Review Article J. med. Genet. (I964). I, II8. Profound Childhood Deafness* G. R. FRASER From the Godfrey Robinson Memorial Unit, Department of Ophthalmology, Royal College of Surgeons, London W.C.2 'It will be a great step forward whn the physician takes part in the work for defec- tives who have hitherto been entrusted wholly to teachers in schools.... The prob- lems of deafness are deeper and more complex, if not more important, than those of blindness. Deafness is a much worse misfortune. For it means loss of the most vital stimulus-the sound of the voice-that brings language, sets thought astir and keeps us in the intellectual company of man.' From The Deaf Child, by J. Kerr Love, Simpkin and Co., London, I9Ii. Definition and Introduction Larsen and Ludvigsen, I946; Robinson, Miller, The term profound childhood deafness is used and Bensimon, I962) and others, and of conductive in preference to the old-established one of deaf- deafness with osteogenesis imperfecta (van der mutism, since it is now clear that, contrary to the Hoeve and de Kleijn, I9I7). Occasionally pro- accepted dogma current from antiquity to recent found childhood deafness will occur in association times, mutism is not due to a pathological lesion with one of these conditions; conversely, persons of the speech apparatus associated with failure to will occasionally suffer from only mild losses of hear, but to a lack of suitable training which can hearing in association with syndromes more usually often be remedied. Profound childhood deafness associated with profound childhood deafness. No is a socio-educational entity and may be defined as biological classification can be expected to follow deafness with an early enough onset and of suffi- very closely lines of demarcation defined on the cient degree to necessitate the use of special or basis of socio-educational criteria. There is even supplementary methods for the learning of speech. no absolute correlation between educational seg- This definition excludes the very common deaf- regation and degree of hearing loss. Thus severe ness of adult life often inherited in a dominant hearing loss in infancy is sometimes compatible manner, whether conductive (otosclerosis) or per- with normal education, and special schooling may ceptive. Many rare genetical syndromes are also occasionally be necessary with a relatively mild excluded of which deafness of a less severe nature deafness. Other, as yet ill-understood, factors and/or of late onset is a component part. These may condition the extent of the child's adaptation include such recessive syndromes as perceptive to the hearing loss. deafness, atypical retinitis pigmentosa, chronic Many other difficulties stand in the way of an polyneuritis and ataxia (Refsum, Salomonsen, and unambiguous biological classification of profound Skatvedt, 1949), and perceptive deafness with childhood deafness. Thus an unequivocal dif- optic atrophy and diabetes (Shaw and Duncan, ferentiation between congenital and postnatal onset I958), with diabetes mellitus, retinal degeneration, is often impossible, since the diagnosis of deafness and obesity (Alstrom, Hallgren, Nilsson, and may only be made when speech fails to develop Asander, I959) with congenital facial paralysis normally in the first two years of life or even later. (Thomas, 1898; Cadwalader, I922), and many Furthermore, congenital and postnatal deafness others; in addition, the dominant syndromes of cannot be equated simply with genetical and ac- perceptive deafness with nephritis (Alport, 1927), quired forms. Congenital deafness may be due to with auditory neurofibromata (Gardner and Frazier, maternal rubella, and, owing to diagnostic diffi- I930), and with ectodermal dysplasia (Helweg- culties in infancy, evidence is lacking as to whether genetical childhood deafness is in fact usually * Received July 20, x964. congenital or rapidly progressive in early life. II8 Profound Childhood Deafness II9

with pigmentary anomalies Dominant C without pigmentary anomalies with goitre with retinitis pigmentosa Genetical Recessive with electrocardiographic abnormalities other syndromes undifferentiable at the clinical level Sex-linked Prenatal Acquired 4 -1Perinatal Postnatal

Complex congenital malformations.

