Congenital hearing loss is a disease affecting 1 to 3 per 1000 live births. For many children born with hearing loss, it is an isolated finding known as a nonsyndromic hearing loss. Alternatively, a syndromic hearing loss is where the patient has hearing loss in addition to other medical anomalies. Of the children with genetic abnormalities causing their hearing loss, approximately 20% of these children have other associated findings along with their hearing loss. This review evaluates further syndromic sensorineural hearing loss (SNHL), or hearing loss due to problems associated with the vestibulocochlear nerve.
Fifty percent of infants whose deafness results from congenital hearing loss have environmental factors as a cause, and the other 50% have genetic abnormalities causing hearing loss. Seventy percent to 80% of congenital hearing loss is non-syndromic, meaning that it is an isolated finding, with 49% of nonsyndromic cases resulting from a mutation of a gene encoding the gap junction protein connexin 26. Connexins are proteins that form channels to permit the exchange of nutrients and ions between cells. Within the inner ear, connexin 26 helps maintain the appropriate intracellular level of potassium. Disruptions in this protein can result in hearing loss. The remaining 20% of children with congenital hearing loss have syndromic losses associated with other findings. 
Congenital hearing loss occurs in 1 to 3 per 1,000 live births. Normal hearing thresholds are between 0 to 20 dB HL (decibels hearing level). At least 3 children per 1000 will have a hearing loss greater than 20 dB HL. Approximately 1 infant in 1000 will have bilateral severe to profound hearing loss (greater than 70 dB HL). The incidence of hearing loss is 10-times higher for infants with 1 or more risk factors associated with hearing loss versus those without risk factors. Risk factors include a family history of hereditary childhood SNHL, craniofacial anomalies, weight less than 1500 g, hyperbilirubinemia, bacterial meningitis, APGAR score of 0 to 4 at 1 minute or 0 to 6 at 5 minutes, or 5 or more days of mechanical ventilation. Other risk factors include TORCH infections (an acronym for certain in utero infections) including toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, and other viral infections.
Syndromic congenital hearing loss is best categorized by mode of inheritance, which can be autosomal recessive (AR), autosomal dominant (AD), or X-linked. Examples of all 3 types will be discussed in the following paragraphs. ,,
The 3 major syndromes associated with an AR mechanism of inheritance are Usher syndrome, Pendred syndrome and Jervell and Lange-Nielsen syndrome.
Usher syndrome is the most common form of autosomal recessive sensorineural hearing loss. This syndrome affects half of the deaf and blind population in the United States. The primary features of this syndrome are retinitis pigmentosa and sensorineural hearing loss. There are three different types with types 1 and 2 comprising 95% of all affected individuals. Type 1 is associated with bilateral profound sensorineural hearing loss and absent vestibular function. Type 2 is associated with moderate hearing loss and normal vestibular function. Type 3 results in progressive hearing loss and variable vestibular function.
Pendred syndrome is associated with abnormal iodine metabolism due to a mutation in the PDS gene on chromosome 7q. These patients often present with a euthyroid goiter detectable around 8 years of age, in addition to bilateral moderate to severe high-frequency sensorineural hearing loss with residual low-frequency hearing. The most common inner ear abnormality associated with Pendred syndrome is an enlarged vestibular aqueduct. This is a structure connecting the vestibule of the inner ear to the brain.
Jervell and Lange-Nielsen syndrome is associated with profound sensorineural hearing loss and cardiac arrhythmias caused by prolongation of the QT interval. This syndrome caused by a genetic defect that affects a potassium channel gene (KCNE1 or KCNQ1; 90% are caused by KCNQ1 mutations). The defect leads to conduction abnormalities in both the inner ear and cardiac muscle. ECG findings in these patients show large T waves and prolongation of the QT interval. The typical presentation in these patients is syncope.
Some autosomal dominant syndromes associated with hearing loss include Waardenburg syndrome, Treacher Collins syndrome, Stickler syndrome, branchio-oto-renal syndrome (Melnick-Fraser syndrome), neurofibromatosis type 2, osteogenesis imperfecta, and otosclerosis.
Waardenburg syndrome is the most common form of autosomal dominant sensorineural hearing loss, associated with 3% of childhood hearing loss. This syndrome is comprised of bilateral or unilateral sensorineural hearing loss, pigmentary anomalies and defining craniofacial features. The pigmentary anomalies include white forelock, heterochromia irides (differently colored irises), premature graying, and vitiligo. The craniofacial features include dystopia canthorum (widely spaced medial canthi), broad nasal root, and synophrys (confluent eyebrows). There are 3 different forms of Waardenburg syndrome. Type 1 is associated with heterochromia iridis, white forelock, patchy hypopigmentation and dystopia canthorum. Congenital sensorineural hearing loss is present in 20% of these patients. Type II patients lack dystopia canthorum, differentiating them from type I. Up to 50% of these patients will have sensorineural hearing loss. Type III has the features of type I plus microcephaly, skeletal abnormalities, and mental retardation.
Treacher Collins syndrome (mandibulofacial dysostosis) results in facial malformations consisting of malar hypoplasia, downward slanting palpebral fissures, coloboma of the lower eyelids, mandibular hypoplasia, malformations of the external ear or canal, dental malocclusion, and cleft palate. Conductive hearing loss is present in 30% of patients, but they may also have sensorineural hearing loss or vestibular dysfunction. Ossicular malformations are common. This syndrome results from a mutation in gene TCOF1 (encoding for the treacle protein) located on chromosome 5q.
