[Clinical protocol: audiological assessment of infants in Russian Federation. Part II]. / Protokol audiologicheskogo obsledovaniya detei pervogo goda zhizni v Rossiiskoi Federatsii. Chast' II.

This is the second part of the previously published clinical protocol of audiological assessment in infants. The goal of the protocol is unification approaches to audiological diagnosis of the infants. The following sections were included in the second part of the protocol: behavioral testing in infants, testing sequence, duration of the examination and necessity in follow-up, hearing assessment in special cases (premature children, children with congenital infections, after meningitis, with external ear abnormalities, single-sided deafness, with hydrocephalus and shunts, with auditory neuropathy spectrum disorder, with mild hearing loss and otitis media with effusion), medical report.

[Clinical protocol: audiological assessment of infants in Russian Federation. Part I]. / Protokol audiologicheskogo obsledovaniya detei pervogo goda zhizni v Rossiiskoi Federatsii. Chast' I.

The clinical protocol of audiological assessment in infants was prepared by the workgroup of Russian pediatric audiologists from different regions. The goal of the protocol is unification approaches to audiological diagnosis of the infants. The protocol has been developed according the evidence based medicine principles, by reviewing current scientific publications on the topic and taking into account the order of providing medical services and other clinical practice guidelines. When direct evidence was not available, both indirect evidence and consensus practice were considered in making recommendations. This guideline is not intended to serve as a standard to dictate precisely how the child should be diagnosed. This guideline is meant to provide the evidence base from which the clinician can make individualized decisions for each patient. The first part of the protocol covers following sections: equipment, staff requirements, timing of the diagnostics, case history and risk factors, preparing the child for the appointment, sedation and general anesthesia, otoscopy, tympanometry and acoustic reflex, otoacoustic emissions, skin preparing, electrode montage, choosing the stimulators, auditory brainstem responses on broadband and narrow-band stimuli, on bone conducted stimuli, auditory steady-state responses, masking, combined correction factors.

[Electrically evoked ABR through cochlear implant in children with auditory neuropathy spectrum disorder]. / Registratsiya elektricheski vyzvannykh korotkolatentnykh slukhovykh potentsialov u detei s zabolevaniem spektra auditornykh neiropatii.

OBJECTIVE: To estimate the applicability of electrically evoked auditory brainstem response (eABR) registration for the estimation of neural integrity after cochlear implantation (CI) in children with auditory neuropathy spectrum disorder (ANSD) and to compare the eABR data with patient's hearing performance. MATERIAL AND METHODS: 4 children, Nucleus (Cochlear) CI users, with ANSD were enrolled in the study. Hearing performance in these children ranged from successful to unsatisfied. eABR were recorded via Eclipse EP25 (Interacoustics). Electrical bipolar stimulation was achieved with Custom Sound EP software (Cochlear). RESULTS: EABR were registered with the use of different stimulation parameters (pulse width, stimulated electrodes) in 3 patients with satisfactory results of rehabilitation. eABR thresholds corresponded to maximum comfortable levels of patients stimulation MAP. eABR were absent in the patient with poor hearing performance. CONCLUSIONS: EABR measurements in children with ANSD demonstrated restoration of neuronal conduction in the auditory pathway up to the brainstem after cochlear implantation in 3 patients. eABR results were well correlated with hearing performance. Thereby, the study of eABR applicability for clinical practice will be expanded.

Early audiological phenotype in patients with mutations in the USH2A gene.