The latter situation is certainly common in the ness, exogenous causes, whether acting in the pre-, case of recessive deafness in mice (Deol, I954). peri-, or postnatal period cannot be ignored, both In these animals rapid degeneration of morpholo- because of diagnostic difficulties in the individual gically normal labyrinthine structures takes place case and because of their intrinsic interest as a when the appropriate genotype is present. In whole. As Hopkins (1954) wrote; 'Any study of man it is known that dominant perceptive deafness the inheritance of deafness must in reality be a is often progressive (Stephens and Dolowitz, I949) study of the different types of deafness.' The and, in fact, this is characteristically a disease of schema above represents an attempt at bio- adult life. Rarer examples of apparently pro- logical classification on which the present review gressive recessive deafness are also known, either is based. The dichotomy, much used in the past, isolated (de Kleyn, I9I5) or in association with between congenital and acquired deafness is dis- other abnormalities such as the Laurence-Moon- carded altogether. It should be noted that when- Biedl syndrome (Burn, 1950; Graf, I964). ever deafness is mentioned in this review, unless These difficulties were clearly perceived as long explicitly otherwise qualified, the entity of pro- ago as I82I by Itard, who, writing of the dis- found perceptive childhood deafness is meant. tinction between congenital and acquired forms, said that the causes of profound childhood deaf- ness would never be more than imperfectly known. Historical Note This judgement, while remaining often valid in Since it was thought on the august authority the individual case, is to a great extent no longer of Hippocrates and Aristotle that those born deaf so if applied to profoundly deaf children as a whole. were unable to speak because of an irreparable By means of thorough clinical, genetical, and organic lesion, no attempt was made to teach speech statistical studies of such populations, a reasonably to profoundly deaf children until the i6th century. accurate picture of the spectrum of causes can be At this time Pedro de Ponce, surnamed Venera- obtained and informed estimates be made of their bilis, a Benedictine monk, achieved great renown relative importance. by teaching the profoundly deaf scions of several While the main emphasis of this review bears noble Spanish families to speak. An excellent dis- on genetical causes of profound childhood deaf- cussion of the problems of profound childhood I20 G. R. Fraser deafness up to and including this period is to be mann and Wilhelmi (i88o), Hartmann (i88i), found in the book of Werner (I932). Hedinger (I882), Schmaltz (I884), and Lemcke Following Pedro de Ponce, rapid advances were (I892) in the provinces of Germany; Bell (I883) made in the provision of educational facilities for and Fay (I898) in the U.S.A.; Wilde (I853) and profoundly deaf children and, pari passu, interest Purdon (I867) in Ireland; and Scott (I844), Toyn- was aroused in wider problems of the causation bee (i86o), and Love (I896) in England and Scot- and dissemination of this condition. In the igth land. The interest which the subject aroused may century profound childhood deafness was in the be gauged by the fact that Meissner was already forefront of scientific medical inquiry. Through able in I856 to provide 53 pages of bibliography. the exertions of governments, the Church, private This entire literature was most ably reviewed in individuals, and charitable institutions, very com- two remarkable books by Mygind (I894) and Ucher- plete censuses of the deaf were made in most of mann (I9OI), who were themselves responsible the states of Europe, and in the U.S.A., and for surveys of deaf populations in Denmark and thorough analyses were made of the causes of Norway respectively. At the beginning of our deafness acquired in childhood. century the time was ripe to apply the ferment of Furthermore, both medical men and educators the newly discovered laws of Mendel to the very became very interested in the aetiology of other solid foundations constructed by these able and types of deafness and, though, in the pre-Mendelian painstaking investigators. era, the mechanism of recessive inheritance was unknown to them, they appreciated the possible importance of such factors as parental age, birth I: Genetically Determined Deafness rank, and prematurity. In I846, moreover, both Mode of Inheritance. It had, of course, been Puybonnieux and Meniere in France stressed the noted in the igth century and even earlier that importance of consanguineous unions in pre- profound childhood deafness tended to affect more disposing to deafness among the offspring. than one child in a sibship. Since, however, only This condition in fact provided for many years direct transmission from parent to child was re- the main battleground for a great philosophical garded as strictly hereditary, recessive deafness polemic between 'consanguinists' and 'anti-con- was ascribed to the influence of an inherited but sanguinists'. Anti-consanguinists were able for arcane predisposition transmitted through the some time to uncover biased statistics in support parents and often manifested by insanity, epilepsy, of their point of view that consanguineous mar- and a host of other abnormalities (Mygind, I894). riages were not of importance in the causation of The merit of Mendel's laws as applied to this deafness and other ills, and that the percentage of problem was that they could explain the nature of such unions among the parents of the congenitally this mysterious predisposition as heterozygosis for deaf was not unduly high. Their discomfiture, an abnormal gene, clinically without effect in however, was only a matter of time, and in I879 the parents, which in homozygous form produced Mygge, by a careful and methodical analysis of deafness in a proportion of the offspring. Further- all available data, was able to demonstrate con- more, in this way, the phenomenon that consan- clusively that these ideas were false and that, in guineous marriages were represented to an unduly fact, matings between relatives were more likely high extent among the parents of the deaf also to produce deaf children than those between un- fell naturally into place, since the relatives of a related persons. This controversy is extensively carrier of a rare gene would have a high chance of discussed in the thesis of Sambuc (I896). being carriers themselves. Many other excellent works on statistical and Lundborg (1912, 1920) was one of the earliest aetiological aspects of profound childhood deaf- investigators to apply himself to the problem of ness appeared in the igth century, sometimes as studying the exact modality of the inheritance of philosophical dissertations, sometimes as reports of deafness using, among others, the data of Fay censuses of particular deaf populations and some- (I898). He and many after him, such as Kraatz times as sections of textbooks devoted to the study (1925), made the very natural mistake that they of ear diseases. Only a few of the more notable transposed the clinical homogeneity of profound ones can be mentioned here, such as those of childhood deafness to the biological level. Lund- Itard (I82I), Meniere (I846, i856), Puybonnieux borg, therefore, came to the conclusion that all (I846), and Saint Hilaire (I900) in France; Sauveur cases of congenital deafness were recessive and due (I847) in Belgium; Schmalz (I830, I838), Kramer to only one abnormal gene. It soon became clear (I835), Meissner (i856), Wilhelmi (I873), Hart- that this was an oversimplification. Jenkins as Profound Childhood Deafness I2I early as I89I, writing of heredity in its relation to Stevenson and Cheeseman (I956). These latter deafness, had said that 'deafness no more implies data have been the subject of several mathematical one defect or disease than cough or jaundice does.... analyses. Slatis (I958) adhered to the now generally Congenital deafness is due not to one but to many discredited idea of polygenic inheritance, i.e. inter- different and unconnected pathological condi- actions between genes at different loci, but Chung, tions.' Robison, and Morton (i959) in a classical analysis Dahlberg (I93I) attempted a comprehensive showed that the data were consistent with the treatment of the problem from the point of view existence of very many (up to 36) different auto- of the geneticist. He pointed out that to fit the somal loci at each of which abnormal genes could oversimplified hypotheses of such authors as determine recessive deafness independently, and Lundborg, Hammerschlag, Orth, Plate, Bauer, that dominant and sex-linked forms were also and Stein, which are fully discussed and des- involved. Sank (I963) concluded that an even great- cribed, the available data had to be distorted beyond er number (at least 45) of different genes were recognition. He proposed a more complex system implicated in the causation of recessive deafness and, while he did clearly envisage the heterogeneity and also stressed the importance of dominant forms. of the problem, his theory of the aetiology of This situation is very similar to that in mice inherited deafness as a 'polyhybrid' interaction where, unlike man, it can be clarified by experi- between several genes, some in heterozygous mental breeding and by tests ofallelism and linkage. (dominant factors) and some in homozygous A large number of genes causing recessive deaf- (recessive factors) form, has not withstood the ness have been described (Gruneberg, I956; test of time. Deol, I954, I956a, i956b, I963; Deol and Kocher, Several families were described in which the I958; Deol and Robins, I962; Kocher, ig60a, offspring of parents, both of whom unequivocally ig60b). Interactions between these genes are suffered from recessive deafness, were normal uncommon, but occasionally double heterozygotes (Miihlmann, I930; Csorsz and Tokay, 1934; will become deaf in later life (Lord and Gates, Hammerschlag, I934; Lehmann, I950) and this I929; Deol, I956a); early deafness, the analogue raised the possibility that in fact a great number of profound childhood deafness in man, does not of different genes were involved, each of them occur, however, in such double heterozygotes. capable of causing deafness in the homozygous At the present time the main interest in the state. The necessity of postulating complex inter- subject of profound childhood deafness in man actions and polyhybrid inheritance was thus elimi- lies in the identification and characterization of nated. the various genes concerned in its causation. This interpretation is supported by the results Man has some advantages, as well as disadvantages, of many complete family surveys of deaf popula- over mice as an organism for genetical studies. tions, some restricted to small inbred isolates First, much more is known of normal human (Albrecht, I922, in Germany; Hanhart, I938; physiology and biochemistry and of pathological Secretan, 1954; Pfandler, I960; Pfandler and aberrations, and, secondly, accurate pedigree data Stucki, I960; and Pfandler and Schnyder, I960, have been kept in some areas, at least, for many in Switzerland), and others to entire provinces or generations. Furthermore, though experimental even countries (Lindenov, I945, in Denmark; breeding is out of the question as a tool for analysis, Stevenson and Cheeseman, I956, in Northern the deaf in fact marry almost exclusively among Ireland; Furusho, 1957, in Kyushu, Japan; Aulbers, themselves by choice. As their social integration I959, in South Holland; Deraemaeker, I960, in proceeds, especially in economically advanced North Belgium; and Sank, I963, in New York, areas of the world, their fertility is approaching U.S.A.). Though these authors come to somewhat normal levels (Rainer and Deming, I963), and conflicting conclusions, it is clear that in fact these highly assortative mating patterns are pro- several different genetical types of recessive deaf- ducing an increasing number of informative ness exist and that no interaction takes place families whose analysis can help in the identifica- between the genes causing them. The number of tion of the various components of the heterogeneous genes involved naturally varies with the geo- entity of profound childhood deafness. graphical extent of the population studied and While in the methodologicallv related field of with demographic factors, such as the degree of mental deficiency the main emphasis has been on inbreeding. Thus while the data of Furusho (1957) biochemical differentiation between the various are consistent with the involvement of only one genes involved (phenylketonuria, galactosaemia, gene, many must be implicated in the data of etc.), among the deaf such differentiation has so 122 G. R. Fraser far been successful only at the clinical level. It is deaf, for acquired deafness affects males pre- remarkable how successful this has in fact been, ferentially (see page I32). Values approaching considering that the organ directly affected, the Mendelian ratios much more closely can be ob- inner ear, is not accessible to direct inspection as tained from these data by the simple expedient is, for example, the eye in the context of another of only assuming recessive inheritance in sibships methodologically related field, the analysis of the containing at least two affected members. Great various clinical entities causing childhood blindness. caution is mandatory in any such analysis of deaf Despite these disadvantages, a large number populations, and clinical distinctions can often be of different genetical syndromes has been de- of much help in defining the cause of deafness. lineated which have only congenital deafness in Certainly it would be dangerous to argue from common, accompanied by an extraordinary variety these data that a unique mutant allele with semi- of other defects. While, thus far, cases of undif- lethal effects in foetal life is responsible for reces- ferentiated, clinically unidentifiable 'simple' gene- sive deafness in Eastern Switzerland. tical deafness remain in the majority, it is to be The preliminary results of a survey of a large hoped that, as the biochemical basis of these population of deaf schoolchildren using clinical, syndromes becomes apparent, so the nature and genetical, and statistical methods of analysis have heterogeneity of the genetical processes involved been published (Fraser, i962a, i964a). From these in the causation of deafness will be revealed. results it is dear that genetically determined causes Elucidation of the basis of this pleiotropism of are responsible for only about a half of all cases of gene action cannot fail but throw much light on profound childhood deafness and that as much as many obscure aspects of normal and abnormal one-sixth of all cases may be due to pre- and peri- human biochemistry and physiology. In the natal exogenous causes which can easily cause individual case such differentiation can be of vital confusion. Three relatively common genes which importance from the point of view of prognosis give rise to readily distinguishable clinical syn- for subsequent sibs and offspring and the vast dromes account for at least 25 % of all cases of problems of treatment, cure, and prevention can autosomal recessive deafness, this being the most hardly be broached until these facts about causa- common mode of inheritance involved in the tion are established. causation of childhood profound deafness. Domi- Insufficient appreciation of the heterogeneity of nant and sex-linked recessive forms are also of profound childhood deafness may lead to diffi- importance. culties in the analysis of population data. Thus the surveys of Pfandler (I960), Pfindler and The Syndrome of Retinitis Pigmentosa Schnyder (I960), and Pfandler and Stucki (I960) with Deafness. Of these three recessive syn- in various areas of Eastern Switzerland reveal a dromes, that of deafness with retinitis pigmentosa great excess of sibship containing isolated cases holds pride of place from the point of view of of profound childhood deafness. As a result the priority of discovery and thorough clinical des- ratios of affected to normal offspring in these cription. It was only a few years after the dis- sibships are lower than those expected on the covery of the ophthalmoscope that von Graefe in hypothesis of recessive inheritance, and these i858 in Berlin mentioned briefly a sibship in which authors are led to postulate various subsidiary 4 of 6 sibs suffered from this condition. A very hypotheses regarding the semi-lethality of the much more thorough survey was made in i86i, genes concerned, a situation that has not been des- also in Berlin, by Liebreich (Fig. i). This