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Home , Genetic disorder, Prelingual deafness

, September/October 1999. Vol. 1 . No. 6 invited review/cme article

A new age in the of deafness

Heidi L. Rehtu, MMSC' ot~dCytltllia C. Morton, PAD'

Over the last several years, an understanding of the genetics SYNDROMIC AND of hearing and deafness has grown exponentially. This progress , The prevalence of severe to profound bilateral congenital has been fueled by fast-paced developments in mapping is estimated at 1 in 1000 births? When milder I and discovery, leading to the recent cloning and characteriza- forms of permanent hearing impairment at birth are included, tion of many critical in the of hearing. Among this estimate increases four-fold. Congenital deafness refers to the most significant advances, especially from a clinical per- deafness present at birth, though the cause of such hearing spective, is the discovery that up to 50% of nonsyndromic re- impairment may be genetic (hereditary) or environmental (ac- cessive deafness is caused by in the GIB2 gene, which quired). Various studies estimate that approximately one-half encodes the 26 protein (Cx26).I.' The clinical use of of the cases of congenital deafness are due to genetic factor^,^ screening for mutations in Cx26 and other genes involved in and these factors can be further subdivided by mode of inher- hearing impairment is still a new concept and not widely avail- itance. Approximately 77% of cases of hereditary deafness are able. However, the eventual availability of an array of genetic autosomal recessive, 22% are autosomal dominant, and 1% are tests is likely to have a major impact on the medical decisions X-linked.-l In addition, a small fraction of hereditary deafness made by hearing-impaired patients, their families, and their (< 1%) represents those families with mitochondria1 inheri- physicians. It is likely that information from these tests will tance in which the trait is passed through the maternal lineage. I simplify the diagnoses, prognoses, and treatment decisions of- ' Aside from mode of inheritance, there are a number of other fered by the physician. Furthermore, the use of descriptions used to classify types of deafness. These include will assist individuals in understanding the molecular basis and age of onset (prelingual vs. postlingual), severity (mild, mod- heritability of their hearing loss. erate, severe, or profound, unilateral vs. bilateral), presence of This review presents an overview of current topics relating other anomalies (nonsyndromic vs. syndromic),etiology (ge- to the genetics of deafness including the different forms of netic vs. acquired), type of pathology (sensorineural, conduc- , deafness and their prevalence. The basic process of hearing and tive, or mixed), and stability of the hearing loss (temporary vs. the functions of the various genes that have been cloned for permanent, stable, progressive, or fluctuating). An important I nonsyndromic deafness will be described. In addition, nonge- distinction exists between sensorineural deafness and conduc- netic causes of deafness will be reviewed, because they are im- tive deafness. Conductive hearing loss typically results from portant in the differential diagnosis when considering a genetic problems associated with the esternal or middle ear, whereas basis for a patient's deafness. The implications of universal sensorineural loss indicates dysfunction of the cochlea or au- newborn hearing screening and its recent implementation in ditory nerve. Although the type of pathology varies widely many states will also be addressed. Furthermore, important among the syndromic forms of deafness, with minor excep- factors involved in the clinical diagnosis of the etiology of deaf- tion, nonsyndromic deafness is typically. - sensorineural. An ad- ness, as well as factors relating to intervention and manage- ditional consideration is whether the hearing loss is prelingual ment of children with hearing impairment, will be discussed. or postlingual. Even though hearing loss can develop at any Finally, this review will consider for deaf- age, this distinction is important because prelingual deafness ness and some of the issues important to the Deaf community. often leads to difficulties with speech and language develop- Although the topics presented here have not seen their last ment. assessment, this review will explore the basics upon which new Although the incidence of prelingual hearing loss is rela- knowledge can be gradually added. tively high as compared with other childhood disorders, an even larger percentage of the population is affected by postlin- gual hearing impairment, with the majority ofthese cases being age-related hearing loss (presbycusis). In fact, it is estimated that hearing impairment affects one-half of the population in the United States by age This emphasizes the finding that hearing loss is a major public concern affecting a large segment of the general population. Despite the observation that the majority of deaf and hear- ing-impaired individuals have no other symptoms, approxi- , Genetics ry5ICdicine 295 Rehm et a1

