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Hereditary childhood hearing loss andintegumentary system disease
THE JOURNAL OF
PEDIATRICS JUNE
SPECIAL
1972
V o l u m e 80 N u m b e r 6
ARTICLE
Hereditary childhood hearing loss and integumentary system disease Fourteen types of hereditary hearing loss associated with integumentary system disease are reviewed. Infants or children with these syndromes can be identified readily because of the obvious ectodermal changes, allowing early treatment of the hearing los~ and parental genetic counseling.
Bruce W. Konigsmark, M.D., Baltimore, Md.
T H E R E ARE over 60 types of hereditary hearing loss? These syndromes can be separated from each Other by their mode of transmission (dominant, recessive, or sexlinked), age of onset, 2 type of hearing loss (conductive or sensorineural), and other clinical signs. A category of hearing loss of interest to pediatricians is the one associated with disease of the integumentary system. These syndromes can be diagnosed readily by the obvious changes in skin, nails, or hair, together with the generally severe hearing loss. Identification of the syndrome in the neonate or infant is important so that (1) early hearFrom the Division of Laryngology and Otology, and the Department of Pathology, The ]ohns Hopkins University School of Medicine. Address: Traflor 301, The Johns Hopkins Hospital, Baltimore, Md. 21205.
ing evaluation is made and therapy instituted and (2) genetic counseling can be given to the parents. There are 14 syndromes of genetic childhood hearing loss associated with disease of the integumentary system. In six of them deafness is associated with skin pigmentary changes ranging from albinism to lentigo. These syndromes are: Waardenburg's syndrome; dominant lentigines and deafness; recessive albinism and congenital deafness; hereditary piebaldness and congenital deafness; recessive vitiligo, congenital deafness, muscle wasting, and achalasia; and sexlinked pigmentary abnormalities and congenital deafness. In two syndromes other skin changes are found. These are: recessive atopic dermatitis and neural hearing loss; and dominant keratopachydermia, digital constrictions, and deafness. In five syndromes Vol. 80, No. 6, pp. 909-919
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Fig. 1. Waardenburg's syndrome in a 3-year-old Negro boy showing the wideIy spaced medial canthi, broad nasal root, and white forelock. He has normal hearing in the right ear and profound deafness in the left ear. there is a combination of hearing loss and abnormalities of the fingernails and toenails. These are: dominant knuckle pads, leukonychia, and hearing loss; dominant onychodystrophy, coniform teeth, and hearing loss; dominant onychodystrophy and congenital deafness; recessive onychodystrophy and congenital deafness; and recessive o nycho, strophy, digital abnormalities, and deaffiess. The other syndrome includes flat, brittle hair characteristic of familial pili torti and hearing loss. WAARDENBURG'S
SYNDROME
The most characteristic features of patients with this syndrome are the widely spaced medial canthi and flat nasal root with confluent eyebrows (Fig. 1). 8 Other features include vestibular hypofunction in about 75 per cent of those affected, congenital mild to severe unilateral or ~ailateral neural hearing loss in about half, hyperplasia of medial eyebrows in about half, heterochromia iridium and loss of pigment
epithelium of the optic fundus in about 25 per cent, white forelock in about 20 per cent, and skin pigmentary changes including vitiligo and spotty hyperpigmentation in less than 10 per cent. The hearing loss may be unilateral. In the patients we studied, the higher frequencies are more severely affected. Of 18 affected patients in a family studied by Marcus, 4 only one had completely normal vestibular function. Patients with this syndrome have prominent facial features, including widely spaced medial canthi producing what appears to be widely spaced eyes; however, the interpupillary distance is normal. The broad nasal root is found in about 75 per cent of those affected; about half have confluent eyebrows. Heterochromia irides were found in about 25 per cent of the cases studied by Waardenburg? The patterns of pigmentary changes involving the iris are varied. While some patients may have the classical heterochromia iridium with one brown and one blue iris, others may have brown sectors in a blue iris and blue sectors in a brown iris or even brown or blue irides bilaterally2 A white forelock originating at the hairline in the middle of the forehead and continuing posteriorly is present in about 20 per cent of those with this syndrome. The size varies from only a few hairs to a large forelock. The types of skin pigmentary changes range from areas of vitiligo 6 to areas of depigmentation with patchy areas of pigmentation. In several patients described by Fisch, 7 areas including the arms and face had a patchy or freckled hyperpigmentation. Transmission of this syndrome is dominant with striking variation in the degree of penetrance of the various traits. Since the original report by Waardenburg, affected persons have been described in most ethnic gr0ups:S, 9 Waardenburg estimated that 1.4 per cent of all congenitally deaf persons in (he Netherlands have this syndrome, whereas in the United States about 2.3 per cent of the congenitally deaf have this disease2
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DOMINANT LENTIGINES DEAFNESS (LEOPARD SYNDROME)
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AND
The major features of this syndrome, from the mnemonic "Leopard," include Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of the genitals, Retardation of growth, and Deafness. Although portions of this syndrome were described by different authors, 1~ Gorlin and associates 1~ put the components together as a single syndrome and coined the mnemonic "Leopard." It is transmitted by a dominant gene with variable penetrance. The most obvious findings in affected persons are the multiple lentigines involving the face (Fig. 2), trunk, and extremities. In the mother and daughter we described, 1'~ the skin w a s normal at birth and clear until about one year of age when freckle-like lesions appeared on the neck and thighs. These increased in size and numbers, spreading to involve the entire skin surface. Although concentrated on the upper trunk and face, some appear o n the scalp, palms, soles, and genitals. Hearing loss occurs in about half of affected persons. Although no mention was made of hearing loss in some, 1~ 12 severe congenital deafness was found in others, 14-1~ including our two patients? ~ Cardiac abnormalities including pulmonary stenosis and muscular subaortic stenosis occur in some patients? ~ 10, ~ One patient with severe pulmonary stenosis required surgery? 4 The most common electrocardiographic abnormalities are conduction defects, although there may be bundle branch block, abnormal P waves, prolongation of the PR interval, ST and T-wave changes, and widening of the QRS complex? ~ 12, 14 There may be retardation in growth and moderate ocular hypertelorism. Other anomalies found by Gorlin and colleagues 14 inelude: pectus carinatum or excavatum, dorsal kyphosis, winging of scapulae, mandibular prognathism, hypogonadism, undescended testis, and late puberty.
Fig. 2. Multiple lentigines over the face of a 16year-old girl with 'dominant lentigines and deafness syndrome.
