Research Library

Review the EVA-Focused Research Library

The team at University Hospitals Rainbow Babies and Children's Hospital in Cleveland, Ohio, believes easy-to-understand educational information is critical for patients and their families to better understand enlarged vestibular aqueduct (EVA) syndrome.

Research, Explained

In addition to sharing resources that offer cutting-edge research, our team has put together some brief summaries of recent scientific publications. Scientific progress is disseminated via these types of publications, so you can keep up with our current understanding of EVA. We included a glossary, too, to help explain what some of the more scientific terms mean. If you'd like a primer on EVA, check out this page.

Usually, researchers will look into an article based on its title. From there, they might read the abstract (which is a short summary). If the abstract is interesting enough, then a researcher might read an entire paper--though, usually, will focus on the results, conclusions, and discussion sections.

If these summaries don't satiate your curiosity, you can learn more about professionals’ progress at the following websites: American Society of Pediatric Otolaryngology and American Academy of Otolaryngology/Head and Neck Surgery.

Abou-elew M, El-khousht M, El-minawi MS, Selim M, Kamel AI. Enlarged vestibular aqueduct in congenital non-syndromic sensorineural hearing loss in Egypt. Indian J Otolaryngol Head Neck Surg. 2014;66(Suppl 1):88-94.

The study estimates the frequency of enlarged vestibular aqueduct (EVA) in patients with non-syndromic sensorineural hearing loss (SNHL) in an Egyptian population sample, looking to correlate EVA size with the degree of hearing loss. Audiograms and temporal bone images were obtained, and vestibular aqueduct (VA) was measured at two points (midpoint & operculum) on both sides of the head. A significant correlation between VA midpoint & operculum was found, and EVA was diagnosed in 6 out of 32 ears (18.75%) in the study sample. However, EVA size was not related to the degree of hearing loss or configuration. Moderate and high frequency sloping SNHL were considered the most common findings seen in patients with EVA.

Adhikary B, Ghosh S, Paul S, et al. Spectrum and frequency of GJB2, GJB6 and SLC26A4 gene mutations among nonsyndromic hearing loss patients in eastern part of India. Gene. 2015;573(2):239-45.

The mutation spectrum of EVA-associated genes varies among different ethnic groups. This study focuses specifically on populations living in the eastern part of India. 215 consecutive nonsyndromic hearing loss patients were screened for mutations in GJB2, GJB6 and SLC26A4, and temporal bone CT imaging was performed in patients with SLC26A4 mutations. In the group, there were no patients with either the SLC26A4 genetic mutation or with CT findings of EVA. These findings are notable because, given the population size, we would expect to find some EVA patients. Such results speak to the distribution of EVA across different populations.

Alemi AS, Chan DK. Progressive Hearing Loss and Head Trauma in Enlarged Vestibular Aqueduct: A Systematic Review and Meta-analysis. Otolaryngol Head Neck Surg. 2015;153(4):512-7.

This study is a meta-analysis of patient-level data that describes EVA, progressive SNHL, and head trauma, using articles identified on systematic review. 23 studies analyzing 1115 ears with EVA met inclusion criteria. Progressive SNHL was found in 39.6% of ears, with trauma-associated progression in 12%. One important conclusion from this study is that long-term progression of SNHL in patients with EVA is common, but its association with head trauma is not strongly supported.

Ascha MS, Manzoor N, Gupta A, Semaan M, Megerian C, Otteson TD. Vestibular Aqueduct Midpoint Width and Hearing Loss in Patients With an Enlarged Vestibular Aqueduct. JAMA Otolaryngol Head Neck Surg. 2017.

We are quite happy to say that this is our very own work. We looked at electronic medical records from the past fifteen years, and looked for a relationship between vestibular aqueduct midpoint width and hearing loss. This work was unique in the sense that we looked at every single one of each patient's hearing test results, rather than a before/after or single-measurement model of hearing. As a result, we were able to precisely identify a positive relationship between vestibular aqueduct midpoint width and hearing loss, where each extra millimeter of midpoint width is associated with an increase of about 17.5 dB in speech reception threshold and a decrease of 21% in word recognition score.

Chai Y, Huang Z, Tao Z, et al. Molecular etiology of hearing impairment associated with nonsyndromic enlarged vestibular aqueduct in East China. Am J Med Genet A. 2013;161A(9):2226-33.

For patients who don’t present with other associated symptoms, the cause of hearing loss may require some extra investigation. Investigators in East China report that, among those hearing loss patients who don’t present with concurrent symptoms, 11% (37/330) had a mutation in the SLC26A4 gene. Interestingly, the specific types of mutations in this gene varied across different populations--that is, patients in East China had different types of mutations than patients from different parts of China. This study highlights the association between population genetics and hearing impairment, emphasizing the usefulness of genetic testing as a tool to further characterize EVA.

Chen JX, Kachniarz B, Shin JJ. Diagnostic yield of computed tomography scan for pediatric hearing loss: a systematic review. Otolaryngol Head Neck Surg. 2014;151(5):718-39.

Computed tomography (CT) has been used in the assessment of pediatric hearing loss, but concern regarding radiation risk and increased utilization of magnetic resonance imaging (MRI) have prompted us toward a more quantitative and sophisticated understanding of CT's potential diagnostic yield. Data from studies describing the use of CT in the diagnostic evaluation of pediatric patients with hearing loss of unknown etiology were evaluated, according to a priori inclusion/exclusion criteria. In 50 criteria-meeting studies, the overall diagnostic yield of CT ranged from 7% to 74%, with the strongest and aggregate data demonstrating a point estimate of 30%. This estimate corresponded to a number needed to image of 4 (range, 2-15). The most common findings were enlarged vestibular aqueduct and cochlear anomalies. The largest studies showed a 4% to 7% yield for narrow cochlear nerve canal. These data, along with similar analyses of radiation risk and risks/benefits of sedated MRI, may be used to help guide the choice of diagnostic imaging.

