Intralabyrinthine schwannoma (ILS) is a rare benign tumor of the inner ear potentially causing unilateral sensorineural hearing loss and vertigo. This study evaluated the outcome of one surgical session comprising microsurgical ILS resection and cochlear implantation in terms of surgical feasibility, complications, and auditory outcome. Ten clinically and histologically confirmed ILS patients included in this study  underwent surgery between July 2015 and February 2020. Eight patients had intracochlear tumor location; the remaining two had vestibulocochlear and intravestibular ILS. One of the three following methods was used for tumor removal: an extended cochleostomy, subtotal cochleoectomy, or a translabyrinthine approach. Although negligible improvement was observed in two of the patients, two patients were lost to follow-up, and one opted out from using CI, the speech perception of the five remaining ILS patients improved as per the Freiburg Monosyllable Test (FMT) from 0% before surgery to 45– 50% after the implantation. Our study supports the presented surgical approach’s feasibility and safety, enabling tumor removal and hearing restoration shortly after surgery. The symptoms associated with VS include hearing loss, vertigo, and tinnitus. The hearing loss induced by sporadic VS is unilateral and can be gradually progressive or sudden. Regarding the latter, VS accounts for approximately 3.0–3.4% [Schwann cells are the main glia of the peripheral nervous system, structurally and physiologically supporting the neurons . Upon ne3.0–3.4% ,6,7,8.A rare form of schwannoma, described for the first time more than a hundred years ago , is the Therapeutic options for the ILS include passive monitoring, called “wait-and-scan,” and active intervention to remove the tumor. The “wait-and-scan” monitoring uses imaging with a gadolinium contrast agent-enhanced cranial MRI (cMRI) to control tumor growth. Usually, imaging is conducted every six months during the first two years, after which once a year is recommended for the patients with the stable, not progressing disease. The active interventions use a transmastoid approach, stereotactic radiosurgery, or fractioned radiotherapy. The choice of approach depends on the ILS location, the patient’s general state of health, and the individual burden of disease.Because of the tumor-induced hearing impairment, ILS patients undergo auditory rehabilitation with either a hearing aid, a contralateral-routing of signals (CROS) device, or a cochlear implant (CI). The therapy choice is based on the residual hearing level and the therapeutic approach chosen. For ILS patients with unilateral severe to profound hearing loss, the standard care includes auditory rehabilitation using cochlear implantation. Cochlear implantation is a well-established surgical method that improves speech perception, binaural hearing, health-related quality of life, and reduces tinnitus percept ,17,18. TThe first resection of translabyrinthine ILS combined with simultaneous cochlear implantation was reported in 2003 . Schutt The present study evaluated the feasibility of performing ILS tumor resection and cochlear implantation during the same surgical session. The auditory outcomes of rehabilitation with CI were analyzed depending on different ILS tumor locations and various surgical approaches.The local Ethics Committee approved the study (appl. no.: EA2/030/13). Written informed consent was obtained from all patients.Three female and seven male patients with ILS (mean age 56.4 ± 8.6) were consecutively included in this study. Secondary care specialists referred all these patients to our tertiary Cochlear Implantation Unit for hearing rehabilitation with cochlear. ILS was detected with cMRI during the pre-implantation diagnostics.Diagnostics included collecting a focused medical history and an ear, nose, and throat examination. The auditory performance of all patients was assessed using pure tone audiometry (PTA) and the Freiburg Monosyllabic Test (FMT) performed in a sound booth at 65 dB sound pressure level (SPL). Before surgery, the PTA and FMT were conducted with patients wearing a hearing aid, whereas with a speech processor after the surgery. In addition, auditory brainstem responses (ABR), vestibular examination, and bedside head impulse test (bHIT) were performed before surgery. In patients with a history of vertigo, caloric testing and videonystagmography were added to the test battery. Imaging included cranial magnetic resonance imaging (cMRI) and computer tomography (CT) scan of the temporal bone. cMRI was acquired with 1 mm slice thickness using intravenous gadolinium contrast. The cMRI protocol included T1 and T2 weighted sequences and included additionally T1 vibe fat-saturated post gadolinium sequences, T2w SPACE sequences, and/or 3D CISS sequences.The cMRI-imaging identified tumor location as intralabyrinthine in all ten cases. According to Salzmann classification (14), three types of schwannomas were present in the sample: intracochlear, intravestibular, and vestibulocochlear .age (older than 18)absence of neurofibromatosis cMRI-assisted diagnosis of intralabyrinthine schwannomafulfillment of CI indication criteria according to the accepted German guidelines for cochlear implantationInclusion criteria for the study were:The aim of cochlear implantation was binaural hearing rehabilitation. The patients in this study were diagnosed with two types of hearing impairments: either single-sided deafness (SSD) or asymmetric hearing loss (AHL). SSD was defined as a profound hearing impairment in the affected ear and a functional hearing in the contralateral ear. The loss of hearing threshold in the contralateral ear did not exceed 30 dB in the pure tone average . AHL was defined as a profound hearing impairment in the poorer ear and a hearing loss in the contralateral ear of more than 30 dB in the four-frequency pure tone average, with a speech perception better than 50% when tested with a hearing aid.The interdisciplinary board  discussed the treatment options with each patient individually. Each time, the option “wait-and-scan” was brought forward. All patients included in the study decided on tumor resection combined with cochlear implantation during the same surgical session. Multichannel cochlear implants were supplied by MED-El  or by Cochlear . The surgical procedures were performed between July 2015 and February 2020.The first symptom of ILS was sudden unilateral hearing loss in nine of the patients, whereas one patient reported tinnitus as a first symptom. Before surgery, five patients had tinnitus and five intermittent vertigo (including patient #6 with an intravestibular schwannoma).Six patients were diagnosed with asymmetric hearing loss (AHL), and four with single-sided deafness (SSD). Seven ILS tumors were located in the left ear and three in the right ear.All patients underwent vestibular examination. Five patients  had a history of vertigo, whereas the other five were vertigo-free. Extended vestibular function testing was conducted with Frenzel goggles, bedside Head Impulse Test (bHIT), videonystagmography (VNG), and caloric testing. Two patients had a total vestibular loss, two had a vestibular weakness, and one had a normal vestibular function.n = 8) was intracochlear: two patients had an ILS in the basal cochlear turn, three in the middle cochlear turn, in two patients the ILS reached from the basal to the middle cochlear turn and in one patient from the basal to the apical turn .n = 7). Patients with basal turn intracochlear ILS had better auditory outcomes than the others. ILS tumor excision was performed in all these cases via the extended cochleostomy approach . Patients #9 and #10 had vertigo with spontaneous nystagmus to the contralateral side.Facial paralysis was treated with a prednisone tapering scheme and physiotherapy. Three months after surgery, the function of the facial nerve recovered. Patients with vertigo were also treated with a prednisone tapering scheme and physiotherapy that included balance training. Vertigo subsided two to three weeks after surgery.Case #1Patient #1 had a vestibulocochlear type of ILS. The tumor extended from the basal cochlear turn towards the vestibulum, ampulla of the superior and horizontal semicircular duct, and the common crus A–D. TumoCase #3Patient #3 had a middle cochlear turn ILS  requirinCase #4Patient #4 had an ILS of the middle cochlear turn of the left ear and intrameatal vestibular schwannoma of the right ear. Molecular genetic testing and clinical examination excluded neurofibromatosis type 2. cMRI visualized the ILS tumor mass on the left side and an intrameatal VS on the right side A–D. The Case #6Patient #6 had intravestibular ILS , were non-users (1 patient), or were lost to follow-up (2 patients). Interestingly, patient #3, who underwent subtotal cochleoctomy, scored 50% in FMT 12 months after surgery, indicating that not the whole modiolus is needed to improve speech perception scores with CI. Our observation corroborates an earlier description of this phenomenon reported by Plontke et al. .n = 262 of ILS cases) [n = 110 of ILS cases) [Nine of ten patients included in our study had unilateral hearing loss as the first symptom of ILS. That agrees with an extensive review (S cases)  and a muS cases)  reportinS cases)  describeS cases)  suggesteS cases)  describen = 110), Dubernard et al. [In our study, eight of ten ILS tumors had intracochlear and two intravestibular/vestibulocochlear locations. These locations corroborate the report of Van Abel et al. , suggestd et al.  reportedd et al.  suggesteThe current treatment options for ILS are microsurgery, radiation therapy (in particular stereotactic radiosurgery), and wait-and-scan. Because of ILS-induced hearing impairment, most patients opt not only for tumor treatment but also for hearing rehabilitation. In the present study, we treated ten ILS patients with ILS-induced hearing loss using microsurgical tumor resection combined with cochlear implantation during the same surgical session. Gosselin et al. and Neff et al. ,32 also The ILS tumor resection is conducted first during sequential surgery, and cochlear implantation is performed during the second surgery. However, a sequential approach can lead to fibrosis in the inner ear tissues after the first surgery, making the implantation very difficult, if not impossible. Kronenberg et al.  reportedTo address the problem of fibrosis, Beutner et al.  and AschThe possible changes in the cochlea occurring during wait-and-scan management of ILS remain unknown. Van Abel et al.  favor waBagattini, Quesnel, and Röösli demonstrated the degree of neurodegeneration caused by untreated ILS . The autNevertheless, our present work and the work of others imply that hearing rehabilitation of ILS patients using CI is a plausible method . In anotAn alternative two-step surgical approach offers the possibility of testing for hearing nerve function. In the first step, tumor removal is performed, and hearing nerve function is tested after surgery with cochleographic and promontory tests. In the second step, cochlear implantation is performed.Plontke et al. ,42 descrn = 7) was 28 ± 16%; the mean FMT at 65 dB for the intracochlear ILS (n = 5) was 32 ± 14%. In addition to various tumor locations and different surgical approaches to remove the tumor, our cohort consisted of patients with SSD and AHL, making the sample heterogeneous and likely contributing to the wide range of auditory outcomes observed in the study. Kronenberg et al. [In the present study, the audiological outcome measured six months after surgery with FMT at 65 dB SPL varied from 0% to 50 %. The mean value of FMT at 65 dB for ILS patients  has been in place only since 2012. Another drawback of our study is that two of the ten ILS patients were lost to follow-up shortly after surgery, and one patient opted out from using the CI. That can only be addressed by extending the sample size or designing a multicenter study. The last pitfall of this study is a lack of information about the degree of neurodegeneration that ILS and surgical intervention could have caused. The functionality of the hearing nerve must be tested before implantation , as it iOur present study demonstrates the outcome of auditory rehabilitation of ILS patients who underwent microsurgical ILS tumor removal and concomitant cochlear implantation during the same surgical session. The obtained results support use of the double surgical procedure. The existing studies and case reports about ILS and their treatment are low in number, reflecting a low incidence of ILS, which increased recently, indicating the actual occurrence rate of ILS and improved disease detection. In addition to presenting encouraging results of hearing rehabilitation of ILS patients, our study creates awareness of this rare disease that in the future might become a more common surgical and auditory challenge in clinical ENT practice.Our present work demonstrated that one-session microsurgical removal of ILS and cochlear implantation is surgically feasible and safe. Although our results imply that only every second ILS patient benefits concerning speech comprehension from the surgical procedure described, increasing the sample size through a multicenter approach and developing a better follow-up scheme could likely improve this success rate.