RECESSIVE ALBINISM AND CONGENITAL DEAFNESS
A syndrome characterized by albinism and congenital severe deafness was found in a sibship described by Reed and colleagues? 7 The two children had classical albinism with totally white skin, white hair, photophobia, and lack of pigment in the iris or retina. Although the boys had intelligence quotients of 22 and 47, respectively, there was mental deficiency on both sides of the family, so that it is not clear if the mental changes are part of this syndrome. Ziprkowski and Adam is described a fibship of nine; two had albinism and deafness, three we:'*" deaf but had normal skin, and four w e r e n o r m a l . Most likely two different recessive genes were involved, one producing recessive congenital deafness and the other producing the combination of albinism and deafness. It is possible that the two sibs with albinism and deafness had the same syndrome as that described by Reed and associatesS
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over their necks and torsos. There were no hyperpigmented spots in these areas. There was marked muscle wasting in the hands, feet, and legs. An anterior tibialis muscle biopsy in the boy revealed grouped muscle atrophy indicating neural atrophy. The sibs had hyperreflexia with flexor plantar responses and normal sensation. Both sibs had a history of frequent vomiting and dysphagia. A barium swallow, esophageal pressure studies, and responses to methacholine indicated achalasia in both. The symptoms in the boy were relieved by esophageal dilatation. In the syndrome of hereditary piebaldness and congenital deafness there are small hyperpigmented spots in the areas of depigmentation, in contrast to the pure vitiligo, muscle wasting, and achalasia seen in the present syndrome. H E R E D I T A R Y PIEBALDNESS AND C O N G E N I T A L DEAFNESS
Fig. 3. Depigmentation involving head, arms, and chest in two brothers with hereditary piebaldness and congenital deafness syndrome. (From Woolf, C. M., Dolowitz, D. A., and Aldous, H. E.: Congenital deafness associated with piebaldness, Arch. Otolaryngol. 82: 244, 1965.) RECESSIVE V I T I L I G O , CONGENITAL DEAFNESS, MUSCLE WASTING, AND ACHALASIA
A brother and sister with congenital severe deafness, congenital depigmented areas of their necks and torsos, marked muscle wasting in the bands, feet, and legs, and achalasia were described by Rozycki and colleagues. 19 The parents were normal and were first cousins, suggesting that this syndrome is transmitted in an autosomal recessive manner. Audiograms showed profound sensorineural deafness. There was no history of ear infections and otologic examinations were normal. Caloric vestibular tests were normal. Both patients had depigmented areas
A syndrome consisting of pigmentary changes including depigmentation of the head and portions of the chest and arms with hyperpigmented spots in depigmented areas, and congenital deafness appeared in two of three Hopi brothers 2~ and sporadically in two other patients? 7 The Hopi boys, 8 and 12 years of age, respectively, had a similar pattern of depigmentationY ~ The piebaldness was present at birth and changed little in the developing yearsY 1 Although the major part of their bodies, including the back and legs. had normal pigmentation, the entire head and hair were depigmented as well as a strip across the upper chest and over the arms (Fig. 3). Within all of these depigmented areas were numerous small pigmented spots. The irides were blue, and very fine clumps of pigment were closely and uniformly spaced throughout the retina. Vision was normal. The remainder of the physical and neurologic examinations were completely normal. The boys had normal intelligence and: we're doing well in school. The two brothers were born deaf. Otologic examinations were normal and there
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was no history of ear infections. Audiograms showed a 60 to 100 db severe neural hearing loss bilaterally. Hearing in the normal sib and in both parents was normal. The affected boys attended a school for the deaf and had no speech but normal intelligence. Caloric vestibular tests were-normal. 2~ Although the parents were Hopi Indians from the southwestern United States, no consanguinity was known. There was no family history of pigmentary defects or of hearing loss in either parent's family. Considering also the two patients presented by Reed and colleagues, 17 a 6-year-old girl and a 21-year-old man with piebaldness and congenital deafness, it is most likely that this syndrome is transmitted by an autosomal recessive gene. This syndrome is quite similar to the syndrome of sex-linked pigmentary abnormalities in which small leopard-like spots of varying intensity of pigmentation are found. In the syndrome of piebaldness and hearing loss, areas of depigmentation are the major skin findings with speckled spots in these areas. Vestibular responses in patients with sex-linked albinism are depressed or absent in contrast to the normal caloric responses in the Hopi brothers. More cases of each type need be studied to define these diseases with greater clarity. SEX-LINKED PIGMENTARY ABNORMALITIES AND CONGENITAL DEAFNESS
A Jewish family containing 14 congenitally deaf males appearing in three generations was described by Ziprkowski and co-workers 22 and by MargolisY 3 Four of the patients were studied in detail, and all had similar clinical features. The boys were albino at birth except for light pigmentation over the gluteal and scrotal areas. These areas and spots increased in size and intensity, involving particularly the gluteal areas, trunk, and extremities (Fig. 4). Only a few spots appeared on the scalp, and the hair remained white. A skin biopsy, from the back of one patient, showed areas of hypopigmentation
Hereditary hearing loss 9 1 3
Fig. 4. Three children with large spots of hyperpigmentation, particularly in inguinal and buttocks areas, on an albino background in syndrome of sex-linked pigmentary abnormalities and congenital deafness. (From Ziprkowski, L., Krakowski, A., Adam, A., et al.: Partial albinism and deaf mutism, Arch. Dermatol. 86: 530, 1969.)
and hyperpigmentation. 22 The hypopigmented areas were only weakly D O P A positive while the hyperpigmented portion was strongly positive. All patients were congenitally deaf. Otologic examination showed normal auricles, canals, and ear drums. Audiologic examination showed no response to air conduction at frequencies above 500 Hz. Caloric vestibular tests showed no response in three patients tested. A fourth patient had a moderate depression of vestibular response. In this kindred no females were affected. Transmission is sex linked by mothers to about half (~ their sons. RECESSIVE ATOPIC DERMATITIS AND NEURAL HEARING LOSS
We found this syndrome, consisting of atypical atopic dermatitis and moderate neural hearing loss, in three of four sibs. 24 Each of the affected sibs, from i1 to 13
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The ]ournal o[ Pediatrics June 1972
cal atopic dermatitis was made. A biopsy from an active skin plaque showed moderate acanthosis and hyperkeratosis with a patchy lymphocytic infiltrate in the upper dermis. The parents were not related nor was there a history in either family of hearing loss or dermatitis. Audiometric tests on both parents and on the fourth sib showed no abnormalities. However, it is most like that this syndrome is t~ransmitted by autosomal recessive mode. DOMINANT KERATOPACHYDERMIA, DIGITAL C O N S T R I C T I O N S , AND DEAFNESS
Fig. 5. Soft tissue constrictions involving the middle phalanges in syndrome of dominant keratopachydermla, digital constrictions, and deafness. (From Drummond, M.: A case of unusual skin disease, Ir. J. Med. Sci. 8: 85, 1939.) years of age, had a similar auditory defect. Hearing loss was first noted when they were three to five years of age, but was not severe enough to cause difficulty in school. Hearing tests at five to six years of age showed a bilateral symmetrical neural hearing loss of 15 to 55 db, both for air and bone conduction. Speech discrimination was over 90 per cent in all three sibs. The small increment sensitivity index was 100 per cent at 2,000 and 4,000 Hz, and tone decay tests were negative, suggesting a cochlear locus of the hearing loss. Repeat tests showed no progression of the hearing loss. Caloric vestibular tests were normal. Dermatitis began in each of the three children at about 10 years of age. T h e skin lesions consisted of a mild ichthyosis with lichenified, excoriated, erythematous eruption involving particularly the forearms, elbows, antecubital spaces, and sometimes the waist. The legs and popliteal spaces were spared. Because of the later onset and the lack of leg involvement, a diagnosis of atypi-
Congenital deafness, hyperkeratosis involving the palms, soles, knees, and elbows, and ring-like furrows developing on the fingers and toes are the major findings of this syndrome affecting four members of a kindred described by Nockemann 25 and a single individual described by DrummondY 6 The affected persons were born profoundly deaf. At about itwo years of age each of Nockemann's patients developed thickening of the palmar and plantar skin followed by involvement of the elbows and knees. Rubbing produced thickenings elsewhere. At about five years of age ring-like small furrows began to develop on the skin and soft tissue of the middle phalanx of all fingers and toes. These were severe enough to require digital amputation in several persons. Roentgenograms of the fingers of one patient showed normal phalanges and jointsY 5 Drummond's patient, a 19-year-old congenitally deaf girl, developed constricting bands one-eighth to one-fourth inch in width about three fingers of each hand (Fig. 5). A marked hyperkeratosis of the palms, knuckles, and knees was present. In the family described by Nockemann, the four affected members included a 20year-old man, his mother, maternal uncle, and grandmother. T h e pedigree suggests autosomal dominant transmission of this syndrome. No family history was presented by Drummond. The Syndrome of keratopachydermia, digital constrictions, and deafness can be dis-
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tinguished from other isolated cases of annular constrictions involving the fingers and toes because of the marked hearing loss and dominant transmission of this syndrome. D O M I N A N T K N U C K L E PADS, LEUKONYCHIA, AND H E A R I N G LOSS This syndrome, characterized by autosomal dominant transmission, congenital leukonychia, childhood onset of knuckle pads, congenital moderate to severe neural or mixed hearing loss, and hypoactive vestibular responses, appeared in 22 members of a family described by Bart and Pumphrey. 27 Audiometric findings in five examined patients were variable. Two patients had a pure neural hearing loss, and three had mixed hearing loss in at least one ear. The proband had a right-sided 10 to 70 db neural hearing loss while the left ear showed a 70 to 90 db mixed hearing loss. Exploration of the left middle ear in one case showed such disorganization of the middle ear structures that the ossicles and facial nerve could not be identified. Caloric vestibular tests were done on three patients. One had a normal response to caloric testing, another had vestibular paresis, and in the third patient the left side was hypoactive and the right side was normal. Since early childhood each of the affected persons had knuckle pads located over the interphalangeal joints of the fingers (Fig. 6) and toes. All of the fingernails and toenails had leukonychia, obscuring the lunula. By history, spoon nails (koilonychia) had developed in some of the family members who were hard of hearing. Most likely they too were involved. The authors, besides studying five affected and one normal family member, found a total of 20 affected persons in six generations. By history seven had only hearing loss, whereas all the remainder had both hearing loss and leukonychia. Possibly leukonychia was not noted on those not examined. It is most likely that the disease is familial, with a dominant mode of transmission.
