Genetic Hearing Loss

Etiology

Genetic hearing loss accounts for 50% of all cases of hearing loss. The remainder is due to acquired causes such as infection, trauma, noise exposure, and ototoxicity. Inherited genetic hearing loss can be categorized as part of a syndrome (30% of cases) or non-syndromic (70% of cases). For non-syndromic hearing loss, autosomal recessive inheritance is the most common mode, accounting for 75 to 80% of cases. Autosomal dominant comprises approximately 20%. X-linked, Y-linked, and mitochondrial-inherited diseases comprise the remaining 5%.[2]

Epidemiology

Hearing loss is the most common sensory system disorder, with 1 in 1,000 children born with hearing impairment. The prevalence of SNHL continues to increase throughout childhood, reaching 2.7 per 1000 children by age 5. Currently, it is estimated that 300 million people suffer from hearing loss.[3]

Pathophysiology

Non-Syndromic Hearing Loss

Non-syndromic hearing loss accounts for the majority of hereditary hearing loss, with over 70 loci identified in its pathogenesis.[4] Each locus is identified with a specialized nomenclature. The prefix DFN (used to refer to deafness) is given to each gene locus and followed by either A for autosomal dominant or B for autosomal recessive inheritance. A number then follows the name to illustrate the order in which the gene was discovered. For example, DFNB1 is a locus responsible for non-syndromic hearing loss inherited in an autosomal recessive fashion and was the first locus to be identified. While many candidate gene loci have been identified, more remain to be discovered, and the precise cause of many cases of non-syndromic deafness remains unknown.[4]

• Autosomal recessive SNHL, where a mutation in both alleles is required to cause the disease phenotype, is the most common form of non-syndromic hearing loss, accounting for 75% to 80% of cases. Autosomal recessive deafness tends to be prelingual in onset, constant in nature, and severe.[5][6] To date, 71 loci have been identified as causing autosomal recessive non-syndromic hearing loss.[4] The protein products of these genes include ion channels, membrane proteins, transcription factors, and various cytoskeletal elements.
  • Connexin 26 (DFNB1) is the most common non-syndrome autosomal recessive locus, accounting for 30 to 40% of all cases of deafness.[7][8][9] Connexins are transmembrane proteins that mediate intercellular signaling via gap junctions.
• Autosomal dominant SNHL requires only 1 mutated allele to cause the disease phenotype. It tends to be post-lingual in onset, progressive, and milder.[5][6] To date, 54 loci have been identified as causing autosomal-dominant non-syndromic hearing loss.
• X-linked inheritance acts as a recessive trait in females who require mutations in both X alleles to cause a disease phenotype. However, since males have only 1 X chromosome, it behaves more like a dominant trait and manifests at a disproportionately higher rate in men than in women. Five loci and 3 genes have been mapped for the X-linked form.
• Mitochondrial disorders are caused by mutations in mitochondrial DNA and are only passed from mother to child. Seven loci and several gene-point mutations have been identified in the mitochondrial form. The A1555G mutation in 12S rRNA is believed to predispose to aminoglycoside-induced deafness, as well as to non-syndromic hearing loss.[10][11]

Syndromic Hearing Loss

Syndrome hearing loss is associated with a constellation of other clinical deficiencies and organ system involvement. There are over 400 syndromes associated with hearing loss. Thus, the diagnosis of hearing impairment in a child should prompt a thorough investigation to rule out a syndromic disorder. The severity of hearing loss can vary across different syndromes, ranging from mild impairment to profound loss. Like non-syndromic deafness, syndromic hearing loss can be inherited in autosomal recessive, autosomal dominant, X-linked, and mitochondrial patterns.

