Funded by the NIH • Developed at the University of Washington, Seattle
Funded by the NIH • Developed at the University of Washington, Seattle
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Authors:
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Richard JH Smith, MD
Guy Van Camp, PhD |
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Initial Posting:
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Last Revision:
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Disease characteristics. Several hundred genes are known to cause hereditary hearing loss and deafness. The hearing loss may be conductive, sensorineural, or a combination of both; syndromic or nonsyndromic; and prelingual (before language develops) or postlingual (after language develops).
Diagnosis/testing. Genetic forms of hearing loss must be distinguished from acquired (non-genetic) causes of hearing loss. The genetic forms of hearing loss are diagnosed by otologic, audiologic, and physical examination, family history, ancillary testing (such as CT examination of the temporal bone), and molecular genetic testing. Molecular genetic tests are available for many types of syndromic and nonsyndromic deafness, often only on a research basis. On a clinical basis, molecular genetic testing is available for the diagnosis of branchiootorenal (BOR) syndrome (EYA1 gene), Mohr-Tranebjaerg syndrome (deafness-dystonia-optic atrophy syndrome; TIMM8A gene), Pendred syndrome (SLC26A4 gene), Usher syndrome type 2A (USH2A gene), Usher syndrome type 3 (one mutation in USH3A), DFNA3 and DFNB1 (GJB2 and GJB6 genes), DFN3 (POU3F4 gene), DFNB4 (SLC26A4 gene), DFNA6/14 (WFS1 gene), DFNA8/12, DFNB9 (OTOF gene), and DFNB21 (TECTA gene). Testing for deafness-causing mutations in the GJB2 gene (which encodes the protein connexin 26) and GJB6 (which encodes the protein connexin 30) plays a prominent role in diagnosis and genetic counseling.
Management. Hereditary hearing loss is managed by a team including an otolaryngologist, an audiologist, a clinical geneticist, and a pediatrician, and sometimes an educator of the Deaf, a neurologist, and a pediatric ophthalmologist. Treatment includes hearing aids and vibrotactile devices; cochlear implantation is considered in children over 12 months of age with severe-to-profound hearing loss. Early auditory intervention through amplification, otologic surgery, or cochlear implantation is essential for optimal cognitive development in children with prelingual deafness; children at risk for hereditary hearing los should receive screening audiometry.
Genetic counseling. Hereditary hearing loss can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive manner, as well as by mitochondrial inheritance. Genetic counseling and risk assessment depend on accurate determination of the specific genetic diagnosis. In the absence of a specific diagnosis, empiric recurrence risk figures, coupled with GJB2 and GJB6 molecular genetic testing results, can be used for genetic counseling.
Hearing loss is described by:
Type
Conductive hearing loss results from abnormalities of the external ear and/or the ossicles of the middle ear.
Sensorineural hearing loss results from malfunction of inner ear structures (i.e., cochlea).
Mixed hearing loss is a combination of conductive and sensorineural hearing loss.
Central auditory dysfunction results from damage or dysfunction at the level of the eighth cranial nerve, auditory brain stem, or cerebral cortex.
Onset
Prelingual hearing loss is present before speech develops. All congenital (present at birth) hearing loss is prelingual, but not all prelingual hearing loss is congenital.
Postlingual hearing loss occurs after the development of normal speech.
Severity of hearing loss. Hearing is measured in decibels (dB). The threshold or 0 dB mark for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. Hearing is considered normal if an individual's thresholds are within 15 dB of normal thresholds. Severity of hearing loss is graded as:
Percent hearing impairment. To calculate the percent hearing impairment, 25 dB is subtracted from the pure tone average of 500 Hz, 1000 Hz, 2000 Hz, 3000 Hz. The result is multiplied by 1.5 to obtain an ear-specific level. Impairment is determined by weighting the better ear five times the poorer ear [JAMA 1979] (see Table 1).
Note: 1) Because conversational speech is at approximately 50-60 dB HL (hearing level), calculating functional impairment based on pure tone averages can be misleading. For example, a 45-dB hearing loss is functionally much more significant than 30% implies. (2) A different rating scale is appropriate for young children, for whom even limited hearing loss can have a great impact on language development [Northern & Downs 2002].
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1. Pure tone average of 500 Hz, 1000 Hz, 2000 Hz, 3000 Hz
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Frequency of hearing loss. The frequency of hearing loss is designated as:
"Hearing impairment" and "hearing loss" are often used interchangeably by healthcare professionals to refer to hearing determined by audiometry to be below threshold levels for normal hearing.
Deaf (small "d"). A colloquial term that implies hearing thresholds in the severe-to-profound range by audiometry.