Fig. 6, Leukonychia and knuckle pads on thumb of patient with knuckle pad, leukonyehia, and deafness syndrome. (From Bart, R. S., and Pumphrey, R. E.: Knuckle pads, leukonychia, and deafness: A dominantly inherited syndrome, N. Engl. J. IVied. 276: 202, 1967.) DOMINANT ONYCHODYSTROPHY, CONIFORM TEETH, AND .HEARING LOSS
A syndrome consisting of small fissured nails, coniform teeth and anodontia, and congenital moderate to severe neural hearing loss was described by Robinson and associates 2s in t962. Of five affected members in the family, four were studied by the authors. Patients had a 10 to 100 db hearing loss. Higher frequencies were more strikingly involved, particularly in one patient who had normal hearing at low frequencies and a 100 db neural hearing loss at frequencies above 4,000 Hz. One child had a 70 db neural hearing loss in all frequencies. Apparently the hearing loss was congenital, for no mention was made of progression in later years. In all patients, fingernails and toenails were small and had furrows and cracks (Fig. 7, A ) ~ a p p a r e n t l y present from birth. Although hair and skin were normal, all had peculiar, coniform teeth, m a n y of which were missing (Fig. 7, B).
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They also had normally formed but rudimentary nails, about one-quarter normal size (Fig. 8). Although the mother was edentulous, her teeth had been normal; her son's teeth were normal. Roentgenograms of the proband's hands and feet showed underdevelopment of the distal phalangeal tufts on the fingers, absence of a phalanx in both little fingers and three toes of one foot, and an extra phalanx in one thumb. No studies were done on the son. It is not clear if those bony changes are part of this syndrome. The proband's husband and his sister were both born deaf but were otherwise normal. There was no history of deafness in his family. It is most likely that they had hereditary recessive congenital deafness, different from the syndrome in the proband and her daughter. Since this syndrome was found only in a mother and one of two children, it is likely that this was the result of a new mutation of an autosomal dominant gene. RECESSIVE ONYCHODYSTROPHY AND CONGENITAL DEAFNESS
Fig. 7. A, Small fissured fingernails. B, Coniform teeth with some teeth missing in syndrome of dominant onyehodystrophy, coniform teeth, and hearing loss. (From Robinson, G. C., Mille~l", J. R., and Bensimon, J. R.: Familial ectodermal dysplasia with sensorineural deafness and other anomalies, Pediatrics 30: 797, 1962.)
Affected were three of four sibs, their mother, and maternal grandmother. Transmission of this disease is as an autosomal dominant trait. DOMINANT ONYCHODYSTROPHY AND CONGENITAL DEAFNESS
This syndrome of rudimentary fingernails and toenails, congenital severe neural hearing loss, and possibly phalangeal abnormalities was found in a mother and son studied by Goodman and colleaguesY ~ It is similar to the syndrome of recessive onychodystrophy and deafness, differing in the nail changes and in mode of transmission. The proband and her 33-year-old son had congenital severe sensorineural hearing loss.
A syndrome characterized by congenital deafness and congenital onyehodystrophy with short fissured finger and toenails, occurred in two of five sibs from a consanguineous marriage, a~ The girls were born deaf and attended a school for the deaf. Audiograms showed a 60 to 100 db sensorineuraI hearing loss, most marked in the higher frequencies. Caloric testing showed hypoaetivity of the labyrinth in the older girl, and normal vestibular reaction in the younger girl. The finger and toenails of the sibs showed similar congenital abnormalities; they were short, spoon shaped, and fissured (Fig. 9). Hair and teeth were normal and there were no other physical abnormalities except for strabismus. The parents were first cousins but had no family history of hearing loss nor of nail dystrophy. Examination of both parents showed n0 abnormalities. It is most likely that this syndrome is transmitted by autosomal recessive mode.
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Hereditary hearing loss
Fig. 8. Rudimentary but normally formed fingernails in dominant onychodystrophy and congenital deafness syndrome. (From Goodman, R. M., Lockareff, S., and Gwinup, G.: Hereditary congenital deafness with onychodystrophy, Arch. Otolaryngo/. 90: 96, 1969.) RECESSIVE
ONYCHODYSTROPHY,
DIGITAL ABNORMALITIES, AND DEAFNESS
A syndrome characterized in two sibs by congenital severe deafness, rudimentary finger and toenails, and digital abnormalities (hypoplastic third phalanges and extra phalanges in the thumbs and great toes) was described by Walbaum and colleagues al in 1970. The 13-year-old boy and his 3~-year-old sister had congenital severe neural deafness. Both sibs had similar hand and foot abnormalities. The thumbs were long, had an extra phalanx, and were in the same plane as the fingers. The little fingers were short and flexed with clinodactyly and camptodactyly. The third phalanx was hypoplastie in the fingers and toes. The distal phalanges of the great toes were very large. Nails were absent on the little fingers, rudimentary on the thumbs, and very short on the rest of the fingers; they were also rudimentary on the toes. Dermatographics were normal. Mental retardation was possibly present. The boy was functioning well in a school for the deaf, but his sister was estimated to have an I.Q. of 50. Both parents were normal and noncon-
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Fig. 9. Short and fissured fingernails in syndrome of recessive onychodystrophy and deafness. (From Feinmesser, M., and Zelig, S.: Congenital deafness associated with onychodystrophy, Arch. Otolaryngol. 74: 507, 1961.) sanguineous. Transmission is apparently by recessive mode. This syndrome is different from recessive onyehodystrophy and congenital deafness because of the digital abnormalities, and it varies from dominant onychodystrophy and congenital deafness because of its recessive transmission. FAMILIAL PILl TORTI HEARING LOSS
AND
A syndrome of pili torti (flat, twisted hair) and neural hearing loss was described by Bjornstad, 3~ by Reed and associates, aa and by Robinson and Johnston. s4 Although 9 of the 10 reported patients had only a 20 to 60 db hearing loss, the patient described by Robinson and Johnston had severe bilateral neural hearing loss. The hair is untidy in appearance, dry, and brittle (Fig. 10). Scalp hair, eyebrows, and eyelashes are affected. Histologically the hairs are grooved, flattened, and twisted about their axes. Bjornstad 32 presented five patients with this disorder; two had affected sibs and one patient had an affected aunt. Of the four patients described by Reed and colleagues, ~a three were brothers of Mexican descent and the fourth boy had a deaf mother who was not examined. Audiograms and physical examinations of the three sibs of the five-yearold girl described by Robinson and Johnston 34 were normal, and there was no faro-
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dreds with a central type of von Recklinghausen's disease have been described.ST. 3s These patients may have occasional caf6-aulait spots. They develop hearing toss due to bilateral acoustic neurinomas in the second or third decades of life and eventually die from this disease. Patients with Refsum's disease a9 develop a progressive neural hearing loss along with ichthyosis, progressive retinitis pigmentosa, hypertrophic peripheral neuropathy, mild ataxia, and increased plasma phytanic acid. The syndrome described by Tietz ~~ as dominant albinism and congenital deafness is not included because of the finding by Reed and colleagues aa that the patients were only blond and not albino. Thus the diagnosis probably was dominant congenital severe deafness. SUMMARY