INTRODUCTION: Nowadays, due to universal newborn hearing screening (UNHS) the number of children with mild-to-moderate hearing loss diagnosed in the first year of life has increased significantly. Aside from that, identification of the genetic cause improves the genetic counselling of the families and allows to reveal possible comorbidities which may need a special approach. OBJECTIVE: To present the characteristics of the early audiologic phenotype in hearing impaired patients with biallelic mutations in the USH2A gene based on systematic analysis of the audiological data. PATIENTS AND METHODS: 13 patients with mutations in the USH2A gene underwent audiological examination. Most of them were found among a large group of infants with bilateral nonsyndromic sensorineural hearing loss (SNHL) examined under 12 months. RESULTS: Eight out of eleven children failed UNHS and were initially diagnosed as having bilateral nonsyndromic SNHL. Seven children underwent an audiological assessment before the age of 9 months. The earliest audiological examination was carried out at 1 and 3 months. The children with pathogenic variants in the USH2A gene in our examined group were identified in the first year of life via UNHS. The hearing threshold levels (HTL) for the USH2A group are compactly distributed between 51.25 dB and 66.25 dB, quartiles are 54 dB and 63.4 dB, with a median of 60 dB. The audiological profile of patients with biallelic USH2A mutations differs from audiograms of patients who had STRC-related hearing loss. We have not found any significant elevation in hearing thresholds in the first decade of life. We also estimated the prevalence of the USH2A and STRC mutations among GJB2-negative infants with bilateral nonsyndromic SNHL examined under 12 months, and it was 7.5% and 16.1%, respectively. CONCLUSION: According to our results, the early hearing phenotype in pediatric patients with biallelic mutations in the USH2A- gene is characterized by nonsyndromic mild-to-moderate SNHL in the first decade of life. Our results indicate that the presence of mutations in the USH2A or STRC genes can be expected in a child with congenital mild-to-moderate nonsyndromic SNHL. This information is of practical importance for parents, as they have to know the prognosis of hearing loss for their child from the very beginning. Post-screening follow-up should include adequate clinical, genetic, and social support for children and their parents.

Clinical features of hearing loss caused by STRC gene deletions/mutations in Russian population.

Congenital sensorineural hearing loss is related to mutations in numerous genes encoding the structures of the inner ear in majority of the cases. Mutations in GJB2 gene are the most frequently identified causes of congenital nonsyndromal hearing loss. GJB2 gene testing became a routine clinical tool. For GJB2-negative patients new genetic approaches including methods based on new generation sequencing give a chance to identify mutations in other genes. The frequent reason of mild-to-moderate hearing loss such as the deletions/mutations of the gene STRC encoding stereocilin protein were recognized (OMIM: 606440). OBJECTIVES: To evaluate the audiological features in hearing impaired patients with deletions and point mutations in the STRC gene. PATIENTS AND METHODS: The group of 28 patients from 21 unrelated families with pathological mutations in the STRC gene underwent audiological examination. The description and analysis of the results of full audiological examination was provided. RESULTS: All patients initially had bilateral nonsyndromal sensorineural hearing loss. Among 11 homozygotes of large deletion harboring STRC to CATSPER2 genes were 7 male individuals indicating the presence of male infertility syndrome. In general, 7 children failed audiological screening and 4 children underwent audiological assessment in the age of 3 and 6 months. The most frequently hearing thresholds were registered between 35 and 55 dB that corresponds to mild-to-moderate hearing impairment. The average age of diagnostics was 7.9 years (ranged from 3 months to 45 years). In the majority of patients the audiological profiles were flat or descending with elevation of thresholds at middle and high frequencies and relatively preserved thresholds at low frequencies. Hearing thresholds are symmetric and stable with age. CONCLUSION: STRC-linked hearing loss is congenital, of mild and moderate severity. Special clinical and genetic approach for children who failed newborn hearing screening with mild-to-moderate hearing loss is necessary.

[Hearing loss due to mutations or lack of the gene coding protein stereocillin]. / Narushenie slukha pri mutatsiyakh ili otsutstvii gena, kodiruyushchego belok stereotsilin.