Clark CM, Patel HH, Kanekar SG, Isildak H. Enlarged vestibular aqueducts and other inner-ear abnormalities in patients with Down syndrome. J Laryngol Otol. 2017;131(4):298-302.

Previous work has shown several anatomic abnormalities are associated with Down's syndrome, including inner ear malformations. Here, the authors examined 75 ears from 38 different people, finding inner ear abnormalities in 20 of the 38 individuals.

Clarós P, Fokouo JV, Clarós A. Cochlear implantation in patients with enlarged vestibular aqueduct. A case series with literature review. Cochlear Implants Int. 2017;18(3):125-129.

This study looks at 11 cases of cochlear implantation, reporting 5 bilateral and 6 unilateral cases of EVA out of 827 subjects implanted over a 22 year period. The authors report no postoperative complications, and explain that all the patients regained "serviceable" hearing and returned to normal work/school life.

Deklerck AN, Acke FR, Janssens S, De leenheer EM. Etiological approach in patients with unidentified hearing loss. Int J Pediatr Otorhinolaryngol. 2015;79(2):216-22.

This article reviews recommended tests for people with hearing loss, in particular, looking to establish clear guidelines about optimal implementation and sequence of genetic tests. Audiometric and etiological data of patients from the otogenetics clinic in the study were collected and analyzed. In 81.2% of the patients, a cause of hearing loss could be determined or suspected. In total, 65.4% had a (presumably) genetic etiology, with connexin 26 (GJB2) mutations as the leading cause. Inquiry of risk factors, associated with congenital hearing loss, and pedigree analysis were found to have the highest diagnostic gain (61.3% and 41.8%). Connexin 26 gene mutations were only present in bilateral hearing impairment, whereas CT abnormalities were related to unilateral (P=0.003), profound (P<0.001) hearing loss. An enlarged vestibular aqueduct was present in 42.9% of all CT abnormalities. Ophthalmologic anomalies were detected in 35.7% of the studied patients. The study concluded that a sequential approach for the etiological diagnosis of unidentified hearing loss could determine or suggest a cause in more than 80% of patients. The approach may vary based on the presenting phenotype.

Demarcantonio M, Choo DI. Radiographic Evaluation of Children with Hearing Loss. Otolaryngol Clin North Am. 2015;48(6):913-32.

This article reviews radiographic approaches to evaluating hearing loss, and provides recommendations on which tests to perform first. Children with hearing loss (without suspected cancer, infectious or inflammatory causes), should undergo fast spin-echo T2-weighted MRI or CISS imaging protocols without IV contrast. 5% of patients with unilateral SNHL have bilateral findings on imaging. This can provide prognostic information. This article notes that EVA is the most common imaging finding in patients with SNHL, where findings are bilateral in up to 87% of patients and associated with a cochlear malformation in 84%.

Gao Y, Xu Y, Li Q, Lang Y, Dong Q, Shao L. Mutation analysis and audiologic assessment in six Chinese children with primary distal renal tubular acidosis. Ren Fail. 2014;36(8):1226-32.

This study looked at two genes that are involved in acid transportation across cell membranes. The study population was six Chinese children from four unrelated families who were all between the ages of 2 and 13 years old, had too much acid in their blood because they couldn’t excrete it in urine, and had bilateral passing newborn hearing tests (except for one patient who passed unilaterally). Two of the patients who had mutation in the ATP6V1B1 gene were found to have EVA and profound hearing loss, one of whom passed the newborn hearing test with both ears and the other with only one ear. Two of the patients had mutation in the ATP6V0A4 gene, one of whom had EVA, and both had moderate hearing loss. This article is important because it examines how non-SLC26A4 mutations may be associated with EVA and hearing loss. One important take-away for people interested in learning about EVA would be that we again see a potential association with cell transportation, except this time it is a matter of acid instead of salt.

He X, Peng Q, Li S, et al. A novel missense mutation in the SLC26A4 gene causes nonsyndromic hearing loss and enlarged vestibular aqueduct. Int J Pediatr Otorhinolaryngol. 2017;95:104-108.

The genetics of EVA remain elusive, likely as a result of the complexity involved in both genetics generally and EVA specifically. Here, He and coauthors report a new mutation that is associated with EVA, and find that modern genetics models predict this mutation to be damaging. As a result, the authors both identified a new EVA-related mutation and demonstrated that this mutation could be harmful.

Ho ML, Moonis G, Halpin CF, Curtin HD. Spectrum of Third Window Abnormalities: Semicircular Canal Dehiscence and Beyond. AJNR Am J Neuroradiol. 2016.

The authors of this study reviewed available scientific articles, rather than conducting an experiment. With that in mind, they provide several interesting facts and figures, the first of which is an image describing one of a few proposed EVA hearing loss mechanisms that you can see on [page 2 of the following]( http://www.ajnr.org/content/38/1/2.full). This mechanism suggests that, rather than sound waves only reaching the inner ear, sound waves propagate through the vestibular aqueduct as well.

Huang CJ, Lei TH, Chang WL, et al. A Novel mutation in the SLC26A4 gene in a Chinese family with Pendred syndrome. Int J Pediatr Otorhinolaryngol. 2013;77(9):1495-9.

Huang and colleagues report a new mutation of SLC26A4. They discuss the patient’s presentation--Pendred syndrome characterized by hearing loss, EVA, and thyroid gland enlargement--and then go on to discuss the genetics of SLC26A4. Part of their paper involves a figure that summarizes mutations seen in SLC26A4, of which there are more than one hundred. Despite the wide variety of potential mutations, though, the authors note that one specific mutation accounts for more than 80% of SLC26A4 mutations.

Jang JH, Jung J, Kim AR, et al. Identification of novel functional null allele of SLC26A4 associated with enlarged vestibular aqueduct and its possible implication. Audiol Neurootol. 2014;19(5):319-26.