Autosomal Recessive Syndromic Hearing Loss

• Pendred Syndrome is the most common cause of syndromic hearing loss, accounting for 10% of all cases of hereditary hearing loss. Pendred syndrome is caused by a mutation in the SLC26A4 gene, which encodes the anion transporter pendrin. Patients present with SNHL, bilateral enlarged vestibular aqueducts or Mondini dysplasia, and euthyroid goiter.[12]
• Usher syndromes are a common cause of autosomal recessive syndromic hearing loss and the most common syndrome affecting both hearing and vision, accounting for 50% of all cases of deaf-blindness.[13] There are 3 subtypes of Usher syndrome: USH1, USH2, and USH3. Each has varying degrees of hearing loss, vestibular dysfunction, and retinitis pigmentosa.[13]
  • USH1 has profound bilateral deafness and severe vestibular dysfunction at birth. Retinitis pigmentosa becomes apparent before age 10.
  • USH2 has moderate to severe hearing loss at birth with normal vestibular function and retinitis pigmentosa that manifests later in the teenage years.
  • USH3 has normal-to-near-normal vestibular function and progressive hearing loss. Retinitis pigmentosa manifests later in the teenage years.[14]
• Jervell and Lange-Nielsen syndrome (JLNS) is characterized by SNHL and prolonged QTc intervals (>500 ms). There is a predisposition for syncope from ventricular tachyarrhythmias, most notably torsades de pointes. A similar syndrome, Romano-Ward syndrome, lacks SNHL. The genetic cause of JLNS is due to mutations in the KCNQ1 and KCNE1 genes, which encode subunits of potassium channels in cardiac and auditory tissues. Thus, children diagnosed with sensorineural hearing loss should also be screened with an EKG to assess for prolonged QTC intervals.
• Miller syndrome is very rare at 1 per 1,000,000 live births. It is characterized by craniofacial and limb anomalies, and conductive hearing loss due to middle-ear abnormalities.[15]
• Nager syndrome consists of facial and limb malformations, ear anomalies, and sensorineural hearing loss.[16]

Autosomal Dominant Syndromic Hearing Loss

• Branchio-oto-renal (BOR) syndrome is a constellation of branchial arch, otologic, and renal defects and accounts for about 2% of profound hearing loss in children. BOR can cause sensorineural, conductive, or mixed hearing and can cause abnormalities in the external, middle, or inner ear. Patients may have preauricular pits, microtia, ossicular malformations, or cochlear hypoplasia.[17] Branchial arch anomalies include fistulae, pits, or sinuses, while renal abnormalities can range from renal hypoplasia to complete agenesis. There are 3 different genes, EYA1 and 2 additional genes, SIX1 and SIX5, responsible for BOR syndrome.
• Waardenburg syndrome has an incidence of 1 in 40,000 live births and is characterized by SNHL and abnormal pigmentation of the eyes, skin, and hair. Patients can have the classic “white forelock” and iris heterochromia.[18] There are 4 subtypes of Waardenburg syndrome, each with slight variations in clinical features and distinct gene mutations.
• Goldenhar syndrome (hemifacial microsomia) is predominantly inherited sporadically, although rarely, it can present in an autosomal dominant manner. It has an incidence of 1 per 5,000 to 25,000 live births and presents with facial and ear anomalies, along with hearing loss encompassing both conductive and sensorineural types, ranging from mild to severe.
• CHARGE syndrome has an incidence of 1 in 8,500 to 10,000 live births and is characterized by coloboma, hearing anomalies, choanal atresia, stunted growth, genitourinary malformations, and ear anomalies. Hearing impairment can occur from a range of anomalies, including a stenotic external auditory canal, Mondini dysplasia, hypoplasia, agenesis of the auditory nerve, ossicular chain anomaly, and absence of middle ear structures.[19]
• Stickler syndrome has an incidence of 1 in 7,500 to 9,000 live births and is most commonly caused by mutations in the COL2A1 gene, which encodes type II collagen. It is characterized by flattened facies, myopia, cleft palate, macroglossia, arthritis, scoliosis, and mitral valve prolapse. Hearing loss can be conductive due to stapes fixation or sensorineural due to a collagen defect in the organ of Corti.[20]
• Treacher Collins has an incidence of 1 per 50,000 live births and has abnormalities of the face, eyes, and ears. Forty to 50% of children have conductive hearing loss or high-frequency sensorineural hearing loss.[21] 
• Apert syndrome occurs in 1 in 65,000 to 88,000 live births and is characterized by craniosynostosis, frontal bossing, syndactyly, and vision and hearing impairment. Patients often have bilateral conductive hearing loss from middle ear effusions or ossicular chain fixation. Sensorineural hearing loss can occur from cochlear dysplasia.[22]
• Crouzon has an incidence of 1 in 50,000 live births with craniosynostosis, high forehead, lagophthalmos, and hearing impairment. 30% of patients have conductive hearing loss from external ear malformations, middle ear effusions, ossicular chain dysplasia, and oval window anomalies. Sensorineural hearing loss is rarely seen.[23]
• Saethre-Chotzen syndrome has an incidence of 1 in 250,000 to 500,000 live births with brachycephaly, vertebral anomalies, and short stature. Hearing loss is usually conductive with anomalies of the external auditory canal, stapes ankylosis, ossicular chain fixation, and middle cavity anomalies.[24]
• Townes-Brocks syndrome has an incidence of 1 in 250,000 with anus imperforata, external ear anomalies, and thumb anomalies.

