Genetic sensorineural hearing loss
Sensorineural hearing loss is a type of deafness that occurs as a result of problems either relating to the inner ear itself, or to the nerves connecting the inner ear to the brain, or to the auditory area of the brain.
Genetic sensorineural hearing loss is also known as: congenital deafness; genetic deafness; genetic hearing loss; inherited hearing loss; nonsyndromic hearing loss and syndromic hearing loss.
Hearing loss is the most common disorder of the sensory system, affecting between 1 and 3 in 1,000 children at birth. Severe hearing loss, which occurs prior to acquisition of spoken language (termed prelingual hearing loss), can have profound effects on oral communication. The treatment of severe and profound hearing loss thus remains an important therapeutic challenge. A thorough understanding and appreciation for the genetic mechanisms of hearing loss is paramount to the work-up and management of patients as it informs both diagnostic and therapeutic approaches.
Hearing loss (HL) is broadly classified as sensorineural (SNHL), which is caused by dysfunction of the inner ear, and conductive (CHL), which is caused by the impedance of sound waves from the external and middle ear to the cochlea. Sensorineural hearing losses can in turn be subdivided into acquired (i.e., environmental) and inherited (i.e., genetic) forms. This article will focus upon genetic causes of SNHL. In addition to location of the anatomic defect and the clinical presentation, age of onset and severity of symptoms are two other commonly used classification schemes. Prelingual refers to the onset of hearing loss prior to the acquisition of speech, whereas postlingual represents hearing loss that develops after the acquisition of speech. As noted earlier, this has profound implications on the development of oral communication. Severity of hearing loss is also defined by the degree of hearing impairment as mild (20–40 dB), moderate (41–55 dB), moderately severe (56–70 dB), severe (71–90 dB), and profound (>90 dB).
Genetics of Hearing Loss
There are several mechanisms by which hearing loss can be inherited. Autosomal recessive, where a mutation in both alleles is required to cause disease phenotype, is the most common form. Autosomal dominant, by contrast, only requires that one allele be mutated to lead to the disease phenotype. Xlinked inheritance generally behaves as a recessive trait, however, since males only have one X-chromosome, it manifests at a disproportionally higher rate in men than women. Mitochondrial disorders are inherited viamutations of the mitochondrial DNA and are hence only passed from mother to child.
Clinical Presentation: Syndromic Versus Nonsyndromic Hearing Loss
The classification of hearing loss into several subcategories has important clinical applications. Syndromic hearing losses are those that are associated with additional organ system involvement. In contrast, in nonsyndromic forms of hearing loss, no other clinical features are associated with the hearing deficit. This distinction is important since it can have severe ramifications on the future health of the individual. Indeed, discovery of hearing impairment in children should prompt a thorough investigation for manifestations of a syndromic disorder.
Nonsyndromic Hearing Loss
Nonsyndromic hearing loss accounts for approximately 70% of all hereditary cases of hearing loss (Mina´rik et al. 2012) and to date over 70 loci have been identified in the pathogenesis of nonsyndromic hearing loss (HHL website). Autosomal recessive patterns of inheritance of nonsyndromic hearing loss are the most common, accounting for 75–80% of cases. Autosomal recessive deafness tends to be prelingual, stable and severe, whereas autosomal dominant hearing loss tends to have a postlingual onset, be progressive and less severe (Morton and Giersch 2010). Thus, because autosomal recessive modes of inheritance comprise the largest portion of cases of nonsyndromic hearing loss, approximately 75–80% of cases are prelingual and severe.
Nonsyndromic hearing loss is given a specialized nomenclature. The prefix DFN (shortened for deafness) is given to each gene locus, and is then followed by either A or B, which represent autosomal dominant and autosomal recessive inheritance, respectively. Finally, the order in which the genes were discovered is reflected numerically with an integer number following DFN. For example, DFNB1, the nonsyndromic human form of deafness caused by the Connexin 26 mutation, represents an autosomal recessive mutation, which was the first autosomal recessive locus to be identified. While the gene candidates of many loci have been identified, not all have, and the precise cause of many cases of nonsyndromic deafness remain unknown (Hereditary Hearing Loss website).
Autosomal Recessive Nonsyndromic Hearing Loss
To date, 71 loci have been identified as causing autosomal recessive nonsyndromic hearing loss, of which 41 genes have been cloned (Hereditary Hearing Loss website). The protein products of these genes include ion channels, membrane proteins, transcription factors, and various cytoskeletal elements. Because of the large number of mutations causing autosomal recessive nonsyndromic hearing loss, only the most common DFNB1 will be discussed below.
