Hereditary hearing loss and deafness

Definition

Hereditary hearing loss and deafness refers to the genetically caused loss or partial impairment of the ability to hear. It is estimated that 50% of congenital and severe early onset deafness occurs due to genetic causes.

Description

Genetic forms of hearing loss may be distinguished as prelingual (beginning before speech develops) or postlingual (beginning after speech develops). These hearing losses can be progressive, in which the hearing impairment increases with time, or, non-progressive, in which the hearing loss is stable over time. Each ear (bilateral) or only one ear (unilateral) may be affected, and the hearing loss may be equal in both ears (symmetric) or different in each ear (asymmetric). Hearing loss may be the only finding the affected person has (nonsyndromic hereditary hearing loss) or the hearing loss may be associated with other physical differences associated with a specific genetic syndrome (syndromic hereditary hearing loss). Hereditary hearing losses cover the entire range from mild hearing loss to total deafness.

Hearing loss can additionally be typed as conductive, sensorineural, or mixed type. Conductive hearing loss results from a blockage of the auditory canal or some other dysfunction of the eardrum or one of the three small bones within the ear (the stapes, the malleus, and the incus) that are responsible for collecting and transmitting sound. In conductive hearing loss, the auditory nerve is normal. Sensorineural hearing loss results from a dysfunction of the auditory nerve. Mixed-type hearing loss involves both conductive and sensorineural types of hearing impairment.

In normal hearing, sound vibrations enter the large fleshy external part of the ear (the pinna) and travel down the auditory canal striking the eardrum (tympanic membrane), which begins to vibrate. As this membrane vibrates, it touches the first of a series of three small bones (the malleus, the incus, and the stapes) that mechanically transfer the vibrations to the cochlea. The cochlea is a fluid-filled tube that bends back on itself such that the two open ends lay one on top of the other. One end is covered by a membrane called the oval window, while the other end is covered by a membrane called the round window. It is the oval window that is struck by the stapes. Since the cochlea is filled with fluid, the oval window cannot vibrate without the assistance of the round window: As the oval window is pushed in by the stapes, the round window bulges out; as the oval window oscillates out, the round window bulges inward.

The vibrations imparted to the oval window by the stapes striking the round window are picked up by the organ of Corti within the cochlea. It is this structure that is the true receptor, in a nerve sense, of sound waves. The organ of Corti consists of hair cells embedded in a gelatinous membrane (the tectorial membrane) that rests on a basilar membrane. Sensory neurons terminate on the hair cells of the organ of Corti. Vibration of the fluid in the cochlea causes the basilar membrane to move, which causes the hairs to bend, creating an electrical signal. This is picked up by the sensory neurons and then transferred to the auditory nerve (or cochlear nerve), which sends the signal to the brain.

The ear is also involved in maintaining balance. As a result, many individuals affected with hearing loss may also have balance problems. Body position, body movement, and balance are assisted by the vestibular apparatus of the inner ear, which consists of three functional parts. Two of these, the saccule and the utricle, signal what the body position is relative to gravity. The third structure of the vestibular apparatus is the semicircular canal, of which there are three in each ear. These canals contain structures (ampulae) that detect movement of the internal fluid of the canals as the head moves. Most hearing-impaired people with balance problems experience difficulties with the proper functioning of the semicircular canals. Since the function of these canals is partially duplicated by the functioning of the saccule and the utricle, most individuals can "learn" to use these other systems to compensate for the dysfunction in the semicircular canals. Therefore, balance problems associated with hearing loss usually diminish over time.

Syndromic hearing loss

The term syndromic hearing loss is used when a person shows hearing loss in addition to other physical differences such as malformations of the external ear or other medical problems related to the hearing loss. Syndromic hearing loss constitutes approximately 30% of genetic hearing loss. Over 400 different genetic syndromes that include hearing loss have been described. Syndromic hearing loss is generally classified by the overall syndrome that leads to hearing impairment. Some of the more common genetic syndromes associated with hearing loss include Waardenburg syndrome , Usher syndrome , Jervell and Lange-Nielsen syndrome , and Alport syndrome. In these syndromes, hearing loss is associated with various other abnormalities. In Waardenburg syndrome, hearing loss occurs in conjunction with pigment differences in the skin, eyes, and hair. In Usher syndrome, hearing loss is associated with eye abnormalities that progress to blindness. In Jervell and Lange-Nielsen syndrome, hearing loss is associated with heartbeat abnormalities. In Alport syndrome, hearing loss is associated with kidney abnormalities.