X-Linked Recessive Syndromic Hearing Loss

• Alport syndrome is secondary to anomalies in type IV collagen, resulting in SNHL, nephritis, and ocular defects. Since type IV collagen is a significant component of the basement membrane, mutations in it can lead to hematuria due to involvement of the glomerular basement membrane. Ocular manifestations include anterior lenticonus, perimacular flecks, and corneal lesions. It is predominantly inherited in an X-linked recessive manner via the gene COL4A5, which encodes the a5 chain of type IV collagen.[25] However, mutations in COL4A3 and COL4A4, which encode a3 and a4 chains, are also implicated in the pathogenesis of Alport syndrome but are transmitted by autosomal recessive inheritance
• Mohr-Tranebjaerg syndrome presents with post-lingual SNHL, dystonia, spasticity, dysphagia, and optic atrophy. It is similar to Friedreich ataxia without cardiomyopathy.
• Mitochondrial-Inherited syndromic hearing loss often presents with bilateral, high-frequency hearing loss. Syndromes include MELAS syndrome (mitochondria encephalopathy, lactic acidosis, and stroke-like episodes), Kearns-Sayre syndrome, and MERRF (myoclonic epilepsy with ragged red fibers).

History and Physical

Children with hearing loss should undergo a complete clinical history, including perinatal details to help identify any environmental influences such as intrauterine infections, trauma, medications, and other medical conditions during pregnancy. A thorough family history should be obtained to assess for any genetic history of hearing loss. The results of newborn hearing screening testing should be ascertained. A physical exam for childhood hearing loss should include a complete head-to-toe exam to assess for any syndromic features. Key organ systems commonly associated with hearing loss include ophthalmologic, endocrine, renal, and cardiac systems.

Evaluation

Newborn hearing screening: The universal newborn hearing screening program (UNHS) has significantly improved the diagnosis of childhood hearing loss and reduced the average age of diagnosis from 24-30 months to 2-3 months. The screening utilizes an otoacoustic emissions (OAE) test, and children who fail undergo a repeat test in several weeks. If the child continues to fail hearing tests, auditory brainstem response (ABR) testing is required to confirm hearing loss. The use of evoked otoacoustic emissions and auditory brainstem response testing has substantially increased the number of children identified to have hearing loss and reduced the number of infants falsely identified as having a hearing impairment.[26]

Genetic testing: 50% of all childhood hearing loss and 66% of prelingual hearing loss result from genetic causes. Current hearing screening programs can only detect hearing loss beyond 35 dB. Thus, genetic screening can help identify children with mild SNHL who are missed with conventional screening. Clinicians should aim to answer 3 key questions: Is there an environmental cause? Is there a constellation of signs and clinical features to suggest a syndrome? Is there a family history of similar patterns of onset and type of hearing loss?

After ruling out environmental causes, genetic testing for DFNB1 in the GJB2 gene is recommended, as it is the most common cause of non-syndromic hearing loss. For children in whom syndromic hearing loss is suspected, gene-specific mutation screening should be performed to confirm the syndrome. Genetic screening for mitochondrial A1555G can also help minimize hearing loss by protecting it against aminoglycoside antibiotics. Additionally, genetic tests depend on the pedigree constructed by the medical geneticist. It is important to note that a negative genetic test does not rule out a genetic cause for hearing loss.[27][28]

Computed tomography: Computed tomography scans can visualize the temporal bones, mastoid, otic capsule, and middle ear to identify any anatomical anomalies responsible for hearing loss. One of the most common computed tomography findings in SNHL is Mondini dysplasia, which is hypoplasia of the basal turn of the cochlea, leading to progressive SNHL. In cases of dilated vestibular aqueducts, genetic screening for Pendred syndrome is warranted.[29]

Magnetic resonance imaging (MRI): High-resolution nuclear MRI can detect deformities of the membranous labyrinth, internal auditory canal, and cerebellopontine angle. Scheibe dysplasia or cochleosaccular dysplasia affects the pars inferior. Alexander malformation affects the cochlear duct and the basal turn of the cochlear nerve, leading to high-frequency hearing loss. MR imaging is also useful for identifying cochlear nerve dysplasia or aplasia that might be responsible for sensorineural hearing loss.[29][30]

Electrocardiogram: Recommended due to the remote possibility of Jervell and Lange-Nielsen syndrome.

