.

Audibility, speech perception and processing of temporal cues in ribbon synaptic disorders due to OTOF mutations.

Mutations in the OTOF gene encoding otoferlin result in a disrupted function of the ribbon synapses with impairment of the multivesicular glutamate release. Most affected subjects present with congenital hearing loss and abnormal auditory brainstem potentials associated with preserved cochlear hair cell activities (otoacoustic emissions, cochlear microphonics [CMs]). Transtympanic electrocochleography (ECochG) has recently been proposed for defining the details of potentials arising in both the cochlea and auditory nerve in this disorder, and with a view to shedding light on the pathophysiological mechanisms underlying auditory dysfunction. We review the audiological and electrophysiological findings in children with congenital profound deafness carrying two mutant alleles of the OTOF gene. We show that cochlear microphonic (CM) amplitude and summating potential (SP) amplitude and latency are normal, consistently with a preserved outer and inner hair cell function. In the majority of OTOF children, the SP component is followed by a markedly prolonged low-amplitude negative potential replacing the compound action potential (CAP) recorded in normally-hearing children. This potential is identified at intensities as low as 90 dB below the behavioral threshold. In some ears, a synchronized CAP is superimposed on the prolonged responses at high intensity. Stimulation at high rates reduces the amplitude and duration of the prolonged potentials, consistently with their neural generation. In some children, however, the ECochG response only consists of the SP, with no prolonged potential. Cochlear implants restore hearing sensitivity, speech perception and neural CAP by electrically stimulating the auditory nerve fibers. These findings indicate that an impaired multivesicular glutamate release in OTOF-related disorders leads to abnormal auditory nerve fiber activation and a consequent impairment of spike generation. The magnitude of these effects seems to vary, ranging from no auditory nerve fiber activation to an abnormal generation of EPSPs that occasionally trigger a synchronized electrical activity, resulting in high-threshold CAPs.

Abnormal Cochlear Potentials in Friedreich's Ataxia Point to Disordered Synchrony of Auditory Nerve Fiber Activity.

BACKGROUND: Friedreich's ataxia (FRDA) is a degenerative disorder caused by mutations of the FXN gene. Sensorineural hearing loss is one of the clinical features of FRDA, and the majority of hearing-impaired patients have shown evidence of auditory neuropathy. OBJECTIVE: This study characterizes the cochlear receptor and auditory nerve potentials in a patient with FRDA who had the clinical profile of auditory neuropathy. The aim was to investigate the site of the lesion and the pathophysiological mechanisms behind the hearing dysfunction. METHODS: Using transtympanic electrocochleography, both receptor (cochlear microphonic, CM, and summating potential, SP) and auditory nerve potentials were recorded in response to trains of clicks with stimulation intensities from 60 to 120 dB SPL. The results were compared with recordings obtained from two groups of subjects, i.e. 20 normally hearing controls and 19 subjects with cochlear hearing loss. RESULTS: The results showed that the synchronized neural response seen in both normally hearing and hearing-impaired subjects was lacking in our patient, replaced by a prolonged, low-amplitude negative potential that decreased in both amplitude and duration for rapid stimulation rates, consistent with adaptation of neural sources. CMs were recorded with a normal amplitude, consistent with preserved outer hair cell function. SP peak latency was within normal limits, whereas SP amplitude was comparable with that of subjects with cochlear hearing loss, consistent with inner hair cell loss. CONCLUSION: These findings suggest that underlying auditory neuropathy in FRDA is a disordered synchrony in auditory nerve fiber discharge, possibly resulting from auditory nerve fiber degeneration and inner hair cell loss.

OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation.