Nonsyndromic hearing loss

The term nonsyndromic hearing loss is used when a person shows hearing loss with no other associated physical differences and no associated medical problems. Persons with nonsyndromic hearing loss will not have any visible abnormalities of the external ear; however, they may have abnormalities of the inner and/or middle ear. Nonsyndromic hearing loss constitutes approximately 70% of genetic hearing loss. Nonsyndromic hearing loss is generally classified by the age of onset, the type and degree of audiological impairment, the progressive or nonprogressive nature of the impairment, and the mode of inheritance . Nonsyndromic prelingual hearing loss is most frequently of the sensorineural type and most frequently inherited in an autosomal recessive pattern.

Otosclerosis is the most common form of nonsyndromic progressive conductive hearing loss in adults. It is caused by a growth of the spongy bone tissue in the middle ear that prevents the ossicles (malleus, incus, stapes) from being able to move as well as they once did. In certain advanced cases of otosclerosis, there may also be damage to the auditory nerve (sensorineural hearing loss). Otosclerosis may be observed in teenagers, but it is generally first observed in people between the ages of 20 and 50. It is very rare for otosclerosis to occur past the age of 50.

Dominant progressive hearing loss (DPHL) and prebycusis (hearing loss related to aging) are the most common forms of nonsyndromic progressive sensorineural hearing loss. DPHL tends to have an earlier age of onset than prebycusis, but this is highly variable between families. Within families, the age of onset of DPHL is generally fairly constant. The typical age of onset of DPHL is early childhood, but in some families it does not show symptoms until early or middle adulthood. Some individuals affected with DPHL also have problems with balance because of an alteration of the semicircular canal structures within their inner ears. These balance problems are not observed in other individuals with DPHL, suggesting that DPHL is caused by more than one gene or gene mutation. Prebycusis is not thought to be due to genetic causes. It is the most common form of hearing loss, and everyone who lives beyond a certain age develops it to some degree. Prebycusis is thought to be caused by the combined effects of aging and the noises from the environment that a person has been exposed to. People who live, work, or entertain themselves in loud environments generally develop prebycusis to a greater degree than those people who exist in quieter surroundings.

Genetic profile

Hearing loss is genetically heterogeneous. This means that nonrelated persons with genetic hearing loss may have hearing loss due to problems in different genes. Also, persons with genetic hearing loss in one family may show differing symptoms from each other. Additionally, different changes in the same gene may cause syndromic hearing loss in one family and nonsyndromic hearing loss in another family. As of early 2005, more than 100 separate genes associated with hearing loss have been identified. This number is expected to increase markedly as the genetic mutations causing the more than 400 syndromes associated with hearing loss are identified.

Hearing loss can be inherited in different patterns: autosomal dominant inheritance, autosomal recessive inheritance, X-linked inheritance, and mitochondrial inheritance. Approximately 75–80% of nonsyndromic hereditary hearing loss is due to mutations that are autosomal (non-X linked) recessive. Approximately 20% are due to autosomal dominant gene mutations . The rare remaining cases of nonsyndromic hereditary hearing loss are attributed to X-linked (about 1%) and mitochondrial disorders (about 1%).

Autosomal dominant hearing loss

Individuals with an autosomal dominant form of hereditary hearing loss have a 50% chance to pass on the gene for the hearing loss in each pregnancy, regardless of the sex of the parent or child. Most persons with this type of hereditary hearing loss have an affected parent; however, this can occur as a new problem in an individual with no family history. In that case, the affected person then has a 50% chance to pass the hearing loss to each of their children.