author cribed elsewhere, except in the context of a very examined a deaf population systematically and well-defined clinical syndrome (see page 127) which was much struck by the high frequency of retinitis these data do not suggest. pigmentosa that he found, especially among the Such hypotheses are not only somewhat im- Jewish deaf. His data were also remarkable for the plausible but unnecessary since it is not improbable large number of consanguineous unions among the that some of the cases of profound childhood deaf- parents of affected persons. ness are in fact due to exogenous causes acting Liebreich's (i86i) survey served as a model for very early in life and causing deafness superficially other studies regarding the frequency of retinitis indistinguishable from the recessive variety. This pigmentosa in the deaf, among the earlier of is especially true of persons whb had been ascer- which may be mentioned those of Adler (I876) tained only from Church books and had long been and of Lee (I883). Hammerschlag (I907) con- dead at the time of survey. This conclusion is firmed, in Vienna, Liebreich's (i86i) finding that strengthened by the excess of males among the this syndrome was more common among the i-rojouna rntsanooa veajness 123 ovarian function is subnormal in members affected * Deaf I 0IHearing with typical Usher's syndrome. If confirmed, this 9 suggestion may provide a clue to the nature of the inborn error of metabolism involved in the causa- tion of this condition and may be of relevance to the findings in the families of Koennecke (I9I9) and Richards and Rundle (I959). In these families ataxia with peripheral muscular wasting is com- bined with underdevelopment of secondary sexual characteristics and mental deficiency. Progressive deafness in childhood is present but no retinitis FIG. I. Recessive inheritance of the syndrome of deafness with pigmentosa. A metabolic block in steroid meta- retinitis pigmentosa among the offspring of both unions between a bolism was detected by Richards and Rundle (1959). man and two sisters after the data of Liebreich (i86I). While these two families do not belong to the classical syndrome of congenital deafness with retinitis pigmentosa, they do throw into sharp Jewish deaf. More recently the survey of Lindenov relief the complex and overlapping involvement (1945) among Danish deaf adults has revealed the of the ear, the eye, and the central nervous system considerable numerical importance of this syn- in a very wide variety of genetically determined drome as has the definitive monograph of Hallgren syndromes. Of this heterogeneous complex, des- (I959), which described a complete country-wide cribed by Kufs (I927) and Hammerschlag (I932, ascertainment from Sweden. I933, I934) as heredodegeneratio acustico-retino- The converse approach has also been attempted cerebralis, or heredopathia-acustico-optico-cerebro- and various workers have estimated the frequency spinalis, retinitis pigmentosa with congenital deaf- of deafness among those affected with retinitis ness undoubtedly forms a distinct entity but it pigmentosa. The methodology of such attempts overlaps in many ways with other component and is, of necessity, less satisfactory since persons as yet ill-defined syndromes. Thus Hallgren (I959) with retinitis pigmentosa do not form a socio- showed that a large number of his cases of Usher's educational isolate like the deaf and are therefore syndrome suffered from ataxia and, in addition, not readily accessible to complete ascertainment. mental deficiency which was not due to lack of The series that are available are usually of educational opportunity on account of sensory cases coming to the clinical attention of ophthal- deprivation. Both he and Stenger (I956) con- mologists, whether personal or collected from the cluded that the ataxia was due to a combination published reports. Among the larger of these of vestibular and visual disturbances and not to surveys are those of Nettleship (1907-o8), Usher any degeneration of the central nervous system. (1914) (who gave his name as an eponym to this Steinberg (1937) and Arnvig (I955) have shown syndrome, though the claim of Liebreich is con- that, of all forms of hereditary deafness, vestibular siderably stronger), Bell (I922), Wibaut (I93I), disturbances are most common in Usher's syn- and Kjerrumgaard (1948). drome. The mental deficiency does, however, Apart from these surveys, a great number of case indicate that a relation exists between this syn- reports of individual families exist, but few con- drome and other genetical conditions in which eye, tribute anything ofimportance. Jackson and Linder ear, and central nervous system abnormalities in (I953) described two affected sibs of a total of various combinations may be associated. These three, who had not only deafness with retinitis include, in addition to the condition described by pigmentosa but also hypophosphataemic glycosuric Koennecke (I9I9) and Richards and Rundle rickets with a defect of renal tubular function. (I959), dwarfism, retinal degeneration, and deaf- This finding is so unrelated to any other reports of ness (Cockayne, I936) and deafness in the Laurence- Usher's syndrome, even the retinal degeneration Moon-Bardet-Biedl syndrome (Burn, I950; Graf, being different in appearance, that it seems at I964), Niemann Pick disease (Oppikofer, I935) least possible, especially as the parents were and juvenile amaurotic idiocy or cerebro-macular second cousins, that two distinct recessive syn- degeneration (Wibaut, I93I; Steinberg, I937; dromes were involved, neither of them being Loebell, 1938) as well as several of the recessive classical Usher's syndrome. The family of Roberto syndromes mentioned in the introduction (Refsum and Carbonara (I959) is also of some interest et al., I949; Shaw and Duncan, 1958; Alstr6m because of the suggestion that gonadotrophic and et al., I959). Furthermore, both visual and audi- I24 G. R. Fraser tory degeneration, either singly or in combination, auditory, and the neurological features of this are relatively common in the genetically deter- complex is well illustrated by the thorough in- mined cerebellar ataxias such as those of Friedreich vestigation of unselected cases of tapeto-retinal (Matthews, I95o) and of Pierre Marie (Clauss, degenerations reported by such authors as Perrin I924; Vitello, I939). It is of some interest that the (1958). The whole question is extensively re- heart is also often involved in this disease complex viewed in the books of Grimaud, Mounier-Kuhn, (Gordon and Hudson, I959 (Refsum's syndrome); Gignoux, Martin, Paufique, Bonamour, Cordier, James and Fisch, I963 (Friedreich's ataxia); and Dureux (I962) on the association between Jeune, Tommasi, Freycon, and Nivelon, I963). troubles of the eye and ear, of Liveriero and Galli The unitary concept of Hammerschlag (I932, della Loggia (I962) on hereditary factors in oto- I933, I934) is untenable as Albrecht pointed out laryngology, and of Franceschetti, Francois, Babel, in I922 and I94I, basing his opinion both on de Rouck, Dieterle, Forni, Klein, Ricci, and genetical and pathological grounds. Though Verriest (I963) on tapeto-retinal degenerations. Albrecht went too far in claiming that every single Since the classical syndrome of retinitis pig- component of the 'heredopathia acustico-optico- mentosa with deafness is so well defined and was cerebro-spinalis' was inherited independently, it described so early in the course of the scientific is equally clear that several genes giving rise to study of profound childhood deafness, it has been several recessive syndromes are involved, there recognized as a distinct clinical entity in most of being no basis for any estimate of the exact number. the surveys, including those of the igth century, Bias introduced by the particular clinical interest mentioned above. As Hallgren (I959) points out, of the observer is undoubtedly a factor making in adults, at least, it is easy to diagnose; and both for additional heterogeneity which is more apparent Lindenov (I945) and Waardenburg (I956) des- than real. The main distinctive feature of the cribe marriages between persons with this syn- syndrome of deafness with retinitis pigmentosa is drome and persons with clinically undifferentiated that the hearing loss is extremely early in onset or recessive deafness, whose children, though double congenital, and frequently leads to profound child- heterozygotes, enjoy normal hearing. Fraser hood deafness, whereas it is usually later in onset (I965a) has described a marriage between a man and progressive, or even absent altogether, in the with deafness with goitre (Pendred's syndrome) other component syndromes of this complex entity, and a woman with Usher's syndrome: their only which are, as a result, poorly represented in the daughter had normal hearing. socio-educational isolate of profound childhood In children the diagnosis, without the benefit deafness. of electro-retinography, is sometimes difficult, as At the biological level, however, even this is retinitis pigmentosa may not be detected ophthal- not an absolute criterion of genetical heterogeneity, moscopically till adult life; nevertheless, many since it has been shown in the papers quoted on cases of Usher's syndrome appear in surveys of page I2I that the age of onset of deafness may vary deaf schoolchildren (Henning, I928, in Sweden; considerably in different strains of recessively deaf Lamy, Doll, and Marillier, I949, in France; Arnvig, mice, and that it is influenced to a large extent by 1954, I955, in Denmark; Diallinas, 1959, in the residual genotype, even when the main gene Switzerland; Fraser, i962a, I964a, in Great Britain; involved is identical. While many of the genes and Danish, Tillson, and Levitan, I963, in the causing recessive deafness in mice are associated U.S.A.). Because of these difficulties of diagnosis with disturbances of equilibrium, whether of in children, however, the true prevalence of the vestibular or central origin, a strain described by syndrome may best be gauged in adult deaf popu- van der Hoeve (1923), in which deafness was asso- lations, and Lindenov (1945) and Hallgren (I959) ciated with a retinal dystrophy, has unfortunately agree on an estimated incidence of 3 cases per not been reinvestigated with modern techniques. IOO,OOO population in Denmark and Sweden Even so, it is abundantly clear that many points respectively. involving qualitative and quantitative variations in the clinical expression of syndromes involving The Syndrome of Goitre with Deafness. deafness in man may be profitably studied in ana- There can be little doubt that Pendred's syn- logous situations in laboratory mammals, a point drome, i.e. the association of sporadic, as opposed that Hammerschlag (I932, I933, 1934) emphasized, to endemic, goitre with profound childhood deaf- basing himself on a lifelong experience of the ness, is more common than Usher's syndrome. problem. There can equally be little doubt that, despite the This clinical heterogeneity of the retinal, the fact that Pendred wrote his original description of Profound Childhood Deafness I25 two affected sisters in I896 (Fig. 2), this condition The reason for this comparative neglect is not has received very little attention until recently. hard to find. For many centuries restricted geo- Thus, though there are plentiful hints of its pre- graphical foci, especially in high mountainous areas sence in surveys of deaf populations, both adults of the Alps, the Andes, and the Himalayas, have and children (Uchermann, I90I; Henning, I928; been described where endemic goitre was prevalent Lindenov, 1945; Hopkins and Guilder, I949; and accompanied by cretinism, idiocy, and deaf- Arnvig, I954; Wildervanck, I957a) and also in ness. The rare examples of Pendred's syndrome case reports of individual families (Pendred, I896; and the true relation of sporadic goitre with pro- found childhood deafness had been completely thrust into the background by being wrongly as- lAinWIcal 'Otcs: sociated in investigators' minds with this relatively common association. It is clear, however, from MEDICAL, SURGICAL, OBSTETRICAL, AND the writings of Bircher (I883) and of Kocher THERAPEUTICAL. (I892) that these unfortunate cretins, in one of their main foci of the igth century (Switzerland), were DEAF-MUTISM AND GOITRE. not all necessarily deaf but could not speak be- By VAUGHAN PNDRUmD, M.R.C.S. ENG., L.R.C.P. LOND., cause of their retarded mental state. A full dis- LATE HOUSE St1EGEON TO GUYS HOSPITAL. cussion of these points is to be found in Fraser THE.CUriOUS association of deaf-mutism and goitre occuring (I960), Trotter (I960), and Fraser (I965a). It is in two members of a large family has induced me to record unlikely that any simple biological relation exists these cases. Why this association? Perhaps some readers between Pendred's syndrome and the endemic of THE LANCET may be able to throw some light on the association of deafness and goitre. In fact, this cause of this combination of diseases: Absence of thyroid- oretinism; overgrowth of thyroid-deaf-mutism. I append whole complex of endemic 'deafness' and/or idiocy the family history as recounted to me by the mother. The cannot properly be included in the definition of family is an Irish one, and the parents have been upwards of profound childhood deafness and will not be dis- forty years resident in Durham. The father,. aged sixty-six years, and the mother, aged sixty - seven years, are cussed here further. alive and healthy. They have had ten children, five Brain (I927) first invoked the hypothesis ot sons and five daughters. In an epidemic of small-pox recessive inheritance with regard to Pendred's twenty-five years ago the whole family was attacked with the exception of the younger of the deaf-mutes, and four syndrome. Furthermore, he clearly foreshadowed males and one female died, although all had been vaccinated, the later findings of Morgans and Trotter (I958) and that recently, as they were children. The remaining son and two of the daughters are healthy and vigorous. that the goitre was associated with an inborn error The first goitre case is the first-born of the family- of thyroxine synthesis, and that it was only one a spare woman now aged thirty-eight years. She is deaf and can only mumble indistinctly; little care has been taken of several such errors existing. Morgans and to educate her and so she is imbecile. The goitre is a laxge Trotter (I958) showed, in fact, that the defect of multilobular hard tumour, the greater part on the right side of the neck; from time to time she suffers from dyspnceic attacks. iodine metabolism involved in this syndrome was The growth was first observed after the small-pox-i.e., similar if not identical to that implicated by Stan- at thirteen years of age. The second surviving girl is now bury and Hedge (1950) in the causation of one aged twenty-eight years, and is the fifth of the family; she is a small, spare, intelligent woman, her expression being type of sporadic goitrous cretinism. This defect in marked contrast to her sister's. She is not absolutely in the incorporation of inorganic iodide into or- deaf and can mumble incoherently; her education has been attended to with so much success that she has been " in ganic form in the thyroid gland may be relatively service." The tumour is larger than in the other case, but easily demonstrated (Fig. 3), and has been con- is of the same character; it has been growing for about firmed many times in Pendred's syndrome (see fifteen years, and during the last year has caused both dyspncea and dysphagia, which have become so urgent that Fraser, I965a, for reiferences). I have sent her to-day to Newcastle Infirmary for operation. The distinction between Pendred's syndrome and Durham. sporadic goitrous cretinism of the type of Stanbury FIG. 2. Dr Vaughan Pendred's original description of the syndrome and Hedge (I950) is not clear cut and may be due, of deafness with goitre from the Lancet (I896), ii, 532.- (By kind in some cases at least, to quantitative rather than permission of the Editor.) qualitative differences in the degree of block of thyroxine synthesis involved. Thus cases of Pen- Brain, 1927; Deraemaeker, I956; Thieme, I957; dred's syndrome that border on clinical cretinism Johnsen, I958; Elman, I958), it was not until I960 exist (Fraser et al., ig60; Fraser, 1965a), and that its true numerical importance as a component furthermore gross speech disturbances, which, in of the heterogeneous entity of profound child- a mentally retarded individual, may well be due to hood deafness was suspected (Fraser, Morgans, undetected deafness, seem to be associated with and Trotter, I960). this type of error in thyroxine synthesis but not I26 G. R. Fraser

