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Hearing Impairment and Pigmentary Disturbance" PETER BEIGHTON, b,e RAJKUMAR RAMESAR! INGRID WINSHIP! DENIS VILJOEN? JACQUIE GREENBERG! KAREN YOUNG! DIANA CURTIS? AND SEAN SELLARSC bh4RC Research Unit for Inherited Skeletal Disorders Depaitment of Human Genetics CDepaitmentof Otoluiyngologv University of Cape Town Medical School Cape Town 7925, South Afnca

dDepartment of Medical Genetics Universityof Shefield Shefield SlO SDN, United Kingdom INTRODUCTION Hearing impairment and pigmentary disturbance are major features of a number of well-defined genetic disorders. These conditions are important in the etiology of profound deafness, and collectively they make a significant contribution to the burden of heritable hearing loss. Developments in molecular biology have facilitated elucidation of the chromosomal localization of the faulty genes in some instances, and it can be foreseen that further advances will follow in the near future. Conditions in which deafness is associated with hypo- or hyperpigmentation of the skin or eyes have been reviewed on a basis of observations made in 4452 children attending special schools for the deaf in Southern Africa'-6 and investigations in extended affected families. Findings that are of practical significance are presented and discussed in this article. See TMLE 1 for a classification of deafness-pigmentary disturbance disorders. This article will be confined to those conditions that are well established; excessively rare or private syndromes are tabulated for the sake of completion and key references are provided, but these entities have not been accorded further consideration. WAARDENBURG SYNDROME The Waardenburg syndrome (WS) is a well-recognized autosomal dominant disorder which is characterized by varying combinations of perceptive deafness, 'This review is based upon research activities supported by the South African Medical Research Council, the Mauerberger Foundation, the Harry Crossley Foundation, and the Staff Research Fund of the University of Cape Town. e Address for correspondence: Department of Human Genetics, University of Cape Town, Observatory 7925, Republic of South Africa. 152

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Deafness-Pigmentary Disturbance Disorders: Classification and Mode of Inheritance

TABLE 1.

1. DeafnessAepigmentation syndromes 1.1Waardenburg syndrome AD 1.2 Piebaldism AD 1.3 Oculocutaneous albinism-deafness’ AR 1.4 Partial albinism-deafness’ XL 1.5 Vitiligo, short stature, muscle wasting, and achalasia’ AR 1.6 Universal dyschromatosis, small stature and high tone deafness’”AR 2. Deafness-cular depigmentation syndromes 2.1 Ocular albinism-late onset sensorineural deafness’’ XL 2.2 Ocular albinism with sensorineural deafness” AD 3. Deafness-hyperpigmentation syndromes 3.1 Acoustic neuroma (central neurofibromatosis, NF-11) AD 3.2 Multiple lentigines syndrome (LEOPARD syndrome) AD 4. Deafness+cular hypelpigmentation syndromes 4.1 Usher syndrome AR 4.2 Retinitis pigmentosa, nystagmus, hemiplegia, migraine and d e a f n e s ~AD ’~ 4.3 Retinitis pigmentosa, progressive quadriplegia, mental retardation, and deafness14 AR 4.4 Retinitis pigmentosa, hypogonadism, mental retardation, and perceptive deafnessIs AR

FIGURE 1. A family with the Waardenburg syndrome. These individuals have the characteristic dystopia canthorum together with variable depigmentation of the irides and hair. None are deaf. (From Reference 22 with permission.)

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disturbed pigmentation of the hair, irides, and skin, and altered anatomical relationships of the periorbital tissues (FIGURES1 and 2). There is widespread ethnic and geographical distribution, and more than 1000 affected persons have been reported.

Historical Background

In August 1947 David Klein of Geneva, an eminent Swiss ophthalmologist and medical geneticist, presented a deaf and mute child at a meeting of the Swiss Society of Genetics. This child, aged 10 years, had partial depigmentation of the hair and skin, blue irides, and malformation of the arms. Klein published a full case report in 1950.16 Petrus Waardenburg (FIGURE3), a Dutch ophthalmologist and medical geneticist, presented a deaf-mute tailor aged 72 years at a meeting of the Dutch Ophthalmological Society, Utrecht, in December 1947 and published a case report in the

FIGURE 2. Waardenburg syndrome. A deaf scholar with dystopia canthorum, synophrys, and eyes of different color. (From Beighton & Sellars. 1982. Genetics and Otology: 55. Churchill Livingstone. Edinburgh, London & New York, with permission.)