mately 30°A) of patients with prelingual deafness also have ad- In general, autosomal recessive forms of deafness are prelin- ditional medical anomalies.' More than 400 such syndromic gual and autosomal dominant ones tend to result in progres- forms ofdeafness have been characterized, with the most com- sive, postlingual deafness. This likely reflects the fact that most plete collection of these disorders found in Gorlin and col- recessive disorders represent a complete loss of a gene's func- leagues' Hcr.cllitclry Hc17rirlg LOSS1111~1 Its S~II~~~OIIIL~S.Many of tion, whereas dominant disorders may mechanistically repre- these syndron~esare quite rare. and the responsible genes are sent an interaction between the activity of the normal gene unknown, yet the genes for the most common syndromes and product and the activity of the mutant product. a few for the rarer forms have been cloned in recent years. The responsible gene has been identified at 15 of these non- Those syndron~eswith higher prevalence are listed in Table 1 syndromic loci, marking great achievement in the last 3 years. with their accompanying (not including deafness) Much of this success can be attributed to the vast contributions and responsible protein. of the Project in establishing high-density The other 70% of hearing impairment cases fall into the genetic maps and other tools for . However, category of nonsyndromic deafness. In these cases, the only there are still many genes to be identified. For a full surnmaryof clinical finding is hearing loss with the exception that some these loci, please refer to the frequently updated Hereditary patients may have accompanying vestibular symptoms. Al- Hearing Loss Homepage, which contains many tables summa- though deafness and vestibular dysfunction do not always oc- rizing the details of these nonsyndromic loci, as well as a wealth cur together, the existence of many disorders involving both ofother information related to research on the genetics ofdeaf- the auditory and vestibular systems reflects their close ana- nes5 This web site represents an excellent resource for the tomic proximity and similar developmental origin and struc- research community and for others interested in hereditary ture. deafness. One of the difficulties in studying nonsyndromic deafness As each gene is cloned, a small piece of the puzzle is assem- and discovering the underlying genetic causes has been the bled in an ongoing attempt to understand cochlear function immense genetic heterogeneity that exists among nonsyn- and how dysfunction can lead to deafness. Although the com- dromic forms of deafness. Although subtle pathologic differ- plexity of the hearing organ has long been appreciated, its in- ences may allow clinical differentiation between certain sub- tricacies are underscored by the great variety of functions pro- types of nonsyndromic deafness, there still exist a plethora of posed for the deafness genes that have already been cloned. The genes whose dysfunction can result in highly similar pheno- functions of these genes and how they may contribute to the types. In fact, mapping efforts have located more than 66 inde- hearing process are described below. pendent loci for nonsyndromic deafness.' Each locus is labeled "DFN" followed by "A" for dominant inheritance, "B" for re- cessive, or no additional letter for X-linked. A unique number Anatomy and Function of the Cochlea is then added to the locus designation to indicate the sequential The hearing organ is an anatomically beautiful structure, order in which the loci were mapped. consisting of many different cell types and unique elements

Table 1 Common forms of syndromic deafness

Syndrome Malor Features (bes~desdeatness) Proteln Nephr~t~s,ocular abnorrnal~tlea type IV a5 (XL) X-llnked (XL) Collagen type IV a3 (AR) Autosomal recesa~veIAR) Collagen type IV a4 (AR) Branchlo-oto-renal syndrome Branchla1 remnants; renal anomalies EYAI lervell and Lange-Nielsen syndrome (JLNS1-2) Cardlac conduction defects

Neurofibrornatosis type 2 Acoustic neuromas Merlin Thyro~dgoiter

Stickler syndrome (STL1-3) Orofacial deform'lties; ocular abnornialities; arthrlt~s Collagen type I1 a1 (STL1) Collagen type XI a2 (STL2) Collagen type XI a1 (STL3) (USHIA-F, USH2A-(1. USH3) Myosin VIIa (USH 1B) Usherin (USH2A) (WS type I-IV) Pigmentary abnormalities PAX3 (WS type 1/11) MITF (WS type 11) Endothelin-B, endothelin-B , SOX10 (WS type IV)