Autosomal recessive mutations in Connexin 26, causing DFNB1, accounts for 30–40% of all cases of deafness in most populations (Zelante et al. 1997; Denoyelle et al. 1999; Dodson et al. 2011). There are as many as 21 genes belonging to the connexin family, 5 of which are involved in deafness (Connexins-deafness, homepage, http://davinci.crg.es/deafness). Connexins are a homogeneous family of transmembrane proteins which are expressed in a variety of tissues and play a role in intercellular signaling by forming channels called gap junctions, which are especially prevalent in the auditory epithelium and cardiac myocytes. The mutant gene in DFNB1 is GJB2, which has been mapped to chromosome 13. As the genotype is highly variable by population, phenotype can also vary in severity from moderate to profound deafness depending on mutation type (Gurtler 2012).
Autosomal Dominant Nonsyndromic Hearing Loss
Fifty-four loci have been identified which cause autosomal dominant nonsyndromic hearing loss, from which 25 genes have been cloned (Hereditary Hearing Loss website). As a general rule, most autosomal dominant forms of nonsyndromic hearing loss are postlingual, whereas most cases of autosomal recessive nonsyndromic hearing loss are prelingual (Hildebrand et al. 2010).
X-Linked and Mitochondrial Nonsyndromic Hearing Loss
Together, X-linked and mitochondrial inheritance patterns account for less than 5% of causes of nonsyndromic hearing loss. Five loci and three genes have been mapped for the X-linked form and seven loci and several gene point-mutations have been identified for the mitochondrial form (HLL website). Mitochondrial nonsyndromic deafness is of particular clinical relevance because the A1555G mutation in 12S rRNA is believed to predispose to aminoglycoside-induced deafness in addition to nonsyndromic hearing loss (Prezant et al. 1993; Estivill et al. 1998).
Syndromic Hearing Loss
In contrast to the more commonly seen nonsyndromic forms of hearing loss, syndromic hearing loss accounts for about 30% of inheritable hearing loss. The term syndromic hearing loss refers to hearing loss that presents with a constellation of other systemic findings. The severity of hearing loss varies across different syndromes, ranging from minor cases of hearing impairment to profound deafness. Like nonsyndromic deafness, syndromic forms can also be inherited in autosomal recessive, autosomal dominant, X-linked, and mitochondrial patterns. A discussion of some of the more common syndromes follows.
Autosomal Recessive Syndromic Hearing Loss
Pendred syndrome is the most common form of syndromic deafness, and accounts for almost 10% of all cases of hereditary hearing loss (Everett et al. 1997; Dror et al. 2011). Pendred syndrome is most commonly caused by a mutation in SLC26A4 – a gene encoding pendrin – an anion transporter present in the kidney, thyroid, and inner ear (Genetics Home Reference 2012; Everett et al. 1997; Dror et al. 2011). As such, patients present with varying severity of sensorineural hearing loss, bilateral enlargement of the vestibular aqueducts and endolymphatic sacs as well as thyroid goiter, which may develop later in life. Of note, mutations in SCL26A4 have also been isolated as a cause of nonsyndromic hearing loss in DFNB4 (Dror et al. 2011).
Usher syndromes are a very common cause of autosomal recessive syndromic hearing loss and are the most common disorders affecting hearing and vision, accounting for approximately 50% of all deafnessblindness cases (NIDCD website; Bonnet and El-Amraoui 2012). Three subtypes of Usher syndrome have been identified, termed USH1, USH2, and USH3, that have varying degrees of early onset, hearing and vestibular dysfunction and retinitis pigmentosa, a progressive degeneration of the retina (Bonnet and El-Amraoui 2012). USH1 is characterized by profound bilateral deafness accompanied by severe vestibular dysfunction which present at birth. Retinitis pigmentosa generally manifests as decreased night vision and becomes apparent before age 10. In contrast to USH1, USH2, and USH3 are characterized by normal to near normal vestibular function. USH2 has moderate to severe hearing loss at birth with normal vestibular function and retinitis pigmentosa that manifests later in childhood closer to the teenage years. USH3 children are born with normal hearing at birth, with progressive impairment throughout childhood and teenage years. Like the hearing deficits, severity of vision impairment also varies with problems generally arising by the teenage years (Bonnet et al. 2011). Of note, like Pendred syndrome, gene mutations causing Usher syndrome are also responsible for nonsyndromic hearing loss.
Jervell and Lange-Nielsen Syndrome
Jervell and Lange-Nielsen syndrome (JLNS) classically involves sensorineural hearing loss and elongated QTc on electrocardiogram (EKG) testing (>500 ms). The prolongation of QTc predisposes to syncope from ventricular tachyarrhythmias, most notably torsades de pointes. JLNS should be distinguished from the closely related and more common Romano-Ward syndrome, which lacks sensorineural hearing loss. The genetic cause of JLNS has been localized to two genes, KCNQ1 and KCNE1, which encode subunits of potassium channels expressed in cardiac and auditory tissue (OMIM #220400). Because of JLNS, newborns and children diagnosed with a sensorineural hearing loss should be screened with an EKG.
