OTOF-Related Deafness

Clinical characteristics: OTOF-related deafness is characterized by two phenotypes: prelingual nonsyndromic auditory neuropathy spectrum disorder (ANSD) and, less frequently, temperature-sensitive auditory neuropathy spectrum disorder (TS-ANSD).

1. OTOF-related ANSD is characterized by congenital or prelingual, typically severe-to-profound bilateral deafness without inner-ear anomalies on MRI or CT examination of the temporal bones. Otoacoustic emissions (OAEs) are present and auditory brain stem response is abnormal at birth. Newborn hearing screening testing of OAEs only will fail to detect this disorder in most individuals. OAEs may decrease or disappear with age in 20%-80% of individuals.

2. TS-ANSD typically presents with normal-to-moderate hearing loss (0-55 dB) at baseline body temperature. An elevation of body temperature (approximately 0.5°C or more) triggers significant bilateral hearing loss ranging from severe to profound, with resolution of hearing loss typically occurring within hours of a return to baseline body temperature.

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

Management: Treatment of manifestations: Hearing aids should be fitted as soon as possible after hearing loss is identified. Consideration of cochlear implants (CIs) as soon as possible if hearing aids are not beneficial, as CIs have been shown to be effective for both phenotypes associated with OTOF-related deafness. Educational programs designed for individuals with hearing impairment should start as early as possible.

Prevention of primary manifestations: For individuals with TS-ANSD, prevent fevers and other activities/ambient conditions that would cause body temperature to rise; treat febrile episodes as quickly as possible.

Surveillance: Audiometry and speech discrimination testing every six months until age 18 years, then annually.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic sibs of a proband shortly after birth by molecular genetic testing for the pathogenic variants found in the proband so that appropriate early support and management can be provided to the child and family.

Genetic counseling: OTOF-related deafness is inherited in an autosomal recessive manner. If both parents are known to be carriers, each sib of an individual with OTOF-related deafness has at conception a 25% chance of being deaf, a 50% chance of having normal hearing and being a carrier, and a 25% chance of having normal hearing and not being a carrier. Once the OTOF pathogenic variants have been identified in the family, carrier testing, prenatal testing, and preimplantation genetic testing for OTOF-related deafness are possible.