Otosclerosis is inherited in an autosomal dominant pattern. Otosclerosis shows reduced penetrance. A dominant condition with complete penetrance should show symptoms of the gene mutation in all individuals possessing the mutation (100% penetrance). However, because of the age-related symptoms of otosclerosis, many individuals possessing the genetic mutation known to cause otosclerosis do not have any symptoms of the disease. Similarly, when obtaining a family history, it is very possible that individuals from previous generations died of other causes prior to showing any signs of being affected with otosclerosis. Otosclerosis has been associated with different genetic locations on four chromosomes: 15, 7, 6, and 3. As of early 2005, no genes for otosclerosis have been identified.

The locations of the genes associated with nonsyndromic autosomal dominant deafness are designated as DFNA loci. By early 2005, 21 deafness-causing genes have been isolated at 18 DFNA loci. No single gene accounts for a majority of nonsyndromic autosomal dominant hearing loss.

Waardenburg syndrome is the most common autosomal dominant form of syndromic hereditary hearing loss. Even in a single family, each affected family member may show varying features of the syndrome. Affected persons may show white patches of skin or hair, differently colored eyes, widely spaced eyes, and/or sensorineural hearing loss in varying degrees. Waardenburg syndrome is differentiated into four types according to other abnormal features. Types I and III of Waardenburg syndrome are caused by mutations in the PAX3 gene. Some cases of Waardenburg syndrome Type II are associated with mutations in the MITF gene. Waardenburg syndrome Type IV has been associated with mutations in three genes: EDNRB, EDN3, and SOX10.

The second most common autosomal dominant form of syndromic hereditary hearing loss is branchiootorenal syndrome (BOR syndrome). Persons with branchiootorenal syndrome have varying symptoms which that differ between affected family members. Affected persons may have sensorineural, conductive, or mixed-type hearing loss, along with abnormalities of the external ear, cysts on the neck, and/or kidney problems. Mutations in the EYA1 gene located on chromosome 8 have been found in about 40% of patients with BOR syndrome. Still other families with BOR syndrome show mutations in the SIX1 gene on chromosome 14. Other genes responsible for BOR syndrome have not yet been characterized.

Autosomal recessive hearing loss

Individuals with an autosomal recessive form of hereditary hearing loss have inherited hearing loss genes from both their mother and their father. Most persons with autosomal recessive hereditary hearing loss do not have parents with hearing loss. In most cases, the parents simply carried silent genes for hearing loss that never caused them problems.

Most of hereditary hearing loss is nonsyndromic and autosomal recessive. The locations of the genes associated with nonsyndromic autosomal recessive deafness are designated as DFNB loci. As of early 2005, 21 deafness-causing genes have been isolated at 19 different DFNB loci. Mutations, or changes, in one gene, the GJB2 gene located at DFNB1 on chromosome 13, account for 50% of all autosomal recessive nonsyndromic hearing loss. GJB2 mutations have been found to account for 30% of hereditary hearing loss where there is no family history. It is estimated that at least 3% of persons with normal hearing carry a silent mutation in one of their GJB2 genes. If a mother and father each are unaffected carriers of a mutation in GJB2, then they have a 25% chance to have a child with hearing loss in each pregnancy.

The most common type of autosomal recessive syndromic hearing loss is Usher syndrome. Persons with Usher syndrome are born with severe sensorineural hearing loss. They later develop retinitis pigmentosa , which is degeneration of the retina, the light sensitive layer of tissue at the back of the inner eye. This leads to visual problems and sometimes total blindness. Usher syndrome is the cause for 50% of cases where people are both deaf and blind. Usher syndrome is estimated to account for 3–6% of all congenital deafness. Usher syndrome has been divided into three types based on the severity of symptoms. The more severe Usher syndrome type I is characterized by vestibular dysfunction and retinal degeneration beginning in childhood. Usher syndrome type I has been localized to seven different chromosomal regions and from these regions five distinct genes have been identified thus far. These genes are designated as USH1B, USH1C, USH1D, USH1F, and USH1G. The moderate Usher syndrome type II is characterized by normal vestibular function and later onset of retinitis pigmentosa. Usher syndrome type II has been localized to three different chromosomal regions; but thus far, from these three regions only one gene, USH2A, has been isolated. The milder Usher syndrome type III is characterized by progressive hearing loss. Usher syndrome type III has been localized to the long arm of chromosome 3, but the gene has not yet been identified.