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FIGURE 3. Petrus Waardenburg (1888-1971). (From Klein, D. 1981. Am. J. Med. Genet. 10 309-311, courtesy Alan R. Liss, New York. Reproduced from Beighton & Beighton 1986. The Man Behind the Syndrome. 188. Springer-Verlag.Heidelberg, Germany, with permission.)

following year.” Waardenburg subsequently visited Geneva, where his interest was excited by Klein’s patient. He then undertook a diagnostic survey of Dutch institutions for the deaf, followed by family studies, and he eventually identified more than 100 affected persons. Waardenburg published a full account of the condition in 1951;18there has been controversy concerning eponymic priority and the conjoined and single eponyms “Klein-Waardenburg” and “Waardenburg” have been used interchangeably. In the more precise sense, the term “Klein-Waardenburg syndrome” is reserved for WS-111, which is distinguished by the presence of limb malformations (see below). Nosology

The issue of heterogeneity in WS was raised when Arias (1971) suggested that the disorder could be subdivided on a basis of the presence or absence of dystopia

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canthorum (WS-I and WS-II).” Hageman and Delleman (1977) studied affected families and provided further evidence to support the contention that WS-I and WS-I1 might be separate entities.” The current classification of WS is WS-I, with dystopia canthorum, AD; WS-11, without dystopia canthorum, AD; WS-111, KleinWaardenburg syndrome (with upper limb abnormalities), ?AD; WS-IV, Waardenburg-Shah syndrome (Hirschsprung disease with pigmentary anomaly), AR. In view of the additional malformations in the putative WS-111, together with the rarity of this disorder, it is possible that this condition results from a minor chromosomal rearrangement or else represents a contiguous gene defect. High-resolution cytogenetic investigations and molecular studies in Klein’s original patients might be revealing in this respect. WS-IV (Waardenburg-Shah syndrome) is a rare potentially lethal disorder in which 12 infants in 5 families had a white forelock and depigmentation of the eyelashes and eyebrows in association with Hirschsprung disease of the long segment type.” Neither deafness nor dystopia canthorum was present, and the patients’ light brown irides differed from those of classical WS. Parental consanguinity and multiple affected sibs with normal parents were suggestive of autosomal recessive inheritance.

Diagnostic Criteria The major manifestations of WS are depigmentation of the hair of the head, face, and body, perceptive deafness, and dystopia canthorum. Leucoderma and synophrys are sometimes present, and a variety of inconsistent additional malformations have been documented. Although diagnosis is an easy matter when the major features are present, it can be difficult in a mildly affected person. As molecular linkage studies are now being undertaken in affected kindreds, a precise positive or negative diagnosis in each family member is crucial. Proposed diagnostic criteria” are given in TABLE2.

Additional Manifestations The occasional presence of Hirschsprung disease (HD) in WS is well documented,23’24 but this combination is evidently rare as it was not encountered in any of the 121 deaf South African children with WSX or 7 multigeneration WS families whom we have studied. Equally, there were no instances of WS in a series of 388 patients with HD seen at a pediatric surgical clinic in Cape Town over a 21-year period.Z6High-resolution cytogenetic investigations have not revealed any chromosomal abnormality in persons with WS-HD; it is uncertain whether this combination is the result of a microdeletion, contiguous gene defect, epistasis, the “two-hit’’ effect, or some other subtle genetic mechanism. In the South African survey of special schools for the deaf, two unrelated males with features of both WS and neurofibromatosis (NF) have been encountered. Both were profoundly deaf with sapphire blue irides characteristic of the Waardenburg syndrome. In addition, they had numerous large cafe-au-lait macules on their trunks and limbs, together with axillary freckling. To the best of our knowledge no family members had stigmata of either of these disorders. The pathogenetic significance of this association of WS and NF is unknown. Patchy hypopigmentation of the fundus of the eye in WS is well documented but

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not widely appreciated. It is not known whether this feature is present in all affected persons, but if so, it would represent a valuable diagnostic pointer in doubtful cases.