Deaf culture (always a capital "D"). Members of the Deaf community in the US are deaf and use American Sign Language. As in other cultures, members are characterized by unique social and societal attributes. Members of the Deaf community (i.e., the Deaf) do NOT consider themselves to be hearing "impaired," nor do they feel that they have a hearing "loss." Rather, they consider themselves deaf. Their deafness is not considered to be a pathology or disease to be treated or cured.
Hard of hearing. This term is more functional than audiologic. It is used by the Deaf to signify that a person has some usable hearing — anything from mild to severe hearing loss. In the Deaf community persons who are deaf do not use oral language, while those who are hard of hearing usually have some oral language.
Physiologic tests objectively determine the functional status of the auditory system and can be performed at any age.
Physiologic tests include:
Auditory brainstem response testing (ABR, also known as BAER, BSER). ABR uses a stimulus (clicks) to evoke electrophysiologic responses, which originate in the eighth cranial nerve and auditory brainstem and are recorded with surface electrodes. ABR "wave V detection threshold" correlates best with hearing sensitivity in the 1500- to 4000-Hz region in neurologically normal individuals; ABR does not assess low frequency (<1500 Hz) sensitivity.
Auditory steady-state response testing (ASSR). ASSR is an electrophysiologic measure of hearing acuity used extensively in Australia, Asia, and Canada, and now more frequently in the United States and Europe. Skin electrodes measure whether the auditory response is phase locking to changes in a continuous tonal stimulus. Since the stimulus is a continuous signal, the average sound pressure level that can be delivered is higher than is possible with ABR, which uses click stimuli. This difference means that ASSR can often provide an estimate of hearing sensitivity in children who demonstrate no response to ABR testing.
Evoked otoacoustic emissions (EOAEs). EOAEs are sounds originating within the cochlea that are measured in the external auditory canal using a probe with a microphone and transducer. EOAEs reflect primarily the activity of the outer hair cells of the cochlea across a broad frequency range and are present in ears with hearing sensitivity better than 40-50 dB HL.
Immittance testing (tympanometry, acoustic reflex thresholds, acoustic reflex decay). Immittance audiometry assesses the peripheral auditory system, including middle ear pressure, tympanic membrane mobility, eustachian tube function, and mobility of the middle ear ossicles.
Audiometry subjectively determines how the individual processes auditory information, i.e., hears. Audiometry consists of behavioral testing and pure tone audiometry.
Behavorial testing includes behavioral observation audiometry (BOA) and visual reinforcement audiometry (VRA). BOA is used in infants from birth to age six months, is highly dependent on the skill of the tester, and is subject to error. VRA is used in children from age six months to 2.5 years and can provide a reliable, complete audiogram, but is dependent on the child's maturational age and the skill of the tester.
Pure-tone audiometry (air and bone conduction) involves determination of the lowest intensity at which an individual "hears" a pure tone, as a function of frequency (or pitch). Octave frequencies from 250 (close to middle C) to 8000 Hz are tested using earphones. Intensity or loudness is measured in decibels (dB), defined as the ratio between two sound pressures. 0 dB HL is the average threshold for a normal hearing adult; 120 dB HL is so loud as to cause pain. Speech reception thresholds (SRTs) and speech discrimination are assessed.
Air conduction audiometry presents sounds through earphones; thresholds depend on the condition of the external ear canal, middle ear, and inner ear.
Bone conduction audiometry presents sounds through a vibrator placed on the mastoid bone or forehead, thus bypassing the external and middle ears; thresholds depend on the condition of the inner ear.
Conditioned play audiometry (CPA) is used to test children from age 2.5 to five years. A complete frequency-specific audiogram for each ear can be obtained from a cooperative child.
Conventional audiometry is used to test individuals age five years and older; the individual indicates when the sound is heard.
Audioprofile refers to the recording of several audiograms on a single graph (Figure 1). These audiograms may be from one individual at different times, but more frequently they are from different members of the same family segregating deafness usually in an autosomal dominant fashion. By plotting numerous audiograms with age on the same graph, the age-related progression of hearing loss can be appreciated within these families. Often the composite picture is characteristic of specific genetic causes of autosomal dominant nonsyndromic hearing loss. One of the most characteristic audioprofiles is associated with DFNA6/14/38 hearing loss caused by mutations in WFS1.
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Figure 1
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Other
In children with delayed speech development, the auditory system should be assessed. In the presence of normal audiometry associated with progressive loss of speech and temporal lobe seizures, the diagnosis of Landau-Kleffner syndrome should be considered.
Delayed speech suggesting possible hearing loss can also be seen in young children with autism (see Autism Overview).