OBJECTIVE: The description of a clinical picture and audiological features at the hearing loss caused by changes of a STRC gene, coding protein stereocillin (MIM: 606440). Mutations in the numerous genes responsible for the inner ear proteins are the reason for congenital sensorineural hearing loss. The main cause of congenital bilateral sensorineural hearing loss in the Russian Federation are mutations in GJB2 gene it reaches up 68% of cases identified in infancy. GJB2 gene tests already became routine around the world. Possibilities of new methods based on sequencing of new generation (NGS, next generation sequencing) allow to conduct a research of more rare genes connected with a hearing impairment. The most often among GJB2 negative patients reveal mutations and deletion of a gene of STRC. PATIENTS AND METHODS: Full audiological examination of 5 children and one adult with a hearing loss from 2 unrelated families is provided. Mutations in STRC gene were identified. All children are examined aged before 8 years, and 3 children failed universal audiological screening in maternity hospital, to two children screening was not carried out as they were born till 2009. RESULTS: The children with the sensorineural hearing loss connected with mutations and deletion of STRC gene failed hearing screening in maternity hospital because of the OAE is not registered, what indicates the congenital nature of a hearing loss. Recently it could not be noticed earlier because of slight increase of hearing thresholds and was regarded only as the early onset. Our data emphasize that the of thresholds from 35 to 60 dB in frequencies 0,5-4 kHz is common for mutations/deletions of STRC gene. CONCLUSION: The development of molecular genetics methods confirms the hereditary causes of GJB2-negative patients and expands indications for family counseling. Special approach for child with hearing loss so early revealed is necessary and the consultation of parents frightened of screening results is very important.

[OTOF-related auditory neuropathy spectrum disorder]. / Zabolevanie spektra auditornykh neiropatii, obuslovlennoe mutatsiyami v gene otoferlina (OTOF).

Otoferlin (OTOF) gene mutations are the most common cause of hereditary ANSD according to investigations in several countries. THE AIM: Of this study was to estimate the prevalence of OTOF mutations in Russian children with ANSD and evaluate audiological and clinical features of OTOF-related ANSD. PATIENTS AND METHODS: 28 children with bilateral ANSDwere enrolled in the investigation. Two step genetic testing was performed: first step - GJB2 gene testing to exclude GJB2-related hearing loss; second step - NGS-based sequencing to explore another 35 hearing loss genes (including OTOF). RESULTS: OTOF mutations, including 6 new variants, were found in 5 children with ANSD (18%). All 5 children had no risk factors for hearing loss and passed hearing screening. OAE and cochlear microphonics were present till the last testing at the age of 4-5 years. ABR were not detectable. The ASSR were measurable bilaterally at all frequencies in all cases, but they did not correlate with behavioral thresholds that revealed severe hearing loss. Hearing thresholds were stable during follow up period. 3 children underwent cochlear implantation. After cochlear implantation auditory nerve action potentials to electric stimulation were detected within normal range. CONCLUSION: Genetic testing of children with ANSD and first of all OTOF testing enables to reveal hearing loss etiology and provide the optimal rehabilitation approach, including cochlear implantation, as early as possible.

[Auditory evoked potentials in children with auditory neuropathy spectrum disorder]. / Slukhovye vyzvannye potentsialy u detei s zabolevaniem spektra auditornykh neiropatii.

The objective of the present study was to estimate peculiarities of the auditory brainstem evoked potentials (ABR), auditory steady-state responses (ASSR) and cortical auditory evoked potentials (CAEP) in the children presenting with bilateral auditory neuropathy spectrum disorder (ANSD). The study included 100 patients with bilateral ANSD diagnosed based on the positive response of otoacoustic emissions (OAEs) and/or cochlear microphonic (CM) detection, while no synchronous neural activity was detected in the ABR test. Cochlear microphonic was the main clue for the ANSD diagnosing, because OAE was absent in both ears of 49 children. ABR testing revealed no response bilaterally in 72 cases (out of 100). In contrast to ABR, the ASSR thresholds were detectable at all the four main frequencies in both ears in 73 % of the cases (47 out of the 64 tested ones). Both ABR and ASSR in most cases were incomparable with the behavioral audiometric thresholds. 28 children underwent CAEP testing. In 7 cases out of 8 with mild hearing loss detectable CAEP were recorded. CAEP registration in l7 children making use of the hearing aids and in 3 children after cochlear implantation revealed, in the majority of the cases, the concordance between CAEP detectability with behavioral thresholds and rehabilitation outcomes with fairly good speech intelligibility. It is concluded that the ABR registration with CM evaluation is the most informative test for ANSD diagnosis. However, ABR as well as ASSR is useless for the estimation of the behavioral thresholds. The results of this study suggest that the presence or absence of CAEPs can provide some indication of the audibility of a speech sound in the children with ANSD; however this method requires further investigation.