Mutations in the SLC26A4 gene, which encodes pendrin, cause congenital hearing loss as a manifestation of Pendred syndrome (PS) with an iodide organification defect or nonsyndromic enlarged vestibular aqueduct (NSEVA, DFNB4). There have been reports of differences between PS and NSEVA, including their auditory phenotypes and molecular genetic bases. This study identified and evaluated a novel null mutation of SLC26A4 and assessed the pathogenic potential of mutations in SLC26A4, one of the most frequent causative genes of deafness in humans. A 3-year-old female with progressive sensorineural hearing loss and her parents were recruited. They underwent clinical, audiological, radiological and genetic evaluations, which revealed that the patient had an enlarged vestibular aqueduct and an incomplete partition type II anomaly in the cochlea bilaterally. Sequencing of the SLC26A4 gene was also performed.

Jung J, Seo YW, Choi JY, Kim SH. Vestibular function is associated with residual low-frequency hearing loss in patients with bi-allelic mutations in the SLC26A4 gene. Hear Res. 2016; 335:33-9.

This article shows that 22% of patients with EVA as a result of SLC26A4 mutation report balancing issues, despite 45% of patients testing positive for vertigo in one ear. They note that balance is related to hearing ability at low frequencies, but that their tests showed no relationship to genetic or anatomic factors.

Jung J, Suh MJ, Kim SH. Discrepancies between video head impulse and caloric tests in patients with enlarged vestibular aqueduct. Laryngoscope. 2016.
 
Kachniarz B, Chen JX, Gilani S, Shin JJ. Diagnostic yield of MRI for pediatric hearing loss: a systematic review. Otolaryngol Head Neck Surg. 2015;152(1):5-22.

The study is a meta-analysis including 29 studies that evaluated 2434 patients with MRIs and 1451 patients with CTs that met inclusion/exclusion criteria. There was a wide range of diagnostic yield from MRI. Heterogeneity among studies was substantial but improved with subgroup analysis. Meta-analysis of yield differences demonstrated that CT had a greater yield than MRI for enlarged vestibular aqueduct (yield difference 16.7% [95% CI, 9.1%-24.4%]) and a borderline advantage for cochlear anomalies (4.7% [95% CI, 0.1%-9.5%]). Studies were more likely to report brain findings with MRI.

Lee HJ, Jung J, Shin JW, et al. Correlation between genotype and phenotype in patients with bi-allelic SLC26A4 mutations. Clin Genet. 2014;86(3):270-5.

The authors of this paper sought to understand what happens when a person has two copies of a mutated gene that is associated with EVA. Because a gene can span a large sequence of DNA, the authors paid close attention to the particular location and type of mutation. They found a potential association between the specific types of mutation and levels of residual hearing, possibly paving the way for further studies into the relationship between types of mutations and hearing loss.

Li X, Zhou F, Marcus DC, Wangemann P. Endolymphatic Naz and Kz concentrations during cochlear growth and enlargement in mice lacking Slc26a4/pendrin. PLoS ONE. 2013;8(5):e65977.

Because EVA develops during pregnancy, understanding how inner ear structures develop could shed significant light on how to approach it. There are several reasons pointing to electrolyte (Na+, K+, Cl-, among others) concentrations as contributing factors: first, the ear is one of the only places in the body where there is a normally high concentration of K+. We can at least say that the ear is unique in its electrolyte concentrations. Second, and perhaps more importantly, a mutation that is strongly associated with EVA, SLC26A4, is an electrolyte transport protein. This means that it moves different salts into and out of cells. Because water follows salt concentrations, this could be a mechanism of inflating certain structures--that is, increase the salt concentration and let water push itself into a structure that needs to grow. The authors of this paper conclude that their data shows this salt-driven growth gets out of hand due to a loss of function of SLC26A4.

Liu Y, Wang L, Feng Y, et al. A New Genetic Diagnostic for Enlarged Vestibular Aqueduct Based on Next-Generation Sequencing. PLoS ONE. 2016;11(12):e0168508.

The authors of this study examined three genes in 46 different EVA-affected patients with the goal of developing a genetic test to identify EVA. These three genes are the most commonly-associated with EVA, and are called "SLC26A4", "FOXI1", and "KCNJ10". Their diagnostic test identified mutations in 87% of the subjects, and identified both maternal and paternal mutations in 59% of their population. Working on the assumption that two mutated copies is a stronger indicator of EVA, the authors conclude that their test can identify up to 59% of people with EVA solely using genetic data. This would open the door to EVA diagnosis before hearing loss is discovered, potentially allowing patients and healthcare providers to start thinking about EVA even before birth.

Maiolo V, Savastio G, Modugno GC, Barozzi L. Relationship between multidetector CT imaging of the vestibular aqueduct and inner ear pathologies. Neuroradiol J. 2013;26(6):683-92.

Here, Maiolo et al looked at previous clinical diagnoses in comparison to diagnoses using newer multidetector CT images. They looked at images of the temporal bones in 88 patients with cochleovestibular disorders (34 male, 54 female), ranging from seven to 88 years old. Each of these patients was divided into diagnostic classes, one of which was EVAS. In multidetector images of six patients who were clinically diagnosed with EVAS, vestibular aqueduct widths were all greater than 1.5mm. One patient with benign paroxysmal positional vertigo (BPPV) was found to have EVA, despite no previous clinical suspicions. In addition to enlarged vestibular aqueduct, the article found an association between narrowed vestibular aqueduct and Meniere’s disease. The article concludes that alterations of vestibular aqueducts are found in pathologies besides EVA, and that advanced imaging (such as multidetector CT) can help diagnose inner ear disorders.

Mey K, Bille M, Cayé-thomasen P. Cochlear implantation in Pendred syndrome and non-syndromic enlarged vestibular aqueduct – clinical challenges, surgical results, and complications. Acta Otolaryngol. 2016;136(10):1064-8.