296 r tienetlcs Invited revie w/CME article

acting in concert to deliver a symphony of sound. Unfortu- brane and tectorial membrane causes deflection of these stere- nately, the delicate nature of the organ, its small size, and the ocilia, which in turn opens me~hanicall~-~atedion channels. fact that it is embedded in the hardest bone in the body, the This allows potassium ions (K+) in the endolymph (a unique temporal bone, make studying this tissue especially difficult. extracellular fluid bathing the hair cells and containing atypi- Despite this, great advances have been made in understanding cally high concentrations of K+), to pass into the hair cell and the mechanical and sensorineural processes of hearing. depolarize it. This stimulation is then relayed to the brain via Hearing begins as sound waves are captured by the auricle, neurons that synapse with the hair cells. travel through the external auditory canal, and hit the tym- panic membrane (Fig. 1). Vibration of this thin membrane causes movement of the auditory ossicles, the three bones of FUNCTIONALROLEOF DEAFNESSGENES the middle ear, which convey the acoustic stimulus to the fluid- filled inner ear. The stapes, the last bone in this series, presses With this basic understanding of the mechanics of hearing against the oval window, a membrane covering one of the flu- described above, the functional roles played by the various id-filled ducts of the cochlea. When the stapes moves, a pres- genes implicated in hearing loss can be interpreted. The largest sure wave is created, which travels down the upper cochlear group of genes responsible for nonsyndromic deafness en- duct (scala vestibuli). Increased pressure pushes on the basilar codes ion channels and gap junctions. Gap junctions create membrane that stretches the length of the cochlear duct, caus- large nonselective pores between cells, allowing intercellular ing it to vibrate with each cycle of the sound. The basilar mem- communication of many small molecules, whereas ion chan- brane varies in its width and thickness causing different regions nels are relatively selective for the subset of ions that can pass to move at different sound wave frequencies. As a result, only through them. The KCNQ4 gene encodes a Kt channel, which the hair cells located over the particular portion of resonating is thought to allow efflux of K+ that has excited the hair cells basilar membrane will be stimulated in response to a given during acoustic ~timulation.~Three other genes known to en- frequency of sound wave (Fig. 2). In fact, this membrane rep- code the gap junction proteins connexin 26, connexin 30, and resents a continuum, with high frequencies detected at its base connexin 31 (GJB2,' GJB3,s and GJB69 ), are likely involved in and low frequencies detected at its apex. the passive diffusion and recycling of the K+ from the hair cells When the basilar membrane moves, it causes movement of to the stria vascularis, a structure important in endolymph both the inner and outer hair cells, which lie on top of this production (Fig. 2). Once in this stria, other K+ channels membrane. On the apical surface of the hair cells are stereo- pump the K+ back into the endolymph. Furthermore, the PDS cilia, which project upwards and are embedded in the tectorial gene encodes pendrin, an anion channel proposed to function membrane (Fig. 2). The relative movement of the basilar mem- in endolymphatic fluid .10 The role of these and

, Fig. I Anatomical diagram of the hearing organ. Sound waves are captured by the auricle, travel through the external auditory canal, and hit the hjmpanic membrane causing movement , of the malleus, Incus, and stapes. When the stapes moves, a pressure wave is created that travels down the upper cochlear duct lscala vestibuli) and pushes on the basilar membrane different regions to move at different sound wave frequencies. (Adapted by lason Lin with perm~sslonfrom Netter. FH. Atlns ofHlcntan At~ntotny.Plate $487. Copyright 1989 ~ih~.~,~~ I Corporation.

~eptember/J&ober f699 . Vol. 1 . No. 6 -" 297 Rehm et a1

Scala media [endolymph) 1 /Fectonai rnembane -1 ,Quler hair

C_- / ' Bas~larnernt~rar~e ,a-,i=-r- L -- Cmhlear neurons Scala tympani

Flg. 2 A cross sectlon of the cochlea. When the basilar membrane moves, it causes movement ofboth the inner and outer ha~rcells. The relative movement of the basilar membrane and tector~almembrane causes deflection of the stereocd~a,wh~ch in turn opens mechanically-gated ion channels. Th~sallows K+ In the endolymph to pass Into the hair cells and depolarize them. Th~sst~mulation is then relayed to the brain ma cochlear neurons that synapse with the hair cells. (Adapted wth perm~ssionfrom Steel, KP. The benefits of recycling. Science. 285:1363-64. Copyr~ght1999 American Association for the Advancement of Sc~ence.)