PERCHLORATE TEST AUDIOGFRAM _ 400mg

-I 120 KC104 3 s 4 100 20 ,> I-

80 40 a I- z 0 60 us I~~~~,oKo.,.2 0I cca 40 ar"';i 80 l- 20 2 100 Wn I 6 Ib 2o 30 0o 5o 256 1024 4096 MINUTES CYCLES/ SEC. FIG. 3. Recessive inheritance of the syndrome of deafness with goitre in two sisters born of a marriage of first cousins (after Fraser et al. (I960), by kind permission of the Editor of the Quarterly 3ournal of Medicine). The response of the thyroid counting rate of the two sisters to KCIO4 given one hour after radioactive iodide is abnormal. The ratefalls dra- matically as iodide still in unbound inorganic form is discharged from the thyroid gland. The heterozygous daughters of the affected sisters show normal responses to KCIO, and normal audiograms. The audiograms of their mothers show the typically greater loss of hearing in the high tones. 0 indicates subject with Pendred's syndrome.

1 any other (for references see Fraser and Trotter, 92 I964; Fraser, I965a). Sibships have been des- ( (j94 cribed (Fraser, i965a) containing both euthyroid and cretinous individuals with Pendred's syndrome, and, indeed, such was the case in Pendred's (I896) original description (see Fig. 2). Furthermore, a re-analysis of a pedigree of Jackson (I954) (Fig. 4) shows that the same person may, at different '114 3 (% (19- l,-3 periods, be diagnosed as a case of goitrous creti- (23~~~5-8 10 nism and of Pendred's syndrome. Fraser and FIG. 4. This family was the subject of the paper of Jackson (x954) Trotter (I964) describe a further family in which a and was restudied by Fraser et al. (i960). The proposita, 11I.x, was in infancy thought to be a goitrous cretin of the type of Stan- female goitrous cretin with normal hearing has two bury and Hedge (I950) but subsequently grew normally with aunts with typical Pendred's syndrome (Fig. 5). thyroxine therapy, though she is profoundly deaf. Both parents (I1.1; I1.2) and her sister (111.3) are typical cases of Pendred's This family is of special interest in view of the syndrome, as are three ofher mother's sibs. Her brother (II1.2) died in possibility (Stanbury, I963) that two genetically infancy and nothing is known of his hearing or thyroid defects in the state. Several marriages between persons both affected with Pen- determined organic incorporation of dred's syndrome with, as expected, affected offspring have been iodide exist, only one of which also affects hearing. ascertained by Fraser (I965a) as a consequence of a strong as- The proposita of Fig. might then be a double sortative mating tendency among the deaf (after Fraser and Trotter 5 (1964), by kind permission of Masson et Cie, Paris.) heterozygote for these two genes which are non- 0 indicates subject with Pendred's syndrome. complementary as far as thyroxine synthesis is Profound Childhood Deafness 127

@ Female with thyroid disease - not deaf

11~~~~~~~~~~q§92 y3 4 y5

"' (t,~~92 &30546T7S9A

V 2 1

FIG. S. The proposita, V.2, is a goitrous cretin of the type of Stanbury and Hedge (I950) but has two aunts (IV.3; IV.4) with typical Pendred's syndrome. She presumably inherited one mutant allele for Pendred's syndrome from her father and a different mutant allele from her mother. Hypothetically these two mutant alleles, whether at the same or different loci, are complementary as far as hearing is concerned but do not complement each other from the point of view of thyroxine synthesis. The mother's mutant allele seems to be expressed rather frequently in heterozygotes as is evidenced by goitre in herself and thyroid disease in several other members of her family marked with a cross (111.9; III1.4; IV.14). (After Fraser and Trotter (1964), by kind permiission of Masson et Cie, Paris.) 0 indicates subject with Pendred's syndrome. concerned but do complement each other from the wide clinical variation in the expression of Pen- point of view of hearing. dred's syndrome, which can often lead to diffi- Whether one or two such genes exist, it is clear culties in diagnosis, especially in children in whom that there is considerable clinical overlap between the goitre has not yet developed, the author con- Pendred's syndrome and goitrous cretinism. As a cludes that the prevalence of Pendred's syndrome result, as in the case of Usher's syndrome, though is of the order of 7-5 cases per ioo,ooo births in probably not to such a great extent, some persons the British Isles. with Pendred's syndrome are mentally deficient because of inadequately compensated thyroid The Syndrome of Electrocardiographic failure interfering with brain development in Abnormalities, Fainting Attacks, and Sudden infancy. These are probably the only two common Death with Deafness. In 1957 Jervell and genetically determined causes of profound child- Lange-Nielsen described a family from Norway hood deafness, which are specifically associated in which four of six sibs suffered from profound with mental deficiency, though occasionally a childhood deafness. All four had been subject mistaken diagnosis in early life will lead to the from early childhood to curious fainting attacks, lifelong confinement of a deaf person of normal during which three had died at the ages of 4, 5, intelligence in an institution for the mentally and 9 years. The only significant clinical finding defective (Grewel and van den Horst, I959a). that could account for this macabre phenomenon Such mistakes, fortunately rare now, were fre- was that the deaf children showed very striking quent in the past and, indeed, until comparatively abnormalities of the electrocardiogram, undes- recent times, little attempt was made to differen- cribed previously and characterized by a gross tiate between profound childhood deafness and prolongation of the QT interval (Fig. 6). Dr F. N. mental deficiency. Wilson, who examined the electrocardiogram of a The published reports on the association of deaf child who died at the age of I3 with an identical deafness with goitre have been extensively re- condition (Levine and Woodworth, I958), was so viewed by Fraser (I965a) in the course of a des- impressed by the tracings that he remarked, 'I am cription of a personal series of 207 families with afraid you will have to place the ECGs in a group Pendred's syndrome. Taking into account the very called "screwballs".' During a screening, using I28 G. R. Fraser