When referring to enlarged vestibular aqueduct (EVA) we should differentiate between nonsyndromic enlarged vestibular aqueduct (NSEVA) and Pendred Syndrome (PDS), a disease continuum associated with pathogenic sequence variants of Pendrin’s Gene (SLC26A4) in about half of the cases. The study was aimed to analyse the clinical and audiological features of a monocentric cohort of Caucasian patients with NSEVA/PDS, their genetic assessment and morphological inner ear features.We retrospectively reviewed the audiologic, genetic and anamnestic data of 66 patients with NSEVA/PDS followed by our audiology service.p < 0.019), with the expression of inner ear malformations (p < 0.001) and with different severity of hearing loss (p = 0.001). Furthermore, patients with PDS showed significantly worse pure tone audiometry (PTA) than patients with NSEVA (p = 0.001). Anatomically normal ears presented significantly better PTA than ears associated with Mondini Malformation or isolated EVA (p < 0.001), but no statistically significative differences have been observed in PTA between patients with Mondini Malformation and isolated EVA.SLC26A4 mutations was significantly correlated with the presence of PDS rather than NSEVA (NSEVA/PDS must be investigated in all the congenital hearing loss, but also in progressive, late onset, stepwise forms. Even mixed or fluctuating hearing loss may constitute a sign of a NSEVA/PDS pathology. Our findings can confirm the important role of SLC26A4 mutations in determining the phenotype of isolated EVA/PDS, both for the type/degree of the malformation, the hearing impairment and the association with thyroid dysfunction. Approximately 20% of congenital hearing loss (SNHL) is associated with inner ear malformations (IEM) , 2. The When referring to EVA, therefore, we should differentiate between nonsyndromic enlarged vestibular aqueduct (NSEVA or DFNB4) and Pendred Syndrome (PDS). Both conditions comprise a wide spectrum of hearing loss, vestibular disfunctions and temporal bone abnormalities, but thyroid pathologies are also present in PDS Fig. . For theNSEVA/PDS is described as being associated with pathogenic sequence variants of Pendrin’s Gene (SLC26A4) in about half of the cases, either as homozygous or compound heterozygous mutations . Even ifAdditionally, the enlargement of the vestibular aqueduct can be associated with cochlear and modiolar defects, defining the Mondini Malformation: the association of EVA, enlarged vestibule and cochlear incomplete partition type 2 , a free field audiometry was performed with and without the device on.Audiometry measures were carried out using the Interacoustics Clinical Audiometer AC40. When measuring the air conduction hearing threshold, we assigned a value of 125 dB to any frequency threshold over the maximum output limit of the audiometer . Any vibrotactile sensation was excluded.All the patients over 16 years old underwent a vestibular assessment with vestibular caloric testing. Responses were recorded through an infrared GN Otometrics eye-tracking system.All the enrolled patients underwent MRI and TC study for the evaluation of the petrous bone. We refer to isolated EVA when the anterior–posterior diameter of the vestibular aqueduct is larger than 1.5 mm, according to Valvassori and Clemis criteria ; we refeSLC26A4 coding region. The patients who underwent the procedure were divided into 4 groups: we refer to M0 for patients without SLC26A4 mutation, M1 for patients with heterozygous mutation, M2 for patients with compound heterozygous mutations and M3 for patients with homozygous mutation.All the patients with NSEVA/PDS who gave their consent to the procedure underwent a genetic research of SLC26A4 gene mutations with PCR. After extracting DNA from whole blood, mutation screening was completed by single-stranded conformational polymorphism and direct sequencing of the P values < 0.05 were considered as statistically significant. All analyses were performed using SPSS v.26 technology.Associations between SCL26A4 mutations groups  and continuous variables were determined using the ANOVA procedure and the Kruskal–Wallis test for nonparametric data. The t-test was used for comparing the means of thresholds in between mutations groups. Associations between SCL26A4 mutations groups and categorical variables (type of mutations) were determined using the Spearman’s rank correlation procedure. The significant independent variables, then, were analysed together by a multivariate model based on multiple linear regression. Of the 66 patients (132 ears) presenting NSEVA/PDS followed by our centre, 26 were males (39%) and 40 were females (61%) with a mean age of 26.2 years (1–69 years).Thirty-nine patients presented a NSEVA (59%), whereas 18 presented PDS (27%); 9 patients (13%) presented other syndromic conditions: 5 cases of dRTA, 3 mild cognitive impairment and 1 case of chromosomic abnormalities.An isolated EVA was reported in 47 patients (71%), unilaterally in 9 cases ; bilaterally in 38 cases (57%); meanwhile, a Mondini Malformation was found in 19 patients (29%), unilaterally in 1 case , bilaterally in 18 cases (27%).All the reported patients presented some grade of hearing loss, unilaterally in 10 cases (15%), bilaterally in 56 cases (85%). Considering each ear singularly, 10 ears (8%) had normal hearing, 9 ears (7%) a mild hearing loss, 21 ears (16%) a medium hearing loss, 15 ears (11%) a severe hearing impairment, and 77 ears (58%) a profound hearing loss. Twenty-one patients presented a mixed hearing loss (32%), with a mean air bone gap of 15.5 dB. No patients presented a pure conductive hearing loss.Three of the 10 patients with unilateral malformation presented a bilateral hearing impairment. In 2 of these cases, the malformed ear presented a worse threshold, while in another case, the worse hearing threshold was reported in the anatomically normal ear. Moreover, 3 of the 10 patients with unilateral hearing impairment presented a bilateral malformation.The mean age at hearing loss onset was 3.9 years . In 23 cases (35%), the hearing loss was congenital. Except for 7 congenital profound hearing-impaired patients (11%), all the other cases (89%) experienced a progression of hearing loss over time, often stepwise or trigger onset.Thirty-two patients in the reported cohort (48%) used hearing aids for hearing rehabilitation, 21 patients (32%) had undergone a unilateral cochlear implantation, and 3 patients (4%) had been bilaterally implanted. The 10 patients that presented a single normal ear (15%) were unaided.A vestibular impairment was reported in 34 of the 44 tested patients (77%), of whom 6 (17%) presented a bilateral vestibular areflexia at caloric vestibular stimulation. Otherwise, 10 patients (23%) did not manifest any vestibular disfunction at caloric stimulation.Fifty-seven of the followed patients  had been submitted to genetic research of SLC26A4 mutations. 24 patients (42.1%) had been found no mutations of Pendrin gene (M0); in 10 cases (17.5%), we found a heterozygous mutation (M1), in 14 patients (24.5%), a compound heterozygous mutation (M2) and in 9 patients (15.7%), a homozygous mutation (M3). In nine patients (13.6%), it was not possible to perform the genetic test, as the patients did not give their consent.p < 0.019). Indeed, PDS was more likely to be present in the M3 or M2 groups than in the M1 and M0 groups.At univariate analysis, we found a significative association between SLC26A4 mutations and the presence of PDS rather than NSEVA (Spearman’s coefficient = 0.269 p < 0.001). In fact, Mondini Malformation was more likely to be present in the M3 group, followed by M2, M1 and then the M0 group. Isolated EVA, on the other hand, was significantly more frequent in patients of the M0 group, then M1, M2 and, finally, M3 group of patients.Furthermore, SLC26A4 mutations were significantly associated with the presence of the different malformations associated with NSEVA/PDS (Spearman’s coefficient = 0.417 p = 0.001). Indeed, the M3 patients presented the worse thresholds, followed by the M2 cohort, then the M1 and M0 groups. At Kruskal–Wallis testing, the difference between groups was statistically significant (p = 0.017). No significant differences in hearing thresholds were found between the M0 and M1 groups (p = 0.39), M1 and M2 groups (p = 0.076), M1 and M3 groups (p = 0.3) or M2 and M3 groups (p = 0.733) at Student t-testing, but significant differences of thresholds were found between the M0 and M2 groups (p = 0.003) and M0 and M3 groups (p = 0.043)  and patients with PDS showed significantly worse PTA than patients with NSEVA (p = 0.001). Furthermore, also the expression of inner ear malformation was found to be correlated with PTA (Spearman’s coefficient = 0.233 p = 0.007). Patients with anatomically normal ears presented better PTA than ears associated with Mondini Malformation or isolated EVA. Even if a significantly worse PTA was found in malformed ears  rather