Genetics The separate syndromic identity of WS-I and WS-I1 is open to some doubt but either way, autosomal dominant inheritance is well established. Phenotypic expression is notoriously variable, and nonpenetrance has been documented. For these reasons accurate diagnosis in mildly affected individuals can be very difficult. The WS gene was initially thought to be located on chromosome 9, when weak Proposed Diagnostic Criteria for Waardenburg Syndrome" (in Order of Significance)

TABLE 2.

Major Criteria a. Pigmentary disturbance of the irides i. Heterochromia, i.e., eyes of different color. ii. Iris bicolor, i.e., segments of blue and brown pigmentation in one or both eyes. iii. Sapphire blue irides. b. Perceptive deafness c. Pigmentary disturbance of the hair (white forelock, white facial or body hair. In adulthood a white forelock may be obscured by premature greying.) d. Dystopia canthorum (increased distance between the inner canthi; heaping up of the medial third of the lower eyelid and lateral displacement of the lacrimal puncta are often associated. It must be recognized that evaluation of dystopia canthorum can be very difficult and that this feature is present in WS-I but absent in WS-11.) Minor Criteria a. Broad nasal bridge (i.e., widening of the nasal bones at their junction with the frontal bones, as seen in the full face, not the profile). b. Hypertelorism (i.e., increased distance between the orbits as expressed by interpupillary distance). c. Synophrys (i.e., confluent eyebrows). d. Poliosis (is., whiteness of individual head hairs. This feature is sometimes interpreted as premature greying). e. Leucoderma (i.e., white skin macules).

"In a sporadic person the diagnosis of WS is confirmed if criteria 1 or 2 are present plus an additional major criterion. In a family the diagnosis of WS is confirmed in a first-degree relative of an affected person if a single major criterion is present. The minor criteria, while helpful as confirmatory features, are strongly influenced by family and ethnic characteristics and they cannot be regarded as significant diagnostic indicators. (From Reference 22 with permission.)

linkage with the ABO blood group system at 9q34 was demonstrated.z9230 An alternative candidate site is on chromosome 4 (4q12-13) as there have been reports of persons with piebaldism, which is phenotypically similar to WS, with chromosomal abnormalities involving this r e g i ~ n . ~ 'A - ' ~Japanese child with WS and a rearrangement of chromosome 2 provided an important pointer to the locus of the faulty gene.34Following this report, Foy et al. (1990) were able to show linkage between WS-I and placental alkaline phosphatase (ALPP), which is situated at 2q37, in several families in the United Kingdom." Provisional investigations by our group indicate linkage between WS-I and 3 probes from the 2q37 region in 4 South African families of mixed ancestry. A maximum lod score of 4.21 at a recombination fraction of 0.00 has been calculated using a combined haplotype of HindIII, RsaI, and TaqI

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polymorphisms detected by probes from the 2q37 locus. In another kindred with WS-I from the same population group, tight linkage was excluded at a recombination fraction of less than 0.001. These findings are suggestive of genetic heterogeneity in ws-I. These British and South African kindreds with linkage have all had WS-I, and it is uncertain whether WS-I1 is allelic. Further advances in the understanding of the molecular basis of WS can be anticipated in the near future. PIEBALDISM Piebaldism or piebald trait (PBT) is an autosomal dominant disorder in which a white forelock is associated with patchy depigmentation of the skin. Involvement of the irides and periocular tissues has been documented in a few instances, and there have been isolated examples of perceptive deafness in persons with ostensible PBT. In our experience skin hypopigmentation in WS is usually not a major feature, but in a few individuals with unequivocal WS and deafness, leucoderma has been extensive

FIGURE 4. A deaf scholar with dystopia canthorum, depigmentation of facial hair, and marked leucoderma. In this instance there is considerable phenotypic overlap between the Waardenburg syndrome and piebaldism. (From Beighton & Sellars. 1982. Genetics and Otology: 56. Churchill Livingstone. Edinburgh, London, & New York, with permission.)

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FIGURE 5. A family with autosomal dominant piebaldism. There is phenotypic overlap with the Waardenburg syndrome. (From Reference 36 with permission.)