III

I

m v-Inam r*,% aVr FIG. 6. Electrocardiogram (cardiac cycle = o-8o sec.) ofa case ofthe recessive syndrome ofdeafness with faint- ing attacks, electrocardiographic abnormalities, and sudden death. This tracing shows the distinctive features characteristic of this condition-the extreme prolongation of the QT interval and the bizarre, often biphasic, T waves (from Fraser et al. (I964a), by kind permission of the Editor of the QuarterlyJournal of Medicine). electrocardiography, of several thousand deaf at necropsy. The two boys were described as people, both children and adults, 9 further cases morose and unsociable and it is conceivable that of this condition were uncovered and described by these epithets cloaked a degree of undetected deaf- Fraser, Froggatt, and James (i964a) and Fraser, ness. On the other hand, it may be that Morquio's Froggatt, and Murphy (i964b). These authors family conforms to that of Ward (I964) without have suggested that this condition be called the deafness rather than to that of Jervell and Lange- cardio-auditory syndrome of Jervell and Lange- Nielsen (1957) with deafness. In either case there Nielsen. is little justification, in the absence of electro- Ward (I964), on the other hand, described a cardiographic documentation, for the claim some- brother and sister with a very similar clinical and times made (Canabal and Dighiero, I951) that electrocardiographic picture but in whom there the cases described by Morquio (I901) represent was no deafness. While the boy died at the age of the first familial example of congenital heart block. i8 months before any definite pronouncement re- Whatever the truth of the exact relation between garding his hearing state could be made, the girl is these families, it is clear that a study of these alive and at the age of 8 years has a normal audio- syndromes has much to contribute to the tragic gram. As in the cases of Usher's and Pendred's problem of sudden deaths in infancy and child- syndrome it seems as if closely similar conditions hood, a proportion of which may be due to un- with and without deafness exist, the genetical suspected cardiac metabolic defects of this type. relation between them, in the absence of the pos- Even though the ECG was introduced as a rou- sibility of experimental breeding tests, being un- tine tool of clinical investigation comparatively re- clear. It should be noted, however, that the cently, it may be asked how the other features of cardiac disturbance, both in Ward's (I964) report this very striking condition escaped detection and in a similar one by Barlow, Bosman, and and characterization among the congenitally deaf Cochrane (I964), seems to be dominant rather for so long. Unfortunately, however, sudden death than recessive. in children was until recently, and still is today in Morquio (I90I) described a family of Uruguayan many parts of the world, a far too common pheno- peasants, five of whose eight children had suffered menon to attract much attention. Nevertheless, from a series of fainting attacks; these attacks had there is little doubt that Meissner's (I856) des- begun at the age of 4 years and four of the children cription fits the syndrome under discussion. He had died during them. Morquio studied two of tells of a deaf girl, named Steinin, in the school for these sibs, one of whom died in his wards at the the deaf in Leipzig, who, while being reproached age of 8 years. No cause of death was apparent by the director for some trifling theft, fell down in Profound Childhood Deafness I29 a faint and could no longer be revived. Her parents cases, unlike those of Wildervanck, retinitis pig- evinced no surprise when informed of her un- mentosa was an additional component. Wilhelmi timely end, for they had lost two children pre- (I873) mentions a deaf person with ectrodactyly viously in a very similar manner. in his survey of the deaf of the province of Magde- The fainting attacks characteristic of this cardio- burg in Germany and Fere (I896) and Urbants- auditory syndrome of Jervell and Lange-Nielsen chitsch (I9IO) also refer to the association, all are sometimes compatible with survival to adult without giving further details. While it is clear life, and there is some evidence that the severity of that this association of deafness with ectrodactyly the cardiac lesion decreases towards the end of cannot be regarded as a coincidence, especially childhood (Fraser et al., I964a, b). In children the since recessive inheritance of ectrodactyly is rare condition may be misdiagnosed as petit mal or (Klein, I932), it may of course sometimes occur even hysteria and the inclusion of a boy born of fortuitously. Thus Yearsley (I934; I935) des- related parents with epileptiform attacks in the cribes a girl who had ectrodactyly, inherited in the survey of Swedish schoolchildren by Henning usual dominant manner from her father, and whose (I928) and two children with fainting spells in the deafness was acquired during an attack of menin- similar survey of Danish et al. (I963) in the gitis in infancy. U.S.A., indicates that this syndrome, though rare, It seems very probable that in many other has a widespread geographical distribution among families the association in some members of pro- deaf children. found childhood deafness with other defects is Because of the high mortality of affected persons fortuitous and due to independent segregation of in infancy and childhood it is difficult to obtain two genes, one causing deafness and the second any good estimate of the prevalence of this con- the other anomalies. Among such coincidental dition in the population at birth. After an ex- defects may be mentioned recessive dystrophia haustive discussion of the problem of ascertain- reticularis laminae pigmentosae retinae (Holmgren, ment, Fraser et al. (i964b) reached the conclusion I950), dominant pulmonary stenosis (Lewis, Son- that this true prevalence may be as high as i per nenblick, Gilbert, and Biber, I958), and recessive IO0,OOO births, though the incidence among total albinism (Ziprkowski and Adam, I964). children of school age is a good deal less. The involvement of profound childhood deaf- ness as a component of a great many syndromes Other Recessive Syndromes Involving Deaf- covering a broad spectrum of associated clinical ness and the Pathogenesis of Recessive Deaf- lesions raises many basic biological problems. It ness. Apart from the three conditions described is known that a variety of drugs and chemicals in the preceding sections and the whole tangled (streptomycin, quinine, arsenic, etc.) exert a toxic pattern of the 'heredopathia acustico-optico-cere- effect on the auditory apparatus. The marked bro-spinalis', discussed in connexion with Usher's selectivity of this effect may well be associated syndrome, many other distinctive accompaniments with the unique features of the VIIIth nerve, im- of profound childhood deafness have been des- plicit in the relation of its end-organ to the en- cribed, often restricted to a single family but dolymph. clearly inherited in a recessive manner. While Like intracellular fluids, the endolymph is rich these associations are likely to be due to the pleio- in potassium (Citron and Exley, 1957). While the tropic action of single abnormal genes in homo- finer details are a matter for controversy, it is zygous form, the possibility of the coincidence of clear that this liquid is formed through a series two such abnormal genes by chance in several of biochemical mechanisms of great complexity sibs cannot be excluded. Among these accompani- and it is very possible that its composition must ments are congenital absence of the tibia (Carraro, be kept constant within rather narrow limits to I931), myoclonic epilepsy (Latham and Munro, maintain the hair cells of the VIIIth nerve in health 1937), and dystrophy of the nails (Feinmesser and and to ensure the propagation of sound. Thus Zelig, I96i). Yearsley (I934; I935) also described quantitative or qualitative changes in endolymph a girl with nail abnormalities in the course of a composition might be expected to lead to degenera- survey of over 4,ooo deaf schoolchildren in London. tion of the membranous labyrinth and to deafness In I963 Wildervanck reported two sibs born of whose extent and rapidity of onset might be de- normal parents with ectrodactyly and profound pendent on the nature and severity of the derange- childhood deafness. This combination had been ment involved. described by Uchermann (I9OI) from Norway, It is clear also that recessive deafness of the type and Kemp (1953) from Denmark, but in these under discussion thus far is in fact due to degen- 130 G. R. Fraser eration of the membranous labyrinth and not to to hand. It may well be, however, that in the any gross malformation of the structures of the future both the normal processes of health and the middle and inner ears. This point is elaborated abnormal pathways involved in deafness will be further in a subsequent section on the pathology of unravelled and that the clinical associations of deafness. Deol (I954), in discussing postnatal deafness in man will provide some useful clues to neural cellular degeneration (abiotrophy in the sense their elucidation. In addition, these syndromes of Gowers (I902) and Collins (I919)) in the laby- are of importance in wider fields of medicine and rinths of various types of recessively deaf mice, human biology in that they are potentially capable wrote as follows: 'It is probably correct to say that of throwing much light on obscure aspects of abiotrophy means the degeneration of cells due to normal and abnormal iodine metabolism and of purely chemical causes. There are many ways in the pathogenesis of sporadic goitre in general which this may happen; they all have one thing in (Fraser, i962b), of cardiac (Fraser et al., i964a) common; a chemical situation is revealed and and of retinal metabolism, and of many other localized by that type of cell which is most sensitive processes, reflected in the diversity of these syn- to the chemical change in question. This selective dromes. Nor is this list exhaustive, for there can effect may be brought about by a shortage of a be little doubt that further such clinical diversity key nutrient; or by an increased demand for a key will be revealed in the future and will eventually be nutrient present in normal quantities; or by an correlated with the underlying inborn errors of increase of a biologically active metabolite; or by metabolism. In the meantime a preliminary gene- an increased sensitivity to such a substance present tical segregation analysis of the data of Fraser in normal quantities; or indeed in many other (i962a, i964a) concerning 2,355 deaf school- ways.) children shows that presently unidentifiable reces- As so little is known of the normal processes sive deafness is responsible for about 26 % of the of the formation of the endolymph and of other total or 26 cases per ioo,ooo births (assuming the features of the normal metabolism of neural cells incidence of profound childhood deafness to be in the labyrinth, it would be idle at this stage to i per i,ooo births (see page I45)). In this computa- speculate further. It is instructive in this context tion allowance is made for the cases of Usher's to note that 30 years after the discovery of phenylke- and Pendred's syndromes which cannot be diag- tonuria by F0oling (I934), the relation between this nosed by clinical inspection in children (see pages inborn error of metabolism and the associated I24 and I27). mental deficiency is still not understood. In the While hereditary deafness which is due to mal- case of deafness, no clues of this sort are, as yet, formation of the middle ears and is conductive

O NORMAL * DEAF 11 Q9t DIED IN INFANCY

III

'IV

VI

FIG. 7. Legend opposite. Profound Childhood Deafness 13I rather than perceptive in character, usually follows whole cause their effects are poorly understood, a dominant mode of inheritance and will be dis- but it is probable that they differ radically from cussed in a subsequent section on congenital mal- the modus operandi of inborn errors of metabolism. formations, one recessive syndrome involving such conductive deafness has been described. Crypt- Sex-linked Recessive Deafness. Kramer ophthalmos is well known to be associated with a (I835) has already been mentioned in the intro- large variety of skeletal and visceral congenital duction as one of the first of that remarkable group malformations (Duke-Elder, I952). Fraser (I962C) of investigators who placed the study of profound described two families containing four affected childhood deafness on a firm scientific footing. sibs, one of who was deaf due to malformations He gave an account of a sibship containing five of the ossicles of the middle ear (see Fig. io, page hearing sisters and six deaf brothers born of 138) and two of who had been born too malformed normal parents and without any other deafrelations, to be viable. though, since the family did not involve transmis- Such deafness was also a feature of the case of sion from one generation to the next, he did not Gupta and Saxena (I962). It may well be that regard it as a bona fide example of heredity. Hints semi-lethal recessive syndromes of this type are of the existence of sex-linked recessive inheritance due to a basically different genetical mechanism may also be obtained from the sex distribution of from the perceptive types of deafness described deafness in the data of Wilde (I853) (see Fraser, above. These latter are probably associated with i965b, for an analysis), and Fay (I898) in his inborn errors of metabolism which, in modern monumental account of 4,471 marriages in which genetical theory, are due to single amino acid one or both partners are deaf does include an substitutions, impairing the function of essential account of a family in which two deaf brothers proteins such as enzymes. Such substitutions are had a deaf uncle and nephew. thought to be due to changes in a single base pair Much better defined examples of sex-linked of the chromosome and do not usually lead to any recessive inheritance have been presented more clinical disturbance in heterozygous form. It may recently, of which undoubtedly the most impressive be that many mutations which often do cause is the pedigree of Dow and Poynter (I930) (Fig. 7). overt clinical effects in heterozygous form (domin- Other families in which the presumption of sex- ant inheritance) are due to changes affecting more linked inheritance is strong, though formal proof is than one base pair, even though such deletions, impossible, have been described by Mitsuda, inversions, or other chromosomal rearrangements Inoue, and Kazama (I952) from Japan; Sataloff, are too small to be detectable by conventional Pastore, and Bloom (I955) from the U.S.A.; karyotype analysis. Complex recessive congenital Parker (I958) from Australia; Deraemaeker (I958) malformation syndromes such as cryptophthalmos from Belgium; Mohr and Mageroy (I960) from may then represent the homozygous state of such Norway; Livan (I96I) from Italy; and Richards small chromosomal rearrangements. The pathways (I963) and Fraser (i965b) from Great Britain. through which chromosomal rearrangements as a Many other families in which deafness has been