than anatomically normal ears (p < 0.001), no statistically significant differences were found in PTA between patients with Mondini Malformation and isolated EVA (p = 0.916).Moreover, we found that the expression of PDS significantly correlated with the expressions of worse PTA (Spearman’s coefficient = 0.265 p < 0.113) or mutations and progression of hearing loss (Spearman’s coefficient = − 0.045 p < 0.791).No significant correlation was found between mutations and age at hearing loss onset (Spearman’s coefficient = − 0.286 p = 0.001) and with the presence of inner ear malformations (RC = 2.709 p = 0.008). On the other hand, the association between the mutations group and PTA lost its significance (RC = 1.152 p = 0.253).At multivariate analysis, the PTA in our cohort was still significantly related with the expression of PDS  is based on the impact that inner ear fluids pressure determine on inner ear structures , 20. EVAA wide spectrum of hearing loss is associated with NSEVA/PDS, and most of the authors reported a bilateral severe-to-profound SNHL. Despite that, unilateral, mild or medium hearing impairments, and even normal hearing patients with NSEVA/PDS have been described in the literature , 22–24.In our cohort, most of the patients presented a severe-to-profound hearing impairment [92 of the 132 ears (70%)]. Considering each ear singularly, 7% (9 ears) presented a mild hearing loss and 16% (21 ears) a medium hearing loss.The hearing loss was bilateral in 56 cases (85%) and unilateral in 10 cases (14%). It is noticeable that even 3 out of 10 anatomically normal ears presented some degree of hearing loss. We can speculate that the molecular mechanism underlying the pathology may cause a hearing impairment even without a radiologically evident malformation of the inner ear.Regarding the type of hearing loss, even if SNHL was reported as the most frequently associated with NSEVA/PDS, patients with mixed and pure conductive cases are also described in the literature  in a widA wide variability is also reported regarding hearing loss progression over time. Many patients present congenital forms of hearing loss, but some grade of progression or fluctuation of the hearing threshold is constantly described in the literature. The reported percentage of progressive hearing loss in patients with NSEVA/PDS varies from 17  to 60% . Even ifIn the present study, we reported a mean age at hearing loss onset of 3.9 years, with 23 cases (35%) of congenital hearing impairment and a higher age at hearing loss onset of 20 years. Furthermore, 89% of patients experienced a progression of hearing loss over time, frequently stepwise or trigger related.One of the most interesting and controversial aspects of NSEVA/PDS is the genetic aspect and the possibility of a correlation between SLC26A4 mutations and the phenotypic expression of the pathology.SLC26A4 (in homozygosis or compound heterozygosis), or a double heterozygosity for one pathogenic variant in SLC26A4 and one pathogenic variant in either FOXI1 or KCNJ10 [In 1999, Usami et al. first demonstrated that mutations in the Pendrin gene were associated with the presence of both NSEVA and PDS . Nowadayr KCNJ10 . Despiter KCNJ10 , 15. Pher KCNJ10  and Parkr KCNJ10  reportedr KCNJ10 , 36. OurPendrin is a trans-membrane protein highly expressed in the thyroid and inner ear, and it is involved in the maintenance of inner ear fluid homeostasis , 38. TheThe hydroelectrolytic imbalance can also explain the association between EVA and other syndromes such as dRTA.Previous studies correlated the genetic features in terms of number of mutated alleles of the SLC26A4 gene to the severity of the associated IEM, to the entity of the hearing impairment, to the tendency to progression over time of the hearing loss and to the expression of thyroid pathology.It is speculated that a more severe impairment of pendrin functionality related to a biallelic mutation may determine a higher inner ear fluid pressure and so worse hearing thresholds and more severe malformations, namely EVA with wider diameters and Mondini Malformation.In this regard, in 2019, Mey et al. demonstrated that individuals with two allele mutations of the Pendrin gene have a higher probability of having Mondini Malformation instead of isolated EVA , 42. Morp = 0.017): no significant differences in hearing thresholds had been found between the M0 and M1 groups, M1 and M2 groups, M1 and M3 groups, or M2 and M3 groups, but significant differences of thresholds were found between the M0 and M2 groups and M0 and M3 groups.Furthermore, King et al. in 2010, Rose et al. in 2017, and Mey et al. in 2019 demonstrated that patients with 2 mutated alleles showed worse thresholds and a tendency to progress faster than the patients with 1 or no mutated SLC26A4 alleles , 41–43. Otherwise, no significant correlations were found between mutations and age at hearing loss onset or tendency to hearing loss progression.Regarding the petrous bone malformations, we found a significant correlation between the SLC26A4 mutations group and the presence of Mondini Malformations rather than isolated EVA, with Mondini Malformation more likely to be present in the M3 group, followed by M2, M1 and then the M0 group and isolated EVA more frequent in patients of the M0 group, then M1, M2 and, finally, the M3 group of patients. In our sample, we did not find significant differences in the thresholds of patients with isolated EVA compared with those presenting a Mondini Malformation, similar to King et al. , who didRegarding the association between EVA and thyroid dysfunction, Azaiez et al. reported that biallelic mutations of SLC26A4 are also correlated with PDS expression . Our finFinally, patients with PDS showed significantly worse PTA than patients with NSEVA.From the literature data and from those herein reported, we can confirm the important role of SLC26A4 mutations in determining the phenotype of isolated EVA/PDS, both for the type/degree of the malformation, the hearing impairment and the association to thyroid dysfunction. A biallelic mutation of the SLC26A4 gene  can lead to a more severe pathology, with increasing ear homeostasis impairment and consisting of a more severe hearing loss, more severe IEM and a higher chance of presenting PDS rather than NSEVA.NSEVA/PDS is a disease continuum presenting a wide spectrum of hearing impairment, vestibular dysfunction, IEM, and thyroid pathologies. Specific genetic mutations of the SLC26A4 gene underlie this pathology.Furthermore, as the findings of our study on European Caucasian subjects confirmed, patients that have biallelic mutations  express a more severe disease, with worse hearing thresholds and a higher tendency to present thyroid pathologies and Mondini Malformations rather than isolated EVA.Given the relatively higher prevalence and the widely variable audiologic presentation, NSEVA/PDS must be investigated in all the congenital hearing loss, but also in progressive, late onset, stepwise forms. Even mixed or fluctuating hearing loss may constitute a sign of a NSEVA/PDS pathology.In patients suspected to present NSEVA/PDS, a diagnostic assessment should include a complete audiological evaluation and vestibular testing to characterize the audio-vestibular features of each subject, a petrous bone radiologic assessment for the evaluation of malformative aspects, a thyroid functionality testing and the genetic study for defining SLC26A4 mutations.Once the diagnosis is completed, therefore, it is important to set up accurate counselling sessions with the patients or their family, underlining the possibility that the hearing loss will progress and the importance of avoiding triggers like head trauma, Valsalva manoeuvre, and scuba diving.Even if our findings confirmed what some previous studies have reported in the literature with a rather large cohort of European Caucasian patients, further research on larger cohorts of patients are needed to better understand the pathogenic mechanism underlying NSEVA/PDS.


Hearing loss is one of the most common comorbidities among persons with dementia, with prevalence of 60->90%. Most go untreated and disparities exist. However, sensory impairment may influence the health of individuals and care partners. We will share findings from a clinic-based cohort of persons with dementia (n=101). Controlling for demographic and clinical factors, we found that every 10 decibel increase in hearing loss was associated with nearly an additional neuropsychiatric symptom  and 1.3-point increase in severity . These findings provide the first estimates that utilize objective audiometry. Furthermore, hearing aid use appeared to be protective. Hearing care may represent an additional, but underutilized, non-pharmacological intervention. We will discuss these findings in the context of the epidemiology of hearing loss in dementia and highlight new opportunities for managing hearing loss through community-based approaches.