Fig. 10. Untidy hair in syndrome of recessive pill torti and hearing loss. (From Robinson, C., and Johnston, M. M.: Pili torti and sensory neural hearing loss, J. PEDIATR. 70: 621, 1967.) ily history of hearing loss or hair defect. It seems likely that these three authors have reported cases of the same syndrome and that this disease is transmitted by recessive mode, although other patients with this syndrome must be studied with particular attention to family history to clarify the mode of transmission. COMMENTS
Several syndromes of integumentary abnormalities and hearing loss are not included in this survey because the hearing loss is not congenital but of later onset and progressive. In the syndrome of dominant piebald trait, ataxia, and neural hearing loss~~ there is congenital piebaldness, ataxia or coordination difficulties, mental retardation (80 per cent), and variable progressive neural hearing loss in about 60 per cent of patients. The syndrome of dominant anhidrosis and progressive hearing loss3~ is characterized by autosomal dominant transmission, congenital anhidrosis, and a progressive neural hearing loss beginning in adulthood. Several kin-
We have reviewed 14 syndromes of hereditary childhood hearing loss and integumentary system disease. All of these syndromes include deafness at birth. Most of the integumentary changes are evident at birth with skin pigmentary change ranging from albinism to Ientigines, nail changes ranging from leukonychia to onychodystrophy, or pili torti. In two syndromes, including atopic dermatitis and keratopaehydermia with digital constrictions, the skin changes occur in childhood. These hereditary syndromes should be kept in mind during routine physical examinations of infants and children in order to secure early treatment of hearing loss and to offer parental genetic counseling. REFERENCES
1. Konigsmark, B. W.: Hereditary deafness in man, N. Engl. J. Med. 281: 713, 774, 827, 1969. 2. Konigsmark, B. W.: Hereditary deafness syndromes with onset in adult llfe. In press. 3. Waardenburg, P. J.: A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness, Am. J. Hum. Genet. 3: 195, 1951. 4. Marcus, R. E.: Vestibular function and additional findings in Waardenburg's syndrome, Acta Otolaryngol. (Stockholm) 229: 5, 1968. ( Suppl. )
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5. Goldberg, M. F.: Waardenburg's syndrome with fundus and other anomalies, Arch. Ophthal. 76: 797, 1966. 6. Klein, D.: Albinisme partiel (leucisme) avec surdimutit~, bldpharophimosis et dysplasie myo-ost6o-artieulaire, Helv. Paediatr. Aeta 5: 38, 1950. 7. Fisch, L.: D~eafness as part of an hereditary syndrome, J. LaryngoI. 73: 355, 1959. 8. Partington, M. W.: Waardenburg's syndrome and heterochromia iridum in a deaf school population, Canad. Med. Assoc. J. 90: 1008, 1964. 9. DiGeorge, A. M., Olmsted, R. W., and Harley, R. D.: Waardenburg's syndrome, J. PEmATR. 57: 649, 1960. 10. Matthews, N, L.: Lentigo and electrocardiographic changes, N. Engl. J. Med. 278: 780, 1968. 11. Moynahan, E. J.: Multiple symmetrical moles, with psychic and somatic infantilism and genital hypoplasia: First male case of a new syndrome, Proc. R. Soe. Med. 55: 959, 1962. 12. Walther, R. J., Polansky, B. J., and Grots, I. A.: Electrocardiographic abnormalities in family with generalized lentigo, N. Engl. J. Med. 275: 1220, 1966. 13. Capute, A. J,, Rimoin, D. L., Konigsmark, B. W., Esterly, N. B., and Richardson, F.: Congenital deafness and multiple lentigines, Arch. DermatoI. 100" 207, 1969. 14. Gorlin, R. J., Anderson, R. C., and Blaw, M.: Multiple lentigines syndrome, Am. J. Dis. Child. 117: 652, 1969. 15. Lewis, S. M., Sonnenblick, B. P., Gilbert, L., and Biber, D.: Familial pulmonary stenosls and deaf-mutism: Clinical and genetic considerations, Am. Heart. J. 55: 458, 1958. 16. Koroxenidis, G. T., Webb, N. C., Moschos, C. B., and Lehan, P. H.: Congenital heart disease, deaf-mutism and associated somatic mMformations occurring in several members of one family, Am. J. Med. 40: 149, 1966. 17. Reed, W. B., Stone, V. M., Boder, E., and Ziprkowski, L.: Pigmentary disorders in association with congenital deafness, Arch Dermatol. 95: 176, 1967. 18. Ziprkowski, L., and Adam, A.: Recessive total albinism and congenital deaf-tourism, Arch. Dermatol. 89: 151, 1964. 19. Rozycki, D. L., Ruben, R. J., Rapin, I., and Spiro, A. J.: Autosomal recessive deafness associated with short stature, vitiligo, muscle wasting and achalasia, Arch. Otolaryngol. 93: 194, 1971. 20. Woolf, C. M., Dolowitz, D. A., and Aldous, H. E.: Congenital deafness associated with piebaldness, Arch. Otolaryngol. 82: 244, 1965. 21. Dolowitz, D. A.: Personal communication. 22. Ziprkowski, L., Krakowski, A., Adam, A., Costeff, H., and Sade, J.: Partial albinism and deaf mutism, Arch, Dermawl. 86: 530, 1962. 23. Margolis, E.: A new hereditary syndrome-sex-linked deaf-mutism associated with total
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albinism, Acta Genet. (Basel) 12: 12, 1962. 24. Konigsmark, B. W., Hollander, M. B., and Berlin, C. I.: Familial neural hearing loss and atopic dermatitis, J. A. M. A. 204: 953, 1968: 25. Nockemann, P. F.: Erbliche Hornhautverdickung mit Schnfirfurchen an Fingern und Zehen und Innenohrschwerh6rigkeit, Med. Weir 37: 1894, 1961. 26. Drummond, M.: A case of unusual skin disease, Ir. J. Med. Sci. 8: 85, 1939. 27. Bart, R. S., and Pumphrey, R. E.: Knuckle pads, leukonychia and deafness: A dominantly inherited syndrome, N, Engl. J. Med. 276: 202, 1967. 28. Robinson, G. C., Miller, J. R., and Bensimon, J. R.: Familial ectodermal dysplasia with sensorineural deafness and other anomalies, Pediatrics 30: 797, 1962. 29. Goodman, R. M., Lockareff, S., and Gwinup, G.: Hereditary congenital deafness with onychodystrophy, Arch. Otolaryngol. 90: 474, 1969. 30. Feinmesser, M., and Zelig, S.: Congenital deafness associated with onychodystrophy, Arch. OtolaryngoL 74: 507, 1961. 31. Walbaum, R., Fontalne, G., Lienhardt, J., and Piquet, J.: Surdit~ familiale avec ost~oonycho-dysplasie, J. Genet. Hum. 18: 101, 1970. 32. Bjornstad, R.: Pili torti and sensory neural loss of hearing, Proceedings XVIIth Meeting Northern Dermatological Society, May, 1965, Copenhagen. 33. Reed, W. B., Stone, V. M., Boder, E., and Ziprkowski, L.: Hereditary syndromes with auditory and dermatological manifestations, Arch. Dermatol. 95: 456, 1967. 34. Robinson, G. C., and Johnston, M. M.: Pill torti and sensory neural hearing loss, J. PEDIATR. 70: 621, 1967. 35. Teller, M. A., Sugar, M., Jaeger, E. A., and Mulcahy, J.: Dominant piebald trait (white forelock and leukoderma) with neurological impairment, Am. J. Hum. Genet. 23" 383, 1971. 36. Helweg-Larsen, H. F., and Ludvigsen, K.: Congenital familial anhidrosis and neurolabyrinthitis, Acta Derm. Venereol. (Stockh.) 26: 489, 1946. 37. Gardner, W. J., and Turner, O.: Bilateral acoustic neurofibromas: Further clinical and pathologic data on hereditary deafness and Recklinghausen's disease, Arch Neurol. Psychiatr. 44: 76, 1940. 38. Moyes, P. D.: Familial bilateral acoustic neuroma affecting 14 members from four generations. Case report, J. Neurosurg. 29" 78, 1968. 39. Refsum, S., Salomonsen, L., and Skatvedt, M.: Heredopathia atactica polyneuritiformis in children, J. PEDIATR. 35: 335, 1949. 40. Tietz, W.: A syndrome of deaf-mufism associated with albinism showing dominant autosomal inheritance, Am. J. Hum. Genet. 15" ?59, 1963.