FIG. 7. Pedigree of sex-linked recessive deafness after Dow and Poynter (1930). (By kind permission of the Editor of Eugenics Quarterly.) 132 G. R. Fraser limited to one sex, either females (de Vido and independently, a large family of Moroccan Jews de Stefani, I952) or males (Cerri and Marcato, living in Israel in which profound childhood deaf- I958), have also unfortunately and erroneously ness associated with partial albinism is clearly been described as examples of sex-linked inheri- inherited in a sex-linked recessive manner. This tance. family is unique in that, though this clinical associa- Fraser (I965b) has shown by an analysis of the tion is well known, it is usually inherited in a careful pedigree data of Hopkins and Guilder (I949) dominant manner, one of several dominant syn- and of Stevenson and Cheeseman (I956) that sex- dromes involving deafness with pigmentary anoma- linked recessive inheritance plays a not insignificant lies (see page I34). One of these is very similar to numerical role in the causation of profound child- the association in the family under discussion and hood deafness. He comes to the conclusion, based extensive pedigrees have been described by Tietz on his own material, that 6-2 % of those cases of (I963) and Fraser (I965a, b). In these two families deafness in males, which are determined by simple affected males have had four children (three af- Mendelian segregation at single loci, are due to sex- fected girls, one normal boy), and sex-linked domi- linked recessive inheritance and that males account nant inheritance is, therefore, a possibility. One for 51I7 % of I,228 such cases. The prevalence of of the families of Fisch (1959) may also fit this sex-linked recessive deafness is about 3 cases per entity but unfortunately the sex is not noted. Ioo,ooo males or about I-5 per IOO,OOO births of Even if the hypothesis that dominant sex- both sexes. This figure is somewhat higher than linked inheritance is involved is accepted, the the estimate derived by Chung et al. (I959) from variability of the pattern of inheritance in this various published surveys of deaf populations. association of congenital deafness with partial It is of interest that the excess of males among albinism remains perplexing. One entirely specu- cases of acquired profound childhood deafness lative possibility is that the locus responsible for in this series (Fraser, I965b) is much greater, and this syndrome is in fact on the X chromosome and males account for no less than 57-8% of I,026 that the mutant allele is usually expressed in such cases, and an even greater proportion (6i %) females (sex-linked dominant inheritance). In of 450 cases known to be acquired after the neo- some families, however, such as that of Margolis natal period. The reason for this marked excess (I962) and Ziprkovski et al. (I962), the X chromo- propensity of males to acquire deafness as a sequel some which carries the mutant allele may undergo of meningitis or other diseases of early life is not inactivation, of the type postulated by Lyon (I96I), clear. It was extensively discussed by Wilde (I853), preferentially, perhaps because of some slight Mygind (I894), Uchermann (I9OI), and Lindenov structural abnormality, giving rise to an appearance (1945), but no convincing explanation has yet of sex-linked recessive inheritance. Alternatively, appeared. This substantial excess of males among the mutant allele may be normally responsible for cases of acquired deafness may be observed in all autosomal dominant inheritance but may have other large series such as those of Shambaugh, been translocated to one of the X chromosomes Hagens, Holderman, and Watkins (I928) and which again may have undergone preferential in- Shambaugh, Hayden, Hagens, and Watkins (I930) activation in carrier females in this family. It may from the U.S.A., and de Reynier (1959) from Swit- be mentioned in this context that female hetero- zerland. zygotes in families exhibiting sex-linked recessive Profound perceptive childhood deafness is often deafness of the usual variety without albinism enjoy present in Hurler's syndrome (gargoylism) of the normal hearing(Fraser, I965b)and that no pedigrees sex-linked, rather than autosomal, recessive variety of dominant deafness without pigmentary anomalies (Herndon, 1954). While the clinical diagnosis of have been described in which apparent sex-linked gargoylism is usually not difficult, chemical studies, inheritance has occurred. both in life (Scheie, Hambrick, and Barness, I962) and at necropsy (Jervis, 1950), have revealed Dominant Deafness with Pigmentary Ano- typical derangements of mucopolysaccharide meta- malies. As the igth-century writers on profound bolism in persons who had not previously been childhood deafness were extremely interested in clinically diagnosed as gargoyles. Thus it may well all unusual clinical associations, it is remarkable be that some cases of apparently uncomplicated that the very striking pigmentary anomalies which sex-linked recessive deafness may be due to this are now recognized as being relatively common disease (see also page I37). among the deaf passed virtually unnoticed. Thus Margolis (I962) and Ziprkovski, Krakowski, white forelock and partial albinism are unmen- Adam, Costeff, and Sade (I962) have described, tioned in the elaborate accounts of these painstaking Profound Child!hood Deafness I33 igth-century surveys. Even heterochromia of the restudied by Waardenburg, by van der Hoeve irides which, in its specific association with deaf- (i9i6), was that most constantly present in carriers ness, takes a form with extreme contrasts between of the mutant allele, whereas the other components deep blue and rich brown hues is mentioned only were seen more irregularly. Even if the irides are in passing by Fere (I896) in an account of 'tera- not heterochromic, Waardenburg (I95i), Bischler tological stigmata of degeneration' among deaf (I956), Diallinas (I959), and Fisch (I959) have children and by Wilhelmi (I873) and Uchermann remarked that they may often be of an unusual (I9OI) in isolated cases, by the former in association blue appearance with a hypoplastic stroma. Again, with 'deep-set' eyes. At a later period hetero- though profound childhood deafness is not in- chromia of the irides was noted in 4 of the variably present in carriers, Waardenburg (I951), 847 Swedish deaf children surveyed by Henning Fisch (I959), and Arnvig (I959) have pointed out (I928). that the deafness may be unilateral or of a milder Reports of isolated families and individuals degree, not causing serious disability. showing an association of deafness with pigmentary Many case reports of Waardenburg's syndrome, anomalies also exist. As early as I828 Hohl des- as it is now generally called, have appeared since cribed a mother and two children who heard poorly his classical description of I95I. For a time it and were fair with blue eyes while the father and was felt that there was some special relation between three remaining children, with normal hearing, the syndrome and Holland and in fact many further were darker with brown eyes. Some of the mem- cases were reported from that country (Keizer, bers of the famous Italian family, described by I952; Wildervanck, I957b). Thus Partington Rizzoli (I877) and Mazzini (I923), in which domi- (1959) stressed the Dutch ancestry of a large family nant inheritance of white forelock could be traced with this condition from England, and Settel- for at least eight generations suffered from pro- mayer and Hogan (I96I) the lack of such ancestry found childhood deafness. Urbantschitsch (I9IO) in a family from the U.S.A. It is now clear, in recognized that partial albinism, so called 'epi- fact, that no such special relation exists and that canthus', and heterochromia of the irides were Waardenburg's syndrome exists among the deaf associated with deafness, and Hammerschlag (I9IO) in all parts of the world. Reports have appeared of suggested that part of this complex might be the effects of this condition in non-white people, inherited as a unit. Van Gilse (1926) reported an in whom the characteristic white forelock, blue isolated case of partial albinism, heterochromia of eyes, and patchy depigmentation of the skin the irides, and deafness. Mende, also in I926, are particularly striking (DiGeorge, Olmsted, and described a family in which dominant deafness of Harley, I960; Scott and van Beukering, I962; the type later defined by Waardenburg (I9si) Calinikos, i963, in Negroes; Zelig, i961, in Jews was segregating. It is interesting that Mende's of Indian ancestry; and Houghton, I964, in a family, like that of von Graefe (I858) (deafness Maori boy). A very large family study covering with retinitis pigmentosa) and that of Kramer I33 members of seven generations has been re- (I835) (sex-linked deafness), also originated from ported from Belgium by Delmarcelle and Pivont Berlin. Some of the members of this family showed (1958). Waardenburg's (I95I) syndrome has been partial albinism of the skin and hair, and the described by Stoller (I962) from the U.S.A. in a peculiar shape of the eyes gave a 'mongoloid' im- boy in association with Sprengel's deformity of pression. Klein (I947) described an isolated case the shoulder. which belongs to the same complex, though with Porot and Filiu (I959a) described it in associa- many additional abnormalities. tion with epilepsy in an Arab boy from North Waardenburg (I9si) brought all these threads Africa. The same authors (1959b) found an ab- together and showed that a dominant syndrome normal electroencephalogram, indicative ofepilepsy, existed, consisting of profound childhood deaf- in a second case, who did not, however, suffer from ness, partial albinism of skin and hair, hetero- any overt attacks. It is not at all clear what these chromia, total or segmental, of the irides, hairy findings indicate, though they may be related to overgrowth of the eyebrows, and a peculiar con- the claim of Fisch (I959) that the skull structure of figuration of the eyes which he was able to show affected persons is abnormal. These abnormal was neither due to epicanthus, nor related to that EEGs cannot be regarded as coincidental since found in mongolism or hypertelorism, but a dy- similar tracings were found independently by stopia canthi medialis lateroversa (see Fig. ii, on Grimaud et al. (I962) in two typical cases of page 138). This last feature, first clearly defined in Waardenburg's syndrome, neither of which had two monozygous deaf female twins, who were overt epileptic attacks. I34 G. R. Fraser Little is known of the EEG in profound child- a relatively inconstant feature of Waardenburg's hood deafness in general. It is normal in the (1951) syndrome, the true incidence of this com- syndrome of deafness with electrocardiographic plex is undoubtedly much higher. There is no abnormalities (Fraser et al., i964a). Tracings have possibility in man of estimating the number of been obtained rather frequently in this condition loci at which mutant alleles are responsible for because of the perplexing nature of the associated these syndromes. Clinical differentiation is dif- syncopal attacks. The EEG may be abnormal ficult because of the considerable overlap. Thus, in the syndrome of deafness with retinitis pig- while the partial albinism with deafness in the mentosa (Grimaud et al., I962), which is not sur- family of Ziprkovski et al. (I962) is distinguished prising in view of the associated involvement of by a sex-linked recessive mode of inheritance (see the central nervous system discussed above. page I32), heterochromia of the irides is present It is clear (Fisch, I959) that more than one syn- as in Waardenburg's (I95i) syndrome, though drome associating dominant deafness with pig- the configuration of the eyelids is normal. It could mentary anomalies exists. One such condition be that only one chromosomal segment is in- (Tietz, I963; Fraser, I965a, i965b) has been dis- volved and that these different constellations of cussed in connexion with sex-linked deafness. pigmentary anomalies, with and without deafness, In this syndrome eye configuration is normal, are due to position effects caused by small chromo- whereas profound childhood deafness and partial somal rearrangements. albinism are constant features in carriers. Analogies These may not be detectable by present methods exist between this syndrome and conditions occur- of examination, and Partington (I964) has, in fact, ring in other mammals. Thus while deafness is not reported a normal karyotype in two typical cases found with recessive albinism in man or animals, of Waardenburg's syndrome. Ziprkovski et al. it has been described in the dominant albinism of (I962), on the other hand, have described a pos- cats, sometimes associated, moreover, with hetero- sible abnormality of the X chromosome in one chromia of the irides. Puybonnieux (I846), quoting affected male. Pending confirmation, however, earlier work of le Bouvier-Desmortier, wrote of a this finding must be interpreted with caution. family of angora cats in which the mother was white and deaf while the father was black and Dominant Deafness Without Pigmentary white and hearing: all the kittens that were born Anomalies. There can be little doubt that pro- white were deaf like the mother, while those that found childhood deafness, without any association resembled the father were hearing. Deaf white with disorders of pigmentation, can also be in- cats are also mentioned by Darwin in his On the herited in a dominant manner. It is strange that Origin of Species (I859) and subsequent works, this has not been generally recognized earlier and, and similarly affected dogs and rabbits are referred in fact, many investigators from Kramer (I835) to by Klein (I947). While these animals seem to to Stevenson and Cheeseman (I956) denied the be totally albinotic, at least as far as the hair is possibility. In the earlier part of the igth century concerned, deafness is associated in other mammals deaf people were extremely handicapped econo- with genes causing spotting of coat colour, and this mically and their fertility was, in consequence, very combination is also iniherited in a dominant man- low (Mygind, I892; Uchermann, I9OI). Thus ner. One such gene is 'varitint-waddler' in mice pedigrees in which deafness was transmitted for (Cloudman and Bunker, 1945; Deol, I954), and several generations did not exist. A possible ex- the same situation may occur in various breeds of ception is mentioned by Adams (I8I4), but his des- dogs (Sorsby and Davey, I954). cription is not clear. Various estimates have been made of the fre- The deaf, however, later overcame these econo- quency of Waardenburg's syndrome among the mic handicaps, especially in the U.S.A., and pro- deaf (Waardenburg, I95i; Wildervanck, I957b; ceeded to procreate to such effect that Bell (I883) DiGeorge et al., I960; Partington, I964). Fraser entitled his monograph 'Upon the formation of a (I964a) found 56 cases associated with Waarden- deaf variety of the human race'. The hypothesis burg's syndrome and other pigmentary anomalies of dominant inheritance can scarcely be avoided of the types discussed above in a group of 2,355 with reference to some of the families described deaf schoolchildren. Assuming (see page I45) that by both Bell (I883) and Fay (I898) from the U.S.A. profound childhood deafness affects I per I,OOO (Fig. 8), and this was in fact realized by Ham- of the population, then the prevalence of such merschlag (I934). The tabulated results of Fay deafness due to these causes is about 2-5 cases per (I898) are even more striking, for the proportion of IOO,OOO births. Since, however, severe deafness is deaf offspring resulting from 599 marriages where Profound Childhood Deafness 135

IJ II

{11 I11 III 95

Iv 9 12 FIG. 9. Probably dominant deafness in the family of Mitchell IV (I863). Carriers who seem to be unaffected (II.2; III.4) may be relatively mildly, or unilaterally, deaf (see text).

speaking authors) and dominant profound child- which in be FIG. 8. Pedigree of dominant deafness in five generations after hood deafness may well, fact, entirely Fay (I898): 1.I is number 507 of that report. Recessive deafness is different entities and also by the fact that carriers likely in the case of the deaf persons who married into the family of the mutant alleles involved, as in Waarden- UII.; III.4; III.8; IV.6; IV.g.) burg's syndrome, may be unilaterally deaf, mildly affected, or even in some cases not affected at all. only one of the partners was deaf was higher than This is strikingly illustrated in a report of dis- that from 2,377 marriages where both partners cordant uniovular twins with dominant deafness were deaf (I2x5 % as opposed to 9 2 %). As Bell (Grewel and van den Horst, I959b), one of who (I883) pointed out, many hearing spouses of deaf is profoundly deaf while one ear of the other is persons may be related to them, or to other deaf relatively spared, enabling him to follow normal people, and thus recessive deafness may be pro- schooling. pagated in such marriages. On the other hand, Bearing these points in mind, it is very likely it is clear that dominant inheritance is also of much that the pedigrees reported by Mitchell (I863) importance in the transmission of deafness from (Fig. 9) and Smith (1939) represent irregularly one generation to the next. manifested dominant deafness. In the latter des- More recently, in economically advanced coun- cription, unilateral deafness was very common tries, the fertility of the deaf has been approaching and transmitted through four generations, though normal limits (Rainer and Deming, I963) and, two cases of bilateral profound childhood deafness as their handicaps have been overcome, they also occurred. An 'obvious resemblance between have been tending to marry almost exclusively deaf members' is mentioned and raises the pos- within their own community. Fay (I898) pointed sibility that in fact Waardenburg's syndrome is out that marriages in which both of the partners segregating in this family. were deaf were more likely, other things being Everberg (I960) has studied unilateral deafness equal, to result happily than those in which one in schoolchildren very thoroughly in Denmark and of the partners was deaf and the other a hearing finds it to be relatively common (i85 cases in person. The formation of this isolate provides i82,934 children screened). He found that one ample opportunity for the observation of gene- such child belonged to a family in which Waarden- tically informative matings (see page I2I). These burg's syndrome was segregating and another to a points are discussed by Fraser (I964b), who gives faniily in which cases of bilateral profound child- several examples of dominant inheritance of pro- hood deafness inherited in a dominant manner found childhood deafness with and without pigmen- occurred. Johnsen (I954a, b), also in Denmark, tary anomalies. studied a group of children who were handicapped Difficulties in the recognition of dominant deaf- by hearing loss but not to a sufficient extent to ness were compounded by a certain confusion need education in a special school, and found, by between dominant adult perceptive deafness (pro- family investigation, that a high percentage suf- gressive heredo-labyrinthine deafness of German fered from dominant deafness. 136 G. R. Fraser Chung et al. (I959), analysing the data of Steven- congenital deafness, which fit this concept better, son and Cheeseman (I956) from Northern Ireland, do exist. first showed that a substantial proportion of the Incomplete forms of the first of these were des- heterogeneous entity of childhood profound deaf- cribed by Berry (I889) and Collins (I900), and it ness was due to dominant inheritance. This con- is sometimes known as the Treacher Collins clusion was supported by Sank (I963). The data syndrome. It was thoroughly reviewed in a mono- of these investigators combined with those of graph by Franceschetti and Klein (I949), who Fraser (i962a, I964a) suggest that the proportion showed that the complete syndrome, which they due to dominant deafness without pigmentary called mandibulo-facial dysostosis, consisted of anomalies is of the order of 8-i2 %, including abnormalities of the outer, the middle, and oc- carriers of fresh mutations. There is no basis for casionally the inner ear, - associated with anti- an estimate of the number of loci involved but mongoloid palpebral fissures, coloboma of the collectively they are therefore responsible for about lower eyelids, hypoplasia of the malar bone and I0 cases of profound childhood deafness per I00,000 mandible, macrostomia, high palate and mal- births. formed teeth, blind fistulae between the angles of the mouth and the ears and abnormal implantation of the facial hair (Fig. I2). These deformities may occur in any combination and with varying degrees II: Deafness due to Involvement of the Ear of severity; they may often be unilateral. Because in Congenital Malformations of this marked variability, the mandibulo-facial The possibility has been discussed that the dysostosis does not often lead to profound child- genetically determined profound perceptive deaf- hood deafness. ness of childhood considered thus far may not be Many other associated deformities, of which truly congenital but due to rapid and thorough dis- the most common is cleft palate, may involve the organization of a normally developed acoustic skeleton and viscera of individuals with the mandi- mechanism. Such a possibility, if only hypothetical, bulo-facial dysostosis, and these are described in has therapeutic implications for the future, by comprehensive reviews by Robbins (I963) and analogy with the present dietary treatment in Maran (I964). It seems probable that only a propor- infancy of such diseases as galactosaemia and tion of cases which can be subsumed under the phenylketonuria. Occasionally, however, as has concept of the first arch syndrome are of genetical already been seen in the case of the recessive origin. While some ofthe large proportion ofisolated syndrome of cryptophthalmos (see page I31), cases may represent fresh mutations, others may be profound childhood deafness is truly connatal and phenocopies. This is especially true of unilateral primarily conductive in character, due to defects cases which often affect the outer and middle ear, of the outer and/or middle ears. usually on the right side and more often in males, It is of the utmost importance that such deaf- with minimal or even no other facial deformi- ness be clearly defined for it is now remediable by ties. Rare examples of dominant inheritance of such operation, and the earlier in life detection and unilateral ear deformities are, however, known treatment take place the greater the chance of the (Suzuki, Takaoka, and Hayasaki, I960). Reports acquisition of normal speech. Such deafness can of the mandibulo-facial dysostosis in large family easily be differentiated from perceptive deafness groups are rare, partly due to the large proportion by systematic audiometry: usually, associated of isolated cases mentioned above and partly to abnormalities of facial structure, which may be the fact that, because of the wide variability of minimal, are sufficient for a diagnosis (Holborow, clinical manifestations, some carriers of the gene I96I). McKenzie (I958a) includes these various responsible are virtually unidentifiable. Wilder- facial deformities in his concept of the first arch vanck (ig6oa) has, however, been able to follow syndrome, suggesting that they have in common the condition through four generations of a Dutch faulty embryonic development of structures de- family. rived from the first branchial arch. Though his Another branchial arch syndrome, which is claim, supported by Campbell, Campbell, and distinct from the mandibulo-facial dysostosis, Swift (I962), that Waardenburg's syndrome forms exists and is occasionally associated with pro- part of this complex is unconvincing, the deafness found childhood deafness. (It may have some being perceptive and the osseous structure of the affinities to the combination of fistula auris con- ear intact (see page I44), at least two other domi- genita, epibulbar dermoid, and auricular appen- nant syndromes involving conductive or mixed dages described by Goldenhar (1952).) In this Profound Childhood Deafness I37 syndrome the abnormal appearance of the face it is perhaps surprising that the auditory apparatus associated with the mandibulo-facial dysostosis is is not systematically involved, in the absence of absent, though asymmetries of the outer ears, overt gross malformations of the outer ear, oc- with occasional atresia, are found. Ear pits (fis- casionally present in the D and E trisomy syndromes, tulae auris congenitae), branchial fistulae, and in any abnormalities of the karyotype. Claims to pre-auricular appendages may also be present. the contrary, such as those of Patau, Smith, Ther- Families demonstrating dominant inheritance have man, Inhorn, and Wagner (I960), based on cursory been described by Precechtel (I927), Fourman tests of hearing in infants with gross mental defect, and Fourman (I955), and Wildervanck (I962). cannot be accepted without much more painstak- Aird (1946) mentions that ear pits are very com- ing investigation of the few survivors of infancy monly associated with deafness. affected with this D (I3-I5) trisomy syndrome. There is some doubt whether gross malforma- Chromosome studies in profound childhood tions of the cranium, also often inherited in a deafness are somewhat sparse. Normal karyo- dominant manner, such as the dyscephalies, Apert's types have been reported, as is to be expected, in acrocephalosyndactyly, Crouzon's cranio-facial dy- the recessive syndrome of deafness with goitre sostosis, Vogt's cephalodactyly and dysostosis (Fraser, I965a) and in the sole survivor of the cleido-cranialis are associated with profound child- sibship with the recessive syndrome of deafness hood deafness. Such an association is not men- with electrocardiographic abnormalities described tioned in a monograph on these skull abnormalities by Jervell and Lange-Nielsen (1957) (A. Jervell, by Nager and de Reynier (1948), though milder personal communication). A normal female hearing loss is common. Profoundly deaf children karyotype was also found in the girl of Fig. io with such malformations are described, however, with the complex congenital malformation syn- by Love (19I3) and Grimaud et al. (I962) and some drome of cryptophthalmos (Fraser, I962C), des- are included in the series of Fraser (I964a). It pite some uncertainty regarding social sex, and also seems unlikely that the association is fortuitous. in one of the girls with Klippel-Feil syndrome It is not clear whether the deafness is con- and deafness of the series of Fraser (i964a). Normal ductive or perceptive but it seems that both karyotypes have been recorded in the mandibulo- may occur. facial dysostosis (Maran, I964) and in Waarden- The coexistence of profound childhood deaf- burg's syndrome (Partington, I964 (see page I34)). ness with the Klippel-Feil syndrome of malforma- It has been suggested (Fere, I896; Brunet, I956) tions of the base of the skull and cervical vertebrae that congenital malformations are especially com- is certainly not coincidental. Cases, almost in- mon in profoundly deaf children and are stigmata variably females, sometimes with retraction of the of a general associated degeneration. In view of eyeball, abducens paralysis, and other associated the very wide spectrum of causes adumbrated in facial abnormalities, have been reported by Wilder- this review, it seems very unlikely that such a vanck (I952), Franceschetti and Klein (1954), generalized tendency exists. In a survey of 2,355 Bardadin and Siedlanowska (I955), Wildervanck deaf schoolchildren, Fraser (I964a) found 56 in (ig6ob), Everberg, Ratien, and S0rensen (I963), whom the deafness was associated with congenital Whetnall and Fry (I964), and Fraser (i964a) malformations of the types discussed here, as well (Fig. I3). It seems that the deafness in this condi- as some hitherto undescribed varieties. In 6 of tion is perceptive in character and radiological these 56, the operation of simple Mendelian abnormalities of the inner ear have been demon- inheritance could be detected from the family strated in several of these reports. There is no history. In some other cases the presence of obvious simple hereditary pattern. sex-linked recessive gargoylism, of a clinically mild Many intermediate forms exist between these variety (see page 132), was suspected. In such various malformation syndromes and precise diag- children, the skull deformity and deafness are not nosis is often difficult; in some cases a malforma- congenital but progressive in infancy. The 56 tion of the middle ear or bony labyrinth may not cases included I9 (17 girls, 2 boys) with the Klip- even be detected as being responsible for deafness. pel-Feil deformity. In a proportion of the re- In common with the majority of other congenital maining 37 children a conductive element of the malformations, the role of heredity is not always deafness, associated with malformation of the clear, though some relatively well-defined domi- middle and/or outer ear, was detected. The pre- nant syndromes exist. Though chromosomal re- valence of such malformation syndromes involving arrangements, too small to be detectable by present deafness may therefore be estimated at 2-5 cases methods, may be associated with these conditions, per I00,000 births. 138 G.LR.'Fraser