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. Auditory neuropathy (AN) is a disorder characterized by alteration of the temporal coding of acoustic signals in auditory fibers with consequent reducction of auditory perceptions ,2,3. DisAuditory neuropathy may be congenital or postlingual in onset. Congenital forms affect the development of language  . When thDiagnosis relies on decrease of speech perception beyond that expected for the hearing loss, absence or profound abnormality of auditory brainstem responses, and normal outer hair cell activities (otoacoustic emissions and/or cochlear microphonic). However, in some AN patients hearing thresholds are normal and the impairment of speech perception is apparent only in the presence of noise ,6,7,8. ICochlear implantation is the only rehabilitative tool potentially able to restore speech perception in patients affected by pre-synaptic AN ,10 or poThe most well-known forms of AN are due to gene mutations and the mechanisms believed to be involved are functional alterations at pre- and post-synaptic sites, including neurotransmitter release from synapses, spike initiation in auditory nerve fibers and the neural dys-synchrony accompanying demyelination and axonal loss, all resulting in impairment of auditory nerve discharge in response to acoustic stimuli ,7.In the last two decades, the identification of many genes involved in the pathogenesis of AN has greatly contributed to the diagnosis and elucidation of the mechanisms underlying this disorder . In thesWe will review how electrocochleography (ECochG) can provide detailed information to help objectively define the sites of auditory neural dysfunction as affecting inner hair cell receptor summating potential (SP) and compound action potential (CAP), the latter reflecting disorders of ribbon synapsis and auditory nerve fibers. This study mostly reflects the experiences from the University of Padua Service of Audiology and Phoniatrics together with the Institute of Neurological Sciences of the University of Bologna and the Servicio de Genética of the Hospital Universitario Ramón y Cajal in Spain.Electrocochleography (ECochG) recording is acquiring importance in the diagnosis of auditory neuropathy since it allows us to define the details of both neural and receptor responses in the various forms of the disorder ,35,36. TThe ECochG potentials evoked in response to acoustic stimuli result from the superimposition of three components, two originating from receptor elements, the cochlear microphonic (CM) and summating potential (SP); and the other, the compound action potential (CAP), arising from auditory nerve fibers  and outer hair cells (OHCs), with the latter contributing more to CM generation because of their greater number .SP is considered to be a gross reflection of the DC component of receptor potentials, which results from asymmetries in the hair-cell transducer function. Because the SP recorded at the round window in chinchillas has been found to decrease in amplitude by over 50% after selective destruction of IHCs, the main contribution to SP generation is believed to arise from activation of IHCs located in the basal cochlear turn Durrant et al. . More reCAP results from the weighted sum of the extracellular components of the action potentials generated by individual auditory nerve fibers in response to acoustic stimulation, with the main contribution coming from fibers showing high characteristic frequency and short latency of activation localized to the basal portion of the cochlea . RecentlDominant optic atrophy (DOA) is the most common genetic optic neuropathy. The hallmark of the disease is progressive visual loss beginning in childhood . About 6Patients carrying missense mutations localized to the GTPase domain show a syndromic form of DOA associated with several extra-ocular manifestations, such as sensorineural hearing loss, peripheral neuropathy, ataxia, external ophthalmoplegia and myopathy ,47. SensOPA1 gene have been diagnosed and followed up at the University of Padua Service of Audiology and Phoniatrics, while their neurological and ophthalmologic evaluation together with genetic analyses were performed at the Institute of Neurological Sciences of University of Bologna [In the last decade, nine hearing-impaired subjects (age range of five–58 years) harboring missense mutations in the  Bologna . In all Transtympanic electrocochleography was performed in patients carrying missense mutations in the OPA1 gene at decreasing stimulus intensities from 120 to 60 dB SPL. ECochG waveforms were compared to the corresponding recordings obtained in 20 normally-hearing controls. CM potentials were significantly larger in OPA1 patients compared to controls, thus confirming preservation of outer hair cell activities. We hypothesized that The increase of CM amplitude might result from reduced activity of the efferent system resulting in turn from abnormal activation of auditory fibers.All patients had tried hearing aids without benefit. Eight patients received unilateral cochlear implants in order to improve speech perception by electrical stimulation of auditory fibers through the cochlear implant. Overall, speech perception remarkably improved in all cochlear implant recipients also in the presence of competing noise, although considerable variation of speech perception scores between was observed. Interestingly, no compound action potential was recorded in response to electrical stimulation through the cochlear implant, which confirmed the presence of neural damage. In contrast, brainstem potentials were restored in response to electrical stimulation. This finding supports the hypothesis that the hearing disorder affecting OPA1 patients is underlain by degeneration of the distal portion of auditory nerve fibers. Cochlear implantation restores synchronous activation of auditory pathways by by-passing the site of the lesion.Overall, these findings indicate that in patients carrying OPA1 missense mutations neural degeneration affecting the terminal dendrites results in a disruption of synchrony of auditory nerve fiber activity. Cochlear implantation improves speech perception in post-synaptic AN associated with OPA1 disease. However, a positive outcome of cochlear implant use was not invariably reported for all forms of post-synaptic AN, variability being possibly dependent on both the sites and extension of the lesion along auditory nerve fibers. Indeed, a variable improvement of speech perception scores has been reported with cochlear implant use in patients with AN associated with Friedreich ataxia ,49.OPA1 gene indicated that combination of findings from genetic research and high-sensitive neurophysiologic recordings plays a crucial role in clarifying both mechanisms and sites underlying the abnormal synchrony of auditory fiber firing.The findings collected in families carrying mutations in the OTOF gene encoding otoferlin [One well-studied form of presynaptic AN is caused by mutations in the toferlin ,50. Otoftoferlin  as well toferlin .OTOF gene result in a disrupted function of the ribbon synapses with an impaired multivesicular glutamate release and vesicle replenishment. The majority of subjects carrying mutations in the OTOF gene present with the phenotype of congenital profound hearing loss, the absence of auditory brainstem potentials associated with preserved cochlear hair cell activities  [Mutations in the AEs, CM) ,50.OTOF gene, as the SP is followed by a low-amplitude negative potential showing a markedly prolonged duration. Nevertheless, a small CAP is superimposed on the prolonged activity at high intensity in some children.In the last ten years, ten hearing-impaired children (age range of four month to three years) harboring biallelic mutations of the OTOF gene have been diagnosed and followed up at the University of Padua Service of Audiology and Phoniatrics, while their genetic analyses were performed at the Hospital Ramón y Cajal in Madrid ,53. All The prolonged potentials are likely to result from the sum of EPSPs arising in the terminal dendrites, which are dispersed in time as a consequence of the impaired multivesicle release. EPSPs only occasionally reach the threshold for triggering action potentials in some OTOF patients, and are recorded as high-threshold CAPs superimposed on the prolonged activity at high intensity. Therefore, the impaired multivesicular release is likely to result in a lesser probability of synchronized neural spiking and in a reduced signaling to the auditory brainstem pathways in comparison with normal hearing.OTOF gene.All children harboring OTOF mutations diagnosed at our department underwent unilateral cochlear implantation. They showed a remarkable improvement in hearing sensitivity and all reached speech perception scores of 90–100% by one year of cochlear implant use. Moreover, language development was in line with the language skills of their peers using cochlear implants whose deafness was related to causes other than mutations in the Unlike patients with post-synaptic AN, the implanted children with otoferlin-related deafness showed electrically-evoked auditory nerve potentials (e-CAPs) in response to electrical stimulation through the cochlear implant, consistent with preservation of auditory nerve function. Based on these findings, the outcome of cochlear implantation in patients with presynaptic AN due to OTOF mutations is expected to be successful.In addition, it is worthy of note that recent studies on animal models of OTOF showed successful preliminary results by using gene therapy ,55.Hidden auditory neuropathy is characterized by reduced performances in challenging auditory tasks with preservation of hearing thresholds. This condition results from loss of synapses which ensues from degeneration of the unmyelinated portion of auditory nerve fibers .Hidden AN has been observed in ten members of a large Italian family affected by DOA associated with the OPA8 locus (age range 19–72 years) . Their nAffected subjects complained of difficulties in understanding speech in the presence of noise. Hearing thresholds and speech perception were normal in the youngest members of this family, whereas the oldest patients showed mild hearing loss at high frequencies and decreased speech perception scores in the presence of noise. OAEs and CM recordings were within normal limits, thus indicating preservation of OHC function in all patients. In contrast, ABRs showed attenuated amplitudes in the youngest patients and severe abnormalities in the oldest. In addition, Wave I amplitude was significantly reduced compared to normally-hearing individuals, consistent with degeneration of IHCs synapses .All subjects were submitted to ECochG recording. The decrease in amplitude of both SP and CAP points to a decrease of the cochlear output, whereas the increase of both CAP peak latency and duration points to a selective reduction of auditory fibers from the basal portion of the cochlea. This is consistent with the audiometric profile of the oldest OPA8 patients showing mild hearing loss at high frequencies.These findings indicate that in OPA8 patients hidden AN results from loss of IHCs synapses. At an early stage of the disease, the functional alterations only consist of abnormalities of ABR Wave I while the cochlear potentials show a decrease in amplitude and prolongation in latency of both SP and CAP. At this stage speech perception is relatively preserved. A reduction in speech perception scores and the worsening of cochlear potentials alterations become apparent only with progression of the disease.AN disorders associated with gene mutations constitute a group of hearing dysfunctions resulting from different pathophysiological mechanisms. The identification of specific gene mutations combined with typical electrophysiological patterns may be the key factor in revealing how the failure of different molecular processes underlies the varieties of AN. This information is crucial for selecting effective rehabilitative options. In addition, the development of new electrophysiological tools may help in identifying neural and receptor components in the ECochG recordings collected from AN patients .