Hearing impairment is the second most prevalent clinical feature after optic atrophy in dominant optic atrophy associated with mutations in the OPA1 gene. In this study we characterized the hearing dysfunction in OPA1-linked disorders and provided effective rehabilitative options to improve speech perception. We studied two groups of OPA1 subjects, one comprising 11 patients (seven males; age range 13-79 years) carrying OPA1 mutations inducing haploinsufficiency, the other, 10 subjects (three males; age range 5-58 years) carrying OPA1 missense mutations. Both groups underwent audiometric assessment with pure tone and speech perception evaluation, and otoacoustic emissions and auditory brainstem response recording. Cochlear potentials were recorded through transtympanic electrocochleography from the group of patients harbouring OPA1 missense mutations and were compared to recordings obtained from 20 control subjects with normal hearing and from 19 subjects with cochlear hearing loss. Eight patients carrying OPA1 missense mutations underwent cochlear implantation. Speech perception measures and electrically-evoked auditory nerve and brainstem responses were obtained after 1 year of cochlear implant use. Nine of 11 patients carrying OPA1 mutations inducing haploinsufficiency had normal hearing function. In contrast, all but one subject harbouring OPA1 missense mutations displayed impaired speech perception, abnormal brainstem responses and presence of otoacoustic emissions consistent with auditory neuropathy. In electrocochleography recordings, cochlear microphonic had enhanced amplitudes while summating potential showed normal latency and peak amplitude consistent with preservation of both outer and inner hair cell activities. After cancelling the cochlear microphonic, the synchronized neural response seen in both normally-hearing controls and subjects with cochlear hearing loss was replaced by a prolonged, low-amplitude negative potential that decreased in both amplitude and duration during rapid stimulation consistent with neural generation. The use of cochlear implant improved speech perception in all but one patient. Brainstem potentials were recorded in response to electrical stimulation in five of six subjects, whereas no compound action potential was evoked from the auditory nerve through the cochlear implant. These findings indicate that underlying the hearing impairment in patients carrying OPA1 missense mutations is a disordered synchrony in auditory nerve fibre activity resulting from neural degeneration affecting the terminal dendrites. Cochlear implantation improves speech perception and synchronous activation of auditory pathways by bypassing the site of lesion.

Temporal bone high-resolution computed tomography in non-syndromic unilateral hearing loss in children.

OBJECTIVE: The aim of this study was to disclose possible inner ear abnormalities/pathologies by means of high-resolution computed tomography (HRCT) of the temporal bone (TBHRCT) in children with unilateral hearing loss (UHL). METHODS: Retrospective review of audiological evaluation and TBHRCT in 22 children with UHL. RESULTS: Two thirds of the children showed profound hearing loss. Review of HRCT scans identified inner ear malformations/pathologies in 9 (41%) cases and a high jugular bulb (HJB), always dehiscent with the vestibular aqueduct, in another 5 (22%). Inner ear malformations included enlarged vestibular aqueduct, common cavity and cochleovestibular hypoplasia, while labyrinthine ossification was the detected pathology. In 1 child, the common cavity of the right ear was associated with congenital melanocytic naevus of the left eyelid and lipomeningocele. To the best of our knowledge, this condition has never been described. CONCLUSIONS: The aetiology of UHL may be revealed in more than half of patients by means of TBHRCT. Besides common inner ear abnormalities, TBHRCT should be evaluated carefully to rule out HJB, dehiscences, diverticulum or erosion of inner ear structures.

Primary tumors and tumor-like lesions of the eustachian tube: a systematic review of an emerging entity.

Eustachian tube (ET) primary tumors and tumor-like lesions are rare diseases presenting with common ear, nose and throat symptoms. Pathology can range from developmental anomalies to high malignant neoplasms. Hence this review aimed at suggesting a classification and outline relevant aspects of ET primary tumors and tumor-like lesions, describing clinical findings, diagnostic management and therapeutic approaches. MEDLINE, CINAHL, OVIDSP, HIGHWIRE, and GOOGLE databases were searched from inception to July 2011 for relevant studies. Further papers were identified by examining the reference lists of all included. Sixty-five papers met the inclusion criteria, enclosing 78 cases. Case reports are increasing in the past few years. Benign lesions and tumor-like lesions of ET have been reported. Moreover, melanomas, carcinomas, and sarcomas can affect the ET as a primary site.

Identification of a novel mutation in the SLC26A4 gene in an Italian with fluctuating sensorineural hearing loss.

