521I Med Genet 1992; 29: 521-526

REVIEW ARTICLE

Genetic deafness

William Reardon

Historical overviewThe concept of heredity as a cause of deafnessgained acceptance in the last quarter of the19th century.'2 Politzer,3 writing in 1882,stated that "the most frequent causes of con-genital deafness are: hereditary, includingdirect transmission from the parents as well asindirect transmission from forefathers andmarriage between blood relatives". This state-ment was based upon the work of ArthurHartmann whose studies were carried outin the Berlin schools for deaf children.4 5Hartmann distinguished between direct trans-mission of deafness from parent to child andindirect transmission, in which he noted a highlevel of consanguinity. This latter finding wassupported by Uchermann's extensive studyof Norwegian schools for deaf children.6Uchermann showed that consanguinity wasfour times as high among the parents of deafchildren as among the parents of their nor-mally hearing counterparts. Moreover, thoseareas of Norway with the highest degree ofconsanguinity were those with the highest pre-valence of deafness.The earliest known author to have recog-

nised that some forms of deafness may beinherited was Schenck.7 A century laterZacchia, physician to the Pope, recommendedthat deaf people be precluded from marriage inview of the evidence that their children weresimilarly afflicted.8 Although Joseph Adamsdistinguished between hereditary (dominant)and familial (recessive) disorders, he was of theview that deafness "is rarely if ever heredit-

" 9ary".In the mid-nineteenth century two men, of

diametrically opposed views, served to raiseotology from quackery to the level of credibleclinical discipline.'0 Wilheim Kramer (1801-1875) did not accept that deafness could beinherited, although he did admit that deaf anddumb children frequently had "numerous deafmutes among their male or female cousins"."In contrast, his eminent Irish contemporary,William Wilde (1815-1876) (fig 1) identifiedpedigrees with "transmission of the disease byhereditary taint" and distinguished betweenthese and pedigrees where "too close consan-guinity among the parents may be looked uponas paramount".'2 Not only did Wilde thusfundamentally identify autosomal dominantand recessive inheritance of deafness, but hefurther emphasised the excess of males amongcongenitally deaf patients, much of which islikely to be explained by the X linked form of

deafness."3 Thus, in the context of humangenetic disease, the three forms of Mendelianinheritance had been documented by Wildemore than a decade before Mendel publishedhis observations on peas in 1865.

Inheritance of deafnessNowadays at least half of severe childhooddeafness in a community is attributed to gen-etic causes,'4 and the approximate prevalenceof genetic deafness has been calculated as 1 per2000.15 The spectrum of hereditary deafness isbroad and ranges from simple deafness with-out other clinical abnormalities to geneticallydetermined syndromes of a more pleiotropicnature in which deafness is one of a number ofclinically recognisable signs, together compris-ing the syndrome. Approximately 30% of gen-etically determined deafness is said to occur insyndromic form and 70% in non-syndromicform. 16

Overall the most common forms of geneticdeafness are the autosomal recessive forms,accounting for >75% of cases.'4 Autosomaldominant inheritance accounts for a further 10

Figure I Sir William Wilde.

MothercareDepartment ofPaediatric Genetics,Institute of ChildHealth, 30 GuilfordStreet, London WC1N1EH.W Reardon

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to 20% 1' of cases, and X linked inheritance for2 to 3%.1718 Deafness may also be a feature ofchromosomal aneuploidy'9 or chromosomal.deletion,202' as well as of mitochondrial in-heritance22 and of mitochondrially determinedpredisposition to deafness inducing environ-mental agents.23Most available data on the subject of genetic

deafness concentrate on congenital or pre-lingual deafness. Deafness of later onset isfrequently likely to reflect genetic factors butprecise reliable data are currently lacking.24Indeed epidemiological data on the prevalenceof hearing disorders in the population are onlynow coming to hand following the first largescale survey of this problem since 1947.2526Early indications suggest that 15 to 20% of thepopulation have a significant hearing impair-ment (>25 dB, average 05 to 4 kHz, betterear).27 While otosclerosis is recognised as agenetically determined cause of post-lingualdeafness,2829 as are several syndromic forms ofdeafness, such as Alport's disease, Alstrom'sdisease, and Refsum's disease, other geneticaspects of aetiological importance in post-lingual deafness remain to be identified.