GJB2, SLC26A4, and MT-RNR1 and 2 uncertain clinical significance variants in GJB3) for 9,506 normal newborns  from 22 ethnic population in South China. A total of 1,079 (11.4%) newborns failed to pass the initial hearing screening; 160 (1.7%) infants failed to pass the re-screening, and 135 (1.4%) infants presented the diagnostic hearing loss. For the genetic screening, 220 (2.3%) newborns who presented at least one of the screened mutations were more likely to fail the hearing screening and have diagnostic hearing loss than mutation-negative newborns. In comparison to the differences of distribution of mutations, we did not identify any significant difference in the prevalence of screened mutations between Han group  and Zhuang group , despite the lack of number of minority ethnic groups. Studies including larger number of minority ethnic populations are needed in the future.Hearing loss is a common sensory deficit in humans with intricate genomic landscape and mutational signature. Approximately 1–3 out of 1,000 newborns have hearing loss and up to 60% of these cases have a genetic etiology. In this study, we conducted the concurrent newborn hearing and genetic screening in 20 mutations (18 pathogenic variants in  In this study of concurrent hearing and genetic newborn screening, for the first time, we reported the distributions and characteristics of 20 hearing-loss-related genetic variants in 9,506 newborns from 22 different ethnic groups in Guangxi province.Guangxi province located in the southwest China has the greatest population of ethnic minorities, including more than 20 groups. Among them, the Zhuang group accounts for about one-third of the total population, which is the largest ethnic minority group in China  in Liuzhou Maternal and Child Health Hospital, who received the concurrent hearing and genetic screening from July 2018 to March 2020. The information of ethnicity was collected from the household certificate. Newborn hearing screening and collection of blood spot specimens for genetic screening were conducted after birth as inpatients. Families were notified This study was reviewed and approved by the Ethics Committee of Liuzhou Maternal and Child Health Care Hospital (NO. 2018-049). All parents of newborns gave written informed consent in accordance with the Declaration of Helsinki.As described previously , the newvia the fluorescent PCR melting curve method. Limited genetic screening included genotyping 20 mutations in GJB2 , GJB3 (c.538C>T and c.547G>A), SLC26A4 , and MT-RNR1 (m.1494C>T and m.1555A>G). According to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines, all variants were pathogenic except for two variants in GJB3, which were classified as of uncertain clinical significance. All samples that presented any of the 20 screened mutations (positive) were confirmed by Sanger sequencing . All homozygous and compound heterozygotes were asked to get the hearing diagnosis tests.The genomic DNA was extracted from dried blood spot specimens and genotyped using the Genetic Testing Kit for Hereditary Deafness  n [%]). The chi-square test was used to compare differences in prevalence of screened mutations among ethnic groups. A two-tailed p < 0.05 was considered statistically significant.Variants were named according to the sequence variant nomenclature recommended by the Human Genome Variation Society. The sequencing data were aligned to the Genome Reference Consortium Human Build 37 (GRCh37/hg19) using the Sequencher software (version 5.1). Statistical analysis was performed by using IBM SPSS version 24.0 software . Categorical variables are presented as frequencies and percentages (p = 0.018) and re-screening (p = 0.007), and higher prevalence of diagnostic hearing loss (p = 0.025), see A total of 9,506 newborns  underwent the concurrent hearing and genetic screening were included in this study. Among them, a total of 1,079 (11.4%) newborns failed to pass the initial hearing screening, who referred to the re-screening at about 42 days age. Eventually, among 160 (1.7%) infants that failed to pass the re-screening, 128 (1.4%) infants presented the diagnostic hearing loss at about 3 months age. For genetic screening, 220 (2.3%) newborns presented at least one of the 20 screened mutations. To explore the association between abnormal hearing screening outcomes with the presence of mutations, we analyzed the distribution of initial screening, re-screening, and diagnostic hearing loss among mutation positive and negative newborns. In comparison with mutation-negative newborns, those mutation positive newborns showed lower percentage of whom were able to pass the initial hearing screening  from Guangxi province are shown in SLC26A4 c.1975G>C/c.919-2A>G, one newborn genotyped SLC26A4 c.919-2A>G/c.754T>C, and one newborn genotyped MT-RNR1 m.1555A>G/m.1494C>T , the disparate number of populations of different ethnic groups might hamper the statistical comparison between majorities with minorities (GJB2 c.299_300de1AT (p = 0.087) and SLC26A4 c.1229C>T (p = 0.063) have the tendency of distinguished prevalence between ethnic groups, which needs further study including larger number of subjects in the future.Although the distribution of hearing loss-associated mutations seemed to be distinct between various ethnic groups  could improve the effectiveness of elucidating etiologies, informing high-risk newborns and their maternal relatives of hearing loss (As a populous country with high incidence of birth defects including hearing loss , the nating loss .In our results, the total positive rate of limited genetic screened mutations was 2.3%, which was within the comparable range of positive rates in previous studies , 28. HowSLC26A4 c.2162C>T and c.749T>C in a South Chinese population, which were absent in the ChinaMAP. Since the sample size of some minority ethnic population was too small for comparative analysis, studies including more minority ethnic populations are needed.It is known that the carrier frequencies of Mendelian disorders, including genetic-associated hearing loss, could be considerably different between various ethnic groups . AlthougIn general, these multi-ethnic population characteristics of Guangxi province provide us a good opportunity to explore genomic contributions to hearing loss that vary by different ethnic populations and to promote the application of this knowledge to clinical care in the future .In this concurrent newborn hearing and genetic screening in a large-scale and multiple ethnic population in South China, we find that newborns who had at least one hearing loss-associated mutation are more likely to fail the hearing screening and have diagnostic hearing loss. However, we did not identify any significant difference in the prevalence of screened mutations between the majority Han ethnic group and Zhuang group, despite the lack of number of minority ethnic groups.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Ethics Committee of Liuzhou Maternal and Child Health Care Hospital. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.XT, TY, and JC contributed to conception and design of the study. LL, SLi, ML, and TL collected the data. XT and SLu performed the genetic and statistical analysis. XT and TY wrote the first draft of the manuscript. JC refined the draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.This study was supported by grant Z20180014 to XT from the Guangxi Medicine and Health Self-financing Research Project.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Age-related hearing loss (ARHL) is a kind of symmetrical and slow sensorineural hearing loss, which is a common condition in older adults. The characteristic of ARHL is hearing loss beginning in the high-frequency region and spreading toward low-frequency with age. Previous studies have linked it to anxiety, suggesting that brain structure may be involved in compensatory plasticity after partial hearing deprivation. However, the neural mechanisms of underlying ARHL-related anxiety remain unclear. The purpose of this cross-sectional study was to explore the interactions among high-frequency hearing loss and anxiety as well as brain structure in older adults. Sixty-seven ARHL patients and 68 normal hearing (NH) controls participated in this study, and the inclusion criterion of ARHL group was four-frequency  pure tone average (PTA) > 25 decibels hearing level of the better hearing ear. All participants performed three-dimensional T1-weighted magnetic resonance imaging (MRI), pure tone audiometry tests, anxiety and depression scales. Our results found gray matter volume (GMV) decreased in 20 brain regions in the ARHL group compared with the NH group, and a positive correlation existed between high-frequency pure tone audiometry (H-PT) and anxiety scores in the ARHL group. Among 20 brain regions, we also found the GMVs of the middle cingulate cortex (MCC), and the hippocampal/parahippocampal (H-P) regions were associated with H-PT and anxiety scores in all participants separately. However, the depressive symptoms indicated no relationship with hearing assessment or GMVs. Our findings revealed that the crucial role of MCC and H-P in a link of anxiety and hearing loss in older adults. Age-related hearing loss (ARHL), also referred to as presbycusis, is a kind of symmetrical and slow sensorineural hearing loss that occurs with age, which is a common condition in older adults . In the Age-related hearing loss has been reported to link a range of negative emotional outcomes, including depression based on the longitudinal studies , social Magnetic resonance imaging (MRI) has become an acceptive technique that can study various neurological diseases’ pathogenic mechanisms . A strucGiven that ARHL begins in the high-frequency region of the auditory spectrum and spreads toward the low-frequency regions with age , the steFor this cross-sectional study, 135 participants aged 50 to 72 years old , including 67 age-related hearing loss patients (ARHL group) and 68 normal-hearing controls (NH group). The inclusion criteria of ARHL group was four-frequency  pure tone average (PTA) > 25 decibels hearing level (dB HL) of the better hearing ear . SubjectDuring the pure tone (PT) audiometry test, subjects were tested in a sound-attenuating booth and were told to keep awake during the test. The audiometer  was used to test hearing thresholds at frequencies of 0.125, 0.25, 0.5, 1, 2, 4, and 8 kHz in each ear. By calculating the average hearing thresholds at 0.5, 1, 2, and 4 kHz in air conductance, the four-frequency PTA hearing threshold of both ears was obtained.By performing factor analysis with principal components extraction and Varimax rotation , the PT To refine the high-frequency region and quantify the audiogram process, the audiogram “steepness” of each adjacent frequencies was calculated in decibels per octave (dB/octave), namely the hearing level difference divided by the frequency difference .HT (fi) is the HL threshold in dB