Between 1/2000 (0.05%) and 1/1000 (0.1%) children are born with profound hearing loss [Marazita et al 1993 , Cohen & Gorlin 1995]. More than 50% of prelingual deafness is genetic, most often autosomal recessive and nonsyndromic. The disorder DFNB1, caused by mutations in the GJB2 gene (which encodes the protein connexin 26) and the GJB6 gene (which encodes the protein connexin 30), accounts for 50% of autosomal recessive nonsyndromic hearing loss. The carrier rate in the general population for a recessive deafness-causing GJB2 mutation is about one in 33. A small percentage of prelingual deafness is syndromic or autosomal dominant nonsyndromic.
In the general population, the prevalence of hearing loss increases with age. This change reflects the impact of genetics and environment, and also interactions between environmental triggers and an individual's genetic predisposition, as illustrated by aminoglycoside-induced ototoxicity (see Nonsyndromic Hearing Loss and Deafness, Mitochondrial), middle ear effusion, and possibly otosclerosis.
The causes of prelingual deafness in children are outlined in Figure 2 .
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Figure 2. Causes of Prelingual Deafness in Children
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The following text provides an overview of all hereditary hearing loss and deafness.
Acquired hearing loss in children commonly results from prenatal infections from "TORCH" organisms (i.e., toxoplasmosis, rubella, cytomegalic virus, and herpes), or postnatal infections, particularly bacterial meningitis caused by Neisseria meningitidis, Haemophilus influenzae, or Streptococcus pneumoniae. Meningitis from many other organisms, including Escherichia coli, Listeria monocytogenes, Streptococcus agalactiae, and Enterobacter cloacae, can also cause hearing loss. Asymptomatic congenital cytomegalovirus (CMV) infection is often unrecognized and can be associated with variable, fluctuating, sensorineural hearing loss [Harris et al 1984 , Hicks et al 1993 , Schildroth 1994]. Acquired hearing loss in adults is most often attributed to environmental factors, especially noise exposure, but susceptibility probably reflects an environmental-genetic interaction. For example, aminoglycoside-induced hearing loss is more likely in persons with an A-to-G transition at nucleotide position 1555 in the mitochondrial genome (mtDNA). (See Nonsyndromic Hearing Loss and Deafness, Mitochondrial .)
Syndromic hearing impairment is associated with malformations of the external ear or other organs or with medical problems involving other organ systems. Nonsyndromic hearing impairment has no associated visible abnormalities of the external ear, nor are there any related medical problems; however, it can be associated with abnormalities of the middle ear and/or inner ear.
This overview focuses on the clinical features and molecular genetics of common syndromic and nonsyndromic types of hereditary hearing loss. Links are provided to the disorders profiled in GeneReviews.
Over 400 genetic syndromes that include hearing loss have been described [Gorlin et al 1995]. Syndromic hearing impairment may account for up to 30% of prelingual deafness, but its relative contribution to all deafness is much smaller, reflecting the occurrence and diagnosis of postlingual hearing loss. Syndromic hearing loss discussed here is categorized by mode of inheritance.
Autosomal Dominant Syndromic Hearing Impairment
Waardenburg syndrome (WS) is the most common type of autosomal dominant syndromic hearing loss. It consists of variable degrees of sensorineural hearing loss and pigmentary abnormalities of the skin, hair (white forelock), and eyes (heterochromia iridis). Since affected persons may dye their hair, the presence of a white forelock should be specifically sought in the history and physical examination. Four types are recognized — WS I, WS II, WS III, and WS IV — based on the presence of other abnormalities. WS I and WS II share many features but have an important phenotypic difference: WS I is characterized by the presence of dystopia canthorum (i.e., lateral displacement of the inner canthus of the eye) while WS II is characterized by its absence. In WS III, upper-limb abnormalities are present, and in WS IV, Hirschsprung disease is present. Mutations in PAX3 cause WS I and WS III. Mutations in MITF cause some cases of WS II. Mutations in EDNRB, EDN3, and SOX10 cause WS IV.
Branchiootorenal syndrome is the second most common type of autosomal dominant syndromic hearing loss. It consists of conductive, sensorineural, or mixed hearing loss in association with branchial cleft cysts or fistulae, malformations of the external ear including preauricular pits, and renal anomalies. Penetrance is high, but expressivity is extremely variable. In approximately 40% of families segregating a BOR phenotype, mutations in the EYA1 gene can be identified; in a few other families mutations have been found in SIX1 [Ruf et al 2004], consistent with the known interaction of EYA1 and SIX1 proteins in transcription regulation. The BOR phenotype is also caused by mutations in other as-yet-unidentified genes.
