Deafness is the most common sensory defect (1 in 1000-2000 births; there are roughly 4 million births in the United States per year).
Early identification allows appropriate intervention as soon as indicated.
Fifty percent of congenital hearing loss is due to nongenetic factors.
Environmental (25% of all congenital hearing loss cases)
Infections (TORCH)
Ototoxicity
Prematurity
Extracorporeal membrane oxygenation (ECMO)
Hypoxia
Idiopathic (25% of all congenital hearing loss cases)
Fifty percent of congenital hearing loss is due to genetic factors
Seventy percent of genetic cases are nonsyndromic
Seventy-five percent to 80% of nonsyndromic deafness is inherited through autosomal recessive (AR) patterns.
Eighteen percent to 20% of nonsyndromic deafness is inherited through autosomal dominant (AD) patterns.
One percent to 3% of nonsyndromic deafness is classified as X-linked, or chromosomal disorders.
Thirty percent of genetic cases are syndromic
The majority of these cases are passed on through AR or X-linked inheritance.
Organism: Protozoan parasite Toxoplasma gondii
Epidemiology: In United States, around 1/10,000 births
Primary infection: Occurs through ingestion of oocytes and ova. Common sources include consuming undercooked meat or the handling of contaminated soils, water, and cat feces.
Infant transmission: Vertical transmission or primary infection in neonatal period
Symptoms: Asymptomatic in majority of patients. If symptomatic, triad includes (a) chorioretinitis, (b) hydrocephalus, and (c) intracranial calcifications
Diagnostics:
Serology: IgM and IgG antibody tests
CSF studies: microscopic visualization of parasite
Amniocentesis: PCR
Cochlear histopathology: encysted organisms within the inner ear causing tissue necrosis and inflammatory changes.
Treatment: Pyrimethamine and sulfadiazine; treatment is capable of preventing hearing loss.
Organism: Togavirus
Epidemiology: In vaccine era, rubella incidence below 1 per 1,000,000 births. Congenital rubella syndrome (CRS) incidence below 1case per 5,000,000 births
Primary infection: Aerosol
Symptoms (CRS): Congenital cataract, cardiovascular anomalies, mental retardation, retinitis, sensorineural hearing loss (SNHL)
Infant transmission: Vertical transmission or primary infection in neonatal period
Diagnostics: PCR identification of IgG and IgM
Cochlear pathology: Degeneration of the organ of Corti, adhesion between the organ of Corti and Reissner membrane, rolled-up tectorial membrane, cochlea–saccule degeneration
Treatment: Supportive care
Organism: Beta-herpesvirus
Epidemiology: The most common viral cause of congenital SNHL. Congenital CMV (cCMV) affects up to 3% of all newborns. Eighty percent to 90% of infants with congenital cCMV are asymptomatic at birth. As many as 15% of these infants will develop late sequlae.
Primary infection: Direct contact with urine, blood, or bodily fluids.
Infant transmission: Vertical transmission or primary neonatal infection.
Symptoms: Microcephaly, intrauterine growth restriction, hepatosplenomegaly, chorioretinitis, jaundice, petechiae, thrombocytopenia, hyperbilirubinemia, SNHL
Prevention: CMV hyperimmunoglobulin in pregnant women with primary CMV
Diagnostics:
Prenatal: More than 21 weeks of gestation and more than 6 weeks after infection → Nucleic acid PCR
Neonate: Less than 3 weeks → PCR of saliva, urine, or both
Cochlear pathology: atrophy of the stria vascularis
Treatment:
Symptomatic: 6-months of Valganciclovir and hearing screens every 6 months for 3 years, then annually for additional 2 to 3 years.
Asymptomatic: no treatment; continued audiometric screening
Asymptomatic with mild SNHL: no treatment; continued audiometric screening
Organism: HSV-1 and HSV-2; Herpesviridae
Epidemiology: 1/3200 births
Primary infection: contact
Symptoms: skin, eye, and mucous membrane lesions, CNS disease (seizures, spasticity, blindness, learning disabilities), constitutional symptoms
Infant transmission: 85% peripartum; 10% postnatal; 5% in-utero
Diagnostics: screening not recommended, if infection suspected then direct viral culture from blood or lesion.
Treatment:
Skin, eye, mucous membranes: intravenous acyclovir for 14 days
CNS or disseminated disease: intravenous acyclovir for 21 days.