Pendred syndrome is the second most common type of autosomal recessively inherited hearing loss syndrome. Persons with Pendred syndrome have severe sensorineural hearing loss that is present at birth or it may develop in early childhood. They then develop a goiter, an enlarged thyroid gland, either in puberty or adulthood. In about half of persons with Pendred syndrome, a mutation can be found in the SLC26A4 gene.

X-linked hearing loss

Individuals with X-linked hearing loss have inherited a gene for hearing loss on the X chromosome. Females have two X chromosomes, whereas a male has an X and a Y chromosome. In the case of an X-linked recessive cause for hearing loss, the vast majority of affected persons are male. Females may be carriers, but they will rarely be affected. In the case of an X-linked dominant cause for hearing loss, all of the daughters of an affected father will show the disorder because all must inherit their father's X chromosome to be female.

The chromosomal locations associated with nonsyndromic X-linked deafness are designated as DFN loci. As of early 2005, four chromosomal locations have been associated with X-linked nonsyndromic hearing loss; however, thus far, the only locus that has had a gene identified is DFN3. The identified gene, POU3F4, is located on the long arm of the X chromosome. Persons with mutations at the DFN3 locus show mixed-type hearing loss. The conductive portion of their hearing loss is caused by abnormal attachment of one of the tiny internal ear bones, specifically, the stapes.

Alport syndrome is one example of an X-linked form of syndromic hearing loss. Males with X-linked Alport syndrome always show progressive kidney problems that lead to kidney failure and early death. Many males with X-linked Alport syndrome will develop progressive sensorineural hearing loss beginning after age 10. Additionally, males with X-linked Alport syndrome may have an abnormality in the shape of the lens called anterior lenticonus. Females with X-linked Alport syndrome may also have kidney problems and deafness, but females are expected to have a later onset and less rapid progression of these problems.

Mitochondrial hearing loss

While most genetic data is carried on the chromosomes in the nucleus of the cell, there is also a tiny amount of DNA in the mitochondria of cells. The method of inheritance of mitochondrial abnormalities is nearly exclusively maternal (through the mother). The mitochondria that develop in a human are almost all produced by replication of the maternal mitochondria from the egg, or ovum. The sperm contains almost no mitochondria. The percentage of hereditary hearing loss due to abnormalities in mitochondrial DNA is estimated to be around 1%. Hearing loss due to mitochondrial inheritance shows highly variable penetrance and may be either syndromic or nonsyndromic.

Nonsyndromic mitochondrial hearing loss is associated with mutations in either the mitochondrial MTRNR1 gene or the mitochondrial MTTS1 gene. Nonsyndromic mitochondrial hearing loss varies from moderate to profound. One specific mutation in MTRNR1 has been reported in families with nonsyndromic hearing loss and in families with hearing loss induced by exposure to a certain class of antibiotics, the aminoglycosides. If persons with this specific MTRNR1 mutation do not have exposure to an aminoglycoside antibiotic, then they show hearing loss with a median age at onset of 20 years. If persons with this specific mutation are exposed to this class of antibiotics, then they develop hearing loss within a few days to weeks of taking the medication. Persons with hearing loss due to MTTS1 mutations often present with hearing loss beginning in childhood.

Syndromic mitochondrial hearing loss is more common than nonsyndromic mitochondrial hearing loss due to the function of the mitochondria themselves. Because the mitochondria are responsible for energy production, faulty mitochondria result in decreased energy production. This lower level of energy production greatly affects the parts of the body that use most energy, including the brain, heart, and muscles. Therefore people with mitochondrial disorders will generally show a spectrum of physical symptoms, including nervous system problems, visual problems, hearing loss, and muscle weakness. MELAS, MERRF, and Kearns-Sayre syndromes all represent mitochondrial syndromes that include hearing loss.

Demographics

Hearing loss is estimated to affect two to three out of 1,000 babies born in the United States. The incidence of hearing loss increases with age. Approximately 17 out of 1,000 children under age 18 have hearing loss. Of people who are over 65 years old, the incidence of hearing loss is approximately 314 per 1,000. Of people who are 75 years old or older, 40–50% have hearing loss.