other channels and gap junctions in hearing and deafness has and no functional studies have yet been reported.I1 As a result, recently been described in more depth.11,12 its role in the cochlea remains to be elucidated. Another group of genes responsible for nonsyndromic deaf- Two last genes involved in nonsyndromic deafness are ness encodes cytoskeletal proteins. These proteins are thought not nuclear encoded genes but are found in the mitochon- to be important in maintaining the structure of the hair cells drial genome. Mutations in these genes are passed on by ma- and their highly organized stereocilia. Two of these genes are ternal inheritance. Both of these genes encode RNA molecules, unconventional myosins, involved in maintaining structural one a ribosomal RNA (12s rRNA) and one a transfer RNA integrity of the stereocilia through membrane trafficking (t~~~Se~(UCN)), and are involved in protein translation in the (MY07A)13 and possibly actin organization (MY015).14An- mitochondria. An excellent review of mitochondria1 deafness other gene encoding human diaphanous (DIAPHI ) is thought was recently published.22 to create a temporary scaffolding for actin during cell divi- It is clear from these gene descriptions that the discovery of sion.15 Relating to the membrane trafficking function of myo- genes involved in deafness is critical to advancing the under- sin VIIa, a gene encoding otoferlin (OTOF) may be involved in standing of how the inner ear functions and how the disrup- vesicle membrane fusion.I6 tion of certain genes can cause deafness. Not described above Yet another group of proteins include are 19 other genes that are implicated in syndromic deafness. proteins. The a-tectorin protein encoded by the TECTA gene Although these genes are not unique to the cochlea, under- is a key component of the acellular tectorial membrane." An- standing their role in this organ has also been helpful in eluci- other gene (COCH) encodes cochlin, which appears to be an dating the molecular basis of the hearing process. In addition, extracellular protein residing in the spiral ligament and spiral many deafness genes have been identified in other organisms. limbus.18 Though cochlin's function is unknown, these areas These studies have not only facilitated the understanding of the are important to the overall structure of the cochlear organ. hearing process but in many cases they have helped identify Two transcription factors have also been implicated in non- homologous human genes, some of which have been found to syndromic deafness (POU3F4 and POU4F3). Although spe- result in human hereditary deafness. cific genetic targets of these transcription factors have not yet been identified, POU4F3 may be involved in directing the dif- NONGENmIC CAUSES OF DEAFNESS ferentiation of hair cells19 and POU3F4 may have a role in the function of spiral ligament fibrocytes.20 Because a large proportion of nonsyndromic hereditary Another gene implicated in nonsyndromic deafness is hearing loss is recessive (go%), there are many instances when DFNA5. This gene lacks homology with any known proteins a couple with no history of deafness will give birth to a deaf