at the frequency fi and fi ∈  kHz. S (i) is the steepness of the audiogram in each adjacent two-frequency. For example, S (1) represents PT between 0.125 and 0.25 kHz. The steepness between two adjacent frequencies was regarded as an audiological marker of discontinuity in the shape of the audiogram  using an eight-channel phased-array head coil as the receiver. T1-weighted three-dimensional TFE images were used as the localizer, acquired with the following parameters: TR = 8.1 ms; TE = 3.7 ms; slice thickness = 1 mm; field of view = 24 cm × 24 cm; and flip angle = 8°. Images were reconstructed with 1 mm × 1 mm × 1 mm isotropic voxels.t-test model, and the total intracranial volume was regressive as a covariable. For multiple comparisons, the analyses were calibrated by using false discovery rate (FDR) criteria, with statistical significance set as p < 0.05 and cluster size > 20 voxels.The MRI images were processed by using the cat toolbox for the SPM12 in Matlab R2020b. We used voxel-based morphological (VBM) measurements to identify statistically significant brain regions. VBM includes spatial normalization, organization and segmentation, and spatial smoothing. In short, each subject’s image is spatially normalized and segmented into gray matter, white matter, and cerebrospinal fluid. After data preprocessing, smoothing was performed on normalized GMV before second-level intergroup analysis. GMV differences between the two groups were calculated using a two-sample All subjects assessed the levels of anxiety and depression without knowing the self-assessment scale scores. The psychiatric evaluation of each subject lasted about 20 min. The questionnaire included two subscales of anxiety and depression, with seven questions for anxiety and depression separately. For anxiety, the questions were 1, 3, 5, 7, 9, 11, and 13, and for depression, the questions were 2, 4, 6, 8, 10, 12, and 14. Some of the mandatory questions that involve anxiety were: “Do you ever feel tensed up?” “Worry a lot?” “Have panic attacks?” “Feel something awful is about to happen?” Each test item was scored from 0 to 3. Scores for depression and anxiety were separately calculated by summing the scores. The scores of the scale were: 0–7 were asymptomatic; 8–10 were suspected; and 11–21 were certainly existed. The score ≥ 8 was considered test positive. Levels of anxiety and depression were assessed according to the hospital anxiety and depression scale .Participants’ gender , age (in years), hypertension (yes or no), diabetes (yes or no), hyperlipidemia (yes or no), smoking (yes or no), and education (in years) were self-reported. Alcohol abuse identification test was assessed by the World Health Organization as a self-report screening, which included three problems about alcohol consumption, three problems about dependence symptoms, and four problems related to alcohol use. Each problem was scored from 0 to 4, generally based on frequency of occurrence, resulting in a total score of 0–40. The score ≥ 8 was considered alcohol abuse .t test. The sex, hypertension, diabetes, hyperlipidemia, smoking, and alcohol abuse were examined by the χ2 test. Partial correlation analyses were performed to explore the relationships both between structural changes and hearing loss, and between hearing loss and anxiety in older adults . Spearman or Pearson correlation was used to analyze the relationships between anxiety and brain structure. Data processing and analysis were performed using SPSS 25.0 . The significance level was examined at p < 0.05. A linear regression model was adopted to evaluate the hearing loss on anxiety symptoms. Then we designed a weighted linear regression to reduce autocorrelation and heteroskedasticity. First, the residuals square of the original linear model was extracted and made as logarithmic transform. Then, we constructed a linear regression, making logarithmic residuals square as the dependent variable and taking the fitted value as the weights for the final linear model between anxiety and each feature. The degree of prediction was indicated by R2 and β. Data processing and analysis were performed using R 3.6.0.All data were tested by the Kolmogorov–Smirnov test to verify normal distribution. The group differences in NH and ARHL group of age, education, anxiety, depression, and auditory test results were assessed by the two-tailed p < 0.001). In psychological assessment, there was no significant difference in anxiety and depression scores between the ARHL and NH groups (p > 0.05). No significant differences in age, sex, education, hypertension, diabetes, hyperlipidemia, smoking, and alcohol abuse were identified between the NH and ARHL groups (p > 0.05).The demographics and clinical characteristics are listed in The hearing thresholds at different frequencies in both ears of NH and ARHL subjects are shown in r = 0.289, p = 0.021) . The results indicated that higher anxiety symptoms were associated with high-frequency hearing loss.The relationship between hearing loss and anxiety scores in each group is listed in = 0.021) . Besidesr = 0.331, p = 0.006)    , anxiety= 0.032) . In all = 0.027) . Figure S (6) of the left ear was negatively correlated with the GMV of H-P regions , S (5) of the left ear was positively associated with the GMV of MCC , S (6) of the right ear was negatively correlated with the GMV of H-P regions , and S (5) of the right ear was positively associated with the GMV of MCC . In all participants, S (6) of the right ear was negatively correlated with the GMV of H-P regions , and S (5) of the left ear was positively associated with the GMV of MCC .In this study, we found gray matter (GM) atrophy in ARHL group compared with NH group. Our results also showed that in older adults, the GMV of MCC was positively associated with steepness between 2 and 4 kHz, but the GMV of H-P regions was negatively associated with steepness between 4 and 8 kHz. In addition, there was a significant association between high-frequency hearing loss and anxiety scores in patients with ARHL. Moreover, anxiety scores were positively associated with the GMV of H-P regions and MCC. Above all, we found an interaction between hearing loss, anxiety, and structural plasticity in older adults.Our study found that high-frequency hearing loss was positively associated with anxiety scores in the ARHL group. Previous study has linked hearing loss to the increased risks of depression, anxiety, and stress . In addiFurthermore, the audiogram steepness was used to refine the frequency range in high-frequency hearing loss. Our study showed that steepness between 2 and 4 kHz was positively correlated with the GMV of MCC in older adults. In other words, our study showed that there was a same variation tendency between the GMV of MCC in the older adults and the variation of hearing thresholds in 2 and 4 kHz. Previous study has found that patients with sensorineural hearing loss showed significantly reduced functional connectivity in the cingulate gyrus . Meanwhivia (a) the parahippocampal cortex or peripheral cortex, or (b) other brain pathways, including the medial frontal cortex, insula, or amygdala. Hippocampal microstructural analysis revealed that compared to normal hearing controls, the more severe the hearing loss in moderate/severe patients with ARHL, the lower the microstructural integrity and the higher of the mean diffusivity in the GM of the hippocampus (Our study showed that the steepness between 4 and 8 kHz was negatively correlated with the GMV of H-P regions in older adults. Other studies have found that the hippocampus received neural input from the central auditory system directly or indirectly pocampus . Furtherpocampus . Consonapocampus . Our stupocampus . Recentlpocampus . In addiThere are some limitations of this study that need to be noted. Firstly, our sample size was relatively modest, and so we should further increase the sample size to conduct the study in the future. Secondly, in our study, the anxiety scale was selected broadly and further examination was not carried out. Thirdly, it was a cross-sectional study, so it was not possible to explore the causal relationship between high-frequency hearing loss and anxiety. Finally, this study used a clinical audiometer to measure hearing loss, and the ultra-high frequency audiometry could be used to study the high-frequency region in the future. In addition, we have assessed the pure tone thresholds at the frequencies of 0.125, 0.25, 0.5, 1, 2, 4, and 8 kHz which were well-set in the audiometer, but lacked the frequencies of 3 and 6 kHz that would contribute to the speech intelligibility of some phonemes. We will supplement these test frequencies in the future.Our study showed that there was a close positive relationship between high-frequency hearing loss and anxiety scores in ARHL group. In addition, we found GM atrophy of MCC and H-P regions in ARHL group compared with the NH group. The GMV of MCC was positively associated with high-frequency hearing loss; however, the GMV of H-P regions was negatively correlated with high-frequency hearing loss. Our results also showed that the GMV of MCC and H-P regions had a significant positive relationship with ARHL-related anxiety in older adults. Taken together, we found an interaction between hearing loss, anxiety, and structural plasticity in older adults. Our findings revealed the crucial role of MCC and H-P in a link of anxiety-hearing loss link in older adults. In the future, it is necessary to conduct longitudinal studies to further clarify the causal relationship between hearing threshold changes and psychological status and structural plasticity in older adults.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Shandong First Medical University institutional review board. The patients/participants provided their written informed consent to participate in this study.YW and FG had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis and concepted and designed the experiments. WM, XL, and FR carried out the experiments. YZ, SL, JY, LX, HL, and YG analyzed the experimental results. WM and YZ wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


