Clinical Guidance

Classes of pathogenic variants

• Biallelic premature stop and frameshift (truncating) OTOF variants cause profound prelingual deafness.

• Biallelic nontruncating OTOF variants (e.g., missense variants) result in a less severe phenotype.

• The presence of one truncating and one nontruncating OTOF variant results in an intermediate phenotype.

All individuals with atypical temperature-sensitive OTOF-related hearing loss have either biallelic nontruncating pathogenic variants in OTOF or one truncating and one nontruncating pathogenic variant in OTOF. Specific nontruncating pathogenic variants associated with atypical OTOF-related hearing loss include the following :

• Temperature-sensitive OTOF-related

Source: GeneReviews — "OTOF-Related Hearing Loss"

Diagnostic Criteria

No consensus clinical diagnostic criteria for OTOF-related hearing loss have been published.

Suggestive Findings

OTOF-related hearing loss should be considered in two scenarios: an abnormal newborn hearing screening (NBHS) result and a symptomatic individual.

Scenario 1: Abnormal Newborn Hearing Screening (NBHS) Result

Universal NBHS using physiologic screening is required by law or rule in all 50 states in the US and is performed on 98% of children in the US typically within days after birth (see 2020 Summary of National CDC EHDI Data).

Source: GeneReviews — "OTOF-Related Hearing Loss"

Differential Diagnosis

Due to the heterogeneity of auditory neuropathy spectrum disorder (ANSD), it is difficult to estimate the prevalence of environmental versus genetic causes. Environmental causes include cytotoxic agents (e.g., cisplatin), prematurity, hyperbilirubinemia, septicemia, loop diuretics, and aminoglycoside use . Infants in the neonatal intensive care unit (NICU) are at particularly high risk for environmental factors, with the prevalence of ANSD approximately 5.6 in 1,000 . As of this writing, more than 85 genes have been associated with autosomal recessive nonsyndromic hearing loss and seven genes have been associated with nonsyndromic ANSD . Up to 8% of congenital nonsyndromic hearing loss is associated with pathogenic variants in OTOF . Among individuals with ANSD, OTOF is found in 41%-91% of those tested . For a list of selected genes associated with distinctive clinical features, see Genetic Hearing Loss Overview, Table 3. For a current, comprehensive list of all identified autosomal recessive nonsyndromic hearing loss genes, see Hereditary Hearing Loss Homepage. Loss of otoacoustic emissions (OAEs) over time is found in other forms of genetic auditory neuropathy, such as with OPA1-related hearing loss . Table 2. Other Nonsyndromic Genetic Auditory Neuropathy Spectrum Disorders

Management Guidelines

No clinical practice guidelines specific for OTOF-related hearing loss have been published. Management ideally occurs in the context of a multidisciplinary clinic with specialists in otolaryngology, audiology, and genetic counseling. See Genetic Hearing Loss Overview, Management.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with OTOF-related hearing loss, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Source: GeneReviews — "OTOF-Related Hearing Loss"

Clinical Guidance

Persons with temperature-sensitive OTOF-related hearing loss, avoid excessive body temperatures whenever possible .

Source: GeneReviews — "OTOF-Related Hearing Loss"

Therapies Under Investigation

Gene therapy for OTOF-related hearing loss is advancing rapidly, with several clinical trials reporting promising results. The main approach involves adeno-associated virus (AAV)-mediated gene delivery, which aims to restore otoferlin expression in cochlear inner hair cells (IHCs).

Source: GeneReviews — "OTOF-Related Hearing Loss"

Surveillance Guidelines

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. For example, initial follow up may include audiometry and speech discrimination testing every six months; however, if a child receives a cochlear implant, the scheduled follow up will change. Post implantation, there will be frequent evaluations as recommended by the cochlear implant team (otolaryngologist, audiologist, and speech-language pathologist). At subsequent follow-up appointments, assessments may include speech recognition testing, equipment checks, and provision of replacement or upgraded equipment . As the cochlear implant recipient and family become comfortable with the cochlear implant, many of the above tasks can be performed at home, markedly decreasing the need for routinely scheduled appointments.

Source: GeneReviews — "OTOF-Related Hearing Loss"