Treatment / Management

Treatments for significant hearing loss include hearing aids, cochlear implants, and implantable bone-conduction devices. Conventional hearing aids are electronic devices that amplify sound to the ears. Generally, they are beneficial for patients with mild-to-severe sensorineural hearing loss who have good-to-excellent speech recognition and hearing clarity. Hearing aids come in 3 different styles: behind-the-ear, in-the-ear, and canal types, either in-the-canal or completely in-the-canal. Most children are fitted with behind-the-ear hearing aids, which facilitate long-term use as the hearing aid molds can be readily fashioned for the growing child while keeping the same hearing aid housing. The non-behind-the-ear hearing aids provide the advantage of being less visible. 

Patients with severe-to-profound hearing loss who derive minimal to no benefit from hearing aids are candidates for cochlear implantation. A cochlear implant is an implantable electronic device that works in conjunction with an externally worn sound processor to stimulate the afferent fibers of the auditory nerve with electrical current. Although they do not replace acoustic hearing, they can provide access to a wider frequency range and improve speech understanding with habilitation and practice.[31][32](B3)

Cochlear implants in children born deaf have been shown to significantly benefit speech and language development, with earlier implantation leading to greater vocabulary. The best cochlear implant results are obtained in post-lingual deafness and in those with early-identified deafness (younger than 2 years) with early cochlear implant intervention. The FDA has now approved cochlear implantation for infants as young as 9-months old who meet the criteria. Cochlear implantation has been found to be effective in CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Waardenburg syndrome, Usher syndrome, and Pendred syndrome.[33][34][35](B2)

Implantable bone-conduction hearing devices are utilized for patients with conductive hearing loss, mixed hearing loss, or single-sided hearing loss. The external and middle ear are bypassed, with sound being transmitted to the cochlea via bone conduction. Bone conduction devices are either percutaneous (skin-penetrating) or transcutaneous (implanted under the scalp). Bone-conduction devices can be particularly beneficial for patients with anatomic abnormalities of the external or middle ear that are not amenable to reconstructive ear surgery. Bone conduction devices have demonstrated effectiveness for patients with Treacher Collins, BOR, Nager, and Goldenhar syndromes.[36][37]

Differential Diagnosis

The differential diagnosis of hearing loss should include all genetic and acquired causes. Aside from genetic causes, as previously mentioned, other congenital forms can be caused by prenatal infections, anatomic malformations, and ototoxic medications.

Treatment Planning

Because of the variable genetic mechanisms of sensorineural hearing loss, the best prevention is achieved by appropriately screening potential parents with a familial history of hearing loss. As discussed, autosomal recessive forms of hearing loss are generally from asymptomatic parents, thus, a thorough genetic screening of couples with a history of familial hereditary hearing impairment is warranted. The timing of rehabilitation initiation is also critical. Hearing amplification should be instituted as soon as possible. The Joint Committee on Infant Hearing recommended in 2007 initiating rehabilitation no later than 6 months of age to minimize the impact on language development.[38] Studies have also documented that earlier cochlear implantation (under 18 months) results in markedly improved performance than children implanted later in life.[39]

Prognosis

Genetic SNHL can have significant social, economic, and medical repercussions. Prognosis is dependent on the etiology and can be improved with early diagnosis and intervention.[39] The longer the time from diagnosis to intervention, the poorer the speech and language outcomes become, as well as poorer cognitive development.[40] Simultaneous exposure to more than 1 spoken language in the home is also associated with worse outcomes.[41] As advances are made in genetic testing and therapy, there are ongoing improvements in the diagnosis of syndromic hearing loss, with the potential to restore hearing function in patients with certain syndromes.[42][43]

Complications

Delayed diagnosis and treatment of hearing loss can have lifelong consequences on verbal and spoken-language communication and social development. Children can suffer speech delay, impaired communication with their peers, social withdrawal, decreased self-esteem, and fewer educational and job opportunities.