Organism: Treponema pallidum, gram-negative spirochete
Epidemiology:
Tamari and Itkin estimated that hearing loss occurred in
– Seventeen percent of congenital syphilis
– Twenty-five percent of late latent syphilis
– Twenty-nine percent of asymptomatic patients with congenital syphilis
– Thirty-nine percent of symptomatic neurosyphilis
Karmody and Schuknecht estimated hearing loss occurred in up to 38%
Primary infection: Contact
Symptoms:
Early (infantile): Severe and bilateral SNHL. These children usually have multisystem involvement and hence a fatal outcome.
Late (tarditive): Progressive SNHL of varying severity and time of onset. Hearing losses that have their onset during early childhood are usually bilateral, sudden, severe, and associated with vestibular symptoms. The symptom complex is similar to that of Méniére disease. The late-onset form (sometimes as late as the fifth decade of life) has mild hearing loss.
Infant transmission: Vertical
Diagnostics: Histologic examination of placenta for spirochetes; in high-risk clinical scenarios (a) long-bone radiographic examination; (b) lumbar puncture for cell count, protein, and VDRL
Cochlear histopathology: Osteitis with round cell infiltration is noticed. With tertiary syphilis, gummatous lesions may involve the auricle, mastoid, middle ear, and petrous pyramid
Treatment: Steroids and penicillin
Other: Two clinical signs are associated with congenital syphilis that deserve special mention—Hennebert sign and Tullio phenomenon. Hennebert sign consists of a positive fistula test without clinical evidence of middle ear or mastoid disease, or a fistula. It has been postulated that the vestibular stimulation is mediated by fibrous bands between the footplate and the vestibular membranous labyrinth. Hennebert sign may also be present in Méniére disease. Another explanation is that the vestibular response is due to an excessively mobile footplate. The nystagmus in Hennebert sign usually is more marked upon application of a negative pressure.
Tullio phenomenon consists of vertigo and nystagmus on stimulation with high-intensity sound, such as the Bárány noise box. This phenomenon occurs not only in congenital syphilis but also in patients with a semicircular canal fistula or dehiscence and in postfenestration patients if the footplate is mobile and the fenestrum patent. It also can be demonstrated in chronic otitis media should the patient have an intact tympanic membrane, ossicular chain, and a fistula—a rare combination.
For Tullio phenomenon to take place, a fistula of the semicircular canal and intact sound transmission mechanism to the inner ear (ie, intact tympanic membrane, intact ossicular chain, and mobile footplate) must be present. The pathophysiology is that the high-intensity noise energy transmitted through the footplate finds the course of least resistance and displaces toward the fistula instead of the round window membrane.
Zika virus: A flavivirus transmitted by mosquito. Associated with microcephaly and SNHL.
Human immunodeficiency virus (HIV): Can present with either conductive hearing loss from otitis media or SNHL secondary to opportunistic infection.
Medications: aminoglycosides, chemotherapeutics, loop diuretics
Predisposing factors: prematurity, diabetes, genetics
Mitochondrial gene mutation predisposes patients to aminoglycoside ototoxicity. Mutation occurs on 12S ribosomal RNA; 1555A>G.
Cretinism consists of retarded growth, mental retardation, and mixed hearing loss.
Seen in conjunction with congenital deafness.
Twenty percent of kernicteric babies have severe deafness secondary to damage to the dorsal and ventral cochlear nuclei and the superior and inferior colliculi nuclei.
High-frequency hearing loss occurs.
Indication for exchange transfusion is usually a serum bilirubin greater than 20 mg/dL.
Note: The genetic nomenclature for inheritable hearing loss follows a standardized methodology. Specific gene loci implicated in the development of congenital hearing loss are labeled DFN for “DeaFNess.” The loci are subcategorized to reflect their inheritance pattern: DFNA signifies AD inheritance, while DFNB signifies an AR inheritance. The number behind this notation reflects the sequential order of discovery within each gene locus family. For instance, DFNA1 was the first DFNA locus discovered, DFNA2 the second, etc. It should be noted that the DFN nomenclature solely reflects the pattern of inheritance for that particular locus and does not indicate if the corresponding phenotype is syndromic or nonsyndromic. Furthermore, unique gene variances allow individual genes to be inherited in either AD or recessive fashion. For this reason, certain genes will be given both DFNB and DFNA distinctions.
Seventy percent of genetic hearing loss.
AR inheritance is the most common form (∼80%).