For people with profound hearing loss, sometimes the best treatment is cochlear implantation. The authors of this work discuss their experiences performing cochlear implantation in 55 patients who had either Pendred or non-syndromic EVA. They note that 36% of implantations had complications, where 5% were major complications. In 10% of cases, the patients undergoing implantation had “gushing” or “oozing”, which the authors explain was associated with post-operative vertigo. For people with EVA who undergo cochlear implantation, this sort of information could be quite useful to set expectations and help guide decisions regarding cochlear implantation.

Miyagawa M, Nishio SY, Usami S. Mutation spectrum and genotype-phenotype correlation of hearing loss patients caused by SLC26A4 mutations in the Japanese: a large cohort study. J Hum Genet. 2014;59(5):262-8.

This is a large study that examines gene sequences of the SLC26A4 gene in 100 patients with bilateral EVA, selected from a larger group of 1511 patients registered in a Japanese hearing loss gene bank. The authors found that 82% of EVA patients had mutations in SLC26A4, and compared this finding to mutation rates among different ethnic populations. This high mutation rate is consistent with that found by other studies of east Asian populations, for example 97.9% in a Chinese cohort and 92% in a Korean cohort. In contrast, only 20% of Americans with EVA have SLC26A4 mutations. Further, still among patients with EVA, the mutations found in Asian populations are different than those found in Caucasian patients. The authors also conclude that, among the patients in this study, there appeared to be wide variation in hearing levels, even within the same genotypes.

Muskett JA, Chattaraj P, Heneghan JF, et al. Atypical patterns of segregation of familial enlargement of the vestibular aqueduct. Laryngoscope. 2015; Epub ahead of print.

Hearing loss associated with enlarged vestibular aqueduct may be inherited in an “autosomal recessive" pattern, notably via mutation of the SLC26A4 gene. The goal of this study was to characterize the genotypes and phenotypes of extended families with an atypical inheritance pattern. Evaluations included pure tone audiometry, temporal bone imaging, SLC26A4 genotype and haplotype analysis, and a pedigree analysis. One family had members with EVA caused by different etiologies. Two families had pseudo-dominant inheritance of recessive mutations. In five families, the etiology remained unknown. The main conclusions of this study were that familial EVA can demonstrate a variety of inheritance patterns, and that a pseudo-dominant inheritance may be more likely in families in which individuals have intermarried.

Musser AB, Golub JS, Samy RN, Phero JC. Intraoperative seizure and cerebrospinal fluid leak during adult cochlear implant surgery. Cochlear Implants Int. 2016; 17(2):116-9.

A seizure can be thought of as uncontrolled electrical activity pulsing through the central nervous system. Though the inner ear has a direct connection to the brain and central nervous system, it is very rare for a cochlear implant surgery patient to experience seizure. This case is notable for two points: first, the patient experienced a loss of the liquid that holds the brain and spinal cord in place, second, the patient experienced three seizures after inserting a cochlear implant and sealing the leak.

Inner ear images that were taken after surgery showed EVA, and also correct cochlear implant placement. Following this surgery, the patient didn’t display warning signs of seizure, and the cochlear implant was successfully activated.

Mutai H, Suzuki N, Shimizu A, et al. Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study. Orphanet J Rare Dis. 2013;8:172.

Next-generation gene sequencing involves rapid, accurate technologies for identifying genetic codes. Using this technique, Mutai et al looked at 84 genes from 58 patients with hearing loss, representing 15 unrelated families. The researchers made sure to include patients who don’t have well-established hearing-loss mutations, with the goal of identifying other potentially relevant genes; the cohort did not have GJB2 mutation, mitochondrial mutation, or EVA. By looking at genetic variation across the subjects and families, the authors concluded that the following genes are candidates for explaining rare hereditary hearing loss: ACTG1, POU4F3, DFNA5, SLC26A5, SIX1, MYO7A, CDH23, PCDH15, USH2A. This sort of discovery could help pave the way towards identifying other genetic causes of hearing loss.

Noguchi Y, Fukuda S, Fukushima K, et al. A nationwide study on enlargement of the vestibular aqueduct in Japan. Auris Nasus Larynx. 2017;44(1):33-39.

This is one of the largest studies of EVA, providing analysis of 380 patients' data from hospitals all over Japan. They were able to conclude that age greater than ten years, bilateral EVA, a history of head trauma, and Pendred syndrome were all significant risk factors for fluctuating hearing loss and vertigo or dizziness.

Noordman BJ, Van beeck calkoen E, Witte B, Goverts T, Hensen E, Merkus P. Prognostic factors for sudden drops in hearing level after minor head injury in patients with an enlarged vestibular aqueduct: a meta-analysis. Otol Neurotol. 2015;36(1):4-11.

The goal of this study was to identify factors associated with sudden drops in hearing level after minor head trauma in patients with an enlarged vestibular aqueduct (EVA). This is a meta-analysis with pooled data of 31 articles included 179 patients with 351 EVAs. Drops in hearing level after minor head trauma were experienced by 34% of the patients. A significant association between sudden deterioration of hearing after minor head trauma and preexisting fluctuating hearing loss (HL) (odds ratio, 8.6; p < 0.001; 95% confidence interval, 3.9-19.3) was found. The diameter of the VA, type of preexisting HL, severity of HL, preexisting progressive HL, and the diagnosis of Pendred syndrome were not significantly associated with sudden drops in hearing levels after head trauma. Only one-third of the patients with a proven EVA experienced sudden drops in hearing level because of head trauma. There is a significant association between preexisting fluctuating HL and the chance of sudden drops in hearing level caused by trauma. Stringent lifestyle advice, like avoiding activities with a risk of minor head trauma such as contact sports, might be restricted to patients with a fluctuating HL and those with a history of sudden drops on minor head trauma.

Oh JH, Chung JH, Min HJ, Cho SH, Park CW, Lee SH. Clinical Application of 3D-FIESTA Image in Patients with Unilateral Inner Ear Symptom. Korean J Audiol. 2013;17(3):111-7.