(FIGURE4). In view of this overlap at the end of the respective phenotypic spectra, it is questionable whether or not WS and PBT are the same disorder. Phenotypic consistency in 7 affected persons with piebaldism in three generations of a South African family of mixed ancestry (FIGURE5 ) is suggestive of syndromic autonomy of this disorder? and it seems possible that previously reported individuals with PBT and ocular involvement really had WS. Molecular linkage investigations have shown that the PBT locus in the South African family is not at 2q37, thus demonstrating nonidentity with WS-I. The recognition of rearrangements of the long arm of chromosome 4 in persons with PBT indicates that the faulty gene might be at 4q12-1331”3;linkage studies in the South African family are currently being undertaken with probes from this region.

X-LINKED OCULAR ALBINISM WITH DEAFNESS X-linked ocular albinism with late-onset sensorineural deafness (XLASD) was documented in an Afrikaner kindred by Winship et al. ( 1984).37Twenty-nine persons in four generations were studied, and 7 affected males and 12 obligate carrier females were recognized (FIGURE6). The 7 affected males all had significant impairment of vision with horizontal nystagmus and pale blue irides. Fundoscopy revealed patchy hypopigmentation with

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clumps of pigment and large choroidal vessels. Hearing loss developed in middle age and progressed slowly. Audiometry revealed sensorineural deafness in affected adult males; prior to the onset of hearing loss, affected boys had normal audiograms, as did adult female obligate gene carriers. The obligate carrier females had normal vision and hearing; some of them had translucent irides and mild fundal changes, which were limited to the periphery of the fundus. Giant pigment granules (macromelanosomes) were present in skin biopsy specimens from affected males and carrier females. High-resolution banding of the X chromosome did not reveal any abnormality. Pedigree data indicate that the condition is X linked, in distinction to a similar AD disorder delineated by Lewis (1978)." The fundal changes and skin macromelanosomes are of value in identifying carrier females but, in view of their age relationship, they are not entirely specific. The chromosomal locus of the faulty gene in XLASD is unknown, but as the gene for classical Nettleship-Falls form of uncomplicated ocular albinism has been localized to Xp22, this general region serves as a potential candidate. So far, however, we have not been able to demonstrate linkage in the Afrikaner family. ACOUSTIC NEUROMA

Acoustic neuroma, also known as central neurofibromatosis and neurofibromatosis type I1 (NF-II), is an important cause of deafness due to tumors of the auditory nerve. Involvement is usually bilateral, and the majority of affected persons develop hearing impairment in early adulthood. In addition, paraspinal neurofibromata of the cervical and upper thoracic regions are a major cause of neurological and skeletal complications and meningiomata of the posterior fossa are also common.38 Cafe-au-lait dermal macules and cutaneous neurofibromata are scanty or absent in NF-I1 and the nosological grouping with classical NF-I is based upon histopathological similarities rather than phenotypic overlap. Other stigmata of NF-I, such as Lisch nodules, optic nerve gliomata, and thoracic asymmetry, are also lacking, and diagnostic differentiation is not a difficult matter. There have been several reports of multigeneration families with NF-11, and of the acoustic autosomal dominant inheritance is well d o ~ u m e n t e d ? ~Bilaterality "~ neuromata is a hallmark of the condition, and unilateral lesions are usually nongenetic. By means of polymorphic markers, Seizinger et af. (1986) demonstrated that there was a loss of genes in chromosome 22 in tumor tissue from patients with NF-II.41These workers subsequently identified a possible site for the faulty gene by demonstrating a break point at 22ql1, and linkage studies indicated that the NF-I1 gene lies between 22q11.21 and 22q13.1.42In the families that were investigated, these observations will form the basis for the development of techniques for diagnostic confirmation, presymptomatic diagnosis, and pregnancy monitoring.