Gene loci nomenclature: DFNB
At least 30 loci identified
Notable loci
DFNB1
– Chromosome 13q12
– Protein: GJB2 (gap junction beta 2)/connexin 26, GJB6/connexin 30
– Function: transmembrane protein subunit of intercellular gap junctions. Facilitates transfer of proteins, ions, and signaling molecules between adjoining cells
– Other: Most common AR inherited cause of genetic hearing loss. Accounts for almost 50% of patients with nonsyndromic deafness and as many as 40% of all hearing loss cases
DFNB2
– Chromosome 11q13
– Protein: MYO7A
– Function: expressed only in the Organ of Corti. Bridges the terocilia to the extracellular matrix
AD next most common (∼20%)
Gene loci nomenclature: DFNA
40 loci identified
Examples
DFNA1
– Chromosome: 5q31
– Protein: DIAPH
– Function: regulation of actin polymerization in hair cells of the inner ear
X-linked next most common form (1%-3%)
Gene loci nomenclature: DFNX
Seven loci identified
30% of genetic hearing loss
This syndrome is estimated to occur in 2% of children with congenital hearing impairment. The syndrome involves branchial characteristics including ear pits and tags or cervical fistula and renal involvement ranging from agenesis and renal failure to minor dysplasia. Seventy-five percent of patients with branchio-oto-renal syndrome have significant hearing loss. Of these, 30% are conductive, 20% are sensorineural, and 50% demonstrate mixed forms. Mutations in EYA1, a gene of 16 exons within a genomic interval of 156 kB, have been shown to cause the syndrome. The encoded protein is a transcriptional activator. The gene has been located on chromosome 8q.
NF presents with café-au-lait spots and multiple fibromas. Cutaneous tumors are most common, but the central nervous system (CNS), peripheral nerves, and viscera can be involved. Mental retardation, blindness, and sensorineural hearing loss can result from CNS tumors.
Neurofibromatosis is classified as types 1 and 2. NF type 1 is more common with an incidence of about 1:3000 persons. Type 1 generally includes many café-au-lait spots, cutaneous neurofibromas, plexiform neuromas, pseudoarthrosis, Lisch nodules of the iris, and optic gliomas. Acoustic neuromas are usually unilateral and occur in only 5% of affected patients. Hearing loss can also occur as a consequence of a neurofibroma encroaching on the middle or inner ear, but significant deafness is rare. The expressed phenotype may vary from a few café-au-lait spots to multiple disfiguring neurofibromas. Type 1 is caused by a disruption of the NF1 gene (a nerve growth factor gene) localized to chromosome 17q11.2.
NF type 2, which is a genetically distinct disorder, is characterized by bilateral acoustic neuromas, café-au-lait spots, and subcapsular cataracts. Bilateral acoustic neuromas are present in 95% of affected patients and are usually asymptomatic until early adulthood. Deletions in the NF2 gene (a tumor suppressor gene) on chromosome 22q12.2 cause the abnormalities associated with neurofibromatosis type 2. Both types of neurofibromatosis demonstrate AD inheritance with high penetrance but variable expressivity. High mutation rates are characteristic of both types of disorder.
Osteogenesis imperfecta is characterized by bone fragility, blue sclera, conductive, mixed, or sensorineural hearing loss, and hyperelasticity of joints and ligaments. This disorder is transmitted as AD disorder with variable expressivity and incomplete penetrance. Two genes for osteogenesis imperfecta have been identified, COLIA1 on chromosome 17q and COLIA2 on chromosome 7q. The age at which the more common tarda variety becomes clinically apparent is variable. van der Hoeve syndrome is a subtype in which progressive hearing loss begins in early childhood.
Otosclerosis is caused by proliferation of spongy type tissue on the otic capsule eventually leading to fixation of the ossicles and producing conductive hearing loss. Hearing loss may begin in childhood but most often becomes evident in early adulthood and eventually may include a sensorineural component.
Otosclerosis appears to be transmitted in an AD pattern with decreased penetrance, so only 25% to 40% of gene carriers show the phenotype. The greater proportion of affected females points to a possible hormonal influence. Recent statistical studies suggest a role for the gene COLIA1 in otosclerosis, and measles viral particles have been identified within otosclerotic foci, raising the possibility of an interaction with the viral genome.
Cleft palate, micrognathia, severe myopia, retinal detachments, cataracts, and marfanoid habitus characterize Stickler syndrome clinically. Significant sensorineural hearing loss or mixed hearing loss is present in about 15% of cases, whereas hearing loss of lesser severity may be present in up to 80% of cases. Ossicular abnormalities may also be present.
Most cases of Stickler syndrome can be attributed to mutations in the COL2A1 gene found on chromosome 12 that causes premature termination signals for a type II collagen gene. Additionally, changes in the COL 11A2 gene on chromosome 6 have been found to cause the syndrome.