Approximately 85–90% of deaf individuals marry another deaf person. Ninety percent of deaf couples have children with normal hearing and 90–95% of deaf children have parents with normal hearing. In general, if a hearing couple has a child with profound childhood deafness of unknown cause, then their risk in each future pregnancy to have another child with hearing loss is approximately one in six.

It is estimated that approximately 10% of the population of the United States has partial hearing loss or deafness. This number is higher worldwide because many nongenetic causes of hearing loss are more prevalent outside of the United States. These nongenetic causes of hearing impairment or loss include rubella, premature birth, meningitis, and incompatibility in the Rh blood factor between mother and fetus.

From studies of pupils at schools for the deaf in the United States, it is estimated that approximately 50% of childhood hearing impairment is genetically based. Another 20–25% of cases are attributed to environmental factors. The remaining 25–30% of cases are classified as of unknown cause.

Otosclerosis is estimated to affect between 10% and 18% of all white and Hispanic women, and between 7% and 9% of all white and Hispanic men. People of Asian descent are affected with otosclerosis at about half the rate seen in whites and Hispanics, with the same observed sex differences. In blacks, only about 1% of the total population is affected with otosclerosis, with minimal differences between males and females. Otosclerosis is exceedingly rare in people of Native American descent.

Signs and symptoms

Syndromic types of hearing loss are generally characterized by the findings and symptoms additional to hearing loss that are associated with the particular syndrome.

Otosclerosis is characterized by an initial loss of hearing in the low frequencies, followed by a loss of the high frequencies, then a loss of the middle frequencies. It may rapidly advance through these stages in some affected individuals, while in other people it may stabilize for a period of years before progressively worsening. Many affected individuals have symptoms only in one ear at first, but otosclerosis almost inevitably will affect both ears. The maximum hearing loss due to otosclerosis without involvement of the auditory nerve is in the moderate range. As an affected person ages and the auditory nerve becomes involved, the hearing loss may progress to severe, or even profound, when this person reaches their 60s and 70s.

There are four main categories of DPHL: early onset, high frequency, mid frequency, and low frequency. Early-onset types of DPHL tend to occur in early childhood and progress at varying rates to deafness. The other three types are categorized by the frequency range in which hearing loss first occurs.

Diagnosis

Hearing is generally tested using earphones. Sounds are sent into the earphones at various decibel and frequency levels. This test allows the observer to determine the amount of hearing loss in decibels and the range of hearing loss in hertz. Since hearing loss is not necessarily the same in both ears, each ear is tested independently. If a hearing loss is found using this simple test, another test is then performed to determine whether the hearing loss is of the conductive or sensorineural type. A device called a bone vibrator is used in place of the earphones. The bone vibrator sends auditory signals through the bones of the ear, bypassing the ear canal and the ossicles of the middle ear. In the case of conductive hearing loss, the affected individual will be able to hear sounds at a lower decibel level using the bone vibrator than using the earphones. In the case of sensorineural hearing loss, the affected individual will generally hear sounds through the bone vibrator at the same decibel level as using the earphones.

Hearing loss is categorized by determining the hearing threshold of the affected person. The hearing threshold is the amount of sound that that individual can just barely hear. The hearing threshold of an individual is the hearing level (HL) of that person. It is measured in decibels (dB). A person with up to a 25 dB HL is categorized as having normal hearing. Mild hearing loss is defined as an HL in the 26–45 dB range. Moderate hearing loss is defined as an HL in the 46–65 dB range. Severe hearing loss is defined as an HL in the 66–85 dB range. Profound hearing loss is defined as an HL greater than 85 dB. The average person speaking English in a conversational tone tends to speak in the 30–60 dB range, depending on the particular sounds being made. Persons with mild hearing loss will generally be able to hear and understand one-on-one conversations if they are close to the speaker. These individuals may have difficulty hearing a speaker who is far away, has a soft voice, or is surrounded by background noise. Persons with moderate hearing loss may have problems hearing conversational speech, even at relatively close range and in the absence of background noises. Persons with severe hearing loss have difficulty hearing in all situations. These people are not usually able to hear speech unless the speaker is talking loudly and is at relatively close range. Persons with profound hearing loss may not hear loud speech or environmental sounds. These people are unlikely to use hearing and speech as primary means of communication.

