Clinical characteristics: SLC26A4-related sensorineural hearing loss (SLC26A4-SNHL), characterized by inner ear malformations also associated with vestibular dysfunction, comprises two phenotypes: (1) nonsyndromic SLC26A4-SNHL (also referred to as DFNB4 or nonsyndromic enlargement of the vestibular aqueduct [NSEVA]) and (2) Pendred syndrome (PDS) that includes thyroid involvement (typically identified more frequently in countries without universal salt iodization programs). The time of onset and type of presentation of the SNHL vary (such that some newborns pass their newborn hearing screening); however, by age three years most children have bilateral and severe-to-profound hearing loss. Manifestations of vestibular dysfunction (such as head-tilting, vomiting, and/or delayed ambulation or clumsiness in a child who previously walked well) can precede or accompany the fluctuations in hearing typical of this disorder. Thyroid enlargement (goiter) occurs gradually and is typically evident in the second decade, especially if iodine is not routinely included in the diet.

Diagnosis/testing: The diagnosis of SLC26A4-SNHL is established in a proband with suggestive findings and biallelic pathogenic variants in SLC26A4 identified by molecular genetic testing.

Management: Treatment of manifestations: Supportive treatment includes multidisciplinary care by specialists in hearing habilitation, as early auditory intervention is critical to the development of speech and language. Habilitation options tailored to the degree and frequency of hearing loss can include hearing aids when hearing loss is mild to severe and consideration of cochlear implantation (CI) when hearing aids have had limited benefit. When considering CI, it is essential that the treating otolaryngologist be aware of the possible perioperative complications (most commonly perilymph gusher/oozing) and postoperative complications (most commonly transient vertigo) in individuals with SLC26A4-SNHL. Educational and early intervention programs designed for individuals with hearing loss are recommended. Medical treatment of thyroid enlargement and/or abnormal thyroid function requires consultation with an endocrinologist.

Surveillance: Audiometric testing every three to six months until age three years and annually thereafter; baseline ultrasound to assess thyroid size at age ten years, followed by repeat ultrasound every five to ten years based on findings on palpation of thyroid size.

Agents/circumstances to avoid: Follow standard recommendations for individuals with hearing loss. Despite anecdotal reports that head injuries resulting in increased intracranial pressure in individuals with enlarged vestibular aqueduct can occasionally trigger a decline in hearing, evidence is insufficient to support that avoidance of these activities decreases the overall risk of progression of hearing loss. While health care providers should alert families to this possible association, it is recommended that families be encouraged to make their own decisions on participation in contact sports.

Evaluation of at-risk sibs: It is appropriate to determine the genetic status of at-risk sibs of a proband with SLC26A4-SNHL (i.e., a proband with known biallelic SLC26A4 pathogenic variants) shortly after birth so that appropriate and early support and management can be provided to the child and family.

Genetic counseling: SLC26A4-SNHL is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC26A4 pathogenic variant, each sib of the proband has at conception a 25% chance of having SLC26A4-SNHL, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the pathogenic variants. Once biallelic SLC26A4 pathogenic variants have been identified in the proband, heterozygote testing for relatives of an individual with SLC26A4-SNHL and prenatal/preimplantation genetic testing are possible.