There is increasing recognition of the role of epigenetics in facilitating the pathogenesis and clinical outcome in patients with a diagnosis of neuroendocrine neoplasia. In this review we outline the different types of epigenetic changes that are observed and their impact. We also highlight novel interventions that can be used to manipulate these epigenetic changes that are being explored in the clinic.Gastroenteropancreatic neuroendocrine neoplasias are a diverse group of neoplasms with different characteristics in terms of site, biological behaviour and metastatic potential. In comparison to other cancers, they are genetically quiet, harbouring relatively few somatic mutations. It is increasingly becoming evident that epigenetic changes are as relevant, if not more so, as somatic mutations in promoting oncogenesis. Despite significant tumour heterogeneity, it is obvious that DNA methylation, histone and chromatin modifications and microRNA expression profiles are distinctive for GEP-NEN subtypes and may correlate with clinical outcome. This review summarises existing knowledge on epigenetic changes, identifying potential contributions to pathogenesis and oncogenesis. In particular, we focus on epigenetic changes pertaining to well-differentiated neuroendocrine tumours, which make up the bulk of NENs. We also highlight both similarities and differences within the subtypes of GEP-NETs and how these relate and compare to other types of cancers. We relate epigenetic understanding to existing treatments and explore how this knowledge may be exploited in the development of novel treatment approaches, such as in theranostics and combining conventional treatment modalities. We consider potential barriers to epigenetic research in GEP-NENs and discuss strategies to optimise research and development of new therapies. Neuroendocrine neoplasias (NENs) are a heterogeneous group of neoplasms that arise from cells of the endocrine glands as well as the diffuse neuroendocrine system . GastroeInvestigation of the NET genetic landscape is characterised predominantly by small, heterogeneous studies driven by advances in next-generation sequencing and other high-throughput technologies. As a result, large numbers of genetic and epigenetic changes have been identified. However, despite the large amount of data, it has not yet been possible to identify key dysregulated pathways that drive carcinogenesis in NETs, a process that would be addressed by large tissue profiling studies that integrate DNA, RNA and methylation. It is clear that there is a paucity of genetic mutations in classical tumour suppressor and oncogenes, which has fueled interest in the role of epigenetics in both oncogenesis and tumour evolution in GEP-NETs. Epigenetics refers to a change in gene expression that does not involve a change to the underlying DNA sequence—a change in phenotype without a change in genotype . EpigeneThis review explores the current understanding of the natural history of GEP-NETs, with specific reference to underlying epigenetic changes and relevance to tumorigenesis. We briefly summarise the main epigenetic pathways before exploring how these are altered or augmented in GEP-NETs. We look at novel biomarkers and potential avenues for therapeutic modulation utilising both pharmacological and theranostic approaches. Finally, we look at the potential difficulties and barriers to research in GEP-NETs and how these may be overcome.Epigenetics refers to a change in phenotype without a corresponding alteration in the genotype . There aDNA promoter methylation is one of the most well-recognised epigenetic modifications in both normal and cancer cells. The methylation of cytosine to 5-methylcytosine is so integral to genomic homeostasis that this is often referred to as the ‘fifth base’ of the genome . MethylaHistones are highly basic proteins that act as spools around which DNA intertwines with chromatin, forming tight compact structures known as nucleosomes. Histone remodelling is a key gene expression regulator and is primarily carried out by two enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs), with inverse functions. HDACs catalyse the removal of acetyl groups, resulting in a closed chromatin structure and generally suppressing gene expression. HATs, in contrast, mediate the reversible acetylation of histones and non-histone proteins, resulting in a local “open chromatin” and allowing gene expression concomitantly through the binding of multiple transcription factors. Other key histone post-translational modifications include methylation, ubiquitination and phosphorylation, which similarly can increase or decrease the transcription of genes .MicroRNAs (miRNAs) are highly conserved, single-stranded non-coding molecules of RNA that are approximately 21 to 25 nucleotides in length. They regulate protein expression by targeting mRNAs for degradation or transcriptional repression ,15. miRNPancreatic NETs (pNETs) comprise 15–20% of all GEP-NETs . They arRas-association domain gene family 1 (RASSF1) is a tumour suppressor gene which functions to arrest the cell cycle in G1 by a mechanism that leads to accumulation of cyclin D1 (yclin D1  19]. Do. DoRas-ap = 0.001), where RASSF1C is believed to play a role in the upregulation of the Wnt pathway through inhibition of β-catenin degradation, suggesting that RASSF1C may also have a pathogenic role in the development of pNETs . In. InO-6-aInsulin Growth Factor-2 gene (IGF2) is a gene that is imprinted through hypermethylation. Loss of imprinting and overexpression of IGF2 has been described in pNETs [in pNETs . Dejeux in pNETs . The autWidepsread CpG island promoter methylation, also referred to as CpG island methylator phenotype (CIMP), has been observed in a significant percentage of pNETs studied (83%) and is associated with the presence of metastases and worse prognosis .House and colleagues reported promoter methylation of MLH1 in two studies associated with microsatellite instability ,47. ThisLong interspersed nucleotide element 1 (LINE1) and Arthrobacter luteus (ALU) homolog are non-coding genomic repetitive sequences, the methylation status of which can be used as a surrogate marker of global hypomethylation . HypometThe most frequently mutated genes in pNETs are MEN1, DAXX or alpha thalassemia/mental retardation syndrome X-linked (ATRX), occurring in 44%, 25% and 18% of pNETs, respectively . MutatioDAXX is a histone H3.3 chaperone which is guided by ATRX and is a nuclear protein of the SWI/ SNF complex of chromatin-remodeling genes. ATRX recruits DAXX, mediating DAXX-dependent H3.3 deposition at H3K9me3-enriched chromatin and telomeres where it mediates both chromatin remodelling and telomere length . Loss-ofWhilst miRNAs are one of the most abundant classes of gene-regulatory molecules, few studies have considered the role of miRNA in the pathogenesis of GEP-NET. Roldo and colleagues investigated global miRNA expression in the normal pancreas. pNETs (twelve insulinomas and 28 non-functioning endocrine tumours) and four acinocarcinomas were evaluated regarding the involvement of miRNA in malignant transformation and progression . ResultsIn a similar study, Thorns and colleagues studied the miRNA profiles of 37 pNETS compared with non-neoplastic pancreas and micro-dissected islet cells . The autDAXX/ATRX alterations, again lending support to the concept that these mutations are late events in pNET pathogenesis driven by MEN1 loss.In a large study of 40 pNETs, three distinct subsets named miR-cluster-1, miR-cluster-2, and miR-cluster-3 were identified which differentially expressed 30 distinct miRNAs. miR-cluster-1 included MEN1-mutant tumours with moderate metastatic potential. miR-cluster-2 was enriched in metastasis-like primaries (MPL) with high metastatic potential, whilst miR-cluster-3 predominantly included insulinomas, none of which were associated with metastatic disease . The aut30. They are classically divided into foregut , midgut  and hindgut . Epigenetic interest in GI-NETs has been, at least in part, fuelled by increased understanding of the role of methylation and CpG island methylator phenotype positivity (denoting a high degree of methylation across multiple CpG sites) in colorectal adenocarcinoma onset and progression. Research into histone modifications and miRNA in SI-NETs has been less informative.NETs of the gastrointestinal tract (GI-NETs) comprise over two third of GEP-NETsAs seen in pNETs, GI-NETs are also frequently methylated in the RASSF1A promoter region. Pizzi and colleagues identified RASSF1A promoter methylation in 32% of 62 GI-NETs studied, although this was restricted to foregut tumours . Of thesCTNNB1 promoter region methylation were more frequent in metastatic lesions compared to primary tumours [In a second study of 33 midgut tumours, Zhang and colleagues found that RASSF1A and  tumours . A major tumours . Additio tumours . This st tumours . Global  tumours . Whilst  tumours , Stricke tumours .Given the observed loss of chromosome 18 in SI-NETs, Edfelt and colleagues investigated the epigenetic regulation of TCEB3C as the only imprinted gene on this chromosome that encodes for elongin A3 . The expIn a study of 101 SI-NETs, the gene SEMA3F, which encodes for semaphorin 3, was observed to be methylated in 50% of tumours and correlated with a higher Ki67 and tumour stage, an observation which warrants further investigation .A number of high throughput studies have been undertaken to study global methylation patterns in SI-NETs. Verdugo and colleagues investigated DNA methylation in 20 SI-NETs and their corresponding metastases . They reKarpathakis and colleagues conducted the largest genome wide study to date, integrating genomic, epigenomic, and transcriptomic analysis to analyse 91 SI-NETs . The autp > 0.01). The expression of DNMT1, 3A and 3B were all higher in advanced stage tumours and correlated with the proliferation index. Taken together, these findings suggest that DNMT may be a therapeutic target that warrants further investigation.Rahman and colleagues investigated the expression of DNMT1, -3A and 3B in 63 GEP-NETs . They reArnold and colleagues investigated MSI and CIMP in 34 malignant poorly differentiated colorectal NET, as well as in 38 well-differentiated benign and malignant fore-/midgut-NETs . Of the Studies looking into histone and chromatin modification in GI-NETs have been limited to small case-controlled studies of primarily SI-NETs, and more research is required in this area. The histones H1 (linker histone) family have a number of genomic roles including promoting structural stability, regulating gene expression and participating in chromatin-based DNA replication and repair. Warnebolt and colleagues showed that, of the 11 H1 homologous proteins described, the H1x subtype is significantly overexpressed in both SI-NETs and pNETs compared to surrounding normal tissue .Methylation of core histones (including histone H3) regulate chromatin structure and gene expression. Histone H3 undergoes extensive post-translational modification and is known to have a number of epigenetic functions in various cancers and beyond  . Magerl Research into MiRNAs in GI-NETs has thus far been relatively limited in comparison to other cancers. Studies have primarily focused on expression differences between primary tumours and metastatic deposits and have suggested a role in disease progression, potentially showing utility in detecting more aggressive variants. Ruebel and colleagues analysed 95 miRNAs in eight matched primary and metastatic ileal NET tumours . They shThe utility of miRNA as a biomarker for diagnoses has also been explored in GI-NETs. Hamfjord and colleagues showed dysregulation of miRNA expression in paired samples of seven colorectal adenocarcinomas and one colonic NET with normal