The purpose of this study was to introduce the clinical usefulness of three-dimensional fast imaging employing steady-state acquisition (3D-FIESTA) MRI in patients with unilateral ear symptoms. Patients with unilateral tinnitus or unilateral hearing loss who underwent 3D-FIESTA temporal bone MRI as a screening test were enrolled. The abnormal findings in the 3D-FIESTA images and ear symptoms using the medical records were reviewed. In patients with unilateral ear symptoms, 51.0% of the patients had tinnitus and 32.8% patients had sudden sensorineural hearing loss. With 3D-FIESTA imaging, twelve patients were diagnosed with acoustic neuroma, four with enlarged vestibular aqueduct syndrome, and two with posterior inferior cerebellar artery aneurysm. Inner ear anomalies and vestibulocochlear nerve aplasia could be diagnosed with 3D-FIESTA imaging. The study concluded that 3D-FIESTA imaging is a highly sensitive method for the diagnosis of cochlear or retrocochlear lesions. 3D-FIESTA imaging is a useful screening tool for patients with unilateral ear symptoms.

Okamoto Y, Mutai H, Nakano A, et al. Subgroups of enlarged vestibular aqueduct in relation to SLC26A4 mutations and hearing loss. Laryngoscope. 2014;124(4):E134-40.

The anatomy of EVA isn’t the same across all patients, so the goal of this study was to determine if there is any genetic basis for different types of anatomy. A cohort of 47 patients was examined, all of whom were diagnosed with EVA according to the standard CT imaging of the inner ear. Then, the researchers assigned patients into four groups by the location of anatomical difference: (1) aperture wider than the midpoint, (2) aperture and midpoint equally wide, (3) midpoint wider than aperture, and (4) borderline enlargement (less than 1.5mm). 44% of subjects fell into category 1; 11% into category 2; 9% into category 3; and 36% into category 4. 97% of subjects in categories 1, 2, and 3 tested positive for SLC26A4 mutation, compared to 39% of patients in category 4. The specific mutations and levels of hearing loss, however, did not significantly correlate to the patient category.

Palomeque vera JM, Platero sánchez-escribano M, Gómez hervás J, Fernández prada M, González ramírez AR, Sainz quevedo M. Cochlear implantation in patients with inner ear bone malformations with posterior labyrinth involvement: an exploratory study. Eur Arch Otorhinolaryngol. 2016;273(4):893-8. PMID: 25971996

In their article, “Cochlear implantation in patients with inner ear bone malformations with posterior labyrinth involvement”, Palomeque et al describe their cohort of five EVA patients, two patients with vestibular aqueduct stenosis, and three patients with semicircular canal disorders. The work was meant to discover differences in hearing ability after cochlear implantation for patients with inner ear bone malformation, though this work is explicitly labeled “exploratory” for its small sample size. In any case, the data showed benefit to all patients who were treated.

Pang X, Chai Y, Chen P, et al. Mono-allelic mutations of SLC26A4 is over-presented in deaf patients with non-syndromic enlarged vestibular aqueduct. Int J Pediatr Otorhinolaryngol. 2015;79(8):1351-3.

Recessive mutations of SLC26A4 are a major cause of hearing impairment associated with enlarged vestibular aqueduct (EVA). In a significant percentage of non-syndromic EVA patients, however, only mono-allelic mutations of SLC26A4 can be identified. The aim of this study was to evaluate whether the presence of mono-allelic mutations of SLC26A4 in those patients was coincidental or etiologically associated with the disorder. This was accomplished by sequencing the exons and flanking splicing sites of SLC26A4 in 150 Chinese Han deaf probands with non-syndromic EVA. Two frequent mutations of SLC26A4 in Chinese Hans, were screened by an allele-specific PCR-based array in 3056 ethnically-matched normal hearing controls. The frequency of mono-allelic mutations was determined in each group. Bi-allelic, mono-allelic and no mutation of SLC26A4 were detected in 98 (65.3%), 18 (12%) and 34 (22.67%) deaf probands with non-syndromic EVA, respectively. The frequency of mono-allelic mutations were significantly higher in the 150 deaf probands with non-syndromic EVA (8.67%) than in the 3056 normal hearing controls. The study concluded that the presence of mono-allelic mutations of SLC26A4 in non-syndromic EVA patients is etiologically associated with this disorder. Additional genetic or environmental causes may be present and further investigation would be helpful.

Park MK, Sagong B, Lee JD, et al. A1555G homoplasmic mutation from A1555G heteroplasmic mother with Pendred syndrome. Int J Pediatr Otorhinolaryngol. 2014;78(11):1996-9.

The study evaluated a young woman presenting with bilateral progressive moderate HL with delayed language development, along with her family. Hearing test, temporal bone CT, and genetic evaluation of GJB2, MT-RNR1, SLC26A4 gene mutations were performed on each family member. Her mother was prelingually deaf and displayed enlarged vestibular aqueduct (EVA) along with goiter. The subject's mother showed both SLC26A4 mutation and mitochondrial A1555G heteroplasmic mutation at the same time. The sisters did not display EVA or goiter. Although the subject's older sister showed both prelingual deafness and mitochondrial A1555G heteroplasmy, her younger sister showed only A1555G homoplasmy, which suggests A1555G homoplasmy as the genetic cause of hearing loss. This is the first report of HL caused by mitochondrial A1555G homoplasmy from a mother with Pendred syndrome coexistent with A1555G heteroplasmy in the Korean population.

Pritchett C, Zwolan T, Huq F, et al. Variations in the cochlear implant experience in children with enlarged vestibular aqueduct. Laryngoscope. 2015;125(9):2169-74.