Treacher Collins syndrome consists of facial malformations such as malar hypoplasia, downward slanting palpebral fissures, coloboma of the lower eyelids (the upper eyelid is involved in Goldenhar syndrome), hypoplastic mandible, malformations of the external ear or the ear canal, dental malocclusion, and cleft palate. The facial features are bilateral and symmetrical in Treacher Collins syndrome.
Conductive hearing loss is present 30% of the time, but sensorineural hearing loss and vestibular dysfunction can also be present. Ossicular malformations are common in these patients. Inheritance is AD with high penetrance. However, a new mutation can be present in as many as 60% of cases of Treacher Collins syndrome.
The gene responsible for Treacher Collins syndrome is TCOF1 which is located on chromosome 5q and produces a protein named treacle, which is operative in early craniofacial development. There is considerable variation in expression between and within families, suggesting other genes can modify the expression of the treacle protein.
WS accounts for 3% of childhood hearing impairment and is the most common form of AD congenital deafness. There is a significant amount of variability of expression in this syndrome. There may be unilateral or bilateral sensorineural hearing loss in patients, and the phenotypic expressions may include pigmentary anomalies and craniofacial features. The pigmentary anomalies include white forelock (20%-30% of cases), heterochromia irides, premature graying, and vitiligo. Craniofacial features that are seen in Waardenburg syndrome include dystopia canthorum, broad nasal root, and synophrys. All of the above features are variable.
There are four different forms of Waardenburg syndrome, which can be distinguished clinically. Type 1 is characterized by congenital sensorineural hearing impairment, heterochromia irides, white forelock, patchy hypopigmentation, and dystopia canthorum. Type 2 is differentiated from type 1 by the absence of dystopia canthorum, whereas type 3 is characterized by microcephaly, skeletal abnormalities, and mental retardation, in addition to the features associated with type 1. The combination of recessively inherited WS type 2 characteristics with Hirschsprung disease has been called Waardenburg-Shah syndrome or WS type 4.
Sensorineural hearing loss is seen in 20% of patients with type 1 and in more than 50% of patients with type 2. Essentially all cases of type 1 and type 3 are caused by a mutation of the PAX3 gene on chromosome 2q37. This genetic mutation ultimately results in a defect in neural crest cell migration and development. About 20% of type 2 cases are caused by a mutation of the MITF gene (microphthalmia transcription factor) on chromosome 3p. Waardenburg syndrome has also been linked to other genes such as EDN3, EDNRB, and SOX10.
The most common pattern of transmission of hereditary hearing loss is AR, compromising 80% of cases of hereditary deafness. Half of these cases represent recognizable syndromes.
Jervell and Lange-Nielsen syndrome is a rare syndrome consisting of profound sensorineural hearing loss and cardiac arrhythmias. The genetic defect is caused by a mutation affecting a potassium channel gene that leads to conduction abnormalities in the heart.
Electrocardiography reveals large T waves and prolongation of the QT interval, which may lead to syncopal episodes as early as the second or third year of life. The cardiac component of this disorder is treated with beta-adrenergic blockers such as propranolol. An electrocardiogram should be performed on all children with early onset hearing loss of uncertain etiology.
Genetic studies attribute one form of Jervell and Lange-Nielsen syndrome to homozygosity for mutations affecting a potassium channel gene (KVLQT 1) on chromosome 11p15.5, which is thought to result in delayed myocellular repolarization in the heart. The gene KCNE1 has also been shown to be responsible for the disorder.
Pendred syndrome is believed to be the most common syndromic form of congenital deafness. It includes thyroid goiter and profound sensorineural hearing loss. Hearing loss may be progressive in about 10% to 15% of patients. The majority of patients present with bilateral moderate to severe high-frequency sensorineural hearing loss, with some residual hearing in the low frequencies.
The hearing loss is associated with abnormal iodine metabolism (defect in tyrosine iodination) resulting in a euthyroid goiter, which usually becomes clinically detectable at about 8 years of age. The perchlorate discharge test shows abnormal organification of nonorganic iodine in these patients and is needed for definitive diagnosis. Radiological studies reveal that most patients have Mondini aplasia or enlarged vestibular aqueduct.
Mutations in the PDS gene, on chromosome 7q31, have been shown to cause this disorder. The PDS gene codes for the pendrin protein, which is a sulfate transporter. Recessive inheritance is seen in many families, whereas others show a dominant pattern with variable expression. Treatment of the goiter is with exogenous thyroid hormone.