USHER SYNDROME

Usher syndrome (US) is an autosomal recessive disorder in which pigmentation of the retina is associated with perceptive deafness. Night blindness, constriction of the visual fields, and hearing impairment are progressive, and hearing and vision may become extinguished in adulthood. Interfamilial variability in the phenotypic manifestations and natural history

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suggest that US is probably heterogeneous. Various classifications have been proposed, and the following simplified version is now in general use: type I, severe hearing loss with absent peripheral vestibular responses and retinitis pigmentosa (RP) of early onset; type 11, moderate hearing loss with normal vestibular responses and RP of delayed onset. Historical Background

In 1858 the German ophthalmologist Albrecht von Graefe reported the combination of retinitis pigmentosa in three brothers who had been studied by his own cousin, Alfred von Graefe. Liebreich (1861) recognized affected persons with consanguineous parents during a survey of deaf individuals in the Jewish population of and Hammerschlug (1907) documented a high frequency of the condition among the Jews of Vienna.“ Charles Usher (FIGURE 7) became involved with the disorder during a survey of deafness and visual disturbance in the United Kingdom, and in 1914 he published a review entitled “On the Inheritance of Retinitis Pigmentosa, with Notes of Cases.”45 He retained his interest for the next two decades, and in 1935 he mentioned the condition in his Bowman lecture to the Ophthalmological Society of the United Kingdom. Since that time the use of his eponym has gained general acceptance. Prevalence In view of the implications of combined visual and hearing loss, US necessitates highly specialized management and for the same reason it is a prime candidate for prevention by genetic measures. In order to achieve these goals accurate information is required concerning the prevalence and population distribution of US. As mentioned in the historical section, a high frequency of US was documented in the Jewish communities of Vienna and Berlin during the last century and it is also comparatively common in the French-speaking “Cajun” isolate of Louisiana4’ and the Lapps of A perspective of the prevalence of US in the general population of the United States can be obtained from the observation that 54% of 600 persons on the Helen Keller National Center register probably had the condit i ~ n . Sixteen ~’ families with US were recognized among 571 kindred in the diagnostic register of the Moorfields Hospital, London,4’ and 15 affected families were identified in a nationwide survey in South Africa.” The minimum population prevalence has been estimated as 3.6 per 100,000 for Norway4’and 4.4 per 100,000 for the United States. On a basis of this latter figure, a carrier rate of 1 in 70 to 1 in 100 for the population as a whole has been estimated. In view of the progressive nature of US, the asynchronous development of visual and hearing disturbance, and different sources that have been surveyed, it is inevitable that there will be disparities in frequency estimates. For instance, in his pioneering survey of special schools for the deaf in the United Kingdom, Fraser (1964) estimated that US was present in no less than 7.5% of the deaf children.” By contrast, in the Southern African surveys of hearing impairment (excluding the deaf-blind), only 12 out of 4452 profoundly deaf scholars (0.27%) were diagnosed as having US. It is uncertain whether the discrepancy between the European and the South African figures is the result of differences in the distribution of the US gene, or whether some form of bias has been operative. The pigmented “tigroid” normal fundus is a source of potential diagnostic confusion in this respect.

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Genetics

The autosomal recessive nature of US is well established, and heterogeneity seems likely in terms of phenotypic analysis in affected kindreds. Obligate heterozygotes sometimes have minor abnormalities of vision or hearing:6ss2 but these problems are inconsistent and do not permit accurate assessment of carrier status in potentially heterozygous relatives of affected persons.

FIGURE 7. Charles Usher (1865 to 1942). (From Duke-Elder, Sir S. 1967. System ofophthalmology, 111. Courtesy: C. V. Mosby, St Louis, Mo. Reproduced from Beighton & Beighton. 1986. The Man Behind the Syndrome: 176. Springer-Verlag. Berlin & Heidelberg, with permission.)

It has been suggested US might be linked to GC on chromosome 4 (4q12-13):3,54 but this observation could not be confirmed?’ Kimberling et al. (1990) made an important breakthrough when they demonstrated strong linkage between US type I1 and the DNA marker THH33 on the distal portion of the long arm of chromosome 1 in 8 affected families from the United States, Sweden, and Italy (lod 6.37).56In 9 families with US type I no linkage was demonstrated, and it is therefore probable that US-I and I1 are nonallelic. Lewis et al. (1990) confirmed these findings, assigning

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US-I1 to 1q32-44.” Accurate recognition of carriers in some affected families will now be possible, using molecular linkage techniques. SUMMARY