298 / ' Genetics Wedicine Invited revie w/CME article child. The underlying cause of these sporadic cases can be es- tis is thought to be secondary to the use of amin~~lycoside pecially difficult to determine because the hearing loss may be antibiotics, but it is clear that most is due to direct damage to either genetic or acquired. It is therefore important to be aware the cochlea." Congenital has also become rare since of nongenetic causes of hearing impairment. For example, in vaccine development, yet hearing loss is still the most common previous decades, infectious agents such as rubella and bacte- permanent manifestation of congenital rubella, leaving it on rial were common causes of environmental hearing the primary list of infectious causes of hearing impairment. loss. Although the frequency of such has dropped One other notable congenital leading to hearing loss with the introduction of vaccines, a concomitant improve- is untreated toxoplasmosis. ment in the survival rates of preterm babies has increased the In addition to infections and NICU-related causes of hear- proportion of hearing loss related to stays in the neonatal in- ing loss, there are several other etiologies including otitis me- tensive care unit (NICU). Thus, the overall incidence of non- dia, noise-induced hearing loss, and head trauma. Otitis media genetic deafness has remained approximately unchanged. is the most common cause of acquired childhood hearing loss Among graduates of the NICU, three factors, outside of in- and typically results in temporary conductive loss, although fectious agents, are most commonly associated with hearing permanent sensorineural loss may sometimes occur.26 The loss. The first of these is hypoxia, a condition often associated most common features associated with otitis media are infec- with apnea, use of ventilation, difficult delivery, low Apgar tion, inflammation, and/or fluid in the middle ear. Noise-in- scores, or low oxygen leveLZ3In addition, hypoxia is also duced deafness and hearing impairment associated with head associated with persistent pulmonaryhypertension and the use trauma can occur at any age; however, noise-induced loss is of extracorporeal membrane oxygenation (ECMO) treatment. usually irreversible, whereas recovery from hearing loss due to Hypoxia is known to be associated with neurodevelopmental head trauma may be p~ssible.'~ deficits but the exact mechanism of hypoxia-related hearing AS this brief look at the nongenetic causes of deafness sug- loss is unclear. This lack of understanding is in part due to the gests, the signs that hearing loss is acquired, and not genetic, multitude of interacting factors present in NICU babies that are not always obvious. However, recognition of these signs is may confound the situation. critical, for in many cases there are interventions that can either A second factor associated with NICU-related hearing im- prevent the hearing loss or stop its progression. Unfortunately, pairment is hyperbilirubinemia, often a result of rhesus in- diagnosis of hearing loss remains difficult even when environ- compatibility. In this situation, high levels of unconjugated mental causes have been ruled out, because the current paucity bilirubin cross the immature blood-brain barrier and deposit of molecular diagnostic tests makes it difficult to positively in the gray matter causing neurotoxicity. This is thought to conclude that a patient's deafness has genetic origins. It is lead to sensorineural hearing loss, which is usually permanent, hoped that as molecular genetic diagnosis improves, such as- although some cases may be reversed once bilirubin levels re- sessments will become easier. turn to normal.24 Hearing loss may also be caused by the use of ototoxic med- UNIVERSAL NEWBORN HEARING SCREENING ication. Several of the suspected causes of such ototoxicity are aminoglycoside antibiotics (e.g., gentamicin, tobramycin, and Newborn hearing screening has been available for some amikacin) and diuretics (e.g., furosemide). There is substantial time, but previously performed only on newborns at high evidence that the ototoxicity of aminoglycosides is signifi- risk." These high risk indicators were generated by the Joint cantly increased by the presence ofthe A1555G in the Committee on Infant Hearing and their most recent list ap- mitochondria1 12s rRNA gene." This ribosomal protein mu- pears in Table 2.2RUnfortunately, it was discovered that only tation is thought to make the protein look more like a bacterial one-half of the children with hearing loss were being detected ribosome, which is the natural target of these aminoglycosides. when only those in high risk registries were ~creened.'~This With the advent of vaccinations, the incidence of hearing meant that hearing impairment was going undetected in many loss due to infectious agents has decreased. However, such children until it was noticed by parents or teachers, usually causes are still responsible for a significant portion of acquired around 2.5 years of age.jOHowever, it is well known that early hearing loss. The biggest contributor in this regard is intrauter- detection of hearing impairment is critical to the development ine cytomegalovirus (CMV)infection, found in approximately of lang~age.~'This is not only true for achieving communica- 1% of newborns. Only 10% of these cases develop clinical man- tion skills but also for reaching other cognitive stages of devel- ifestations of the infection, of which 60% develop hearing opment, because learning is often dependent on the attain- loss.23 However, a significant proportion of asymptomatic ment of language. For this reason many states are passing laws CMV patients also develop hearing impairment leading to the mandating that all newborns be screened for hearing loss. overall estimation that 12% of congenital sensorineural hear- Facilitating this legislative process is the existence of two ing loss is due to CMV infection.23Although the incidence of different automated tests for assessing hearing function in bacterial meningitis has decreased since the introduction of the newborns. One test assesses auditory brainstem responses H. influenza type B vaccine, other infectious agents (e.g., S. (ABR) by measuring electroencephalographic waves detected pneumoniae) have kept meningitis-related deafness from dis- using three electrodes on the infant's scalp. These waves are appearing. A portion of the deafness associated with meningi- normally generated by the cochlea in response to a sound stim-

~eptember/#tober-img . Vol. 1 . No. 6 1 -. Rehm et a1

Table 2 A careful family history must always be elicited to help de- Indic'1tors associated with at.n.\orineural 'lnd/or conductive hearing loss termine if the hearing loss is genetic. Unfortunately, many ge- 1. Fatnlly history ot heredtt.~rychildhood sensorineural hearing loss netic cases are sporadic, meaning that neither parent has hear- 2. In utero infection (CblV. r~lhell'~,to~~plasni~sis. , herpes) ing impairment, nor is a family history present. In these cases, possible environmental causes of deafness must be excluded 3. Craniof.acial .~nom~~lies prior to considering that the hearing loss may be genetic. In 4. Birth we~ghtless th,ln 1500 g addition, possible syndromic forms of deafness must also be

5. Hy~erhiliruhincrni~~dt .I acrum level requiring exchange transfusion identified so that other features of the syndrome can be ad-

6. Ototosic rnedii.~tions,including hut not limited to the ~minoglycosides, dressed if necessary. The clinical can be very helpful used in multiple courses or in conib~nationwith loop diuretics in this regard, helping to recognize subtle anomalies associated