Pendred syndrome is an autosomal recessive disorder characterized by congenital sensorineural deafness, goitre and defective iodide organification. Congenital and profound hearing loss is the hallmark of the syndrome, while goitre and thyroid dysfunction are highly variable even within the same family. Clinical features are due to altered formation of pendrin, a chloride/iodide transporter protein expressed in the inner ear, thyroid gland and kidney. A novel substitution was found in exon 7 of the pendrin encoding gene (SLC26A4) that leads to a stop codon, S314X. The new variation was found in compound heterozygosity with L445W mutation in a hearing impaired patient with bilateral Mondini's dysplasia and goitre.

Abnormal cochlear potentials from deaf patients with mutations in the otoferlin gene.

Otoferlin is involved in neurotransmitter release at the synapse between inner hair cells (IHCs) and auditory nerve fibres, and mutations in the OTOF gene result in severe to profound hearing loss. Abnormal sound-evoked cochlear potentials were recorded with transtympanic electrocochleography from four children with otoferlin (OTOF) mutations to evaluate physiological effects in humans of abnormal neurotransmitter release from IHCs. The subjects were profoundly deaf with absent auditory brainstem responses and preserved otoacoustic emissions consistent with auditory neuropathy. Two children were compound heterozygotes for mutations c.2732_2735dupAGCT and p.Ala964Glu; one subject was homozygous for mutation p.Phe1795Cys, and one was compound heterozygote for two novel mutations c.1609delG in exon 16 and c.1966delC in exon 18. Cochlear potentials evoked by clicks from 60 to 120 dB peak equivalent sound pressure level were compared to recordings obtained from 16 normally hearing children. Cochlear microphonic (CM) was recorded with normal amplitudes from all but one ear. After cancelling CM, cochlear potentials were of negative polarity with reduced amplitude and prolonged duration compared to controls. These cochlear potentials were recorded as low as 50-90 dB below behavioural thresholds in contrast to the close correlation in controls between cochlear potentials and behavioural threshold. Summating potential was identified in five out of eight ears with normal latency whilst auditory nerve compound action potentials were either absent or of low amplitude. Stimulation at high rates reduced amplitude and duration of the prolonged potentials, consistent with neural generation. This study suggests that mechano-electrical transduction and cochlear amplification are normal in patients with OTOF mutations. The low-amplitude prolonged negative potentials are consistent with decreased neurotransmitter release resulting in abnormal dendritic activation and impairment of auditory nerve firing.

Hearing loss features in GJB2 biallelic mutations and GJB2/GJB6 digenic inheritance in a large Italian cohort.

The aim of this study was to describe the clinical features of hearing loss due to mutations on connexin 26/30 coding genes (GJB2/GJB6). Mutations in the GJB2 gene are found to account for approximately 50% of cases of autosomal recessive non-syndromic deafness. Several European studies have estimated that the GJB2 healthy carrier condition involves about 2-4% of the population, with the 35delG mutations being the most common. A 342-kb deletion truncating the GJB6 gene (encoding connexin-30) has been associated with autosomal recessive non-syndromic deafness, mostly as digenic inheritance of the Cx30 deletion/Cx26 mutation. The following retrospective study describes audiological features and genotypes of a large cohort of 376 Italian hearing-impaired patients who underwent genetic screening for the GJB2/GJB6 genes and received follow-up care at our centre between January 2002 and October 2006. Sixteen different genotypes causing deafness in more than 27% of patients with either biallelic mutations or digenic inheritance GJB2/GJB6 were identified. The most frequent mutations were 35delG, M34T, L90P, and R184P.

A novel missense mutation in the Connexin 26 gene associated with autosomal recessive nonsyndromic sensorineural hearing loss in a consanguineous Tunisian family.

Nonsyndromic sensorineural hearing impairment is inherited in a predominantly autosomal recessive manner in up to 70% of cases. The gene more often involved is GJB2, encoding the gap junction protein Connexin 26. We report here a novel missense mutation in the GJB2 gene found in a Tunisian family. A homozygous change C/G at nucleotide 263 was detected in the 4-year-old girl of this family, affected by congenital moderate hearing loss. This transversion leads to the replacement of a highly conserved alanine with glycine at codon 88 (A88G). The consanguineous parents of the child are healthy carriers of the mutation.