[Results of molecular genetic testing in Russian patients with Pendred syndrome and allelic disorders].

Pendred syndrome is an autosomal recessive inherited disorder characterized by a combination of sensorineural hearing impairment and euthyroid goiter; its clinical manifestation in children is hardly distinguishable from nonsyndromic hearing loss. Pendred syndrome is one of the most frequent types of syndromic hearing loss. Hearing impairment is accompanied by abnormal development of the bony labyrinth­enlarged vestibular aqueduct (EVA) and occasionally combined with Mondini dysplasia. Mutations in the SLC26A4 gene, which encodes the pendrin protein, are responsible for both Pendred syndrome and for allelic disorder (nonsyndromic enlarged vestibular aqueduct). The present study for the first time conducted molecular genetic analysis in 20 Russian patients with Pendred syndrome, EVA and/or Mondini dysplasia. As a result, six pathogenic mutations in the SLC26A4 gene were revealed in four patients. The mutation c.222G>T (p.Trp74Cys) was detected for the first time. Mutations were found in patients with Pendred syndrome and nonsyndromic EVA with or without Mondini dysplasia. Mutations were not detected in patients with isolated Mondini dysplasia. One proband with clinical diagnosis Pendred syndrome was homozygous for the c.35delG mutation in the GJB2 gene. The absence of frequent mutations, including well-known ones or "hot" exons in the SLC26A4 gene, was reported. Therefore, the optimal method to search for mutations in the SLC26A4 gene in Russian patients is Sanger sequencing of all exons and exon-intron boundaries in the SLC26A4 gene.

[The clinical definition and etiology of Pendred syndrome (a review of the literature and clinical observations)]. / Sindrom Pendreda (obzor literatury i klinicheskie nablyudeniya).

The aim of this work was a clinical study of the patients with mutations in the SLC26A4 gene and clinical diagnosis of the Pendred syndrome. The Pendred syndrome is a hereditary autosomal recessive disorder characterized by combined pathology of the inner ear and the thyroid gland. CT of the temporal bones demonstrates the Mondini-type structural anomaly in the inner ear and enlarged vestibular aqueduct. Examination of the thyroid gland reveals hypothyroidism and euthyroid goiter. A total of 20 unrelated children at the age from 2 to 16 years presenting with the hearing loss of different severity were available for the examination. High-resolution CT of the temporal bones demonstrated abnormal development of the inner ear including the Mondini-type structural anomaly and enlarged vestibular aqueduct. Five children with congenital hypothyroidism suffered from bilateral sensorineural impairment of hearing. The routine methods of audiological and molecular genetic examination were used throughout the study. RESULTS: As a result of molecular genetic studies, four out of the 20 patients were found to carry six recessive mutations of the SLC26A4 gene in the compound heterozygous and one such gene in the homozygous state which confirmed the hereditary nature of the disease. The children suffered the hearing loss of varying severity diagnosed at different age. The thyroid hypofunction in one child was identified when it was 2 years of age, and in two children at the age of 8 and 9 years. CONCLUSION: The first step in the diagnosis of the Pendred syndrome among children with congenital hearing loss was a CT scan of the temporal bones that showed incomplete separation of the curls of the cochlea and enlarged vestibular aqueduct. It is necessary to continue to study epidemiology, clinical and molecular genetics of the Pendred syndrome in the Russian population.