7. Bacteri,ll meningitis with hearing loss, allowing specific diagnosis of a syndromic form of deafness. Furthermore, because a high proportion of 8. Apgdr scores 010 to 4 at 1 minute or 0 to 6 at 5 minutes children with hearing loss have ocular anomalies, it is usually 9. Mech~nii,llver~tll~tion lasting 5 days or longer worthwhile to enlist the help of an ophthalmologist. This spe- 10. Stigmata or other findings associated with a syndrome known to include cialist can aid in diagnosing ocular defects associated with syn- .I sensorineural and/or conductive hearing loss dromic deafness (e.g., Usher or Waardenburg syndromes) or infectious agents (e.g., CMV and toxoplasmosis). Part of the decision to perform certain diagnostic tests may be related to the yield that the test may bring. For instance, ulus and sent to the brain through the cochlear nerve. A second examination for a particular infectious agent, such as toxoplas- test detects otoacoustic emissions (OAE), which are sound mosis, may be warranted when there is a treatment for the waves generated by the inner ear and detected using a micro- infection, which could prevent further hearing loss and other phone in the ear canal. It is thought that physical movement of sequelae. It may also be important to test for particular syn- the outer hair cells generates these emissions during the nor- dromic disorders if there are grave consequences when undi- mal cochlear transduction process, thus indicating proper co- agnosed. For example, Jervell and Lange-Nielsen syndrome is a chlear function. Although OAE screening is faster and easier syndromic form of hearing loss that includes deafness and car- than ABR, the test has significant false positive rates. However, diac conduction defects (long QT). Unfortunately, the first when the two tests are combined, or when a rescreen is per- sign of the cardiac defect may be sudden death. Thus, it may be formed, the false positive rate can decrease to less than 3%.32 If highly advantageous to perform an electrocardiogram to diag- a newborn does not pass this initial screening, the child is then nose this rare disorder so that preventative measures can be referred for further evaluation by an audiologist. At this point, taken. a more extensive diagnostic ABR test is performed, allowing Until recently, very few molecular tests were available to aid assessment of a wider range of frequencies. This test may also in the diagnosis of genetic causes of deafness. This is less irn- include both air and bone conduction tests, allowing the audi- portant when dealing with syndromic deafness, which is often ologist to differentiate between conductive and sensorineural accompanied by an array of defining symptoms. However, hearing losses. In addition, further OAE testing allows discrim- without any other guiding features, the lack of molecular tests ination between sensory and neural types of hearing loss. If a makes diagnosis of nonsyndromic hereditary deafness partic- hearing impairment is found, the child is referred to an otolar- ularly difficult. Fortunately, the recent explosion in the discov- yngologist and appropriate habilitative services. ery of nonsyndromic deafness genes provides a number of op- tions for confirming the diagnosis. Although 15 genes are DIAGNOSIS OF THE ETIOLOGY OF DEAFNESS currently on this list, with minor exception, the only gene for which screening is being performed clinically is connexin 26 Despite the diagnosis of hearing loss becoming relatively (Cx26). This is because most of the other genes are relatively straightforward, an understanding of the etiology of the im- rare causes of deafness and many of the genes are so large that pairment has traditionally been very difficult, especially in screening is very costly. However, as new screening methodol- young children. This is in large part due to the numerous ge- ogies are developed, additional genetic tests for hearing will be netic and environmental causes of deafness, many of which do considered. not have definitive tests to aid in their diagnosis. The primary care physician is often faced with the difficult task of either INTERVENTION AND MANAGEMENT ordering an exhaustive battery of tests, which may not provide further insight as to the etiology, or trying to handpick specific As soon as a diagnosis of hearing loss is made, an effective tests that may be indicated in a given case. Neither situation is habilitation plan needs to be developed. Such decisions may be ideal and a more expedient plan may be to refer the child to an less complex with adult-onset deafness, in which language ac- otolaryngologist, who may also enlist the help of a team of quisition and other developmental issues are not of concern professionals including an audiologist, a clinical geneticist, an and the patient is capable of making decisions for him or her- ophthalmologist, a genetic counselor, and other specialists. self. However, when dealing with a child, these decisions be- Invited revie w/CME article come much more involved. In addition to considering the pa- coming possible to "test" for characteristics that are tradition- tient, a plan of care should include input from a number of ally viewed as "normal" variants. It is unlikely that the ability to other parties including the otolaryngologist, the audiologist, test for such variation will cause certain differences to carry the the genetic counselor, those involved in the education of the stigma of "." child, and most importantly, the parents themselves. For pro- As for the eradication ofthe deafculture by cochlear implan- found deafness, a deaf couple inay prefer that their child learn tation, it must be noted that implantation is not an appropriate , while a hearing couple might opt for a cochlear treatment for all