2017 Sec 1 Green Book

EVA and proposed that EVA was a congenital malforma- tion of the temporal bone that predisposes affected individuals to the early onset of hearing loss and vestibu- lar disturbance. Valvassori and Clemis, as well as other authors, maintained that enlargement of the endolym- phatic sac and duct is the underlying process causing the bony change of the vestibular aqueduct. 7–9 Spiegel and Lalwani proposed that the underlying pathophysiology of EVA is similar to that of endolymphatic hydrops. 10 EVA was initially defined as a vestibular aqueduct > 1.5 mm at the midpoint. 6 This measurement was based on polytomographic studies, which are somewhat crude in comparison to our current technology. Although early generation CT scans allowed for a clearer view of the vestibular aqueduct, the advent of high-resolution CT per- mitted more accurate and quantifiable aqueduct assessment; this enabled researchers to distinguish between normal and enlarged aqueducts. In view of this technological advancement, Vijayasekaran et al. were able to specifically define EVA. 11 Using a standardized measure- ment algorithm, they studied 73 children with normal hearing and determined a normal vestibular aqueduct mid- point to be at 0.9 mm and a normal vestibular aqueduct operculum to be 1.9 mm. These measurements have since been used as the radiographic standard for defining EVA. The otologic phenotype of EVA is exceedingly vari- able. This phenotype can be associated with fluctuating and progressive hearing loss 12,13 as well as disequili- brium and vertigo. 14 The age at diagnosis of the hearing loss ranges from infancy to adulthood. The reported se- verity of hearing loss ranges from normal hearing (rare) to profound hearing loss, which is usually bilateral. 15,16 Although unilateral hearing loss in patients with EVA has been reported, 12,17,18 it is not well described. Pre- ciado et al. 19 found that the diagnostic yield of imaging studies in children with EVA was significantly higher in those with unilateral vs. bilateral SNHL. In patients with bilateral SNHL, there was a statistically significant trend toward a higher prevalence of EVA with increasing severity of the hearing loss. No specific analysis was per- formed on patients with unilateral EVA in this study. A conductive component of the hearing loss has been observed at 250 Hz, despite a clinically normal middle ear and tympanogram. 9,12,20 The prevalence of an accompanying low-frequency conductive or mixed hearing loss ranges from 28% to 80% of ears with EVA. 7,12,20 Although the clinical sig- nificance of the conductive component is unknown, some investigators have proposed that it may represent the audio- logic effect of a third inner ear window. 20 Others have suggested that it may represent an inherent increased stiff- ness of the ossicles due to the inner ear fluid disturbance. 5,20 The prevalence of progressive SNHL in patients with EVA varies from 12% to 65%. 9,12,13,16,21 Hearing loss pro- gression can occur in a stepwise fashion over a prolonged period of time, or suddenly, after minor head trauma, baro- trauma, or in idiopathic SNHL. In a seminal study, Boston et al. 9 found a linear relationship between the size of the aqueduct and the likelihood of hearing loss progression. Additionally, these authors found that the presence of a low-frequency conductive hearing loss was associated with an increased risk of hearing loss progression.

The most common genetic etiology for EVA is muta- tions in the SLC26A4 gene (also known as PDS ). 22 This gene produces a protein called pendrin, which is responsi- ble for iodine and chloride ion transport in the inner ear and thyroid gland. Biallelic mutations in SLC26A4 cause Pendred syndrome and are present in 10% to 20% of patients with EVA. 23,24 Patients with this syndrome typi- cally have severe to profound hearing loss and inner ear anomalies such as EVA; they can also develop a thyroid goiter and hypothyroidism. Single SLC26A4 mutations have been found in 15% to 20% of patients with EVA. These patients typically have a less severe hearing pheno- type than patients with Pendred syndrome, have less severe abnormalities of the vestibular aqueduct, and have no thyroid dysfunction. It has been proposed that sequence changes in other gene(s) interact with the single mutations in SLC26A4 . 23–25 Recently, mutations have been identified in FOXI1 , which reduce the transcription of SLC26A4 , resulting in an EVA phenotype. 26 Mutations in the KCNJ10 gene have also been implicated in EVA when present in combination with SLC26A4 heterozy- gotes. 27 Additionally, EVA has been associated with disorders such as CHARGE syndrome, 28 Waardenburg syndrome, 29 and branchio-otorenal syndrome. 30 Children with bilateral EVA and any SLC26A4 muta- tions are more likely to have greater aqueduct enlargement and are more likely to experience progression of hearing loss. 25 Data pertaining to the prevalence of SLC26A4 muta- tions in patients with unilateral EVA is scant. Berrettini et al. 18 reported on two patients with unilateral EVA who did not have mutations in SLC26A4 . Consistent with this finding, Madden et al. 25 observed a lower prevalence of these mutations in a clinical population of patients with unilateral EVA than in those with bilateral EVA. In a review of studies investigating patients with EVA, Zalzal et al. 12 found that reported prevalence rates of unilateral EVA ranged from 6% to 40%. 7,31 Although unilateral EVA is not uncommon, its audiometric and temporal bone phenotype, natural history, and genetic etiology are not well understood. This gap in knowledge creates several problematic clinical questions: 1) How should families be counseled in regard to their child’s hearing loss and imaging findings?; 2) How should patients be monitored in regard to their hearing loss and the potential risk of disease progression?; and 3) What is the positive predictive value of genetic testing? In light of these issues, the purpose of the current study was to describe the clinical phenotype of patients with unilateral EVA and then to compare the findings to two clinically related phenotypes: bilateral EVA and unilateral hearing loss without EVA. Taking into account our clinical observations and the aforementioned data, we hypothesized that patients with unilateral EVA would have a much higher rate of contralateral hearing loss than patients with unilateral hearing loss without EVA. MATERIALS AND METHODS Enlarged Vestibular Aqueduct Population We performed a database search of all children seen at our center who were diagnosed with EVA or unilateral hearing

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