PEDIATRICS JUNE
SPECIAL
1972
V o l u m e 80 N u m b e r 6
ARTICLE
Hereditary childhood hearing loss and integumentary system disease Fourteen types of hereditary hearing loss associated with integumentary system disease are reviewed. Infants or children with these syndromes can be identified readily because of the obvious ectodermal changes, allowing early treatment of the hearing los~ and parental genetic counseling.
Bruce W. Konigsmark, M.D., Baltimore, Md.
T H E R E ARE over 60 types of hereditary hearing loss? These syndromes can be separated from each Other by their mode of transmission (dominant, recessive, or sexlinked), age of onset, 2 type of hearing loss (conductive or sensorineural), and other clinical signs. A category of hearing loss of interest to pediatricians is the one associated with disease of the integumentary system. These syndromes can be diagnosed readily by the obvious changes in skin, nails, or hair, together with the generally severe hearing loss. Identification of the syndrome in the neonate or infant is important so that (1) early hearFrom the Division of Laryngology and Otology, and the Department of Pathology, The ]ohns Hopkins University School of Medicine. Address: Traflor 301, The Johns Hopkins Hospital, Baltimore, Md. 21205.
ing evaluation is made and therapy instituted and (2) genetic counseling can be given to the parents. There are 14 syndromes of genetic childhood hearing loss associated with disease of the integumentary system. In six of them deafness is associated with skin pigmentary changes ranging from albinism to lentigo. These syndromes are: Waardenburg's syndrome; dominant lentigines and deafness; recessive albinism and congenital deafness; hereditary piebaldness and congenital deafness; recessive vitiligo, congenital deafness, muscle wasting, and achalasia; and sexlinked pigmentary abnormalities and congenital deafness. In two syndromes other skin changes are found. These are: recessive atopic dermatitis and neural hearing loss; and dominant keratopachydermia, digital constrictions, and deafness. In five syndromes Vol. 80, No. 6, pp. 909-919
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Fig. 1. Waardenburg's syndrome in a 3-year-old Negro boy showing the wideIy spaced medial canthi, broad nasal root, and white forelock. He has normal hearing in the right ear and profound deafness in the left ear. there is a combination of hearing loss and abnormalities of the fingernails and toenails. These are: dominant knuckle pads, leukonychia, and hearing loss; dominant onychodystrophy, coniform teeth, and hearing loss; dominant onychodystrophy and congenital deafness; recessive onychodystrophy and congenital deafness; and recessive o nycho, strophy, digital abnormalities, and deaffiess. The other syndrome includes flat, brittle hair characteristic of familial pili torti and hearing loss. WAARDENBURG'S
SYNDROME
The most characteristic features of patients with this syndrome are the widely spaced medial canthi and flat nasal root with confluent eyebrows (Fig. 1). 8 Other features include vestibular hypofunction in about 75 per cent of those affected, congenital mild to severe unilateral or ~ailateral neural hearing loss in about half, hyperplasia of medial eyebrows in about half, heterochromia iridium and loss of pigment
epithelium of the optic fundus in about 25 per cent, white forelock in about 20 per cent, and skin pigmentary changes including vitiligo and spotty hyperpigmentation in less than 10 per cent. The hearing loss may be unilateral. In the patients we studied, the higher frequencies are more severely affected. Of 18 affected patients in a family studied by Marcus, 4 only one had completely normal vestibular function. Patients with this syndrome have prominent facial features, including widely spaced medial canthi producing what appears to be widely spaced eyes; however, the interpupillary distance is normal. The broad nasal root is found in about 75 per cent of those affected; about half have confluent eyebrows. Heterochromia irides were found in about 25 per cent of the cases studied by Waardenburg? The patterns of pigmentary changes involving the iris are varied. While some patients may have the classical heterochromia iridium with one brown and one blue iris, others may have brown sectors in a blue iris and blue sectors in a brown iris or even brown or blue irides bilaterally2 A white forelock originating at the hairline in the middle of the forehead and continuing posteriorly is present in about 20 per cent of those with this syndrome. The size varies from only a few hairs to a large forelock. The types of skin pigmentary changes range from areas of vitiligo 6 to areas of depigmentation with patchy areas of pigmentation. In several patients described by Fisch, 7 areas including the arms and face had a patchy or freckled hyperpigmentation. Transmission of this syndrome is dominant with striking variation in the degree of penetrance of the various traits. Since the original report by Waardenburg, affected persons have been described in most ethnic gr0ups:S, 9 Waardenburg estimated that 1.4 per cent of all congenitally deaf persons in (he Netherlands have this syndrome, whereas in the United States about 2.3 per cent of the congenitally deaf have this disease2
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DOMINANT LENTIGINES DEAFNESS (LEOPARD SYNDROME)
Hereditary hearing loss 9 1 1
AND
The major features of this syndrome, from the mnemonic "Leopard," include Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of the genitals, Retardation of growth, and Deafness. Although portions of this syndrome were described by different authors, 1~ Gorlin and associates 1~ put the components together as a single syndrome and coined the mnemonic "Leopard." It is transmitted by a dominant gene with variable penetrance. The most obvious findings in affected persons are the multiple lentigines involving the face (Fig. 2), trunk, and extremities. In the mother and daughter we described, 1'~ the skin w a s normal at birth and clear until about one year of age when freckle-like lesions appeared on the neck and thighs. These increased in size and numbers, spreading to involve the entire skin surface. Although concentrated on the upper trunk and face, some appear o n the scalp, palms, soles, and genitals. Hearing loss occurs in about half of affected persons. Although no mention was made of hearing loss in some, 1~ 12 severe congenital deafness was found in others, 14-1~ including our two patients? ~ Cardiac abnormalities including pulmonary stenosis and muscular subaortic stenosis occur in some patients? ~ 10, ~ One patient with severe pulmonary stenosis required surgery? 4 The most common electrocardiographic abnormalities are conduction defects, although there may be bundle branch block, abnormal P waves, prolongation of the PR interval, ST and T-wave changes, and widening of the QRS complex? ~ 12, 14 There may be retardation in growth and moderate ocular hypertelorism. Other anomalies found by Gorlin and colleagues 14 inelude: pectus carinatum or excavatum, dorsal kyphosis, winging of scapulae, mandibular prognathism, hypogonadism, undescended testis, and late puberty.
Fig. 2. Multiple lentigines over the face of a 16year-old girl with 'dominant lentigines and deafness syndrome.