deafness. It relies on the presence of a well- implant, an electronic device that can allow certain deaf chil- developed cochlear structure that can be augmented by the dren to hear a comparable sound level to their peers? De- implanted device. Many individuals with profound deafness pending on the level of hearing loss, other options include the do not have such a scaffold and are therefore inappropriate use of hearing aids and other assistive learning devices. The candidates for implantation. main goal, however, is that the strategy be appropriate for the child and agreed upon and initiated as soon as possible so that SUMMARY the child can develop a method of communication, a critical step in reaching other developmental milestones. Recent advancements have been made in understanding, diagnosing, and treating deafness. In particular, much has been learned from the discovery of a small fraction of the genes GENDIC COUNSELING AND DHICAL ISSUES IN THE responsible for deafness. This understanding will doubtless in- crease as additional genes are cloned and their functions eluci- As with any inherited genetic disorder, deafness requires the dated. Trailing close behind these achievements will be more input of the trained genetic counselor. However, this particular clinical advancements facilitating diagnosis of the etiologies of phenotype carries many of its own unique and sensitive issues. deafness. Integrating these genetic and clinical perspectives is The desire to share a common language has resulted in the critical to the development of better treatments and interven- development of a tightly organized Deaf culture. Even if a deaf tional strategies for deafness and its associated difficulties. Al- person does not participate in this "culture," it is likely that a though opinions toward these advancements are likely to vary deaf person may choose a partner who is also deaf because they between the hearing population and the Deaf community, a share a common language, referred to as linguistic homogamy. growing understanding of the hearing process and how genetic The choice to select a mate of similar phenotype is known as variations result in deafness is ultimately likely to offer benefits assortative mating. Unfortunately, this can sometimes lead a to both groups. couple to incorrectly assume that they will have deaf children because they are both deaf. In fact, due to the enormous genetic Acknowledgments heterogeneity discussed above, 90% of deaf by deaf matings The authors thank several colleagues of the Harvard Center result in hearing children.' for Hereditary Hearing Loss for their helpful comments on the One difficulty for the many people who work in the field of manuscript, Mr. Stefan Waversik for his editing of the manu- deafness is accommodating opposing attitudes toward deaf- script, and Jason Lin for his artwork on Figure 1. ness. On one , the average hearing couple, when unsus- pectingly presented with a deaf child, may be devastated to References discover their child's "deficiency." In stark contrast, a deafcou- 1 Denn~elleF, Xlarl~nS, \!'ell D. hlodtt~L. Chauv~nP. G~rabed~anFN. Pet~tC. Cl~n- ple may be equally devastated to learn that their child can hear. leal feature\ of the prevalent torm of ih~ldhooddeahea,. DFNRI, due to a con- nex~n-26gene defect: Impl~catlonafor genetlc coun.\ell~ng.Lorlir,~ 1999.353:1?98- These differing perspectives are rooted not only in the desire to 1303 communicate most effectively with one's child, but also in the 2 Cohn FS. Kelley Phl. Fo\\-ler n\'.Gorp hlP. LeAo\\.1t7 LJhl. Kuehn HI. Schaefer more global attitude ofwhat traits are "normal" or "desirable." GB. Gohar L.S. H~hnFI. Harrl* Dl. K~mherl~ng\!'l Clln~cdlstudler ottam~l~es~v~th hearing lo\> dttrlhutdhle to mutatlonr In the connexln 26 gene (GIB2IDFNRI ). The definitions ofthese words clearly lie in the subjective opin- Pc,lr<~lr190Y,103:5Jh-550 ions of their users. 3 Gorlln R1. Torlello Hi'. Cohen hlhl. Heredltan. hear~ngloss and 11s s!ndromes. The conviction that deafness is simply another way of life Oxfirrd. Oxford Llnl\,ersity Preh*, 1995 runs strongly within the Deaf community. As a result of this 4. hlorton NF Genet~cepldenllnlop of hedrlng Impalrnlent. Anrr N ).Aroci Sn 1991; h30:lh-31 perspective, many supporters of the Deaf culture are opposed 5 Van Cdmp G. Sni~thKIH. Hered~tan.Hedrlng Loss Homep~ge,1949 http://dnalab- to the use of genetic testing for deafness, feeling that it stigma- wm\?\,.u~.~.ac.heldn.~ldhihhh tizes their deafness as a "disease." In addition, many are op- 6. Kub~schC. Schroeder RC. Frledrlih T. Lutiohann R. El-Amraoul A, hlarlin S. Petit C, lentach TI. KCNQ-I. a novel potdsslum chdnnel expressed in senson. outer halr posed to the use of cochlear implantation, believing that it iella. I!. mutated In donllnant dedfness. Ccll 1999:96:437-446. could eradicate their culture through the elimination of hear- i. Kel.*ell IIP. Dunlop I. Stevena HP. Lenih N1. Llang IN. Parw G, hlueller RF. Leigh ing loss. Although these views should be respected, they are, at IM. Connerln 26 niutrtlon* In hereditary non-syndrom~isensorineural deafness. Norlire IYV7;387.80-83. least in part, unfounded. For instance, although genetic testing 8. Sla IH. I.IUCY. Tdng RS. Pan Q, Huan~L. DJI HP. Zhang BR. XieM'. Hu DS. Zheng is often used in clinical diagnostics, the "disease" categoriza- D, Shl SL. Wdng 1)A. Sla K. Yu KP. Liao SD. Feng Y. Yang YF, Xiao n', Xie DH, tion is primarily associated with societal views of "the norm." Huang IZ. blutat~on*In the gene encoding gap ~unct~onprotein beta-3 associated with autosomdl doni~nanthearlng Impairment. Nnl Gotct 1998:?0:370-373. Furthermore, as the field of genetics expands, it is quickly be- 9. Grlfa A. Wagner CA. D'Anibros~oL. Melchionda S, Bernard1 F, LoFez.Blgds N,