The study describes the clinical experience and outcomes of cochlear implantation (CI) in children with isolated enlarged vestibular aqueduct (IEVA) vs. children with enlarged vestibular aqueduct (EVA) associated with other bony labyrinth abnormalities. The clinical course and outcomes of 55 children with EVA undergoing CI between 1991 and 2013 were reviewed. Test measures included speech perception tests, and various speech and language measures. In 18 children (32.7%), IEVA was the only defect present. In 33 children (60%), EVA occurred concomitantly with incomplete partition type 2 (IP 2) bilaterally, and three children with incomplete partition type 1 bilaterally. Ninety-two percent (51 of 55) occurred bilaterally and had matching bony defects. Mean age of CI was 73.4 months. A statistically significant defect-related and linguistic-status pattern was noted. IEVA children demonstrated superior performance on speech perception tests and speech and language tests. The study concluded that children with hearing loss secondary to EVA respond well to cochlear implantation. However, the severity of temporal bone anomalies in these children has clinical relevance.

Prosser JD, Cohen AP, Greinwald JH. Diagnostic Evaluation of Children with Sensorineural Hearing Loss. Otolaryngol Clin North Am. 2015;48(6):975-82.

This article provides an overview of the typical diagnostic workup for a child with SNHL. Typically, patients undergo thorough otolaryngologic and audiometric evaluations, including laboratory tests and temporal bone imaging. These tests may prompt additional consultation with geneticists or ophthalmologists. A sequential diagnostic approach (outlined in the article) has been shown to be both prudent and cost-effective. While a definitive cause is still being established, hearing amplification and a comprehensive treatment plan are noted as the best way to avoid developmental delay and missed milestones. For patients whose EVA is identified on the temporal bone imaging, the authors advocate genetic testing for mutations in the SLC26A4 gene.

Qing J, Zhou Y, Lai R, et al. Prevalence of mutations in GJB2, SLC26A4, and mtDNA in children with severe or profound sensorineural hearing loss in southwestern China. Genet Test Mol Biomarkers. 2015;19(1):52-8.

The paper studies the distribution characteristics of common mutations in the GJB2, SLC26A4, and mtDNA genes in children with severe or profound sensorineural hearing loss (SNHL) in southwestern China. A total of 1,164 individuals were recruited to screen for the common mutations. All mutations were analyzed in association with medical imaging. In this study, 28.43% of all subjects carried mutations. The mutation frequencies in the GJB2, SLC26A4, and mtDNA genes were 17.27%, 7.04%, and 4.12%, respectively. The frequency of the GJB2 mutations in urban as opposed to suburban groups was 23.38% and 15.99%, respectively. The enlarged vestibular aqueduct (EVA) was the most common inner ear malformation and ∼79.10% of EVA cases were associated with the SLC26A4 mutations. The study concluded that more than one-fourth of children with severe or profound SNHL carried the common deafness mutations. The proportions of ethnic minorities and urban subjects could impact the frequency of the GJB2 and mtDNA mutations. The SLC26A4 hotspot mutations are prevalent and correlate strongly with EVA.

Rah YC, Kim AR, Koo JW, Lee JH, Oh SH, Choi BY. Audiologic presentation of enlargement of the vestibular aqueduct according to the SLC26A4 genotypes. Laryngoscope. 2015;125(6):E216-22.

The study looks to determine the distribution of the number and types of mutant alleles of SLC26A4 and their correlations with hearing phenotypes in Korean bilateral enlargement of vestibular aqueduct (EVA) patients. The SLC26A4 gene was sequenced for 56 patients with bilateral EVA, and the relationships of these sequences to hearing ability were analyzed based on 0.5-, 1-, 2-, and 3-kHz air conduction averages of pure-tone audiometry. Most patients with bilateral EVA (83.9%) carried two mutant versions of SLC26A4 (“M2”), and all others (16.1%) had only one detectable mutant allele of SLC26A4 (“M1”). There was no significant difference in hearing threshold, progression, or fluctuation of hearing level between the M1 and M2 groups. However, focusing on the type of mutations exclusively in the M2 group, some mutations were associated with more frequent progression of hearing loss during the follow-up period. The study concluded that the auditory phenotype of Korean bilateral EVA patients is more strongly correlated with the type rather than the number of mutations in SLC26A4.

Roberts DM, Bush ML, Jones RO. Adult progressive sensorineural hearing loss: is preoperative imaging necessary before cochlear implantation? Otol Neurotol. 2014;35(2):241-5.

Before many surgeries, it is common to do imaging studies such as x-ray or CT scans to make sure the patient is a good candidate for that surgery. On the other hand, these imaging techniques incur significant cost and exposure to ionizing radiation. The purpose of this retrospective study was to examine whether a specific set of low-risk patients benefit from cochlear implant preoperative imaging. The authors answered this question by comparing cochlear implant surgeries with and without preoperative imaging in terms of whether there was an abnormal event during surgery. They found that, for patients who are over 21 years of age, have progressive hearing loss, a history of COM or no otologic history, that it may not be necessary to perform imaging before cochlear implantation. As far as potential applicability to EVA, the article does recommend that patients who are less than 21 years old or who have congenital hearing loss proceed to imaging prior to surgery.

Roesch S, Moser G, Rasp G, Tóth M. CT-scans of cochlear implant patients with characteristics of Pendred syndrome. Cell Physiol Biochem. 2013;32(7):166-72.

This study sought to understand the reasons why patients develop sensorineural hearing loss (SNHL) by screening 75 cochlear implant patients for EVA and another condition, “Mondini malformation” (MM), using MRI and CT imaging of the temporal bone. MM was also examined because, like EVA, MM is a known potential sign of EVA. Of the 75 cochlear implant patients who participated, three had only EVA (4%), two had only MM (2.7%), and one had both EVA and MM (1.3%). Given these results, the authors recommend further thyroid function surveillance in this patient population.

Rose J, Muskett JA, King KA, et al. Hearing loss associated with enlarged vestibular aqueduct and zero or one mutant allele of SLC26A4. Laryngoscope. 2017;127(7):E238-E243.