Hearing impairment is a variable manifestation of several heritable conditions in which pigmentation of the skin or eyes is abnormal. Some of these disorders are well recognized although uncommon, while others are virtually private syndromes. Practical issues concerning the major conditions of this type are reviewed in this article on a basis of a survey of 4452 profoundly deaf children attending special schools in Southern Africa, together with investigations in affected families. The Waardenburg syndrome (WS), which is the most common deafnessdepigmentation disorder, was present in 121 (2.7%) of the 4452 deaf scholars. Further studies in 7 multigeneration affected families confirmed phenotypic variability and indicated a need for internationally agreed diagnostic criteria. In 4 Cape Town families of mixed ancestry the WS-I gene was linked to the 2q37 locus, but in another large kindred no linkage could be demonstrated. Nonallelic heterogeneity is possible. There is uncertainty concerning possible interrelationship between WS and piebaldism. The phenotypic consistency of a South African family in which 7 persons in 3 generations had gross piebaldism in the absence of disturbance of hearing or involvement of the eyes and periorbital structures is suggestive that this disorder and WS are separate entities. Molecular investigations indicate that the gene for piebaldism in this kindred is not situated at the WS-I locus 2q37. Deafness and hyperpigmentation are present in neurofibromatosis type I1 (acoustic neuromata) and the multiple lentigines syndrome, while retinal pigmentation is a feature of the Usher syndrome. This Iatter entity is apparently much less common in Southern Africa than in other parts of the world. ACKNOWLEDGMENTS We are grateful to Gillian Shapley for preparing the manuscript. REFERENCES 1. SELLARS, S., E. NAPIER& P. BEIGHTON. 1975. Childhood deafness in Cape Town. S. Afr. Med. J. 4 9 1135-1138. 2. SELLARS,S., L. GROENEVELDT & P. BEIGHTON. 1976. Aetiology of deafness in white children in the Cape. S. Afr. Med. J. 5 0 1193-1197. 3. SELLARS, S., G. BEIGHTON, F. HORAN& P. BEIGHTON. 1977. Deafness in black children in southern Africa. S. Afr. Med. J. 51: 309-312. 4. SELLARS, S. & P. BEIGHTON.1983. Childhood deafness in southern Africa. J. Laryngol. OtoI. 97: 885-889. 5. BEIGHTON,P., S. L. SELLARS,J. GOLDBLATT, D. L. VILJOEN & G. BEIGHTON. 1987. Childhood deafness in the Indian population of Natal. S. Afr. Med. J. 72: 209-211. 6. VIUOEN,D. L., G. M. DENT,A. G. SIBANDA, M. SEYMOUR, R. CHIGUMO, A. KARIKOGA& P. BEIGHTON. 1988. Childhood deafness in Zimbabwe. S. Afr. Med. J. 73: 286-288. 7. ZIPRKOWSKI, L. & A. ADAM.1964. Recessive total albinism and congenital deaf-mutism. Arch. Dermatol. 89: 151-156. L., A. KRAKOWSKI, A. ADAM,H. COSTEFF,& J. SADE.1962. Partial albinism 8. ZIPRKOWSKI, and deaf mutism due to recessive sex-linked gene. Arch. Dermatol. 8 6 190-199.