Stickler syndrome consists of progressive sensorineural hearing loss, cleft palate, and spondyloepiphyseal dysplasia resulting in osteoarthritis. The syndrome is quite common, and three types are recognized, based on the molecular genetic defect: STL1 (COL2A1), STL2 (COL11A1), and STL3 (COL11A2). STL1 and STL2 are characterized by severe myopia, which predisposes to retinal detachment; this aspect of the phenotype is absent in STL3 because the COL11A2 gene is not expressed in the eye. Causative mutations have been found in the genes causing STL1, STL2, and STL3.
Neurofibromatosis 2 (NF2) is associated with a rare, potentially treatable type of deafness. The hallmark of NF2 is hearing loss secondary to bilateral vestibular schwannomas. The hearing loss usually begins in the third decade, concomitant with the growth of a vestibular schwannoma, and is generally unilateral and gradual, but can be bilateral and sudden. A retrocochlear lesion can often be diagnosed by audiologic evaluation, although the definitive diagnosis requires magnetic resonance imaging (MRI) with gadolinium contrast. Affected persons are at risk for a variety of other tumors including meningiomas, astrocytomas, ependymomas, and meningioangiomatosis. Mutations in NF2 are causative. Molecular genetic testing of the NF2 gene is available for presymptomatic at-risk family members to facilitate early diagnosis and treatment.
Autosomal Recessive Syndromic Hearing Impairment
Usher syndrome is the most common type of autosomal recessive syndromic hearing loss. It consists of dual sensory impairments: affected individuals are born with sensorineural hearing loss and then develop retinitis pigmentosa (RP). Usher syndrome affects over 50% of the deaf-blind in the United States. The vision impairment from retinitis pigmentosa (RP) is usually not apparent in the first decade, making funduscopic examination before ten years of age of limited utility. However, electroretinography (ERG) can identify abnormalities in photoreceptor function in children as young as two to four years of age. During the second decade, night blindness and loss of peripheral vision become evident and inexorably progress.
Three types of Usher syndrome are recognized based on the degree of hearing impairment and result of vestibular function testing.
Pendred syndrome is the second most common type of autosomal recessive syndromic hearing loss. The syndrome is characterized by congenital severe-to-profound sensorineural hearing impairment and euthyroid goiter. Goiter is not present at birth and develops in early puberty (40%) or adulthood (60%). Delayed organification of iodine by the thyroid can be documented by a perchlorate discharge test. The deafness is associated with an abnormality of the bony labyrinth (Mondini dysplasia or dilated vestibular aqueduct) that can be diagnosed by CT examination of the temporal bones. Vestibular function is abnormal in the majority of affected persons. Mutations in SLC26A4 are identified in about 50% of multiplex families. Such genetic testing is appropriate for persons with Mondini dysplasia or an enlarged vestibular aqueduct and progressive hearing loss.
Early studies reported that Pendred syndrome accounted for up to 7.5% of congenital deafness, but contemporary studies suggest that the prevalence of Pendred syndrome is lower; mutations of the SLC26A4 gene are also a cause of nonsyndromic hearing loss (DFNB4).
Jervell and Lange-Nielsen syndrome is the third most common type of autosomal syndromic hearing loss. The syndrome consists of congenital deafness and prolongation of the QT interval as detected by electrocardiography [the abnormal QTc (c=corrected) is greater than 440 msec]. Affected individuals have syncopal episodes and may have sudden death. Although a screening EKG is not highly sensitive, it may be suitable for screening deaf children. High-risk children (i.e., those with a family history that is positive for sudden death, SIDS, syncopal episodes, or long QT syndrome) should have a thorough cardiac evaluation. Mutations in two genes have been described in affected persons.
Biotinidase deficiency is caused by a deficiency in biotin, a water-soluble B-complex vitamin that covalently attaches to four carboxylases essential for gluconeogenesis (pyruvate carboxylase), fatty acid synthesis (acetyl CoA carboxylase), and catabolism of several branched-chain amino acids (propionyl-CoA carboxylase and beta methylcrotonoyl-CoA carboxylase). If biotinidase deficiency is not recognized and corrected by daily addition of biotin to the diet, affected persons develop neurologic features such as seizures, hypertonia, developmental delay, and ataxia, as well as visual problems and some degree of sensorineural hearing loss in at least 75% of children who become symptomatic. Cutaneous features are also present and include a skin rash, alopecia, and conjunctivitis. With biotin treatment, neurologic and cutaneous manifestations resolve; however, the hearing loss and optic atrophy are usually irreversible. Therefore, whenever a child presents with episodic or progressive ataxia and progressive sensorineural deafness, with or without neurologic or cutaneous symptoms, biotinidase deficiency should be considered. To prevent metabolic coma, diet and treatment should be initiated as soon as possible [Heller et al 2002 , Wolf et al 2002].
