OTOF-Related Hearing Loss

Excerpt

Clinical characteristics: OTOF-related hearing loss is an auditory synaptopathy that results from defective synaptic transmission from normally functioning cochlear inner hair cells (IHCs) to the auditory nerve. Thus, newborn hearing screening (NBHS) that relies on otoacoustic emission (OAE) testing, which primarily assesses function of outer hair cells (OHCs), is usually normal, whereas hearing tests that rely on auditory brain stem response (ABR) testing are abnormal given the failure of signal transmission from IHCs to the auditory nerve. All individuals with OTOF-related hearing loss have severely impaired speech discrimination.

The two phenotypes comprising OTOF-related hearing loss are typical OTOF-related hearing loss and atypical OTOF-related hearing loss. Typical OTOF-related hearing loss is characterized by congenital or prelingual, typically severe-to-profound bilateral hearing loss (70 to ≥90 dB) associated with normal OAEs and abnormal ABRs. With age, OAEs decrease or disappear in 20%-80% of individuals. Atypical OTOF-related hearing loss is characterized by either temperature-sensitive OTOF-related hearing loss or progressive OTOF-related hearing loss. Temperature-sensitive OTOF-related hearing loss is characterized by hearing that ranges from normal hearing to moderate hearing loss (0-55 dB) at baseline body temperature and declines to bilateral hearing loss ranging from severe (71-90 dB) to profound (>90 dB) with an elevation of body temperature (approximately 0.5 °C or more). The increased hearing loss resolves typically within hours of baseline body temperature returning to normal. Progressive OTOF-related hearing loss ranges from mild to moderate at onset, and over the course of a few months or years could progress to profound. Rate of hearing loss progression is variable.

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

Management: Treatment of manifestations: There is no cure for OTOF-related hearing loss. Early auditory intervention is critical to the development of speech and language. Habilitation options are tailored to the degree and frequency of hearing loss. While hearing aids may be trialed in persons with mild-to-severe hearing loss, these are unlikely to be beneficial due to auditory synaptopathy being the underlying cause. In contrast, cochlear implants may provide clinical benefit because they bypass the dysfunctional synapse and stimulate the auditory nerve directly. Educational and early intervention programs designed for individuals with hearing loss should start as early as possible. For individuals with atypical temperature-sensitive OTOF-related hearing loss, prevent febrile episodes and avoid exercise and/or ambient conditions that would cause body temperature to rise. Treat febrile episodes as quickly as possible.

Surveillance: To monitor the individual's response to supportive care and the emergence of new manifestations, the primary focus should be routine audiometric follow up. The frequency of follow up should be individualized and is likely to vary over time.

Agents/circumstances to avoid: For individuals with temperature-sensitive OTOF-related hearing loss, prevent fevers and other activities/ambient conditions that would cause body temperature to rise.

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