mucosa . The expThe potential utility of miRNAs as serum biomarkers in GI-NETs has been recently explored by Bowden and colleagues . In a muEpigenetic modifications play critical roles in tumorigenesis by altering the expression of oncogenes and tumour suppresser genes through various mechanisms, including DNA methylation, histone and chromatin remodeling and miRNA expression. These epigenetic modifications are reversible, opening an innovative area of drug development in neuroendocrine cancers. With increased understanding of the epigenetics in GEP-NETs, we review the potential for translation into meaningful treatments for patients.DNA methyltransferase inhibitors (DNMTIs) are one of the most successful classes of epigenetic drugs for the treatment of malignancies, such as myelomonocytic leukaemia . The proAlexander and colleagues showed the effects of 5-aza-dC on three carcinoid cell lines—human ileal (CDNT2.5), pulmonary (H727), and pancreatic (BON-1) . A dose-Histone deacetylation inhibitors (HDACIs) have been tested in GEP-NETs with promising results, although the toxicity profile observed is similar to that observed with DNMTIs with problematic myelosuppression limiting clinical use .One target of HDACIs is the p21 tumour suppressor gene, where upregulation leads to the blockade of the cyclin/CDK complex, leading to cell cycle arrest . HDACIs Baradari and colleagues investigated the antineoplastic effects of three different HDACIs, (trichostatin A (TSA), sodium butyrate (NaB), and MS-275, on the growth and apoptosis of GEP-NET cell lines CM and BON-1 . All thrShah and colleagues explored the use of depsipeptide, an HDACI, in 15 patients with metastatic NETs . UnfortuKunnimalaiyaan and colleagues found that the activation of the Notch-1 gene significantly reduces tumour growth in vitro . They hy68Ga)DOTA (0)-Phe (1)-Tyr (3)-octreotide (DOTATOC) or –DOTA-(Tyr3)-octreotate (DOTATATE)) and consists of radiolabeled SSAs with beta-emitting radioisotopes, either (90Y) or (177Lu), that bind specifically to SSTR on the tumour surface, becoming internalised and delivering tumoricidal radiation. The NETTER-1 trial reported a significant improvement in progression-free survival and overall survival in those patients with lower grade small bowel NETs receiving 177Lu-DOTA0-Tyr3–octreotate ((177Lu)DOTATATE) compared to single agent SSAs; this is approved in the EU for the management of grade 1 and 2 GEP-NETs [177Lu)DOTATATE due to limited SSTR2 expression. Exploring the role of epigenetics in the expression of SSTR2, Torrisani and colleagues identified a region in the promoter sequence of SSTR2 that undergoes promoter methylation, such that in vitro treatment with a demethylating agent, in this case decitabine, resulted in re-expression of SSTR2 in high-grade cell lines [68Ga)DOTA-PET is used to assess SSTR2 re-expression. Utilizing epigenetic modifiers to allow the re-expression of a receptor of interest has the potential to improve the clinical outcome in a significant number of GEP-NET patients who would otherwise not be suitable for PRRT.NETs are characterised by the presence of somatostatin receptors (SSTRs) on cell surfaces, typically including subtypes SSTR2, and to a lesser extent SSTR5 . Stable GEP-NETs . Howeverll lines . These fll lines . ExtendiDespite recent advances in both genetic and epigenetic research in GEP-NETs, significant barriers remain to effective research in this area. Current studies have been fragmented, caused by the relatively low incidence of GEP-NETs, limited availability of neoplastic tissue for integrated analysis and inadequate animal models to recapitulate the disease. Typical studies in GEP-NETs involve fewer than 100 disease cases and are further confounded by significant disease heterogenicity.Disease models which fully recapitulate GEP-NETs are indispensable for the translation of pre-clinical programs to the clinic; however, attempts to establish patient-derived xenografts have been unsuccessful and currently available cell lines (such as GOT1 and BON-1) and mouse models more closely resemble poorly differentiated neuroendocrine carcinoma rather than well-differentiated NETs. The developing field of organoid research may potentially offer a new platform for GEP-NET research, with the potential to give valuable insight into both aetiology and progression.The limited availability of preclinical models and human tissue of GEP-NETs and the performance of non-selective translational research has negatively impacted research, hindering the optimal development of treatments ,106. In Ongoing projects, such as the National Institute for Health Epigenomics program, are generating new research tools, datasets and testing infrastructure to accelerate our understanding and have particular relevance for diseases such as GEP-NETs with significant epigenetic pathophysiology .Cancer research has traditionally focused on genetic alterations which underpin tumorigenesis, leading to the defined hallmarks of cancer. However, in neoplasms with few somatic mutations, such as GEP-NETs, the increasing importance of epigenetic changes, such as methylation patterns, histone and chromatin remodeling alterations and miRNA, has been identified. Despite the limitations of small heterogeneous studies, the high frequency of mutations in genes encoding for epigenetic modifiers suggest a fundamental role in both the tumorigenesis and metastatic progression of GEP-NETs. Further dissection of the GEP-NET epigenome will be crucial for characterisation of specific epigenetic subtypes. Currently, the armamentarium for the management of GEP-NETs does not deliver personalized oncology, which has transformed the management of other cancers. The characterisation of specific epigenetic GEP-NETs subtypes will hopefully lead to better patient stratification for clinical trials and, ultimately, more effective therapies.


The genetic architecture of hearing impairment in Finland is largely unknown. Here, we investigated two Finnish families with autosomal recessive nonsyndromic symmetrical moderate‐to‐severe hearing impairment.Exome and custom capture next‐generation sequencing were used to detect the underlying cause of hearing impairment.CAPB2 that is known to cause autosomal recessive nonsyndromic hearing impairment. Four CABP2 variants have been reported to underlie autosomal recessive nonsyndromic hearing impairment in eight families from Iran, Turkey, Pakistan, Italy, and Denmark. Of these variants, the pathogenic splice site variant c.637+1G>T is the most prevalent. The c.637+1G>T variant is enriched in the Finnish population, which has undergone multiple bottlenecks that can lead to the higher frequency of certain variants including those involved in disease.In both Finnish families, we identified a homozygous pathogenic splice site variant c.637+1G>T in CABP2 splice site variant c.637+1G>T.We report two Finnish families with hearing impairment due to the  CAPB2 that is known to cause autosomal recessive nonsyndromic hearing impairment.The genetic architecture of hearing impairment in Finland is largely unknown. Here, we investigated two Finnish families with autosomal recessive nonsyndromic symmetrical moderate‐to‐severe hearing impairment. Exome and custom capture next‐generation sequencing were used to detect the underlying cause of hearing impairment. In both Finnish families, we identified a homozygous pathogenic splice site variant c.637+1G>T in  It belongs to the CaBP family that is related to calmodulin and is expressed in the cochlea and hair cells. CABP2 facilitates normal functioning of the peripheral auditory system by inhibiting CaV1.3 Ca2+‐channel inactivation   c.637+1G>T . CABP2 has not yet been reported to be involved in ARNSHI in Finland. We report on two Finnish families with ARNSHI due to the splice site variant c.637+1G>T. This variant is classified as pathogenic according to the American college of medical genetics (ACMG) guidelines. The Finnish population has a unique genetic architecture in which certain variants are enriched while the variant diversity is reduced compared to other populations  nonsyndromic (NS) hearing impairment (HI), genes have been identified, including 3) Table , GJB2 ha22.1The study was approved by the ethics committee of the Oulu University Hospital (EETTMK: 55/2018 and 186/2020) and from the institutional review board (IRB) Columbia University (IRB‐AAAS2343). Two children in family FINHEAR1 and one child in family FINHEAR2 with HI were born to parents of Finnish origin from the Kainuu and Central Ostrobothnia regions, respectively. No other family members were reported to be hearing impaired. Available medical records as well as familial and clinical history were evaluated. Physical examination, transient otoacoustic emissions (TEOAE), and pure‐tone audiometry were performed at 125–8000 Hz for the affected children of FINHEAR1. TEOAE, auditory steady‐state response (ASSR), and auditory brainstem response (ABR) were evaluated for the affected child of FINHEAR2. DNA samples were obtained from the unaffected parents and their affected children.2.2GJB2 via Sanger sequencing. DNA samples from II:1 and II:4 of family FINHEAR1 and II:3 of family FINHEAR2       c.637+1G>T is the causative variant    in gnomAD with no homozygous individuals. FinnGen . There are four individuals who are likely homozygous for the imputed c.637+1G>T variant. FinnGen reports no association between the c.637+1G>T variant and sensorineural hearing loss  . Although this variant is enriched in the Finnish population, CABP2 is likely a rare cause of HI in Finland. The estimated prevalence of HI in Finland due to homozygous c.637+1G>T variants ranges from 0.7 to 1.9 per 100,000 individuals. As the allelic spectrum of pathogenic CABP2 variants in Finland is unknown, the frequency of HI due to CABP2 could be higher if there are other yet to be identified causal variants.The AF of the  FinnGen , which iThe Finns are an isolated population and their genetic architecture has been molded by several ancient and recent migratory and multiple bottleneck events as well as rapid population growth in the last 10 generations (Chheda et al., CABP2 c.637+1G>T variant that segregates with moderate‐to‐severe ARNSHI in two families of Finnish origin. To the best of our knowledge, these are the first reported cases of CABP2‐related ARNSHI in Finland.In conclusion, we identified the All authors declare no conflict of interest.S.M.L. developed the concept of the study. S.M.L., I.S., M‐L.V., M.K., E.R., I.J., and J.K. organized and coordinated the study. M‐L.V., M.K., E.R., I.J., and J.K. gathered the clinical information. I.S., T.B., and A.A. analyzed the data. A.A. and L.M.N‐S conducted molecular experiments. T.B. wrote the first draft of the manuscript. S.M.L and I.S. reviewed and revised the manuscript. All authors have agreed to the final version of the manuscript.Table S1Click here for additional data file.Table S2Click here for additional data file.