Embryology of the inner earMost of the published data on genetic deafnessrelate to pathological and histopathologicalstudies in man and in other mammals. Beforeattempting to interpret these or draw any con-clusions relevant to human genetic deafness, itis essential to be conversant with the basicsequence of events involved in the embryologyof the cochlea.The membraneous inner ear is of ectoder-

mal derivation. At three weeks an ectodermalthickening, the otic placode, appears on thelateral surface of the head. Subsequently theplacode invaginates, forming the otic pit,which grows downwards into the underlyingmesoderm. As the surface ectoderm closesover the otic pit, the otic cyst is formed, theprocess being complete by about four weeks.From the otic cyst develop two primitivestructures, the dorsal (vestibular) and ventral(cochlear) parts. At six weeks the vestibularpart forms two pouches, a dorsal pouch fromwhich will develop the two vertical semicircu-lar canals and a lateral pouch from which willdevelop the lateral semicircular canal. By thenine week stage the basis of the vestibularsystem, the utricule and semicircular canals,are well established, but the cochlear systemlags behind.303'At about this time the mesoderm enveloping

the developing otic cyst becomes cartilaginousand ossification starts at approximately 16weeks, being completed by the third trimester.Meanwhile the cochlear system starts to de-velop and, by 12 weeks, the two and a halfturns are discernible with further developmentof the membraneous elements of the cochlearsystem continuing into the second trimester.The fundamental importance of normal

neural tube development for correct otic cystdevelopment in the mammal has long beenappreciated.32-34 More recent evidence

suggests that melanocytes, derived from theneural crest, have an important role in thenormal development of the stria vascularis andendocochlear potential within the membran-eous system of the cochlea,35 a normal endo-cochlear potential being of crucial importancein the physiology of hearing.

Bearing these considerations in mind, it ishardly surprising that the phylogeneticallyolder vestibular system appears more resistantto disease than the later developing cochlea. Itis the cochlea which is the more sensitive torubella, measles, and mumps damage andequally it is the cochlea alone which is the seatof most genetically determined hearing loss.

Temporal bone pathology in deafnessFour main classes of abnormality have beendescribed as a result of temporal bone studiesin deaf human subjects'637: (1) Michel type,characterised by total underdevelopment ofthe inner ear; (2) Mondini type (more correctlyMundini38), in which the cochlea appears as asingle basal turn with the rest of the cochleacomprising a single sac, as if to suggest inter-rupted development. Vestibular structuresmay be similarly underdeveloped, thoughseveral cases are known where this abnormal-ity was accompanied by a normal vestibularlabyrinth'9; (3) Bing-Siebenmann type, inwhich the bony labyrinth is well formed butthe membraneous labyrinth is not developed;(4) Scheibe (cochleosaccular) type, in whichthe underdevelopment is restricted to themembraneous cochlea and saccule only, butthe vestibular part of the ear is functional.The latter is thought to be the most common

form of abnormality in deafness of geneticorigin. However, no direct relationship existsbetween pathological class and mode of in-heritance.

Correlations between temporal bonepathology and genetic deafnessAs they involve abnormalities of bone, Micheland Mondini types may be diagnosed radiolo-gically.4" Although some residual hearing, par-ticularly in the low frequencies, has beendocumented in association with the normalbasal cochlear coil of the Mondini deformity,38this is unlikely to be a universal finding.4111The Mondini deformity is rare in geneticforms of deafness, but is seen in the autosomaldominant condition of branchio-oto-renal syn-drome and in the autosomal recessive con-dition of Pendred's syndrome. Michel abnor-mality is not a consistent finding in geneticdeafness.

Indeed, as few as 20% of congenitally deafpatients have radiologically detectable abnor-malities of the inner ear.4' For these reasonsdetailed radiological examination of the ear isdifficult to justify in all cases of genetic deaf-ness. Cochlear lesions apart, the other innerear lesions which benefit from CT scans of thecochlea are those in which congenital abnor-malities of the labyrinth are associated withcerebrospinal fluid (CSF) fistulae. Clinically

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such labyrinthine abnormalities present asCSF otorrhoea, CSF rhinorrhoea, recurrentepisodes of meningitis, or stapes 'gusher' atsurgery.404 The value of CT scanning in Xlinked deafness associated stapes 'gusher' hasbeen shown45 and similar investigation is likelyto be of predictive value in preoperative identi-fication of other patients at risk of this surgicalcomplication.2"Temporal bone studies in human subjects

with genetic deafness indicate that lesions con-fined to the membraneous cochlea are the mostcommon form of pathology24 and these aregenerally of the Scheibe type. Accordingly,blanket cochlear CT scanning in genetic deaf-ness is likely to give a disappointing yield.