RECESSIVE ALBINISM AND CONGENITAL DEAFNESS
A syndrome characterized by albinism and congenital severe deafness was found in a sibship described by Reed and colleagues? 7 The two children had classical albinism with totally white skin, white hair, photophobia, and lack of pigment in the iris or retina. Although the boys had intelligence quotients of 22 and 47, respectively, there was mental deficiency on both sides of the family, so that it is not clear if the mental changes are part of this syndrome. Ziprkowski and Adam is described a fibship of nine; two had albinism and deafness, three we:'*" deaf but had normal skin, and four w e r e n o r m a l . Most likely two different recessive genes were involved, one producing recessive congenital deafness and the other producing the combination of albinism and deafness. It is possible that the two sibs with albinism and deafness had the same syndrome as that described by Reed and associatesS
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The Journal o[ Pediatrics June 1972
over their necks and torsos. There were no hyperpigmented spots in these areas. There was marked muscle wasting in the hands, feet, and legs. An anterior tibialis muscle biopsy in the boy revealed grouped muscle atrophy indicating neural atrophy. The sibs had hyperreflexia with flexor plantar responses and normal sensation. Both sibs had a history of frequent vomiting and dysphagia. A barium swallow, esophageal pressure studies, and responses to methacholine indicated achalasia in both. The symptoms in the boy were relieved by esophageal dilatation. In the syndrome of hereditary piebaldness and congenital deafness there are small hyperpigmented spots in the areas of depigmentation, in contrast to the pure vitiligo, muscle wasting, and achalasia seen in the present syndrome. H E R E D I T A R Y PIEBALDNESS AND C O N G E N I T A L DEAFNESS
Fig. 3. Depigmentation involving head, arms, and chest in two brothers with hereditary piebaldness and congenital deafness syndrome. (From Woolf, C. M., Dolowitz, D. A., and Aldous, H. E.: Congenital deafness associated with piebaldness, Arch. Otolaryngol. 82: 244, 1965.) RECESSIVE V I T I L I G O , CONGENITAL DEAFNESS, MUSCLE WASTING, AND ACHALASIA
A brother and sister with congenital severe deafness, congenital depigmented areas of their necks and torsos, marked muscle wasting in the bands, feet, and legs, and achalasia were described by Rozycki and colleagues. 19 The parents were normal and were first cousins, suggesting that this syndrome is transmitted in an autosomal recessive manner. Audiograms showed profound sensorineural deafness. There was no history of ear infections and otologic examinations were normal. Caloric vestibular tests were normal. Both patients had depigmented areas
A syndrome consisting of pigmentary changes including depigmentation of the head and portions of the chest and arms with hyperpigmented spots in depigmented areas, and congenital deafness appeared in two of three Hopi brothers 2~ and sporadically in two other patients? 7 The Hopi boys, 8 and 12 years of age, respectively, had a similar pattern of depigmentationY ~ The piebaldness was present at birth and changed little in the developing yearsY 1 Although the major part of their bodies, including the back and legs. had normal pigmentation, the entire head and hair were depigmented as well as a strip across the upper chest and over the arms (Fig. 3). Within all of these depigmented areas were numerous small pigmented spots. The irides were blue, and very fine clumps of pigment were closely and uniformly spaced throughout the retina. Vision was normal. The remainder of the physical and neurologic examinations were completely normal. The boys had normal intelligence and: we're doing well in school. The two brothers were born deaf. Otologic examinations were normal and there
Volume 30 Number 6
was no history of ear infections. Audiograms showed a 60 to 100 db severe neural hearing loss bilaterally. Hearing in the normal sib and in both parents was normal. The affected boys attended a school for the deaf and had no speech but normal intelligence. Caloric vestibular tests were-normal. 2~ Although the parents were Hopi Indians from the southwestern United States, no consanguinity was known. There was no family history of pigmentary defects or of hearing loss in either parent's family. Considering also the two patients presented by Reed and colleagues, 17 a 6-year-old girl and a 21-year-old man with piebaldness and congenital deafness, it is most likely that this syndrome is transmitted by an autosomal recessive gene. This syndrome is quite similar to the syndrome of sex-linked pigmentary abnormalities in which small leopard-like spots of varying intensity of pigmentation are found. In the syndrome of piebaldness and hearing loss, areas of depigmentation are the major skin findings with speckled spots in these areas. Vestibular responses in patients with sex-linked albinism are depressed or absent in contrast to the normal caloric responses in the Hopi brothers. More cases of each type need be studied to define these diseases with greater clarity. SEX-LINKED PIGMENTARY ABNORMALITIES AND CONGENITAL DEAFNESS
A Jewish family containing 14 congenitally deaf males appearing in three generations was described by Ziprkowski and co-workers 22 and by MargolisY 3 Four of the patients were studied in detail, and all had similar clinical features. The boys were albino at birth except for light pigmentation over the gluteal and scrotal areas. These areas and spots increased in size and intensity, involving particularly the gluteal areas, trunk, and extremities (Fig. 4). Only a few spots appeared on the scalp, and the hair remained white. A skin biopsy, from the back of one patient, showed areas of hypopigmentation
Hereditary hearing loss 9 1 3
Fig. 4. Three children with large spots of hyperpigmentation, particularly in inguinal and buttocks areas, on an albino background in syndrome of sex-linked pigmentary abnormalities and congenital deafness. (From Ziprkowski, L., Krakowski, A., Adam, A., et al.: Partial albinism and deaf mutism, Arch. Dermatol. 86: 530, 1969.)
and hyperpigmentation. 22 The hypopigmented areas were only weakly D O P A positive while the hyperpigmented portion was strongly positive. All patients were congenitally deaf. Otologic examination showed normal auricles, canals, and ear drums. Audiologic examination showed no response to air conduction at frequencies above 500 Hz. Caloric vestibular tests showed no response in three patients tested. A fourth patient had a moderate depression of vestibular response. In this kindred no females were affected. Transmission is sex linked by mothers to about half (~ their sons. RECESSIVE ATOPIC DERMATITIS AND NEURAL HEARING LOSS
We found this syndrome, consisting of atypical atopic dermatitis and moderate neural hearing loss, in three of four sibs. 24 Each of the affected sibs, from i1 to 13
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The ]ournal o[ Pediatrics June 1972
cal atopic dermatitis was made. A biopsy from an active skin plaque showed moderate acanthosis and hyperkeratosis with a patchy lymphocytic infiltrate in the upper dermis. The parents were not related nor was there a history in either family of hearing loss or dermatitis. Audiometric tests on both parents and on the fourth sib showed no abnormalities. However, it is most like that this syndrome is t~ransmitted by autosomal recessive mode. DOMINANT KERATOPACHYDERMIA, DIGITAL C O N S T R I C T I O N S , AND DEAFNESS
Fig. 5. Soft tissue constrictions involving the middle phalanges in syndrome of dominant keratopachydermla, digital constrictions, and deafness. (From Drummond, M.: A case of unusual skin disease, Ir. J. Med. Sci. 8: 85, 1939.) years of age, had a similar auditory defect. Hearing loss was first noted when they were three to five years of age, but was not severe enough to cause difficulty in school. Hearing tests at five to six years of age showed a bilateral symmetrical neural hearing loss of 15 to 55 db, both for air and bone conduction. Speech discrimination was over 90 per cent in all three sibs. The small increment sensitivity index was 100 per cent at 2,000 and 4,000 Hz, and tone decay tests were negative, suggesting a cochlear locus of the hearing loss. Repeat tests showed no progression of the hearing loss. Caloric vestibular tests were normal. Dermatitis began in each of the three children at about 10 years of age. T h e skin lesions consisted of a mild ichthyosis with lichenified, excoriated, erythematous eruption involving particularly the forearms, elbows, antecubital spaces, and sometimes the waist. The legs and popliteal spaces were spared. Because of the later onset and the lack of leg involvement, a diagnosis of atypi-
Congenital deafness, hyperkeratosis involving the palms, soles, knees, and elbows, and ring-like furrows developing on the fingers and toes are the major findings of this syndrome affecting four members of a kindred described by Nockemann 25 and a single individual described by DrummondY 6 The affected persons were born profoundly deaf. At about itwo years of age each of Nockemann's patients developed thickening of the palmar and plantar skin followed by involvement of the elbows and knees. Rubbing produced thickenings elsewhere. At about five years of age ring-like small furrows began to develop on the skin and soft tissue of the middle phalanx of all fingers and toes. These were severe enough to require digital amputation in several persons. Roentgenograms of the fingers of one patient showed normal phalanges and jointsY 5 Drummond's patient, a 19-year-old congenitally deaf girl, developed constricting bands one-eighth to one-fourth inch in width about three fingers of each hand (Fig. 5). A marked hyperkeratosis of the palms, knuckles, and knees was present. In the family described by Nockemann, the four affected members included a 20year-old man, his mother, maternal uncle, and grandmother. T h e pedigree suggests autosomal dominant transmission of this syndrome. No family history was presented by Drummond. The Syndrome of keratopachydermia, digital constrictions, and deafness can be dis-
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Hereditary hearing loss
9 15
tinguished from other isolated cases of annular constrictions involving the fingers and toes because of the marked hearing loss and dominant transmission of this syndrome. D O M I N A N T K N U C K L E PADS, LEUKONYCHIA, AND H E A R I N G LOSS This syndrome, characterized by autosomal dominant transmission, congenital leukonychia, childhood onset of knuckle pads, congenital moderate to severe neural or mixed hearing loss, and hypoactive vestibular responses, appeared in 22 members of a family described by Bart and Pumphrey. 27 Audiometric findings in five examined patients were variable. Two patients had a pure neural hearing loss, and three had mixed hearing loss in at least one ear. The proband had a right-sided 10 to 70 db neural hearing loss while the left ear showed a 70 to 90 db mixed hearing loss. Exploration of the left middle ear in one case showed such disorganization of the middle ear structures that the ossicles and facial nerve could not be identified. Caloric vestibular tests were done on three patients. One had a normal response to caloric testing, another had vestibular paresis, and in the third patient the left side was hypoactive and the right side was normal. Since early childhood each of the affected persons had knuckle pads located over the interphalangeal joints of the fingers (Fig. 6) and toes. All of the fingernails and toenails had leukonychia, obscuring the lunula. By history, spoon nails (koilonychia) had developed in some of the family members who were hard of hearing. Most likely they too were involved. The authors, besides studying five affected and one normal family member, found a total of 20 affected persons in six generations. By history seven had only hearing loss, whereas all the remainder had both hearing loss and leukonychia. Possibly leukonychia was not noted on those not examined. It is most likely that the disease is familial, with a dominant mode of transmission.