Even though the genetics of EVA are very complex, we have been able to identify some of its associated genetic mutations. One of the genes that has been repeatedly identified is called "SLC26A4", which codes for a protein called "pendrin". We have two copies of every gene, one from the mother and the other from the father, so we can have zero, one, or two mutated copies of SLC26A4. This study identified that EVA patients with zero SLC26A4 mutations have a pure-tone average of 62.6 dB, people with one SLC26A4 mutation have a pure-tone average of 52.9 dB, and people with two SLC26A4 mutations have a pure-tone average of 88.1 dB. Notably, they did not find any association between the number of copies and hearing loss progression.

Sagong B, Baek JI, Lee KY, Kim UK. A Novel Frameshift Mutation of SLC26A4 in a Korean Family With Nonsyndromic Hearing Loss and Enlarged Vestibular Aqueduct. Clin Exp Otorhinolaryngol. 2016.

In this study, Sagong and coauthors examine the SLC26A4 gene sequence of two siblings with bilateral profound and severe hearing loss, compared to their parents' and non-hearing-loss subjects' copies of SLC26A4. Each of the children's parents were carriers for an SLC26A4 mutation, but the authors report that one of these mutations is likely the cause of hearing loss. In addition to the 170 mutations already known, these children had a never before seen mutation that makes a significant contribution to medical knowledge of EVA.

Seo YJ, Kim J, Choi JY. Correlation of vestibular aqueduct size with air-bone gap in enlarged vestibular aqueduct syndrome. Laryngoscope. 2015; Epub ahead of print.

This paper examines the relationship between diameter of VA and degree of air bone gap on audiometric testing. 98 ears in 49 patients with Pendred syndrome were studied by measuring the VA at the fundus, midpoint, and porous width and correlating with air bone gap. They found that patients with an air bone gap have larger diameters of the VA. The hypothesis and conclusion were that an EVA introduces a third mobile window into the inner ear, resulting in the low frequency air-bone gap.

Suzuki M, Ota Y, Tanaka T, Ota Y. Lateral Semicircular Canal-enlarged Vestibular Aqueduct Fistula Associated With Paroxysmal Positional Nystagmus. Otol Neurotol. 2015.

A case report of a 48 year old man with bilateral congenital hearing loss. He had a five year history of hearing loss and paroxysmal vertigo, from the sitting to supine position. The episodes also occurred while lifting heavy objects. He had bilateral sensorineural hearing loss. ENG was abnormal, depending on his position. His MRI showed bilateral Mondini malformations. There was a fistula between a right semicircular canal defect and an EVA. This study is important because cases can indicate what is or is not possible, as opposed to larger population studies that indicate what to expect on average.

Tamplen M, Schwalje A, Lustig L, Alemi AS, Miller ME. Utility of preoperative computed tomography and magnetic resonance imaging in adult and pediatric cochlear implant candidates. Laryngoscope. 2015; Epub ahead of print.

This study was a retrospective review of 121 patients (101 adults and 20 children) who underwent cochlear implantation. Preoperative CT was obtained in 110 patients, MRI in 102, and both in 94. 2.0% of the adult patients were noted to have EVA on MRI. Three out of 20 pediatric patients had EVA on CT imaging. The authors noted that, “Both CT and MRI can identify anomalies in pediatric patients. MRI does not offer substantial benefit over CT for routine evaluation of pediatric inner ear and temporal bone anatomy." We included this article because of the previous statement--this study explains that neither imaging technique is better than the other for EVA diagnosis.

Van nierop JW, Huinck WJ, Pennings RJ, Admiraal RJ, Mylanus EA, Kunst HP. Patients with Pendred syndrome: is cochlear implantation beneficial? Clin Otolaryngol. 2016;41(4):386-94.

Some patients who have EVA also have another health issue called “Pendred syndrome”. This is when a patient has a mutation in a gene (SLC26A4) that encodes the protein called “pendrin”. Unfortunately, EVA symptoms affect patients with Pendred syndrome more so than those patients who do not have Pendred syndrome.

This article demonstrates that, in hearing tests after cochlear implantation, Van nierop and his co-authors found no difference between EVA with or without Pendred syndrome.

Wendt WJ, Hashikawa A. Enlarged Vestibular Aqueduct Syndrome: Sudden Hearing Loss in a Child with a Cerebral Shunt. Pediatr Emerg Care. 2017.

These authors present the case of a patient born with ventriculoperitoneal shunt (this is when someone has a hole leaking brain/spinal cord fluid into the belly) who developed sudden hearing loss at age 4 without any history of trauma or infection. This child's case is interesting because it offers evidence that the typical EVA patient's hearing loss occurs between ages 1 and 5, even if they have spinal cord fluid pressure under close watch and control.

Wieczorek SS, Anderson ME, Harris DA, Mikulec AA. Enlarged vestibular aqueduct syndrome mimicking otosclerosis in adults. Am J Otolaryngol. 2013;34(6):619-25.

This article is notable for its discussion of newly-diagnosed EVA causing hearing loss in adults, where the hearing loss deceptively appears to be caused by hardening of the middle ear bones. The authors state that the article represents the “longest reported audiometric follow up of an individual with EVA”, referring to one of the cases whose audiograms were available dating back to the 1960s. In their discussion, they note that universal newborn hearing screening and high-resolution CT scanning has allowed for routine diagnosis of EVA since the 1990s. Therefore, there may be a cohort of adults born before 1990 whose EVA will present later in life, potentially mimicking other diagnoses.

Yamazaki H, Naito Y, Moroto S, et al. SLC26A4 p.Thr410Met homozygous mutation in a patient with a cystic cochlea and an enlarged vestibular aqueduct showing characteristic features of incomplete partition type I and II. Int J Pediatr Otorhinolaryngol. 2014;78(12):2322-6.

Mutations of SLC26A4 are associated with incomplete partition type II (IP-II) and isolated enlargement of the vestibular aqueduct (EVA). This is a case report of a congenitally deaf 6-year-old boy with a rare p.Thr410Met homozygous mutation in SLC26A4 who underwent bilateral cochlear implantation. He had bilateral inner ear malformation, in which the dilated vestibule and EVA were identical to those in IP-II, but the cochlea lacking a bony modiolus resembled that in incomplete partition type I. These results suggest that homozygous mutations in SLC26A4 are always associated with EVA, while the severity of cochlear malformation may vary depending on the type of SLC26A4 mutation.

