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Background: Marshall syndrome is a dominant disorder characterized by craniofacial and skeletal abnormalities, sensorineural hearing loss, myopia, and cataracts, and is associated with splicing mutations in COL11A1. Objective: To determine the auditory and vestibular phenotypes associated with a COL11A1 splicing. Design: Clinical otolaryngologic, audiologic, vestibular, and radiologic evaluations of the auditory and vestibular systems. Subjects: Three affected individuals from a family cosegregating Marshall syndrome and a COL11A1 splice site mutation. Results: The study subjects have progressive sensorineural hearing loss that is predominantly cochlear in origin and asymptomatic dysfunction of the central and peripheral vestibular systems. Computed tomography detected no malformations of temporal bone structures. Conclusions: The observed auditory and vestibular abnormalities are not caused by defective morphogenesis of the osseous labyrinth, but by more direct effects of the COL11A1 mutation on the membranous labyrinth and the central nervous system. The onset and degree of hearing loss associated with COL11A1 mutations are useful clinical features to differentiate Marshall syndrome from the phenotypically similar Stickler syndrome. [ABSTRACT FROM AUTHOR]

Importance: Approximately one-half of all subjects with unilateral or bilateral hearing loss with enlargement of the vestibular aqueduct (EVA) will have SLC26A4 gene mutations. The number (0, 1, or 2) of mutant alleles of SLC26A4 detected in an individual subject with EVA is each associated with a distinct combination of diagnostic and prognostic information as well as probability of recurrence of EVA in siblings., Objective: To evaluate the results of SLC26A4 mutation testing in subjects with unilateral EVA. (The study objective was formulated before data were collected.), Design: Prospective cross-sectional study of cohort ascertained between 1998 and 2012., Setting: National Institutes of Health Clinical Center, a federal biomedical research facility., Participants: Twenty-four subjects (10 males, 14 females) with unilateral EVA, defined as a midpoint diameter greater than 1.5 mm, who were referred or self-referred to participate in a study about the clinical and molecular analysis of EVA. Twenty-one (87.5%) of 24 subjects were white. Mean age was 10.3 years (age range, 5-39 years)., Intervention: SLC26A4 mutation analysis., Main Outcomes and Measures: Audiometric results, the presence or absence of EVA, and the number of mutant alleles of SLC26A4., Results: Approximately 8.3% of the subjects with unilateral EVA had 2 mutant SLC26A4 alleles, 16.7% had 1 mutant allele, and 75.0% had 0 mutant alleles., Conclusions and Relevance: Unilateral EVA can be associated with all possible SLC26A4 genotype results. The distinct combination of prognoses and recurrence probability associated with each genotype supports the clinical use of testing for SLC26A4 mutations in subjects with unilateral EVA.

Objective: To evaluate thyroid structure and function in patients with enlargement of the vestibular aqueduct (EVA) and sensorineural hearing loss., Design: Prospective cohort survey., Setting: National Institutes of Health Clinical Center, a federal biomedical research facility., Patients: The study population comprised 80 individuals, aged 1.5 to 59 years, ascertained on the basis of EVA and sensorineural hearing loss., Main Outcome Measures: Associations among the number of mutant alleles of SLC26A4; volume and texture of the thyroid; percentage of iodine 123 ((123)I) discharged at 120 minutes after administration of perchlorate in the perchlorate discharge test; and peripheral venous blood levels of thyrotropin, thyroxine, free thyroxine, triiodothyronine, thyroglobulin, antithyroid peroxidase and antithyroglobulin antibodies, and thyroid-binding globulin., Results: Thyroid volume is primarily genotype dependent in pediatric patients but age dependent in older patients. Individuals with 2 mutant SLC26A4 alleles discharged a significantly (P < or = .001) greater percentage of (123)I compared with those with no mutant alleles or 1 mutant allele. Thyroid function, as measured by serologic testing, is not associated with the number of mutant alleles., Conclusions: Ultrasonography with measurement of gland volume is recommended for initial assessment and follow-up surveillance of the thyroid in patients with EVA. Perchlorate discharge testing is recommended for the diagnostic evaluation of patients with EVA along with goiter, nondiagnostic SLC26A4 genotypes (zero or 1 mutant allele), or both.

Objective: To determine whether congenital cytomegalovirus (CMV) infection is an etiologic factor in the pathogenesis of enlarged vestibular aqueducts (EVA)., Design: Two different cohort studies. Subjects The study population comprised 19 subjects with a history of congenital CMV infection and sensorineural hearing loss (cohort 1); 39 subjects with nonsyndromic EVA and their unaffected mothers (cohort 2); and 16 control subjects with EVA associated with Pendred syndrome and bi-allelic mutations of the SLC26A4 gene and their unaffected mothers., Results: In cohort 1, we detected EVA in 0 of 19 subjects with congenital CMV infection and sensorineural hearing loss. In cohort 2, anti-CMV serologic profiles were consistent with possible congenital CMV infection in 10 (26%) of 39 subjects with nonsyndromic EVA and 6 (38%) of 16 control subjects with Pendred syndrome (P = .52). These seroprevalence rates are similar to those expected in the general population (40%)., Conclusion: In spite of their auditory phenotypic similarities, congenital CMV infection is not a significant factor in the etiology of EVA.