*....;+

FIG. 1O. Recessive cryptophthalmos with outer and middleTear FIG. II. Waardenburg's (195x) dominant syndrome. This child malformations leading to conductive deafness. showsithe white forelock and dystopia canthi medialis lateroversa. The deafness is perceptive in character due to lesions of the mem- branous labyrinth.

..

I*:

ti .9 ...... '! .:

FIG. 12. Dominant mandibulo-facial dysostosis. The deafness is FIG. 13. Klippel-Feil syndrome with pre-auricular tubercle. The predominantly conductive in character but may be mixed. deafness is perceptive and associated with malformations of the bony labyrinth.

FIGS. 10-13. Malformations affecting thejhead associated with profound childhood deafness. Profound Childhood Deafness 139 IH: Acquired Deafness in fact observe a new disease, though this does not Causes Acting in Prenatal Life. Of all in the least detract from the merit of this classical acquired causes of deafness, those operating in paper. Cases born in I930 and 1936 were des- foetal life may most readily be confused with cribed by Beswick, Warner, and Warkany (I949) genetical causes. The human mind abhors the and suggestive earlier accounts exist of a boy with unknown, and it is particularly easy to inculpate deafness and congenital cataracts (Wardrop, I813) events of a distant and dimly remembered preg- and another with deafness and congenital pul- nancy for the family tragedy which the diagnosis monary stenosis (Leuch, I892). Furthermore, of deafness in a child provokes. Some such causes cataract was a not uncommon accompaniment of are dearly factitious, ranging from the 'pium desi- deafness in surveys of ocular abnormalities among derium peculiare gravidae' of Wilhelmi (I873) tO deaf children discussed on page I22 in connexion the permanent wave, sometimes invoked by modem with retinitis pigmentosa (Adler, I876; Lee, I883). mothers; others, such as congenital syphilis and The epidemiological surveys of Lancaster (I954) toxoplasmosis and maternal rubella, are well covering Iceland, New Zealand, and Australia substantiated. have also shown that increased numbers of births Exaggerated claims have, in fact, been made for of deaf children occurred following rubella epi- all these infections. Thus, though congenital demics from I898 onwards. Again Ivstam (i95i) syphilis was undoubtedly more important as a cause gives convincing details of an increase of deafness of deafness in the past than it is in most countries in Sweden following, the rubella epidemics of today (Love, I913), it could hardly have been res- 1936-7. ponsible for the ravages ascribed to it by de Parrel One of the lesser known features of rubella and Lamarque (I925) who considered it as the embryopathy is a widespread retinal pigmenta- aetiological factor in almost all cases of profound tion, often restricted to the peri-macular area, childhood deafness. Again while congenital deaf- not interfering with visual acuity. This was men- ness due to toxoplasmosis is well documented tioned by Gregg (194I) in two of his patients in (Kelemen, 1958, from the pathological, and Fein- whom the cataract was restricted to one eye, and messer and Landau, I96I, from the clinical was well described by Marks (I946), Bourquin viewpoint), the claim of Theissing and Kittel (1948), and Emerson (I958). This retinopathy in (I962) that it is responsible for 10-20% of all deaf children without cataracts is a useful pointer profound childhood deafness is entirely unconvinc- to the aetiology of the deafness (Fraser, i962d), ing. It is far more likely that the high proportion especially in cases when, as may often happen, of positive reactors in toxoplasmosis tests, which the mother is not aware of a sub-clinical attack these authors found among deaf children as op- of rubella in pregnancy. Other corroboratory fea- posed to hearing controls, is an acquired phenom- tures, indicating a diagnosis of rubella embryo- enon associated with the institutional life which the pathy, are a low birth weight and the season of former lead, predisposing to early infection with birth corresponding to the seasonal incidence of toxoplasma. In any case, it cannot be sufficiently rubella (Fraser, i962d). In the western hemisphere emphasized that positive tests, whether for toxo- most such births take place between October and plasmosis, rubella, or syphilis in postnatal life March. cannot be accepted as unequivocal evidence of the There can be little doubt that the 'new syn- prenatal aetiology of deafness, but only as circum- drome' described by Diallinas (I959), Amalric stantial evidence which has to be fitted into the (I960), Amalric and Bessou (I962), Grimaud et al. remainder of the disease picture. Thus Burkin- (I962), and Remky, Klier, and Kobor (I964), of a shaw, Kirman, and Sorsby (I953) were quite un- primarily peri-macular tapeto-retinal degeneration, able to correlate positive tests for toxoplasmosis affecting 6-I2% of children with profound deaf- with the clinical features of mental retardation in ness, is in fact rubella embryopathy. A considera- a study of 698 mental defectives in an institution. tion of the dates of birth, when given by these Since the first description by Gregg (I94I) of authors, is revealing in this respect. Fraser (I964a) the association of congenital cataracts with con- found a similar incidence of this retinal lesion in a genital heart disease due to maternal rubella and series of 2,355 deaf schoolchildren and, making the demonstration by Swan, Tostevin, Moore, use of all the diagnostic criteria mentioned above, Mayo, and Black (I943) that deafness could also combined with information from the mother, came be a component of this entity, the literature on to the conclusion that I33 (5 -6 %) owed their deaf- rubella embryopathy has swelled to vast propor- ness to rubella. These children were seen in I960-I tion. There is no doubt that Gregg (194I) did not and do not include those rendered deaf during the I40 G. R. Fraser rubella epidemic of I940. At that time the pro- Thus Winckel (I948) has pointed out that, though portion of children deaf due to rubella was much a few cases of congenital deafness due to admini- higher (Martin, I946). stration of quinine to pregnant mothers have been The rubella virus does not attack only the eye, reported, there was no systematic increase of deaf- heart, and ear but is a generalized disease of the ness prevalence in the Southern as opposed to the embryo. Dental deformities and microcephaly Northern States of the U.S.A., though quinine have been described in rubella children, as have was extensively consumed as an anti-malarial drug generalized slight physical and mental retarda- in the former. tion. The peculiar behaviour pattern and facial Finally suggestions have been made that endo- appearance of these children is well known to teach- crine diseases of the mother, such as pseudohypo- ers of the deaf and blind. It is of interest that parathyroidism (Hinojosa, I958) and diabetes Grimaud et al. (I962) found abnormal EEGs mellitus (J0rgensen, I96I) may predispose to in all 22 of their cases of deafness with retinal de- congenital deafness in her children. Such oc- generation of the rubella type whom they tested. currences, if they exist at all, must be very rare. Excellent reviews of the problem of the re- Rubella is the only substantial known cause of lation of virus diseases, especially rubella, in prenatally acquired deafness today in countries pregnancy to congenital malformations are pro- with a high standard of medical care; the pos- vided by Kuntzel (I952) and Rhodes (I96I). sibility cannot, of course, be excluded that other, It may be said that no other virus has been con- as yet unsuspected, causes exist. clusively incriminated as far as deafness is con- cerned. In particular, Heider (I934) in the U.S.A. Causes Acting in the Perinatal Period. and Candiotti (I949) in France showed that the Misfortunes in the perinatal period account for 19I8 pandemic of influenza did not cause any deaf- many severe handicaps in children, and this applies ness among the offspring of affected pregnant no less to deafness than to blindness, mental de- women, though the epidemiological data of the ficiency, and spasticity. In fact, since the causative former author might be interpreted as indicating mechanisms are sometimes the same, it is not un- that some acquired deafness due to infection in common for two or more of these defects to be infants may have occurred. present together. Thus severe neonatal jaundice The results of two prospective investigations of due to rhesus incompatibility, formerly fatal in maternal rubella in the first twelve weeks of preg- most cases, caused deafness with various neuro- nancy (Manson, Logan, and Loy (I960) from logical and mental defects, especially in the first England, and Barr and Lundstrom (I96I) based on years of treatment (Crabtree and Gerrard, I950). smaller numbers from Sweden) concur in esti- This damage is thought to be caused by a direct mating the risk of the incidence of hearing loss toxic effect of high bilirubin levels on the brain, in the offspring at about 20 %, of which a third is the deafness being due not to involvement of the of sufficient degree to constitute a severe handicap. peripheral auditory apparatus, as in the types dis- These facts are now generally well known and an cussed thus far, but of the cochlear nuclei. interesting result is that occasionally women will Apart from rhesus incompatibility, perinatal adduce a fictitious attack of rubella in pregnancy to causes of deafness preferentially involve the pre- explain deafness in their child because of their mature child. The biology of prematurity is ex- anxiety to avoid the supposed stigma of an un- ceedingly complex, and many factors, both genetical known cause. and environmental, are involved in its causation. Occasionally other possible prenatal causes of The especial hazards that the premature child deafness are proposed. Since many drugs are faces in adapting to the extrauterine environment known which cause postnatal deafness, there seems may lead to deafness in several ways. Thus im- little reason to doubt that congenital deafness may mature liver function may cause difficulties in the sometimes be caused by unwisely large doses of conjugation of bilirubin and profound jaundice such drugs, of which streptomycin is an example as in rhesus incompatibility (Crosse, Meyer, and (Leroux, I950; Kern, I962), given to pregnant Gerrard, I955). Immature kidney function may women. Then again, foetal malformations due lead to difficulties in the excretion of ototoxic to thalidomide may include aplasia or hypoplasia drugs such as streptomycin and dihydrostrepto- of the entire auditory apparatus (Rosendal, i963). mycin and the consequent high blood levels of Such mishaps are rarities, however, and there is these drugs may exert a particularly deleterious no evidence that profound childhood deafness effect on the auditory apparatus of the premature on any large scale is due to such mechanisms. newborn (Fraser, I96I; Marcus, Small, and Profound Childhood Deafness I4I Emanuel, I963). Finally birth trauma may lead environment. The possibility cannot be excluded particularly easily to haemorrhages from im- that such additional difficulties, affecting metabolic mature blood vessels and capillaries (Dollinger, processes involved in the auditory pathway, may I927). The possibility of deafness being due to exist, of whose nature nothing as yet is known. such haemorrhages in the inner ear was explored The data of Johnsen (I952), Barton et al. (I962), by Voss (1923) and Albrecht (I930), and the par- and Fraser (i962a, i964a) suggest that not less ticular predisposition of the premature child was than io% of profoundly deaf children owe their mentioned. It is likely that neonatal attacks of deafness to such misfortunes occurring in the peri- asphyxia, again especially common in premature natal period. children, aggravate this process, though it is also possible that the attendant anoxia has a speci- Causes Acting After the Perinatal Period. fically deleterious effect on hearing. That hearing Deafness acquired through disease in childhood is often involved in the generalized central nervous does not often cause confusion with genetically system damage due to birth injury, described from determined forms, though an important source the anatomical viewpoint by Schwartz (1927), of bias is introduced by the tendency, discussed is demonstrated by the finding of Fisch (I955a) above, of parents to seek for an explanation of the that a high proportion of children with cerebral deafness of their child. Thus, in analyses based on palsy have significant hearing loss. Conversely the parents' story, measles and whooping cough Fraser (I964a) found neurological evidence of have been invested with an importance that is birth injury in 24 out of 2,355 deaf schoolchildren. totally disproportionate to their very smal] actual Anoxia and/or birth injury may of course also, role, for these are diseases through which many though less often, be responsible for deafness in children pass by the age that parents realize that normally mature children. speech development is seriously retarded. In the It is not easy to define exactly the various dis- past otitis media was a common sequel of these turbances of the normal transition between the diseases, and of scarlet fever, and often caused intra- and extrauterine environment that may pref- serious disability; profound childhood deafness due erentially affect the premature child. Such mech- to otitis media is a rarity in economically advanced anisms may be responsible for the excess of pre- countries today. mature children among those deaf due to un- In such countries meningitis is undoubtedly the known causes about who no convincing history of most common cause of profound childhood deaf- profound jaundice, drug administration, or gross ness, acquired after the end of the neonatal period, birth injury can be elicited (Johnsen, I952; Barton, and recently a very important numerical role in Court, and Walker, I962; Fraser, i962a, i964a), causation has been played by tuberculous menin- though it must be remembered that records of gitis. This disease, formerly almost invariably unfavourable perinatal events may be lost, for- fatal, often left survivors with serious neurological gotten, or otherwise unobtainable. The only known sequelae, including deafness, in the first years after prenatally determined cause of deafness which is effective treatment was introduced. As in the case often associated with prematurity is maternal of the improved treatment of rhesus incompati- rubella, and it is possible, therefore, that unsus- bility, such iatrogenic disasters are much rarer pected foetal infections, whether with the rubella today. This applies also to deafness caused by virus or with other organisms, account for part of ototoxic drugs. Their mode of action is proble- this excess. Johnsen (1952) points out that deafness matical but ototoxicity is determined at least to of unknown aetiology affects especially firstborn some extent by idiosyncratic reactions of the premature children and the firstborn of twin patients, partly under genetical control, and pairs, both these groups being especially liable to familial streptomycin deafness has been des- difficult births. Twins are, in addition, frequently cribed (Horiguchi and Moiyama, 1957). Such premature and their perinatal difficulties have the phases in the advance of medicine produce very interesting and confusing consequence that sub- interesting secular variations in the spectrum of sequent concordance and discordance with respect causes of deafness and there can be little doubt to deafness are largely unrelated to zygosity. that acquired deafness, especially that due to Thus some deafness of unknown aetiology, childhood disease, will in fact cease to be of great especially in premature children, may be ascribed numerical importance in the near future, since, to difficulties in the adaptation, in the widest with prompt treatment and the judicious use of possible sense of the word, of the auditory mech- ototoxic drugs, there is no reason why even menin- anism of the newborn child to the extrauterine gitis should be followed by destruction of hearing. 142 G. R. Fraser There is a great excess of males (up to 6o %) than otologists. This situation is now changing, among those deafened by childhood disease. however, and otological investigations of the This was noted especially by Uchermann characteristics of the lesions involved are being (I9OI), who discussed the great increase of deaf- undertaken with increasing frequency. The per- ness due to epidemics of cerebrospinal meningitis ceptive rather than conductive nature of the in the last century; this was apparent in the Ameri- deafness in the vast majority of cases is well docu- can data of Bell (I883), those from Denmark of mented, despite McKenzie's (I958b) noncon- Mygind (I892), his own from Norway, and many formist claim to the contrary, and Secretan (I953) others. The reason for this increased predisposition and Fraser (I965a) have localized the lesion to the of males is not clear, but it applies also in the cochlear hair cells of the VIIIth nerve in certain case of a disease of infancy, first described by types of recessive deafness. Voltolini (I882) and called by him otitis labyrin- A beginning has been made on the important thica seu intima. This disease runs a far milder problem of the correlation between audiometric course than meningitis, though the two may be pattern and aetiology of deafness by Fisch (I955b). confused, but it frequently leaves deafness in its The flat pattern, characteristic of rubella deafness, wake. The exact status of this nosological entity is ascribed to an interference with normal matura- is problematical, though it may well bear some tion affecting the entire organ of Corti. The re- relation to the loss ofhearing due to virus infections, tention of hearing in the low tones to a greater or sometimes complete and bilateral, which has been lesser extent (Fig. 3) in recessive deafness (Hall- described in adults and older children by van gren, I959; Fraser et al. I964a; Fraser, i965a) Dishoeck and Bierman (I957) and Dawes (I963). may be connected with the fact that the postnatal Escudero (I948) in Spain ascribed a very im- degeneration of the organ of Corti in recessively portant numerical role in the causation of profound deaf mice (Deol, i956b) usually proceeds from childhood deafness to this entity. While his the base to the apex, the apical part being res- claim is in all probability exaggerated, that of ponsible for the transmission of low tones. This Claverie (I956) that deafness due to such a cause type of audiogram is often also found in Waar- is an extreme rarity probably errs on the side of denburg's (I95I) syndrome (Fisch, I959), though excessive caution. in dominant deafness as a whole a flatter pattern is A large excess of male deaf children in the common (Wildervanck, I953; van Egmond, I954). group of unknown aetiology (Fraser, I965b) is In sex-linked recessive deafness, too, retention of very suggestive in this respect, and there can be some hearing at all frequencies is common (Fraser, little doubt that 'Voltolini's disease' and other un- i965b). recognized acquired causes play a substantial role There can be little doubt that similar audio- in profound childhood deafness. Basing his esti- metric patterns occur, as is to be expected, in mate on such considerations, Fraser (I965b) members of the same family, affected with gene- comes to the conclusion that about 30% of 2,355 tically determined deafness, despite the inter- deaf schoolchildren owe their disability to acquired vention of many secondary environmental factors causes operating after the end of the perinatal such as trauma, noise, infection, and ageing. These period. Of this total no less than I05 are deaf similarities were clearly demonstrated by Ciocco, following tuberculous meningitis. Hughson, and Palmer (I939) and are also ap- It cannot be too strongly emphasized that parent from the audiograms of Fisch (i955b) and these figures refer to the British Isles in I960oI Wildervanck (1957c). Very striking similarities and that the proportion may be very different in were described by Parker (I958) in members of a other countries. Thus even in comparatively large family with sex-linked recessive deafness. prosperous countries, such as Poland, bacterial No significant hearing loss has been described dysentery, typhoid, and diphtheria are still con- in heterozygotes for recessive deafness in man, sidered to be important causes of deafness in whether autosomal (Wildervanck, I957c) or sex- childhood (Bystrzanowska, Kus, Osuch, and Woj- linked (Fraser, I965b). Even double heterozy- narowska, I960), while in parts of Africa epidemic gotes for two types of recessive deafness are un- cerebrospinal meningitis still poses a