Stickler syndrome is characterized by cleft palate, micrognathia, myopia, retinal detachment, cataracts, and marfanoid habitus. This syndrome is a result of mutations in COL2A, COL11A1, and COL11A2. There are 3 types of Stickler syndrome. In type 1, the patient presents with progressive myopathy, retinal detachment, and vitreoretinal degeneration. In type 2, patients do not have retinal detachment. In type 3 those affected have no eye abnormalities. In 80% of Stickler syndrome patients, there is some degree of hearing loss; 15% of these will have significant loss.
Branchio-oto-renal (Melnick-Fraser) syndrome is present in approximately 2% of children with congenital hearing loss. This syndrome features ear pits/tags, branchial cleft sinuses, and renal involvement (from minor dysplasia to complete agenesis). It is caused by mutations in the EYA1 gene on chromosome 8q. Forty percent of these patients have cochlear dysplasia; 75% have a significant hearing loss. These patients can have either a conductive or sensorineural hearing loss with some of them having a mixed loss.
Neurofibromatosis type 2 is caused by deletions in NF2 on chromosome 22 leading to alterations in the merlin protein. Features of this disease include bilateral vestibular schwannomas, cafe-au-lait spots, and subcapsular cataracts. The bilateral vestibular schwannomas are present in up to 95% of affected individuals but do not usually become symptomatic until early adulthood.
Patients with osteogenesis imperfecta have fragile bones, blue sclera, hyperelasticity of joints and ligaments, in addition to conductive, sensorineural, or mixed hearing loss. It is associated with 2 genes: COLIA1 on chromosome 17q and COLIA2 on chromosome 7q. There is a subtype of osteogenesis imperfecta called Van der Hoeve syndrome where progressive hearing loss begins in early childhood.
Otosclerosis (otospongiosis) occurs when there is a proliferation of spongy tissue on the otic capsule, typically surrounding the stapes footplate, causing fixation of the ossicles and resultant conductive hearing loss. This hearing loss typically presents in early adulthood.
There are 3 main X-linked syndromes associated with hearing loss. These include Alport syndrome, Norrie syndrome, and otopalatodigital syndrome.
Alport syndrome affects basement membrane collagen in the kidney and inner ear and leads to renal failure and progressive sensorineural hearing loss. This is caused by a mutation in COLIA5, which codes for a form of type V collagen. This almost exclusively affects males, but there is a much clinically milder form that may be seen in females.
Norrie syndrome is characterized by ocular symptoms, progressive sensorineural hearing loss, and mental retardation.
Otopalatodigital syndrome is associated with hypertelorism and craniofacial deformities causing flattened midface, small nose, and cleft palate. These patients also have short stature with toes and fingers of varying lengths and space between digits, along with conductive hearing loss due to ossicular abnormalities.
Important historical elements to note are a family history of hearing loss, ocular abnormalities, and congenital heart disease. Other important information to obtain includes a prenatal history including TORCH infections, gestational diabetes, hypothyroidism as well as maternal drug, alcohol, and tobacco use during pregnancy. ,
A full head and neck exam should be performed, taking note of any of the following abnormalities: microtia, aural atresia, periauricular skin tags, anterior cervical pits, ocular abnormalities (visual acuity, color of eyes and intercanthal distance), cleft lip or palate, abnormal skull size or asymmetry, excessive or missing digits, and areas of hypopigmentation or hyperpigmentation including cafe au lait spots. Otoscopy may be normal, but the presence of middle ear fluid should be noted.
Early detection of hearing impairment is critical to improved prognosis. Newborn hearing screening programs are available in all 50 states, and these programs recommend universal newborn hearing screening be performed within the first 3 months of life. The American Academy of Pediatrics program called Early Hearing Detection and Interventions has goals of screening by 1 month, diagnosis of hearing loss by 3 months and entry into early intervention services by 6 months. The initial screening test may be auditory brainstem response (ABR) or otoacoustic emissions (OAE) testing. If an infant fails their newborn hearing screening, further diagnostic testing is recommended to confirm the presence of hearing loss, which may be followed by MRI or CT scan of the temporal bones and internal auditory canal. Historically CT of the temporal bones was the initial choice of imaging, but more recently MRI has been found to offer some advantages in comparison to CT. The timing of imaging as well as which patients should undergo imaging remains controversial. ,
In the case of syndromic hearing loss, further workup may depend on other associated findings. A genetics consultation is typically recommended. An integral part of the work up in bilateral severe to profound SNHL has become genetic testing for mutations in the gap junction beta-2 gene (GJB2) which encodes connexin 26. Further investigation regarding syndromic hearing loss includes obtaining hearing testing of family members. Routine laboratory testing in children with bilateral SNHL has had limited literature to support its utility and has a low diagnostic yield. Serology can be considered to look for signs of infection, past or present. Particular history or physical exam findings may yield further work up. In cases of a family history of syncope, an EKG may be warranted. In patients with additional symptoms concerning for hypothyroidism, thyroid function studies may be indicated.
A recently published study showed that 57% of children with syndromic hearing loss had significant ophthalmologic findings, and therefore, it is recommended for children with severe-profound SNHL to be referred for ophthalmologic examination.
The management of syndromic hearing loss depends on the degree, the timing of onset, and laterality of the hearing loss. Management can include standard amplification, bone anchored hearing aid (BAHA) implants, or cochlear implants in cases of bilateral severe to profound sensorineural hearing loss.
In cases of congenital hearing loss, an improved prognosis is associated with earlier diagnosis and treatment, even in cases of severe or profound losses. The earlier provision of aural rehabilitation can mitigate the deleterious effects of hearing loss on speech and language development.
Education regarding congenital hearing loss begins as soon as there is an abnormal newborn screening test result. Management of these patients and their families should begin in the first few days of life and can prevent the effects of delayed diagnosis.