Fig. 6, Leukonychia and knuckle pads on thumb of patient with knuckle pad, leukonyehia, and deafness syndrome. (From Bart, R. S., and Pumphrey, R. E.: Knuckle pads, leukonychia, and deafness: A dominantly inherited syndrome, N. Engl. J. IVied. 276: 202, 1967.) DOMINANT ONYCHODYSTROPHY, CONIFORM TEETH, AND .HEARING LOSS
A syndrome consisting of small fissured nails, coniform teeth and anodontia, and congenital moderate to severe neural hearing loss was described by Robinson and associates 2s in t962. Of five affected members in the family, four were studied by the authors. Patients had a 10 to 100 db hearing loss. Higher frequencies were more strikingly involved, particularly in one patient who had normal hearing at low frequencies and a 100 db neural hearing loss at frequencies above 4,000 Hz. One child had a 70 db neural hearing loss in all frequencies. Apparently the hearing loss was congenital, for no mention was made of progression in later years. In all patients, fingernails and toenails were small and had furrows and cracks (Fig. 7, A ) ~ a p p a r e n t l y present from birth. Although hair and skin were normal, all had peculiar, coniform teeth, m a n y of which were missing (Fig. 7, B).
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The Journal of Pediatrics June 1972
They also had normally formed but rudimentary nails, about one-quarter normal size (Fig. 8). Although the mother was edentulous, her teeth had been normal; her son's teeth were normal. Roentgenograms of the proband's hands and feet showed underdevelopment of the distal phalangeal tufts on the fingers, absence of a phalanx in both little fingers and three toes of one foot, and an extra phalanx in one thumb. No studies were done on the son. It is not clear if those bony changes are part of this syndrome. The proband's husband and his sister were both born deaf but were otherwise normal. There was no history of deafness in his family. It is most likely that they had hereditary recessive congenital deafness, different from the syndrome in the proband and her daughter. Since this syndrome was found only in a mother and one of two children, it is likely that this was the result of a new mutation of an autosomal dominant gene. RECESSIVE ONYCHODYSTROPHY AND CONGENITAL DEAFNESS
Fig. 7. A, Small fissured fingernails. B, Coniform teeth with some teeth missing in syndrome of dominant onyehodystrophy, coniform teeth, and hearing loss. (From Robinson, G. C., Mille~l", J. R., and Bensimon, J. R.: Familial ectodermal dysplasia with sensorineural deafness and other anomalies, Pediatrics 30: 797, 1962.)
Affected were three of four sibs, their mother, and maternal grandmother. Transmission of this disease is as an autosomal dominant trait. DOMINANT ONYCHODYSTROPHY AND CONGENITAL DEAFNESS
This syndrome of rudimentary fingernails and toenails, congenital severe neural hearing loss, and possibly phalangeal abnormalities was found in a mother and son studied by Goodman and colleaguesY ~ It is similar to the syndrome of recessive onychodystrophy and deafness, differing in the nail changes and in mode of transmission. The proband and her 33-year-old son had congenital severe sensorineural hearing loss.
A syndrome characterized by congenital deafness and congenital onyehodystrophy with short fissured finger and toenails, occurred in two of five sibs from a consanguineous marriage, a~ The girls were born deaf and attended a school for the deaf. Audiograms showed a 60 to 100 db sensorineuraI hearing loss, most marked in the higher frequencies. Caloric testing showed hypoaetivity of the labyrinth in the older girl, and normal vestibular reaction in the younger girl. The finger and toenails of the sibs showed similar congenital abnormalities; they were short, spoon shaped, and fissured (Fig. 9). Hair and teeth were normal and there were no other physical abnormalities except for strabismus. The parents were first cousins but had no family history of hearing loss nor of nail dystrophy. Examination of both parents showed n0 abnormalities. It is most likely that this syndrome is transmitted by autosomal recessive mode.
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Hereditary hearing loss
Fig. 8. Rudimentary but normally formed fingernails in dominant onychodystrophy and congenital deafness syndrome. (From Goodman, R. M., Lockareff, S., and Gwinup, G.: Hereditary congenital deafness with onychodystrophy, Arch. Otolaryngo/. 90: 96, 1969.) RECESSIVE
ONYCHODYSTROPHY,
DIGITAL ABNORMALITIES, AND DEAFNESS
A syndrome characterized in two sibs by congenital severe deafness, rudimentary finger and toenails, and digital abnormalities (hypoplastic third phalanges and extra phalanges in the thumbs and great toes) was described by Walbaum and colleagues al in 1970. The 13-year-old boy and his 3~-year-old sister had congenital severe neural deafness. Both sibs had similar hand and foot abnormalities. The thumbs were long, had an extra phalanx, and were in the same plane as the fingers. The little fingers were short and flexed with clinodactyly and camptodactyly. The third phalanx was hypoplastie in the fingers and toes. The distal phalanges of the great toes were very large. Nails were absent on the little fingers, rudimentary on the thumbs, and very short on the rest of the fingers; they were also rudimentary on the toes. Dermatographics were normal. Mental retardation was possibly present. The boy was functioning well in a school for the deaf, but his sister was estimated to have an I.Q. of 50. Both parents were normal and noncon-
9 17
Fig. 9. Short and fissured fingernails in syndrome of recessive onychodystrophy and deafness. (From Feinmesser, M., and Zelig, S.: Congenital deafness associated with onychodystrophy, Arch. Otolaryngol. 74: 507, 1961.) sanguineous. Transmission is apparently by recessive mode. This syndrome is different from recessive onyehodystrophy and congenital deafness because of the digital abnormalities, and it varies from dominant onychodystrophy and congenital deafness because of its recessive transmission. FAMILIAL PILl TORTI HEARING LOSS
AND
A syndrome of pili torti (flat, twisted hair) and neural hearing loss was described by Bjornstad, 3~ by Reed and associates, aa and by Robinson and Johnston. s4 Although 9 of the 10 reported patients had only a 20 to 60 db hearing loss, the patient described by Robinson and Johnston had severe bilateral neural hearing loss. The hair is untidy in appearance, dry, and brittle (Fig. 10). Scalp hair, eyebrows, and eyelashes are affected. Histologically the hairs are grooved, flattened, and twisted about their axes. Bjornstad 32 presented five patients with this disorder; two had affected sibs and one patient had an affected aunt. Of the four patients described by Reed and colleagues, ~a three were brothers of Mexican descent and the fourth boy had a deaf mother who was not examined. Audiograms and physical examinations of the three sibs of the five-yearold girl described by Robinson and Johnston 34 were normal, and there was no faro-
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The Journal of Pediatrics June 19'72
dreds with a central type of von Recklinghausen's disease have been described.ST. 3s These patients may have occasional caf6-aulait spots. They develop hearing toss due to bilateral acoustic neurinomas in the second or third decades of life and eventually die from this disease. Patients with Refsum's disease a9 develop a progressive neural hearing loss along with ichthyosis, progressive retinitis pigmentosa, hypertrophic peripheral neuropathy, mild ataxia, and increased plasma phytanic acid. The syndrome described by Tietz ~~ as dominant albinism and congenital deafness is not included because of the finding by Reed and colleagues aa that the patients were only blond and not albino. Thus the diagnosis probably was dominant congenital severe deafness. SUMMARY
