Clinical and Genetic Analysis of Enlarged Vestibular Aqueducts

Clinical and Molecular Analysis of Enlarged Vestibular Aqueducts

This study will try to identify and understand the genetic factors that lead to an inner ear malformation called "enlarged vestibular aqueducts", that can be associated with hearing loss.

Patients with sensorineural hearing loss with or without inner ear malformations and their parents and siblings may be eligible for this study. Participants and their immediate family members, may undergo some or all of the following tests and procedures:

• Medical and family history, including questions about hearing, balance and other ear-related issues, and review of medical records.
• Routine physical examination.
• Blood draw or buccal swab (brushing inside the cheek to collect cells) - Tissue is collected for DNA analysis to look for changes in genes that may be related to hearing loss.
• Hearing tests - The subject listens for tones emitted through a small earphone.
• Balance test (VEMP) to see if balance functions of the inner ear are associated with the hearing loss Electrodes will be placed behind your ear and at the base of your neck. From a reclining position, you will be asked to raise your head while clicking sounds are played into your ears. - Ultrasound tests - An inner ear malformation called EVA (enlargement of the vestibular aqueduct) indicates that a genetic disorder called Pendred syndrome may be the cause. Because thyroid abnormalities are also associated with Pendred syndrome, an ultrasound examination of the thyroid gland may be done.
• Computed tomography (CT) and magnetic resonance imaging (MRI) scans - These tests show the structure of the inner ear. For CT, the subject lies still for a short time while X-ray images are obtained. For MRI, the patient lies on a stretcher that is moved into a cylindrical machine with a strong magnetic field. The magnetic field and radio waves produce images of the inner ear. The radio waves cause loud thumping noises that can be muffled by the use of earplugs.

Study Overview

• Status: Completed
• Conditions: Sensorineural Hearing Loss; Cytomegalovirus Infection

Detailed Description

Nonsyndromic hereditary hearing impairment is a genetically heterogeneous disorder that can be caused by mutations in any one of at least 60 different genes. Enlargement of the vestibular aqueduct (EVA) is a radiologic finding known to be associated with mutations in one of these genes, the Pendred syndrome gene (SLC26A4, formerly known as PDS). EVA may thus serve as a clinically useful marker to facilitate the diagnosis of hearing impairment. Recent data from our laboratory and others indicates that only a subset of individuals with EVA have SLC26A4 mutations, and therefore some EVA cases are likely to be caused by other genes, nongenetic factors, or a combination of these etiologies. Families with two or more individuals with hearing impairment and EVA will be enrolled in this study in order to identify other genetic factors that cause EVA. Siblings and parents may also be enrolled in order to define inheritance and to perform molecular genetic analyses.

• Study Type: Observational
• Enrollment (Actual): 324

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 99 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Affected and non-affected family members and affected single sporadic subjects with sensorineural hearing loss and enlarged vestibular aqueducts.

Description

• INCLUSION CRITERIA:

Subjects must have or be a family member of a participant with known or non-syndromic SNHL associated with EVA or have evidence of other findings that suggest that EVA might be part of a novel phenotype

There must be at least two participating affected family members with one exception: if there is only one participating affected family member, there must be genetic test results identifying only one pathogenic mutant allele of SLC26A4

Adults must be able to provide informed consent

Minors must have a parent or guardian able to provide consent

Age between 0-99.

EXCLUSION CRITERIA:

Subjects with known exposure to physical or chemical teratogens in utero that could account for their inner ear malformations such as thalidomide or radiation

Any hearing loss that is associated with symptoms which meet the criteria of already known syndromes, such as, branchio-oto-renal (BOR) syndrome, which comprises system malformations and branchial cleft abnormalities and is caused by heterozygous mutations in the EYA1 gene.

Previous genetic testing identifying two pathogenic mutant alleles of SLC26A4.

Prospective study subjects who are cognitively impaired and lack consent capacity, will not be enrolled.

Study Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
1; Patients with known or suspected nonsyndromic SNHL associated with EVA
2; Patients with nonsyndromic EVA
3; unaffected siblings and parents of affected family members
4; Other unaffected relatives; included if there is more than one sibship with affected family

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
By using genetic linkage, identify and map possible additional mutant alleles of SLC26A4 or other genes causing nonsyndromic EVA in patients with one or no detectable mutant allele of SLC26A4	Identify genes other than SLC26A4 that cause EVA.	ongoing

Collaborators and Investigators

• Sponsor: National Institute on Deafness and Other Communication Disorders (NIDCD)
• Investigators: Principal Investigator: Thomas B Friedman, Ph.D., National Institute on Deafness and Other Communication Disorders (NIDCD)

Publications and helpful links

General Publications

• Bauman NM, Kirby-Keyser LJ, Dolan KD, Wexler D, Gantz BJ, McCabe BF, Bale JF Jr. Mondini dysplasia and congenital cytomegalovirus infection. J Pediatr. 1994 Jan;124(1):71-8. doi: 10.1016/s0022-3476(94)70256-x.
• Dahle AJ, Fowler KB, Wright JD, Boppana SB, Britt WJ, Pass RF. Longitudinal investigation of hearing disorders in children with congenital cytomegalovirus. J Am Acad Audiol. 2000 May;11(5):283-90.
• Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazani E, Nassir E, Baxevanis AD, Sheffield VC, Green ED. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet. 1997 Dec;17(4):411-22. doi: 10.1038/ng1297-411.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2001

Study Registration Dates

• First Submitted: August 21, 2001
• First Submitted That Met QC Criteria: August 21, 2001
• First Posted (Estimated): August 22, 2001

Study Record Updates

• Last Update Posted (Estimated): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: June 27, 2023

More Information

Terms related to this study

• Keywords: Genetics; Natural History; Genetic Markers; Deafness; Hearing Impairment; SNHL; Genetic Analysis; GENETIC LINKAGE; Nonsyndromic Hereditary Hearing Impairment; Inner Ear; Enlarged Vestibular Aqueducts; EVA
• Additional Relevant MeSH Terms: Nervous System Diseases; Virus Diseases; Infections; Neurologic Manifestations; Otorhinolaryngologic Diseases; DNA Virus Infections; Ear Diseases; Sensation Disorders; Herpesviridae Infections; Hearing Disorders; Hearing Loss; Hearing Loss, Sensorineural; Cytomegalovirus Infections
• Other Study ID Numbers: 010228; 01-DC-0228

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No