Hearing loss is also measured in terms of the frequency of the sounds that can or cannot be heard. Frequency is measured in hertz (Hz). The normal hearing range for humans is from approximately 100–8,000 Hz. The normal frequency of the sounds of the English language falls between approximately 240 Hz and 7,500 Hz. In individuals with progressive conductive hearing loss, it is generally the highest frequency range or the lowest frequency range that is lost first; the middle frequency range is generally lost last. In individuals affected with progressive sensorineural hearing loss, it may be any of the three frequency ranges that is lost first. Hearing loss is generally plotted on a graph called an audiogram. This is a graph of frequency (in Hz) versus HL (in dB).

Syndromic hereditary hearing loss is differentially diagnosed by the presence of the nonhearing loss symptoms that the person also possesses. Nonsyndromic hereditary hearing loss is differentially diagnosed from syndromic by the absence of such other symptoms. Types of nonsyndromic hereditary hearing loss are differentially diagnosed by the age of onset of the symptoms; the progressiveness, or nonprogressiveness, of the hearing loss; the degree of symmetry of the hearing loss from one ear to the other; and the type of hearing loss: conductive, sensorineural, or mixed. Occasionally, a differential diagnosis also includes the inheritance pattern of the nonsyndromic hearing loss. This inheritance pattern is generally determined by obtaining family medical history information on the affected person's family. Tests looking for specific gene changes in specific genes for certain nonsyndromic hearing losses, including prenatal testing, are also beginning to become more available.

Treatment and management

Certain types of conductive hearing loss can be treated by surgery to correct the dysfunctional portion of the ear. Sensorineural hearing loss is generally not able to be repaired by surgery.

Most people with partial hearing loss can benefit from the use of hearing aids and/or sign language. Sign language and writing are often the primary forms of communication used by people suffering from severe, profound, or complete hearing loss.

Prognosis

The prognosis for individuals affected with hereditary hearing loss is largely dependent on the type of hearing loss experienced. In the absence of nonhearing lossrelated symptoms, the loss of hearing does not generally present any increased risk of illness and death. Hearing aids and/or the use of sign language can often improve the quality of life of those affected with a hereditary hearing loss.

Resources

BOOKS

Toriello, Helga V., William Reardon, and Robert J. Gorlin, eds. Hereditary Hearing Loss and Its Syndromes, 2nd ed. Oxford: Oxford University Press, 2004.

ORGANIZATIONS

American Society for Deaf Children. PO Box 3355 Gettysburg, PA 17325. (800) 942-2732 (parent hotline); (717) 334-7922 (business V/TTY). Fax: (717) 334-8808. Email: [email protected]. (April 4, 2005.) <http://www.deafchildren.org>.

Laurent Clerc National Deaf Education Center at Gallaudet University. 800 Florida Ave. NE, Washington, DC 20002. (April 4, 2005.) <http://clerccenter.gallaudet.edu/>.

League for the Hard of Hearing. 50 Broadway, 6th Floor, New York, NY 10004. Voice: (917) 305-7700. Fax: (917) 305-7888. TTY: (917) 305-7999. (April 4, 2005.) <http://www.lhh.org/index.htm>.

National Association of the Deaf. 814 Thayer, Suite 250, Silver Spring, MD 20910-4500. Voice: (301) 587-1788. TTY: (301) 587-1789. Fax: (301) 587-1791. Email: [email protected]. (April 4, 2005.) <http://www.nad.org>.

WEBSITES

"Deafness and Hereditary Hearing Loss Overview." Gene Reviews. (April 4, 2005.) <http://www.genereviews.org//profiles/deafness-overview/>.

"Hearing, Ear Infections, and Deafness." National Institute on Deafness and other Communication Disorders. (April 4, 2005.) <http://www.nidcd.nih.gov/health/hearing/>.

Hereditary Hearing Loss Homepage. (April 4, 2005.) <http://webhost.ua.ac.be/hhh/>.

National Center for Biotechnology Information. (April 4, 2005.) <http://www.ncbi.nlm.nih.gov/>.

Paul A. Johnson

Judy C. Hawkins, MS, CGC