Yang CJ, Lavender V, Meinzen-derr JK, et al. Vestibular pathology in children with enlarged vestibular aqueduct. Laryngoscope. 2016;126(10):2344-50.

The title of this article begins with “vestibular pathology”, which means any disease or problem associated with the balance organs of the inner ear. Because EVA is an inner ear malformation, it follows that there might also be issues with the balance sensors of the inner ear.

This is a strong study because the authors decided to test each of the patients specifically for research purposes before any data was collected (this is called “prospective”) instead of relying on medical record information. The authors found that 24 of 27 patients with EVA showed signs of balance problems, and that vestibular aqueduct width was related to the extent of balance problems.

Yao J, Qian X, Bao J, et al. Probing the Effect of Two Heterozygous Mutations in Codon 723 of SLC26A4 on Deafness Phenotype Based on Molecular Dynamics Simulations. Sci Rep. 2015;5:10831.

A Chinese family was identified with clinical features of enlarged vestibular aqueduct syndrome (EVAS). The mutational analysis showed that the proband had EVAS with bilateral sensorineural hearing loss and carried a rare compound heterozygous mutation of SLC26A4 which was inherited from the same mutant alleles of a heterozygous father and a heterozygous mother. Compared with another confirmed pathogenic biallelic mutation in SLC26A4, these two biallelic mutations shared one common mutant allele and the same codon of the other mutant allele, but led to different changes of amino acid and both resulted in the deafness phenotype. Structure-modeling indicated that these two mutant alleles changed the shape of pendrin protein encoded by SLC26A4 with increasing randomness in conformation, and might impair pendrin's ability as an anion transporter. The molecular dynamics simulations also revealed that the stability of mutant pendrins was reduced with increased flexibility of backbone atoms, which was consistent with the structure-modeling results. These evidences indicated that codon 723 was a hot-spot region in SLC26A4 with a significant impact on the structure and function of pendrin, and acted as one of the genetic factors responsible for the development of hearing loss.

Yazdanpanahi N, Tabatabaiefar MA, Bagheri N, Azadegan dehkordi F, Farrokhi E, Hashemzadeh chaleshtori M. The role and spectrum of SLC26A4 mutations in Iranian patients with autosomal recessive hereditary deafness. Int J Audiol. 2015;54(2):124-30.

The study attempts to determine the prevalence and types of SLC26A4 mutations and the relevant phenotypes in a series of Iranian deaf patients. The results probably suggest a high prevalence and specificity of SLC26A4 mutations among Iranian deaf patients. Molecular study of SLC26A4 may lead to elucidation of the population-specific mutation profile which is of importance in diagnostics of deafness.

Zalewski CK, Chien WW, King KA, et al. Vestibular Dysfunction in Patients with Enlarged Vestibular Aqueduct. Otolaryngol Head Neck Surg. 2015;153(2):257-62.

This study examines the effects of EVA on the vestibular system in patients with EVA. A prospective, cross-sectional study of a cohort from 1999 to 2013. In total, 106 patients with unilateral or bilateral EVA, participated in a study of the clinical and molecular aspects of EVA. Clinical history was ascertained with respect to the presence or absence of various vestibular signs and symptoms and history of head trauma. Videonystagmography (VNG), cervical vestibular evoked myogenic potential (cVEMP), and rotational vestibular testing (RVT) were performed to assess the vestibular function. Of the patients with EVA, 45% had vestibular signs and symptoms, and 44% of tested patients had abnormal VNG test results. An increased number of vestibular signs and symptoms was correlated with the presence of bilateral EVA (P = .008) and a history of head injury (P < .001). Abnormal VNG results also correlated with a history of head injury (P = .018). The study concluded that vestibular dysfunction is common in patients with EVA. However, not all patients with vestibular signs and symptoms have abnormal vestibular test results. Clinicians should be aware of the high prevalence of vestibular dysfunction in patients with EVA.

Zhang F, Bai X, Xiao Y, et al. Identification of a novel mutation in SLC26A4 gene in a Chinese family with enlarged vestibular aqueduct syndrome. Int J Pediatr Otorhinolaryngol. 2016;85:75-9.

Two generations of a Chinese family were found to have EVA, so scientists looked at the sequences of that family’s genes and found a new mutation that can contribute to understanding EVA and even Pendred Syndrome. This mutation is notable because it is rarely seen across even very different mammals (frogs and dogs do not even have this mutation, for example). Seeing this mutation in two generations of a family with EVA could help doctors better understand how different mutations contribute to EVA.

Zhao FF, Lan L, Wang DY, et al. Correlation analysis of genotypes, auditory function, and vestibular size in Chinese children with enlarged vestibular aqueduct syndrome. Acta Otolaryngol. 2013;133(12):1242-9.

A recently-developed technique called “exome sequencing” was used to examine the sequences of SLC26A4 genes in patients with a history of insufficient thyroid development. Two patients were found to have two copies for the mutated gene, one from each parent. Previously, each of those patients had been noted to have EVAS and non-syndromic hearing loss. The authors conclude that, for patients with insufficient thyroid development, it is important to check this gene for mutation. Further, this study emphasizes that mutations in the SLC26A4 gene can lead to a variety of outcomes.

Zhou YJ, Wu YZ, Cong N, et al. Contrasting results of tests of peripheral vestibular function in patients with bilateral large vestibular aqueduct syndrome. Clin Neurophysiol. 2017;128(8):1513-1518.

This study reports that people with bilateral EVA have abnormal balance sensation test results. The authors explain that there is too much excitability in one area of the inner ear (called otolithic organs) and not enough excitability in another area (called the semicircular canals). Either one of these dysfunctional sensory organs could contribute to balance issues, so this article is particularly important because it helps characterize the specific issues faced by people with EVA.

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