Refsum disease consists of severe progressive sensorineural hearing loss and retinitis pigmentosa caused by faulty phytanic acid metabolism. Although extremely rare, it is important that Refsum disease be considered in the evaluation of a deaf person because it can be treated with dietary modification and plasmapharesis. The diagnosis is established by determining the serum concentration of phytanic acid. (See also Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum .)
X-Linked Syndromic Hearing Impairment
Alport syndrome is characterized by progressive sensorineural hearing loss of varying severity, progressive glomerulonephritis leading to end-stage renal disease, and variable ophthalmologic findings (i.e., anterior lenticonus). Hearing loss usually does not manifest before age ten years. Autosomal dominant, autosomal recessive, and X-linked forms are described. X-linked inheritance accounts for about 85% of cases, and autosomal recessive inheritance accounts for about 15% of cases. Autosomal dominant inheritance has been reported on occasion.
Mohr-Tranebjaerg syndrome (deafness-dystonia-optic atrophy syndrome) was first described in a large Norwegian family with progressive, postlingual, nonsyndromic hearing impairment. Re-evaluation of this family has revealed additional findings, including visual disability, dystonia, fractures, and mental retardation, indicating that this form of hearing impairment is syndromic rather than nonsyndromic. The gene for this syndrome, TIMM8A, is involved in the translocation of proteins from the cytosol across the inner mitochondrial membrane (TIM system) and into the mitochondrial matrix.
Mitochondrial Syndromic Hearing Impairment
Mitochondrial DNA mutations have been implicated in a variety of diseases ranging from rare neuromuscular syndromes such as Kearns-Sayre syndrome (see Mitochondrial DNA Deletion Syndromes), MELAS , MERRF , and NARP , to common conditions like diabetes mellitus, Parkinson disease, and Alzheimer disease (see Mitochondrial Disorders Overview). One mutation, the 3243 A-to-G transition in the gene MTTL1, has been found in 2% to 6% of individuals with diabetes mellitus in Japan. Sixty-one percent of persons with diabetes mellitus and this mutation have hearing loss. The hearing loss is sensorineural and develops only after the onset of the diabetes mellitus. The same mutation is associated with MELAS , raising questions of penetrance and tissue specificity, issues further confounded by heteroplasmy.
More than 70% of hereditary hearing loss is nonsyndromic [Cremers et al 1991 , van Camp et al 1997]. Disorders discussed in this section are organized by mode of inheritance. The different gene loci for nonsyndromic deafness are designated DFN (for DeaFNess). Loci for genes inherited in an autosomal dominant manner are referred to as DFNA, those for genes inherited in an autosomal recessive manner as DFNB, and those for genes inherited in an X-linked manner as DFN. The number following these designations reflects the order of gene mapping and/or discovery.
Autosomal Dominant Nonsyndromic Hearing Impairment
Family studies of autosomal dominant nonsyndromic hearing loss have shown that heterogeneity is high. Unlike autosomal recessive nonsyndromic hearing loss, which is also extremely heterogeneous but in which the majority of cases are caused by mutations in a single gene in many world populations, a single gene responsible for the majority of cases of autosomal dominant nonsyndromic hearing loss has not been identified. In spite of this limitation, the audioprofile can be distinctive and useful in predicting candidate genes for mutation screening. For example, mutations in WFS1 are found in 75% of families segregating autosomal dominant nonsyndromic hearing impairment that initially affects the low frequencies while sparing the high frequencies. Characteristic audioprofiles are noted in Table 2 , which lists the genes known to be associated with autosomal dominant nonsyndromic hearing impairment.
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Autosomal Recessive Nonsyndromic Hearing Impairment
In many world populations, 50% of persons with autosomal recessive nonsyndromic hearing loss have mutations in GJB2 [Zelante et al 1997 , Estivill et al 1998 , Kelley et al 1998]. The other 50% of cases are attributed to mutations in numerous other genes, many of which have been found to cause deafness in only one or two families [Scott et al 1998]. (See DFNB1 .) Extensive genotype-phenotype studies have shown that it is possible to predict the hearing loss associated with GJB2 mutations based on the specific genotype [Snoeckx et al 2005].
The other 50% of cases are attributed to mutations in numerous other genes, many of which have been found to cause deafness in only one or two families [Zbar et al 1998].
Clinical manifestations and molecular genetics of known genes causing autosomal recessive nonsyndromic hearing impairment are summarized in Table 3 .
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