vast problem. affected (see page 124). A possible exception is a woman in pedigree 234 of the Clarke School IV: Otological Features of Studies (Hopkins, Macklin, Mann, and Whitney, Profound Childhood Deafness I946; Hopkins and Guilder, 1949). Both her Profound childhood deafness has until recently parents were deaf and had deaf sibs but hearing been primarily the concem of educators rather parents. She herself had four older hearing sibs Profound Childhood Deafness I43 but was hard of hearing from infancy. Deafness of available, especially in the German language. late onset in some double heterozygotes in mice Many excellent reviews of the subject have been has already been mentioned on page 121. written, among them those of Denker (1913), Fraser It is generally recognized that the audiogram (I922), Denker (1927), Albrecht (1940), Altmann cannot provide conclusive evidence of the aetio- (I950), Gull and Bonetti(i956),andOrmerod(ig6o). logy of deafness in the individual case. At best it In the case of recessive deafness, the correlation provides circumstantial evidence that can be used between pathological, clinical, and genetical find- in conjunction with information derived from ings is surprisingly good, considering the diffi- other sources in arriving at a putative diagnosis. culties involved. Changes seem to be uniformly There are so many exceptions to Langenbeck's of the type first described clearly by Scheibe (1936) law of symmetry (identical or very similar (I892) and involve degeneration of the organ of hearing loss in the two ears in inherited deafness, Corti, sometimes predominantly of the basal coil, dissimilar in acquired) that it is virtually useless. and abnormalities of the stria vascularis, tne tec- It may, however, be said with some confidence torial membrane, and the spiral ganglion. Evidence that, if in a normally intelligent child, no response about more central auditory tract and brain de- at all takes place at maximum intensities of the generation is sparse, but probably the hearing audiometer over the whole frequency range, then pathway beyond the spiral ganglion is normal. the deafness is likely to have been acquired. The vestibular apparatus is affected to a variable Nor can the claims made in favour of vesti- extent but its involvement is very pronounced in bular function tests in the differential diagnosis cases with the syndrome of deafness with retinitis of the cause of deafness be said to have been sub- pigmentosa (Siebenmann and Bing, I907). There stantiated. While it is true that reduction of vesti- are no abnormalities of structure of the bony bular function is more common in postnatally labyrinth or the middle ear. No post-mortem acquired than in hereditary deafness, the survey examination of the ear of a well-documented case of Arnvig (I955) showed that this difference be- of the syndrome of deafness with goitre is available. tween the two groups is only relative rather than The syndrome of deafness with unique electro- absolute, as had previously been claimed. Further- cardiographic disturbances (see page I27) is an more, vestibular disturbances are extremely com- exception to the rule that the deaf do not die of mon in some genetically determined syndromes, causes related to their deafness. Several affected such as that of deafness with retinitis pigmentosa children have died while under observation, and (see page I23). Muller (I936) described disturb- Fraser et al. (I964a) report the post-mortem ex- ances of vestibular function in four members of a amination of the temporal bones of one such girl. family with dominant profound childhood deaf- Changes of the type described by Scheibe (I892) ness, and Stoller (I962) reported complete absence are present; vestibular involvement is not marked. of response to caloric stimuli in a boy with Waar- While histochemical studies of the labyrinths of denburg's (I951) syndrome. Much remains to be deaf persons are rare, it may be of significance that done in the otological investigation of profound lobules of periodic acid-Schiff-positive material childhood deafness. It is to be expected that were found in the stria vascularis that were similar systematic study of VIIIth nerve function in to those found in the ears of a case of deafness with combination with thorough clinical and genetical retinitis pigmentosa (slides prepared from the appraisal can help considerably in arriving at a case of Nager, 1927) and of a case of clinically diagnosis of the cause of deafness in the individual undifferentiated recessive deafness by Buch and case. J0rgenSen (I963). Fraser et al. (I964a) have also examined the hearts of two children of their series V: The Pathology of and have found that the normal glycogen-contain- Profound Childhood Deafness ing perinuclear zone is absent in the Purkinje nerve Despite the fact that those with profound child- fibres. While the relevance of this finding to the hood deafness do not usually die of this condition ECG abnormalities is not clear, it is of considerable and, therefore, only infrequently die in circum- interest in view of the fact that glycogen is normally stances of which pathologists interested in the ear present in considerable amounts in the hair cells are aware, and despite the difficulties of producing of the normal organ of Corti of guinea-pigs and is good histological preparations of the inner ear thought to play an important role in their anaerobic without intravital staining, a vast number of publi- metabolism (Falbe-Hansen and Thomsen, I963). cations regarding the appearances of the auditory These pathological findings correlate very well apparatus in profound childhood deafness are with the predominantly high-tone deafness, at any 144 G. R. Fraser rate in younger age-groups, associated with reces- ed to represent an important class ofprofound child- sive deafness and the infrequent presence of hood deafness. This lesion may be related to that disturbances of vestibular function except in the described by Everberg et al. (I963) on radiological case of the syndrome of deafness with retinitis evidence in deafness associated with the Klippel- pigmentosa. They also correlate very well, allowing Feil syndrome. for differences in the methods of collection and Deafness due to profound neonatal jaundice preparation, with the findings in deaf mice (see (see page I40) is thought to be due to the central page I2I) and guinea-pigs (Lurie, 194I). Recessive toxic effect of bilirubin on the cochlear nuclei, deafness in these laboratory animals is also marked especially those concerned with the transmission by an earlier degeneration of the basal part of the of high tones (Crabtree and Gerrard, I950; Fisch, memnbranous cochlea and variable involvement of 1955b). The flat audiogram in deafness due to the vestibular apparatus. In most cases the structure maternal rubella is considered to be due to the of the bony labyrinth is normal, though mutants fact that it represents an interference with normal in mice are known in which recessive bony de- maturation processes rather than a postnatal de- formities do occur, either with deafness (Hertwig, generation of the organ of Corti; the end result is 1944) or without (Truslove, I956). histologically much the same (Lindsay and Har- In the case of dominant deafness, on the other rison, I954). Finally Altmann (I949, I955) has hand, the correlation of pathological with clinical provided scholarly reviews of the pathological and genetical findings is poor except in the case processes associated with congenital atresia of the of Waardenburg's (ig5i) syndrome in which ear in man and animals. As discussed above (see predominantly high-tone deafness is associated page I36), these are often associated with mal- with histological changes similar to those found in fornation of the middle ear but only rarely with recessive deafness (Fisch, I959). Similar changes changes in the inner ear. are found in dominant deafness associated with spotting of the coat colour in dogs (Lurie, I948) and in 'varitint-waddler' mice (Deol, I954), and VI: An Attempt at a Synthesis in dominant deafness in white cats (Alexander, The complexity of the problem of the causation I900; Wilson and Kane, i959). The status of the of profound childhood deafness is amply illus- malformation of the bony labyrinth first described trated by the heterogeneity revealed in these by Mondini (I79I) is unclear, as is the relation of pages. Many surveys have taken place in recent the entity of 'progressive dominant heredo-laby- years with as many proposed classifications and rinthine deafness' with which it is supposed to be numerical assessments- of the various causes associated to dominant profound childhood deaf- involved. None of these surveys is free of defects; ness. The flatter and even saucer-shaped (Martens- nor in view of the difficulties involved can per- son, I960; Williams and Roblee, I962) patterns of fection be expected. hearing loss associated with these conditions may Three types of investigative procedure have betoken a different pathogenesis from that involved been followed. The first, of which the more in recessive deafness. Radiology could be of con- notable examples have been mentioned on page I2I, siderable assistance since malformations of the has been to ascertain completely all deaf persons bony labyrinth can now be seen on special x-ray within a limited geographical area, supported by views. In uncomplicated sex-linked recessive deaf- extensive family studies. The second is to survey ness the audiogram is also relatively flat; no post- groups of children segregated in special schools, mortem examination of a well-documented case is and this approach may sometimes overlap with available. Wolff (1942), however, has examined the first, as in the series of Furusho (1957) from at necropsy the ears of a deaf male with sex-linked Japan. Other examples of this type are the studies recessive gargoylism (see page I32) and has found of Henning (I928) in Sweden, Shambaugh et al. changes of the Scheibe type affecting the mem- (I928, 1930), Hughson, Ciocco, and Palmer (1942), branous labyrinth. Hopkins and Guilder (I949) (with extensive gene- If the status of the Mondini (I79I) malformation tical analysis of the pedigrees by Hopkins et al. is far from clear, that of Michel (I863) rests on (I946)) and Danish et al. (I963) from the U.S.A., even less sure foundations. Though clinical and Lamy et al. (I949) in France, Arnvig (I954) in genetical details are lacking, this isolated observa- Denmark, Wildervanck (I957a) in Holland, Berna- tion of the total absence of the inner ear and audi- bei and di Brino (I957) in Italy, and Barton tory nerves has been handed down and passed on et al. (I962) and Fraser (i962a, I964a) in the through several hundred publications and consider- British Isles. Profound Childhood Deafness 145 The third type of investigation, which again basis of the analysis of the data of Fraser (i962a, overlaps to some extent with the second, has I964a, i965b), the nature of which has only partly been the study of children referred to otological been explained in these pages. clinics, and such series have been reported in TABLE many parts of the world. They include those of Goodhill (1950), Bordley and Hardy (I95I), Percentage Fowler and Basek (I954), and Zonderman (I959) Recessive Withretinitispigmentosa 75 Withgoitre 3-0 from the U.S.A., Hata (I955) from Hawaii, WithabnormnalECG I-0 Siedlanowska from Poland, Finzi and Others 26-o (I955) Genetical Dominant Withpigmentary Leonardelli (1956) from Italy, Lacina and Sed- anomalies 2-5 Without pigmentary lackova (I957) from Czechoslovakia, Liu, Liu, Li, anomalies 10-0 Teng, and T'an (I957) from China, Suzuki et al. Sex-linked I-5 Prenatally 6-o (I960) from Japan, Gerc (I960) from Yugoslavia, IPerinatally(including excess of I0-0 Acquired prematurity) and Ballantyne (i960), Livingstone (I96I) and Postnatally(aftertheendofthe 30-0 Whetnall and Fry (I964) from England. pentlperiod) Congenitalmalformations 2 5 All these three types of survey have their ad- vantages and their disadvantages and all cover a It may be expected that the proportion of pro- slightly different aspect of the problem. The found childhood deafness attributable to acquired different methods of selection involved and the causes will fall with improved medical care during different interests of the investigators will in- pregnancy, birth, infancy, and childhood, especially fluence the spectrum of causes; all these surveys as awareness of the particular dangers to which the are isolated in space and time and further hetero- auditory apparatus is exposed increases. The geneity is introduced on this account. Yet all question of the treatment and prevention of here- these and many more such investigations are ditary deafness is, on the other hand, a long-tern needed to obtain a composite picture of the total problem to which no easy solution is in sight. In biological burden of profound childhood deafness the meantime, further study of the various com- as by such is discussed, from different viewpoints, ponents ofhereditary deafness cannot fail to provide Wildervanck (I953), van Egmond (I954), Caw- thorne and Hinchcliffe (I957), Cerri and Maffei insight into the pathways of gene action involved Schwarz, Becker, which, in turn, will throw light on many presently (1958), Whetnall and Fry (i964), obscure aspects of normal embryogenesis and nor- and J0rgensen (I964), and Froggatt (I964) among others. mal postnatal physiology and biochemistry. It is difficult to obtain a reliable estimate of the The help of the National Deaf Children's Society in prevalence of profound childhood deafness. If defraying expenses incurred in the preparation of this the definition of the introduction is extended to paper is gratefully acknowledged. cover those who are ineducable and those who are RFERENCES able to follow normal schooling but with difficulty, Adams, J. (I8I4). A Treatise on the Supposed Hereditary Properties of Diseases. Callow, London. such as are revealed by the surveys of Kinney Adler, H. (I876). Beobachtungen und Bemerkungen uber das (I953) in the U.S.A. and Johnsen (1954a, b) in Sehen der Taubstumnmen. Klin. Mbl. Augenheilk., i4, 64. Aird, I. (I946). Ear-pit (congenital aural and pre-auricular fistula). Denmark, then certainly i per i,ooo of the child Edinb. med. J., S3. 498. population would not anywhere be an overestimate, Albrecht, W. (1922). Ylber die Vererbung der konstitutionell and in some parts of the world with a relatively sporadischen Taubstummheit, der hereditaren Labyrinthsch- werhorigkeit und der Otoscierose. Arch. Ohr.-, Nas.-, u. 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Diallinas, N. P. (I959). Les alterations oculaires chez les sourds- -, Froggatt, P., and James, T. N. (1964a). Congenital deafness muets. J. Ginet. hum., 8, 225. associated with electrocardiographic abnormalities, fainting DiGeorge, A. M., Olmsted, R. W., and Harley, R. D. (I960). attacks and sudden death-a recessive syndrome. Quart. J. Med., Waardenburg's syndrome. J. Pediat., 57, 649. 33, 36I. Dollinger, A. (I927). Geburtstrauma und Zentralnervensystem. -, -, and Murphy, T. (Ig64b). Genetical aspects of the Ergebn. inn. Med. Kinderheilk., 31, 373. cardio-auditory syndrome of Jervell and Lange-Nielsen (con- Dow, G. S., and Poynter, C. I. (I930). The Dar family. Eugen. genital deafness with electrocardiographic abnormalities.) Ann. News, I5, I28. hum. Genet., 28, 133. Duke-Elder, S. (I952). Text-book of Ophthalmology, Vol. V, -, Morgans, M. E., and Trotter, W. R. (I960). The syndrome p. 4644. Kimpton, London. of sporadic goitre and congenital deafness. Quart. J. Med., 29, Elman, D. S. 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- (1932). Uber kombinierte Heredopathien und ihre mutmass- Jervell, A., and Lange-Nielsen, F. (1957). Congenital deaf-mutism, lichen Erbgang. Wien klin. Wschr., 45, 772 and 808. functional heart disease with prolongation of Q-T interval, and - (1933). Die hereditare Innenohrerkrankung im Lichte der sudden death. Amer. Heart J., 54, 59. Vererbungslehre. Klin. Wschr., 12, 1903. Jervis, G. A. (I950). Gargoylism (lipochondrodystrophy). Study - (1934). Einfuhrung in die Kenntnis einfacher Mendelistischer of I0 cases with emphasis on formes frustes ofthe disease. Arch. Vorgange. Perles, Vienna. Neurol. (Chic.), 63, 68i. Hanhart, E. (I938). Die 'sporadische' Taubstummheit als proto- Jeune, M., Tommasi, M., Freycon, F., and Nivelon, J. L. (I963). typ einer einfach-recessiven Mutation. Z. menschl. Vererb.- Syndrome familiale associant ataxie, surdite et oligophrenie. u Konstit.-Lehre, 2I, 609. Sclerose myocardiaque d'evolution fatale chez l'un des enfants. Hartmann, A. (I88I). Deafmutcsm and the Education of Deafmutes. Pidiatrie, I8, 984 by Lip-reading and Articulation, translated by J. P. Cassels. Johnsen, S. (1952). Natal causes of perceptive deafness. Acta Bailliere, London. oto-laryng. (Stockh.), 42, 5I. - - and Wilhelmi, A. T. (i88o). Deaf-mute statistics of the (19s4a). Some aetiologic aspects of high tone perceptive Province of Pomerania and the District of Erfurt. Arch. Otol., deafness in children. ibid., 44, I75 and 205. N.Y., 9, 307. - (1954b). Clinical aspects of high tone perceptive deafness in Hata, T. (i955). Genetic analysis of the deaf in Hawaii. Hawaii children. ibid., 44, 25. med. J., 14, 307. - (I958). Familial deafness and goitre in persons with a low Hedinger, A. (I882). Die Tabibstummen und die Taubstummen Anstaltmn serum level of protein-bound iodine. ibid., Suppl. 140, I68. nach seinen Untersuchungen in den Instituten des Konigreichs J0rgensen, M. B. (I96I). 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Hereditary ectrodactylism in siblings. Amer. Hohl, A. (1828). Einige Beitrage zur physiologischen und patho- J. Dis. Child., 43, 136. logischen Anatomie. Archiv. Anat Physiol., Lpz., I77. Kocher, T. (1892). Zur Verhutung des Cretinismus und creti- Holborow, C. A. (I96I). Deafness and the Treacher Collins syn- noider Zustande nach neuen Forschungen. Dtsch. Z Chsr., drome. J. Laryng., 75, 978. 34, 556. Holmgren, S. (I950). Congenital deaf-mutism in a family with Kocher, W. (ig60a). Untersuchungen zur Genetik und Pathologie dystrophia reticularis laiinae pigmentosae retinae (Sjogren). der Entwicklung spat einsetzender hereditarer Taubheit bei Acta ophthal. (Kbh.), 28, 297. der Maus (Mus musculus). Arch. Ohr.-, Nas.- u. Kehlk.-Heilk., Hopkins, L. A. (I954). Heredity and deafness. Eugen. Quart., 177, I08. 1,193. - ( o6b). Untersuchungen zur Genetik und Pathologie der -, and Guilder, R. P. (I949). Clarke School Studies Concerning Entwicklung von 8 Labyrinthmutanten (Deaf-Waltzer-Shaker- the Heredity of Deafness. Monograph No. I. Pedigree Data, Mutanten) der Maus (Mus musculus). Z. indukt. Abstamm.-u. 1930-1940. Clarke School for the Deaf, Northampton, Mas- Vererb.-L, 9I, I14. sachusetts. Koennecke, W. (I919). Friedreichsche Ataxie und Taubstumm- -, Macklin, M. T., Mann, H. B., and Whitney, R. (1946). heit. Z. ges. Neurol. Psychiat., 53, i6i. Studies in the inheritance of deafness in the Clarke School for Kraatz, J. J. (1925). Hereditary deaf-mutism: a study of the the deaf. Laryngoscope (St. Louis), 56, 570. Mendelian factors in the inheritance of deaf-mutism. J. Hered., Horiguchi, S., and Moiyama, S. (I957). Observations on strepto- I6, 265. mycin deafness as familial occurrence. Nipon Jibi-Inkoka Kramer, W. (1835). Die Erkenntniss und Heilung der Ohrenkrank- Gakkai Kaiho, 29, 143. heiten. Nicolai, Berlin. Kufs, H. (1927). 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Lehmann, W. (I950). Ein weiterer Beitrag zur Frage der Hetero- Mende, I. (I926). UYber eine Familie hereditar degenerativer Taub- genie der recessiven Taubstummheit. Z. menschl. Vererb.-u stummer mit mongoloidem Einschlag und teilweisem Leukismus Konstit.-Lehre, 29 825. der Haut und Haare. Arch. Kinderheilk., 79, 214. Lemcke, C. (I892). Die Taubstummheit im Grossherzogthum Meck- Meniere, P. (I846). Recherches sur l'origine de la surdi-mutite. lenburg-Schwerin, ihre Ursachen und ihre Verhutung. Langkammer, Gaz. mid. Paris, Ser. 3, I, 223 and 243. Leipzig. (I856). Du mariage entre parents considere comme cause de Leroux, L. (i95o). Existe-t-il une surdite congenitale acquise la surdi-mutite congeniale. ibid., Ser. 3, II, 303. due a la streptomycine? Ann. Oto-laryng. (Paris), 67, I94. Michel (I863). Memoire sur les anomalies congenitales de l'oreille Leuch, G. (I892). Klinische Beitrage zu den Krankheiten des interne avec la premiere observation authentique d'absence Pulmonalostium. 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Corrigenda

A Family Apparently Showing Transmission of a Translocation between Chromosome 3 and one of the 'X-6-12' or 'C' Group. G. Clarke, A. C. Stevenson, Pamela Davies, and C. E. Williams. Vol. I, p. 27. The Table on p. 3I requires the following corrections: II.5 Substitute MSMs for MNS III.7 Substitute MSNs for MsNs II.6 ,, MSMs for MMs III.7 ,, R,r for R2r