Correlations between genetic deafnessin man and animal modelsMore than 70 different mutations are known toaffect the inner ear of the mouse46 and 151forms of inherited deafness have been docu-mented in man by drawing distinctions, somemore justified than others, between differentpedigrees.24 Many of the inner ear abnormalit-ies observed in mice appear to be grosslysimilar to abnormalities documented in manand suggest that the responsible mouse muta-tions are candidates for specific forms of gen-etic deafness in man. Unlike colleagues work-ing with mice, the human geneticist has rarelybeen in a position to relate specific abnormalit-ies to the effects of a particular gene. Thenumber of human pedigrees with known innerear pathology in all affected members is smalland when families whose deafness is ostensiblysimilar on clinical grounds differ in respect oftemporal bone pathology, differentiation tendsto be made between them on this basis. Mousestudies have, however, shown that the samegene may produce a wide variety of clinical andpathological abnormalities.4748 This probablyreflects the genetic background factors againstwhich the gene is being expressed. For thisreason attempts to relate specific inner earabnormalities on a one to one basis to particu-lar single gene causes of deafness in man areliable to be disappointing and misleading.Moreover, this observation is important inunderstanding the limitations of phenotypestudies as a guide to shared genotype in thestudy of human deafness.49Notwithstanding the limitations of the rela-

tionship between inner ear abnormalities andspecific genes in man, it has been possible todefine certain similarities between human her-editary inner ear abnormalities and those inmice. Broadly speaking such abnormalities inthe mouse may be of three distinct types.50

(1) Morphogenetic, which includes all casesof structural abnormality and corresponds tothe Michel and Mundini defects in man. Aswith Michel and Mundini abnormalities inman, asymmetry is a frequent finding betweenthe two ears in affected cases.

(2) Neuroepithelial, characterised by aprimary organ of Corti abnormality and avariable degree of vestibular degeneration. Nostrict corresponding form is described in the

classification of temporal bone findings inman.37

(3) Cochleosaccular, characterised by aprimary lesion involving the stria vascularisand corresponding to the Scheibe abnormalityin man (fig 2).There may be certain benefits from an

interspecific comparative system such as this.Classifying animal models of deafness in thismanner may facilitate the future selection ofappropriate models for study of comparableforms of genetic deafness in man. It also de-fines a better framework for classifying tem-poral bone findings in human cases. Althoughthe limitations of this approach are formidable,nevertheless expanding our knowledge in thisarea may help identify mechanisms common toboth species which are important in the de-velopment of normal hearing and geneticallydetermined aberrations thereof. Other avenuesof insight into these same mechanisms arelikely to be provided by mouse mutants whichare not thought to be murine counterparts ofhuman hearing disorders but rather serve asmodels of interrupted developmental biologyof the ear. Study of such mutants shouldelucidate several of the factors important innormal cochlear development.

Clinical genetics and deafnessGiven the aetiological heterogeneity of geneticdeafness and the complexity of possiblemechanisms underlying this heterogeneity, itis not surprising that genetic counselling fordeafness continues to be empirical. The stat-istical basis of such counselling in regard todeafness has been authoritatively reviewedelsewhere.5l153 Perhaps the main role of theclinical geneticist is in attempting to recognisesyndromic forms of deafness and provide ap-propriate counselling for other family mem-bers on the basis of the diagnosis. Diagnosticpossibilities may be suggested by the historyand clinical examination which may be furtherrefined by reference to an authoritative data-base.54 Frequently special procedures may berequired to confirm a syndrome diagnosis andreference to a guide to the appropriate invest-igation of isolated cases of hearing loss may behelpful.5556

Perhaps the area of greatest confusion re-lates to the value of the audiogram not only inrelation to phenotype definition but also as ascreening measure for gene carriers. Severaldifferent forms ofnon-syndromic genetic deaf-ness have been delineated on the basis ofaudiogram findings24 but the validity of thesefindings as a guide to shared genotype remainsunproven. Indeed the only study which hasevaluated the audiogram in affected membersof a number of families with apparently thesame form of non-syndromic genetic deafnesshas shown no reliable correlation betweenaudiogram and genotype.57Syndrome related autosomal recessive forms

of deafness have been said to be characterisedby a preferential high tone loss of hearing.'8 Incontrast the hearing loss in X linked recessivenon-syndromic deafness has been said to give a

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Cochleo-saccular degeneration

1. Reissner's membrane collapsed2. Primary strial abnormality3. Damage to organ of Corti,

occasional signs of fluid imbalance4. Frequent collapse of saccule, while

rest of vestibular labyrinth is normal5. Variable expression, often leading

to asymmetry6. Endocochlear potential probably

absent

Figure 2 Cochlear duct sections showing normal animal (top), neuroepithelialdegeneration (bottom left), and cochleosaccular degeneration (bottom right).