September/(J&JBEr 1999 . Vol. 1 . No. 6 ' 1, Rehm et a1

Rdhionet R. Arbones kl, hionled hlL>. E\t~v~llS. Zelante L. Ldng F, Gasparln~P. Minowd 0, lkeda K, Sugltani Y, Oshima T, Nakai S, Kator~Y, Suzuki M, Furukawa hlutatlons In GlBb iduse non\yndromli .~uto\omdldomlndnt deafnesr at DFNA3 M, Kawase T, Zheng Y, Ogura M. Asada Y, Watanabe K, Yamanaka H, Gotoh S, locu:.. Naf Goicr l999;23:16-18 NIS~I-Takesh~maM, Sugimoto T, Kikuchi T, Takasaka T. Noda T. Altered cochlear 10 Everett LA, Morsl~H. Wu DR. Green El). Espress~onpattern of the mouse ortholog fihrocytes in a mouse model of DFN3 nonsyndromic deafness. Science 1999;285: of the Pendred':. .*yndromc gcnc (PA)\uggc\t\ a key role h~rpendrln In the inner 1408-141 1. edr. Proc N'ltl A~.~zciScrLISA 1999;Yh:97?7-Y7??. Van Laer L, Hulzing EH. Verbtreken M, van Zuijlen D, Wauters IG, Bossuyt PI, Van I I. Holt IR. Corcy DP. Ion channel defect, In lirred~taryhe.~r~nl: lo\:.. Nt.~rrort1999;??: de Hcyning P, McGuirt WT, Smith RJ, Willems PI, Legan PK, Richardson GP, Van 217-219. Camp G. Nonsyndromic hearing impairment is associated with a mutatlon in 12. Stccl KP The benefit:. ot recycling. Sirr'trrt 149Y;285:13h3-l364. DFNA5. Nat Genet l998;20:194-197. I3 H.>.*ronT. Gillc:.plc PG. Z.ircld lA, M.~cI)on.~IciRB. Zhdo Y. Yee AG, Mooseker MS. F~achel-Ghoda~anN. Mitochondria1 deafness mutations reviewed. Hum Mutat C'orey DP. Llnconventlonal myoslnh In inner-car :.ensory cpitheli.1. I C1.11 Biol 1997. 1999: 13:261-270. l?i:1?87-1307. Ro17en NJ. Etiology of hearing loss In chlldren: nongenetic causes. Pediatr Clin I4 Prohst FI. Fr~dcllRA. Raphael Y. Saundrr\TI.. Wang A. L1.1ng Y. klorell RI. Toucli- Norfh Aln 1999;46:49-64. man I\V. Lvon* RH. Nohen~Tr.~utliK. Frledrndn TB. Campcr SA. Correct~onof tiuriyama M, Tomlwa K, Kon~shiY, Mlkawa H, Improvement in auditory bran deatness In sh.~Ler-?mlie hv an unconvcnt~on.~lrnyosln In a BAC: . Sc~twca stern rebponse of hyperbll~rubinemic infants after exchange transfusions. Pediatr 1498;280:l444-1447. Nc~rroI191162 127-132 15. Lynch ED. Lee hlK. Morrow IE. Welc.\h PL, Leon PE. King MC. Nonsyndrom~c Franco~rM. Laccourreye L. Huy ET, Narcy P. Hearing impairment In infants after deafneb.\ DFNAI auoc~atedwlth mut.~ti