Autosomal Dominant Syndromic Hearing Loss
As the name implies, branchio-oto-renal (BOR) syndrome is characterized by the constellation of branchial arch, otologic, and renal defects. Unlike other hearing loss syndromes discussed thus far, otologic involvement in BOR may affect the external, middle or inner ear, and as a result hearing loss can be sensorineural, conductive, or mixed. Major otologic manifestations generally include preauricular pits and external ear abnormalities as well as a lower incidence of microtia, ossicular malformation, and cochlear hypoplasia (Chang et al. 2004). Branchial anomalies manifest as fistulae, pits, or sinuses, while renal abnormalities are extremely variable and can range from renal hypoplasia to complete agenesis. Mutations have been isolated to three different genes – EYA1 as well as two additional genes SIX1 and SIX5 (OMIM), which act to regulate organogenesis.
Waardenburg syndrome is a rare autosomal dominant syndrome characterized by sensorineural hearing loss, and pigmentation abnormalities of the eyes, skin and hair, including the classic “white forelock” and iris pigmentary disturbances (Zhang et al. 2012). There are four clinically described subtypes of Waardenburg syndrome with slight variations in clinical features and different responsible genes.
X-Linked Recessive Syndromic Hearing Loss
Alport syndrome is caused by a hereditary defect in the synthesis of type IV collagen, resulting in sensorineural hearing loss, nephritis, and ocular defects. While predominantly X-linked recessive, it can also occur by autosomal transmission (Artuso et al. 2012). Type IV collagen is a principal component of the basement membrane, and thus its mutation causes defective glomerular basement membrane formation, which leads to gross or microscopic hematuria and eventually end-stage renal disease. Ocular manifestations include anterior lenticonus, perimacular flecks, and corneal lesions. Several genes have been identified, COL4A5, which encodes the a5 chain of type IV collagen, is inherited via X-linked recessive transmission. Mutations in COL4A3 and COL4A4, which encode a3 and a4 chains, respectively, are also implicated in the pathogenesis of Alport syndrome, but are transmitted by autosomal recessive inheritance.
The evaluation of child with significant hearing loss should ideally take place by a multidisciplinary team involving geneticists, audiologists, and otolaryngologists as well as other specialists depending on the systemic findings. A complete clinical history including details about the pregnancy and postpartum periods can help identify environmental causes such as intrauterine infections, which are known to cause hearing loss. A well-documented family history including evidence of consanguinity is also important for the evaluation of possible inheritable forms of hearing loss. A well-performed physical exam is also necessary to evaluate for cases of syndromic hearing loss, which, as previously discussed, can affect a wide range of organ systems. For reasons explained above, thorough evaluation of the head and neck, endocrine, renal, and cardiac systems are necessary. Because of the common association of otologic and ophthalmologic manifestations, a thorough eye examination should also be performed on children with hearing loss.
Newborn Hearing Screening
Newborn hearing screening programs have played an instrumental role in the diagnosis of infants born with hearing impairment. Technological advances have also facilitated this increase in prominence of the hearing test, as they have made it possible to make audiologic diagnosis at an earlier age. In fact, the development of technologies such as evoked otoacoustic emissions and auditory brainstem response testing has substantially reduced the number of infants falsely identified as having hearing impairment (i.e., false positives), and likewise increased the number of infants correctly identified as having hearing impairment (i.e., true positives) (Norton et al. 2000). Additionally, because not all forms of inheritable hearing impairment manifest immediately at birth, routine screening and follow-up throughout childhood are necessary to ensure timely diagnosis. Screening typically takes the form of an otoacoustic emissions test in the nursery with a follow-up scheduled for several weeks if the child fails the test. Confirmation with auditory brainstem evoked testing ensues if the loss persists.
As previously discussed, genetic causes are implicated in about 50% of cases of hearing loss in children, providing a rationale for genetic testing in infants born with congenital hearing loss.
As more culprit genes are discovered, the battery of genetic tests that could potentially be ordered by clinicians continues to grow. However, it is important that genetic screening be done in a reproducible and efficient manner. If syndromic hearing loss is suspected based on the constellation of symptoms, gene-specific mutation screening should be done to confirm the etiology. In cases where nonsyndromic hearing loss is suspected, environmental causes (i.e., intrauterine infection with CMV or rubella) should first be ruled out with the proper serologic testing. In the absence of serologic evidence of intrauterine infection, genetic testing for GJB2 is advisable (ACMG statement: Genetic evaluation of congenital hearing loss expert panel, from ACMG website). Because of the high prevalence of DFNB1, the autosomal recessive mutation in the connexin26 gene GJB2, it is prudent to screen for this mutation first. Additionally, the choice and order of genetic tests will depend on the pedigree constructed by the medical geneticist, as the inheritance pattern of hearing impairment can inform the diagnostic approach to a certain extent. Computed tomography scans can also be used to visualize the temporal bones. In cases where vestibular aqueducts appear dilated, genetic screening for Pendred syndrome is warranted, given that it is another common cause of inherited deafness. Most importantly, it must be conveyed to patients that a negative genetic test does not rule out a genetic cause for the hearing loss. Lastly, an EKG is recommended due to the remote possibility of Jervell and Lange-Nielsen syndrome.