Audiological and electrocochleography findings in hearing-impaired children with connexin 26 mutations and otoacoustic emissions.

We recorded cochlear potentials by transtympanic electrocochleography (ECochG) in three hearing-impaired children with GJB2 mutation who showed otoacoustic emissions. Pure tone thresholds, distortion product otoacoustic emissions (DPOAEs) and, auditory brainstem responses (ABRs) were also obtained. Subjects 1 (35delG/35delG) and 3 (M34T/wt) had profound hearing loss and showed the picture of auditory neuropathy (AN) as DPOAEs were detected with absent ABRs in both ears. The hearing impairment found in subject 2 (35delG/35delG) was profound in the right ear and moderate in the left ear. Both DPOAEs and ABRs with normal latencies and morphology were recorded only from the left ear. On the ECochG recording the cochlear microphonic was obtained from all children. No compound action potential (CAP) was detected in subject 1. A neural response was recorded only from the left ear in subject 2 with a threshold corresponding to the audiometric threshold while no CAP was detected on the right side. The ECochG obtained from subject 3 showed a low-amplitude broad negative deflection which was identifiable down to low stimulus levels. This response decreased in amplitude and duration when utilizing a high-rate stimulation paradigm. The amount of amplitude reduction was close to that calculated for normal ears, thus revealing the presence of an adapting neural component. These findings indicate that patients with GJB2 mutations and preserved outer hair cells function could present with the picture of AN. The hearing impairment is underlain by a selective inner hair cell loss or a lesion involving the synapses and/or the auditory nerve terminals. We suggest that neonatal hyperbilirubinemia may play a role in protecting outer hair cells against the damage induced by GJB2 mutations.

Pathogenetic role of the deafness-related M34T mutation of Cx26.

Mutations in the GJB2 gene, which encodes the gap junction protein connexin26 (Cx26), are the major cause of genetic non-syndromic hearing loss. The role of the allelic variant M34T in causing hereditary deafness remains controversial. By combining genetic, clinical, biochemical, electrophysiological and structural modeling studies, we have re-assessed the pathogenetic role of the M34T mutation. Genetic and audiological data indicate that the majority of heterozygous carriers and all five compound heterozygotes exhibited an impaired auditory function. Functional expression in transiently transfected HeLa cells showed that, although M34T was correctly synthesized and targeted to the plasma membrane, it inefficiently formed intercellular channels that displayed an abnormal electrical behavior and retained only 11% of the unitary conductance of the wild-type protein (HCx26wt). Moreover, M34T channels failed to support the intercellular diffusion of Lucifer Yellow and the spreading of mechanically induced intercellular Ca2+ waves. When co-expressed together with HCx26wt, M34T exerted dominant-negative effects on cell-cell coupling. Our findings are consistent with a structural model, predicting that the mutation leads to a constriction of the channel pore. These data support the view that M34T is a pathological variant of Cx26 associated with hearing impairment.

A rare case of metastases to the maxillary sinus from sigmoid colon adenocarcinoma.

Metastases of malignant tumors to the nasal cavity and paranasal sinuses are rare. A review of the world's literature reports only four cases of antral metastases from carcinoma of gastrointestinal tract. We present a case of a stenosing adenocarcinoma of the sigmoid colon with metastases within the maxillary sinus. The ENT physical examination revealed a mass involving the right alveolar ridge, the right hard palate. CT scan of the head and the neck showed a large and irregular mass involving the right maxillary sinus, the infratemporal fossa and the pterygoid muscles with resorption of the bone of the posterior portion of the right alveolar ridge and of the posterior wall of the right maxillary sinus. The neoplastic tissue showed marked positivity for CEA and expressed cytokeratin 20, confirming the diagnosis of metastases to the maxillary sinus from colorectal adenocarcinoma. When a differential diagnosis between a second primary tumor of the maxillary sinus and a metastasis has to be carried out, the gastrointestinal tract should be taken into account and detailed immunohistochemical should be performed.