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9. RozYCH, D. L., R. J. RUBIN,I. RAPIN& A. J. SPIRO.1971. Autosomal recessive deafness associated with short stature, vitiligo, muscle wasting and achalasia. Arch. Otolaryngol. 93: 194-197. 10. RYCROFT,R. J., C. D. CALNAN & R. S. WELLS. 1977. Universal dyschromatosis, small stature and high-tone deafness. Clin. Exp. Dermatol. 2(1): 45-49. 11. WINSHIP,I., G. GERICKE& P. BEIGHTON.1984. X-linked inheritance of ocular albinism with late-onset sensorineural deafness. Am. J. Med. Genet. 19: 797-803. 12. LEWIS,R. A. 1978. Ocular albinism and deafness. Am. J. Hum. Genet. 3 0 57a. 13. YOUNG,G. F., C. A. LEON-BARTH & J. GREEN.1970. Familial hemiplegic migraine, retinal degeneration, deafness and nystagmus. Arch. Neurol. 23: 201. 14. GORDON,A. M., A. J. CAPUTE& B. W. KONIGSMARK. 1976. Progressive quadriparesis, mental retardation, retinitis pigmentosa and hearing loss: report of two sibs. Johns Hopkins Med. J. 138 142. 15. EDWARDS, J. A., P. K. SETHI,A. J. SCOMA,R. M. BANNERMAN & L. A. FROHMAN. 1976. A new familial syndrome characterized by pigmentary retinopathy, hypogonadism, mental retardation, nerve deafness, and glucose intolerance. Am. J. Med. 6 0 23-32. 16. KLEIN,D. 1950. Albinisme partiel (leucisme) avec surdi-mutite, blepharophimosis et dysplasie myo-osteo-articulaire. Helv. Paediatr. Acta 5: 38-58. P. 1948. Dystopia punctorum lacrimalium, blepharophimosis en patiele 17. WAARDENBURG, iris atrophie bij een doofstomme. Ned. Tijdschr. Geneeskol. 92: 3463-3467. P. 1951. A new syndrome combining developmental anomalies of the 18. WAARDENBURG, eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness. Am. J. Hum. Genet. 3: 195-201. 19. ARIAS,S. 1971. Genetic heterogeneity in the Waardenburg syndrome. Birth Defects Orig. Art. Ser. 7(4): 87-101. 20. HAGEMAN, 1977. Heterogeneity in Waardenburg syndrome. Am. M. J. & J. W. DELLEMAN. J. Hum. Genet. 29: 468485. 21. SHAH,K. N., S. J. DAHL,M. P. DESAI, P. N. SHETH,N. C. JOSHI& L. M. ABANI.1981. White forelock, pigmentary disorder of irides and long segment Hirschsprung disease: possible variant of Waardenburg syndrome. J. Pediatr. 9 9 432-435. Phenotypic discriminants in the Waardenburg syndrome. 22. WINSHIP,1. & P. BEIGHTON. Clin. Genet. (In press.) 23. MCKUSICK,V. A. 1973. Congenital deafness and Hirschsprung’s disease. (Letter.) N. Engl. J. Med. 2 8 8 691 only. 24. LOWRY,R. B. 1975. Hirschsprung’s disease and congenital deafness. (Letter.) J. Med. Genet. 12: 114-115. S. & P. BEIGHTON. 1983. Waardenburg syndrome in deaf children in southern 25. SELLARS, Africa. S. Afr. Med. J. 63: 725-728. 26. MOORE,S. 1990. Personal communication. M. F. 1986. Waardenburg’s syndrome with fundus and other anomalies. Arch 27. GOLDBERG, Ophthalmol. 7 6 797-810. 1978. Ophthalmological findings in 34 patients with J. W. & M. J. HAGEMAN. 28. DELLEMAN, Waardenburg syndrome. J. Pediatr. Ophthalmol. 15: 341-345. G. MORILLO-CUCCI, F. H. ALLEN,JR. & J. GERMAN.1974. J. L., C. T. FALK, 29. SIMPSON, Analysis for possible linkage between the loci for the Waardenburg syndrome and various blood groups and serological traits. Humangenetik 23: 45-50. 30. ARIAS,S., M. MOTA,A. DE YANEX& M. BOLIVAR. 1975. Probable loose linkage between the ABO locus and Waardenburg syndrome type I. Humangenetik 27: 145-149. S. J. & B. F. CRANDELL. 1974. Dominant piebald trait in a retarded child 31. FUNDERBURK, with a reciprocal translocation and small intercalary deletion. Am. 3. Hum. Genet. 2 6 715-723. M. C. TRACY & M. 2. PELIAS.1977. Piebald trait in a Y., T. F. THURMAN, 32. LACASSIE, retarded child with interstitial deletion of chromosome 4. (Letter.) Am. J. Hum. Genet. 2 9 641-642. 1986. Tentative assignment of piebald trait 33. Hoo, J. J., R. H. A. HASLAM& C. VAN ORMAN. gene to chromosome band 4q12. Hum. Genet. 73: 230-231. 34. ISHIKIRIYAMA, S., H. TONOKI, Y. SHIBUYA, S. CHIN,N. HARADA,K. ABE& N. NIIKAWA. 1989. Waardenburg syndrome type I in a child with de novo inversion (2) (q35q37.3). Am. J. Med. Genet. 33: 505-507.

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