The Molecular Approach: Utility of the Mouse Model
The vast numbers of transgenic mice that have been created and studied has contributed greatly to the understanding of auditory function. Mouse models of deafness have emerged in part because genetic linkage analyses are difficult to execute in small families and histologic observation of the human cochlea is only possible in postmortem studies. Thus, many investigators are turning to the mouse model to answer molecular and genetic questions related to hearing loss.
In depth histologic, immunohistochemical, and electronmicroscopic examinations of cochleae have allowed for a more concrete understanding of the functions of the inner ear and the repercussions of single ormultiple gene mutations. Additionally, molecular studies have allowed for proper identification of the genes involved,which has helped pave the way for therapeutic approaches.
As technology and genomics continue to evolve, so too will the capacity to deliver targeted therapies for genetic causes of hearing loss.
Hearing loss is an objective finding that can be confirmed with formal audiologic techniques such as pure tone audiometry as well as electrophysiological modes such as measured acoustic brainstem responses (ABR). Once confirmed, the differential diagnosis includes all genetic and environmental causes of hearing loss. Conductive hearing loss must be differentiated from sensorineural and mixed forms. Disruption of the external or middle ear canal can lead to a conductive hearing loss. In addition to genetic forms of sensorineural hearing loss other congenital forms can be caused by prenatal infectious etiologies, structural malformations, or ototoxic trauma.
Because of the variable genetic mechanisms of sensorineural hearing loss, the best prevention can be achieved by appropriate screening of potential parents. As discussed, autosomal recessive forms of hearing loss are generally from parents who are asymptomatic, thus a thorough genetic screening of couples with a history of hereditary hearing impairment is warranted.
The general approach to treatment should closely follow the suspected diagnosis. In cases where multiorgan syndromic involvement is apparent, treatment and proper follow-up of associated comorbidities is paramount. In cases of nonsyndromic hearing loss, this is less of a concern.
An important issue that must be considered is the approach to genetic counseling. Because many deaf infants are born to non-deaf parents, it is extremely important to ensure information is delivered by the most qualified health care professional. In these circumstances, it is advisable to consult a medical geneticist who can accurately relay recurrence risk to the parents.
Currently, the two main treatment possibilities for patients with significant hearing loss are hearing aids and cochlear implants.
Hearing aids amplify ambient sounds to the cochlea and are helpful in patients with mild to severe sensorineural hearing losses. The three general types of hearing aids include behind the ear (BTE), in the ear (ITE), and completely within the canal (CIC) aids. The location depends on the severity of the hearing loss as well as the functionality of the patient. For example, hearing aids completely in the canal are less desirable for young children because of the risk of damage to the ear.
For patients with severe to profound hearing loss, cochlear implantation is an excellent option (Kral and O’Donoghue 2010). It is an internally implantable electronic device that directly stimulates the auditory nerve afferent fibers, bypassing the damaged organ of Corti. Implants do not completely restore “normal” hearing, but they can provide significant benefit for speech understanding. Studies have clearly demonstrated that appropriately placed cochlear implants in children born with deafness can provide near-normal to normal speech and language development, and younger implantation leads to steeper growth rates of vocabulary (Svirsky et al. 2004; Hayes et al. 2009).
Timing of initiation of rehabilitation is also critical. Hearing amplification should be instituted as soon as possible. The Joint Committee on Infant Hearing recommended in 2007 the initiation of rehabilitation no later than 6 months of age to minimize the impact on language development (JCIH 2007). Studies have also documented that earlier cochlear implantation (under 18 months) results in markedly improved performance compared to children implanted later in life (Kral and O’Donoghue 2010).
Genetic sensorineural hearing loss comprises approximately 50% of congenital cases of hearing loss, and is a problem with social, economic, and medical repercussions. As has been discussed, there are several causes of genetic hearing loss and proper identification is necessary to prevent untoward health complications. Prognosis is highly dependent upon etiology and severity of hearing loss, but as discussed above, early intervention has shown promise for improvement (Kral and O’Donoghue 2010). A well-coordinated approach by a comprehensive medical staff is crucial to the delivery of adequate medical care to patients with hearing loss from genetic causes.
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