Fig. 10. Untidy hair in syndrome of recessive pill torti and hearing loss. (From Robinson, C., and Johnston, M. M.: Pili torti and sensory neural hearing loss, J. PEDIATR. 70: 621, 1967.) ily history of hearing loss or hair defect. It seems likely that these three authors have reported cases of the same syndrome and that this disease is transmitted by recessive mode, although other patients with this syndrome must be studied with particular attention to family history to clarify the mode of transmission. COMMENTS
Several syndromes of integumentary abnormalities and hearing loss are not included in this survey because the hearing loss is not congenital but of later onset and progressive. In the syndrome of dominant piebald trait, ataxia, and neural hearing loss~~ there is congenital piebaldness, ataxia or coordination difficulties, mental retardation (80 per cent), and variable progressive neural hearing loss in about 60 per cent of patients. The syndrome of dominant anhidrosis and progressive hearing loss3~ is characterized by autosomal dominant transmission, congenital anhidrosis, and a progressive neural hearing loss beginning in adulthood. Several kin-
We have reviewed 14 syndromes of hereditary childhood hearing loss and integumentary system disease. All of these syndromes include deafness at birth. Most of the integumentary changes are evident at birth with skin pigmentary change ranging from albinism to Ientigines, nail changes ranging from leukonychia to onychodystrophy, or pili torti. In two syndromes, including atopic dermatitis and keratopaehydermia with digital constrictions, the skin changes occur in childhood. These hereditary syndromes should be kept in mind during routine physical examinations of infants and children in order to secure early treatment of hearing loss and to offer parental genetic counseling. REFERENCES
1. Konigsmark, B. W.: Hereditary deafness in man, N. Engl. J. Med. 281: 713, 774, 827, 1969. 2. Konigsmark, B. W.: Hereditary deafness syndromes with onset in adult llfe. In press. 3. Waardenburg, P. J.: A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness, Am. J. Hum. Genet. 3: 195, 1951. 4. Marcus, R. E.: Vestibular function and additional findings in Waardenburg's syndrome, Acta Otolaryngol. (Stockholm) 229: 5, 1968. ( Suppl. )
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5. Goldberg, M. F.: Waardenburg's syndrome with fundus and other anomalies, Arch. Ophthal. 76: 797, 1966. 6. Klein, D.: Albinisme partiel (leucisme) avec surdimutit~, bldpharophimosis et dysplasie myo-ost6o-artieulaire, Helv. Paediatr. Aeta 5: 38, 1950. 7. Fisch, L.: D~eafness as part of an hereditary syndrome, J. LaryngoI. 73: 355, 1959. 8. Partington, M. W.: Waardenburg's syndrome and heterochromia iridum in a deaf school population, Canad. Med. Assoc. J. 90: 1008, 1964. 9. DiGeorge, A. M., Olmsted, R. W., and Harley, R. D.: Waardenburg's syndrome, J. PEmATR. 57: 649, 1960. 10. Matthews, N, L.: Lentigo and electrocardiographic changes, N. Engl. J. Med. 278: 780, 1968. 11. Moynahan, E. J.: Multiple symmetrical moles, with psychic and somatic infantilism and genital hypoplasia: First male case of a new syndrome, Proc. R. Soe. Med. 55: 959, 1962. 12. Walther, R. J., Polansky, B. J., and Grots, I. A.: Electrocardiographic abnormalities in family with generalized lentigo, N. Engl. J. Med. 275: 1220, 1966. 13. Capute, A. J,, Rimoin, D. L., Konigsmark, B. W., Esterly, N. B., and Richardson, F.: Congenital deafness and multiple lentigines, Arch. DermatoI. 100" 207, 1969. 14. Gorlin, R. J., Anderson, R. C., and Blaw, M.: Multiple lentigines syndrome, Am. J. Dis. Child. 117: 652, 1969. 15. Lewis, S. M., Sonnenblick, B. P., Gilbert, L., and Biber, D.: Familial pulmonary stenosls and deaf-mutism: Clinical and genetic considerations, Am. Heart. J. 55: 458, 1958. 16. Koroxenidis, G. T., Webb, N. C., Moschos, C. B., and Lehan, P. H.: Congenital heart disease, deaf-mutism and associated somatic mMformations occurring in several members of one family, Am. J. Med. 40: 149, 1966. 17. Reed, W. B., Stone, V. M., Boder, E., and Ziprkowski, L.: Pigmentary disorders in association with congenital deafness, Arch Dermatol. 95: 176, 1967. 18. Ziprkowski, L., and Adam, A.: Recessive total albinism and congenital deaf-tourism, Arch. Dermatol. 89: 151, 1964. 19. Rozycki, D. L., Ruben, R. J., Rapin, I., and Spiro, A. J.: Autosomal recessive deafness associated with short stature, vitiligo, muscle wasting and achalasia, Arch. Otolaryngol. 93: 194, 1971. 20. Woolf, C. M., Dolowitz, D. A., and Aldous, H. E.: Congenital deafness associated with piebaldness, Arch. Otolaryngol. 82: 244, 1965. 21. Dolowitz, D. A.: Personal communication. 22. Ziprkowski, L., Krakowski, A., Adam, A., Costeff, H., and Sade, J.: Partial albinism and deaf mutism, Arch, Dermawl. 86: 530, 1962. 23. Margolis, E.: A new hereditary syndrome-sex-linked deaf-mutism associated with total
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albinism, Acta Genet. (Basel) 12: 12, 1962. 24. Konigsmark, B. W., Hollander, M. B., and Berlin, C. I.: Familial neural hearing loss and atopic dermatitis, J. A. M. A. 204: 953, 1968: 25. Nockemann, P. F.: Erbliche Hornhautverdickung mit Schnfirfurchen an Fingern und Zehen und Innenohrschwerh6rigkeit, Med. Weir 37: 1894, 1961. 26. Drummond, M.: A case of unusual skin disease, Ir. J. Med. Sci. 8: 85, 1939. 27. Bart, R. S., and Pumphrey, R. E.: Knuckle pads, leukonychia and deafness: A dominantly inherited syndrome, N, Engl. J. Med. 276: 202, 1967. 28. Robinson, G. C., Miller, J. R., and Bensimon, J. R.: Familial ectodermal dysplasia with sensorineural deafness and other anomalies, Pediatrics 30: 797, 1962. 29. Goodman, R. M., Lockareff, S., and Gwinup, G.: Hereditary congenital deafness with onychodystrophy, Arch. Otolaryngol. 90: 474, 1969. 30. Feinmesser, M., and Zelig, S.: Congenital deafness associated with onychodystrophy, Arch. OtolaryngoL 74: 507, 1961. 31. Walbaum, R., Fontalne, G., Lienhardt, J., and Piquet, J.: Surdit~ familiale avec ost~oonycho-dysplasie, J. Genet. Hum. 18: 101, 1970. 32. Bjornstad, R.: Pili torti and sensory neural loss of hearing, Proceedings XVIIth Meeting Northern Dermatological Society, May, 1965, Copenhagen. 33. Reed, W. B., Stone, V. M., Boder, E., and Ziprkowski, L.: Hereditary syndromes with auditory and dermatological manifestations, Arch. Dermatol. 95: 456, 1967. 34. Robinson, G. C., and Johnston, M. M.: Pill torti and sensory neural hearing loss, J. PEDIATR. 70: 621, 1967. 35. Teller, M. A., Sugar, M., Jaeger, E. A., and Mulcahy, J.: Dominant piebald trait (white forelock and leukoderma) with neurological impairment, Am. J. Hum. Genet. 23" 383, 1971. 36. Helweg-Larsen, H. F., and Ludvigsen, K.: Congenital familial anhidrosis and neurolabyrinthitis, Acta Derm. Venereol. (Stockh.) 26: 489, 1946. 37. Gardner, W. J., and Turner, O.: Bilateral acoustic neurofibromas: Further clinical and pathologic data on hereditary deafness and Recklinghausen's disease, Arch Neurol. Psychiatr. 44: 76, 1940. 38. Moyes, P. D.: Familial bilateral acoustic neuroma affecting 14 members from four generations. Case report, J. Neurosurg. 29" 78, 1968. 39. Refsum, S., Salomonsen, L., and Skatvedt, M.: Heredopathia atactica polyneuritiformis in children, J. PEDIATR. 35: 335, 1949. 40. Tietz, W.: A syndrome of deaf-mufism associated with albinism showing dominant autosomal inheritance, Am. J. Hum. Genet. 15" ?59, 1963.