Usher syndrome has a prevalence of 3.5 per 100,000 people; it is the most common type of AR syndromic hearing loss. This syndrome affects about one-half of the 16,000 deaf and blind persons in the United States. It is characterized by sensorineural hearing loss and retinitis pigmentosa (RP). Genetic linkage analysis studies demonstrate three distinct subtypes, distinguishable on the basis of severity or progression of the hearing loss and the extent of vestibular system involvement.
Usher type 1 describes congenital bilateral profound hearing loss and absent vestibular function; type 2 describes moderate hearing losses and normal vestibular function. Patients with type 3 demonstrate progressive hearing loss and variable vestibular dysfunction and are found primarily in the Norwegian population.
Ophthalmologic evaluation is an essential part of the diagnostic workup, and subnormal electroretinographic patterns have been observed in children as young as 2 to 3 years of age, before retinal changes are evident fundoscopically. Early diagnosis of Usher syndrome can have important rehabilitation and educational planning implications for an affected child. These patients may benefit from a cochlear implant.
Linkage analysis studies reveal at least five different genes for type 1 and at least two for type 2. Only type 3 appears to be due to just one gene.
X-linked disorders are rare, accounting for only 1% to 2% of cases of hereditary hearing impairment.
Alport syndrome affects the collagen of the basement membranes of the kidneys and the inner ear, resulting in renal failure and progressive sensorineural hearing loss. The renal disease may cause hematuria in infancy, but usually remains asymptomatic for several years before the onset of renal insufficiency. The hearing loss may not become clinically evident until the second decade of life. Dialysis and renal transplantation have proven important therapeutic advances in the treatment of these patients.
COL4A5, which codes for a certain form of type IV collagen, has been identified as the gene locus for this syndrome. Genetic mutation results in fragile type IV collagen in the inner ear and kidney resulting in progressive hearing impairment and kidney disease.
These collagens are found in the basilar membrane, parts of the spiral ligament, and stria vascularis. Although the mechanism of hearing loss is not known, in the glomerulus there is focal thinning and thickening with eventual basement membrane splitting. Assuming a similar process occurs in the ear, it has been suggested that mechanical energy transmission is likely affected by loss of integrity of the basilar and tectorial membranes.
Classic features of Norrie syndrome include specific ocular symptoms (pseudotumor of the retina, retinal hyperplasia, hypoplasia, and necrosis of the inner layer of the retina, cataracts, phthisis bulbi), progressive sensorineural hearing loss, and mental disturbance. One-third of the affected patients have onset of progressive sensorineural hearing loss beginning in the second or third decade.
A gene for Norrie syndrome has been localized to chromosome Xp11.4, where studies have revealed deletions involving contiguous genes. A number of families have shown variable deletions in this chromosomal region.
Otopalatodigital syndrome includes hypertelorism, craniofacial deformity involving supraorbital area, flat midface, small nose, and cleft palate. Patients are short statured with broad fingers and toes that vary in length, with an excessively wide space between the first and second toe. Conductive hearing loss is seen due to ossicular malformations. Affected males manifest the full spectrum of the disorder and females may show mild involvement. The gene has been found to be located on chromosome Xq28.
Wildervanck syndrome is comprised of the Klippel-Feil sign involving fused cervical vertebrae, sensorineural hearing or mixed hearing impairment, and cranial nerve VI paralysis causing retraction of the eye on lateral gaze. This syndrome is seen most commonly in females because of the high mortality associated with the X-linked dominant form in males. Isolated Klippel-Feil sequence includes hearing impairment in about one-third of cases. The hearing impairment is related to bony malformations of the inner ear.
Mohr-Tranebjaerg syndrome (DFN-1) is an X-linked recessive syndromic hearing loss characterized by postlingual sensorineural deafness in childhood followed by progressive dystonia, spasticity, dysphagia, and optic atrophy. The syndrome is caused by a mutation thought to result in mitochondrial dysfunction.
It resembles a spinocerebellar degeneration called Friedreich ataxia, which also may exhibit sensorineural hearing loss, ataxia, and optic atrophy. The cardiomyopathy characteristic of Friedreich ataxia is not seen in Mohr-Tranebjaerg.
X-linked CMT is inherited in a dominant fashion and is caused by a mutation in the connexin 32 gene mapped to the Xq13 locus. Usual clinical signs consist of a peripheral neuropathy combined with foot problems and “champagne bottle” calves. Sensorineural deafness occurs in some.
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