flat audiogram.'7 However, X linked deafnessappears to be a heterogenous disorder5859 andgeneral remarks as to audiogram pattern areunlikely to be helpful. One way of evaluatingthe audiogram is to look at the consistency ofpattern and degree of hearing loss in a singlegroup of patients likely to be genetically homo-geneous. Such a group is Pendred's syndrome,in which condition audiogram involvementmay vary from profound hearing loss throughall frequencies to minimal loss of function.'8Other authors have evaluated the audiogram asa means of discriminating between aetiologic-ally different forms of deafness but have notfound it a reliable tool.60With regard to the carrier state in autosomal

recessive deafness there have been severalstudies attempting to identify audiologicalcharacteristics of such patients. Wildervanck6'performed audiograms on normally hearingconsanguineous couples who were the parentsof at least two deaf children and could not findany abnormality in the parental audiograms. Asubsequent report indicated 'peculiarities' ofhearing in almost all parents of children withpresumed autosomal recessive deafness.62 Itwas unclear whether these 'peculiarities' were

sufficiently similar in all cases to form the basisof a carrier detection test. Similar techniquesof Bekesy audiometry and stapedial reflex ex-amination have been used by other authors butwithout observing significant findings.60

The benefits of audiological tests as an aid togenetic counselling in autosomal dominantnon-syndromic deafness are better docu-mented. In general, dominant deafness is saidto be milder than recessive.'8 Reduced penet-rance and variable expressivity of autosomaldominant non-syndromic deafness genes arewell documented'8 and, for this reason, audio-grams of first degree relatives of index cases areusually undertaken, although the sensitivityand specificity of such testing is open to ques-tion.

Genetic counselling in deafnessIn the USA 90% of deaf adults marry anotherdeaf person and, in view of this assortivemating, genetic counselling may often be ap-propriate to persons whose deafness may benon-genetic in aetiology. Perhaps nowhere ingenetic counselling is an appreciation of cul-tural factors said to be more important.6"5Many deaf patients have no desire to be curedand are hostile to any suggestion that the aimof counselling is to prevent deafness. Thus, thecounsellor may find his/her personal viewsbeing challenged by the preference of a deafcouple to have deaf children. These culturalconsiderations aside, several other generalphenomena have been observed in relation togenetic counselling in deaf communities.Questionnaires have been successfully used toelucidate aspects of medical, pregnancy, andfamily history which may influence counsel-ling. Limited knowledge of family history isfrequently observed and may necessitate con-tacting other family members, with the pro-band's consent, for relevant details. Moreoverthe collection of data relevant to counsellingmay be limited by educational and communi-cation factors.These phenomena have been well docu-

mented in the USA as a result of the geneticsservice programme established in 1984 at Gal-ludet University, an institution for deaf stu-dents. Though valuable in highlighting factorsunique to this population which would not beobserved otherwise, it is unclear how generallyapplicable they may be to less educationallyprivileged, less culturally aware groups of deafpeople elsewhere. Similar studies outside thishighly selective group are needed to facilitate abalanced overview of the more general situ-ation.

Molecular genetics and deafnessSeveral methods of investigating genetic deaf-ness have been outlined. Irrespective ofwhether this group of conditions is approachedclinically, histologically, radiologically, audio-logically, or by means of animal model correla-tion, the problem of non-specificity remainsunsurmounted. In terms of applying linkageanalysis and other tools of modern genetics todeafness this non-specificity in the clinical andinvestigative findings of conditions which aregenetically distinct means that it has not beenpossible to define a genetically homogeneouspatient group. Accordingly the strategies

Normal

Neuroepithelial degeneration

1. Reissner's membrane in place2. Stria normal at first3. Primary organ of Corti

abnormality4. Variable vestibular

degeneration5. Regular expression6. Endocochlear potential

present

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which have met with such spectacular success

in other human genetic diseases have had theirimpact limited to well defined clinical subtypesof genetic deafness, such as Waardenburg syn-drome,66 Usher syndrome,6768 Treacher Col-lins syndrome,69 and X linked deafness.70Comparative gene mapping represents one

such tack. Knowledge of the chromosomallocation of a deafness causing mouse mutationmay be exploited to predict the likely chromo-somal location of the human homologue.7' Theidentification of loci in mice responsible formutations whose effects are confined to theauditory system offers a possible basis forgenetic analysis of non-syndromic deafness inmany.727' Homologous human genes may thenbe isolated and evidence of their possibleinvolvement in deafness sought. While thisapproach to overcoming the problems ofheterogeneity may seem cumbersome, it isclear that innovative approaches are required ifprogress in identifying the genetic basis ofnon-syndromic deafness is to be made.Nevertheless, the technology of moleculargenetics is the most sophisticated method yetapplied to genetic deafness and must, withimaginative use, represent the best chance ofresolving the genetic complexities inherent tothe group of conditions.

The author wishes to acknowledge the Well-come Institute Library, London, for fig 1. Fig2 is reproduced by permission of Dr Steel andthe Editor of Archives of Otolaryngology. Help-ful comments on the manuscript were receivedfrom Dr Dafydd Stephens and Dr MichaelBaraitser.

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