American Journal of Medical Genetics 2:241-252 (1978)

Genetic Aspects of the BOR SyndromGBranchial Fistulas, Ear Pits, Hearing Loss, and Renal Anomalies F. Clarke Fraser, Daniel Ling, Donald Clogg, and Bernadette Nogrady Departments o f Paediatrics (F.C. F., D.C., B.N.), Biology (F.C.F.), and Diagnostic Radiology (8. N.), and School of Human Communication Disorders (0. L.), McGill University, Montreal; and Director o f Medical Genetics (F.C. F.), Director of the Medical Clinic (D.C.), and Department o f Radiology (B.N.), The Montreal Children’s Hospital A pedigree of branchio-oto-renal dysplasia (the BOR syndrome) is reported, including the documentation b y serial audiometric studies of the onset and rapid progression of hearing loss in the twin sister of an affected child. The literature on this syndrome is analyzed t o derive some figures for use in genetic counseling of such families. Branchio-oto-renal dysplasia is an autosomal dominant disorder in which affected individuals may have preauricular pits, lachrymal duct stenosis, hearing loss, branchial fistulas or cysts, structural defects of the outer, middle, and inner ear, and rcnal anomalies, which may range from mild hypoplasia to complete absence. Not all features of the syndrome are expressed in all carriers of the gene, b u t few carriers lack all the features, and the pits, branchial clefts, and hearing loss, are frequently cxpressed. Those offspring of affected persons who have pits o r fistulas are likely (about 80%) to have hearing loss of varying degrees of severity. A minority of heterozygotes (about 7%) may have hearing loss without pits o r fistulas. The risk of severe renal malformation is probably fairly low. Whether families that show dominant inheritance of pits, clefts, and deafness without renal anomalies represent variants of the BOR syndrome or a separate entity ( t h e BO syndrome), is still not clear. At present, any individual with preauricular pits and branchial clefts deserves both otologic and renal investigation. Key words: hereditary deafness, branchial cleft anomalies, renal dysplasia, preauricular pits

publication No. 472 from the McGill University-Montreal Children’s Hospital Research Institute. Reccivcd for publication Scptcmber 30, 1977; revision received April 18, 1978. Address reprint requests t o Dr F.C. Fraser, Dept of Medical Genetics, Tric Montreal Children’s Hospital, 2300 Tupper St, Montreal. Quebec H3H 1P3, Canada.

0148-7299/78/0203-0241$02.60 0 1978 Alan R. Liss, Inc

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INTRODUCTION

Branchio-oto-renal dysplasia, the BOR syndrome [21,22] ,is an autosomal dominant disorder in which affected individuals may have sensorineural, conductive, or mixed hearing loss, preauricular pits, structural defects of the outer, middle, and inner ear lachrymal-duct stenosis, branchial fistulas or cysts, and renal anomalies ranging from mild hypoplasia to complete absence. The present report describes such a family (Fig 1) in which hearing loss, documented serially in a pair of probably monozygotic twins, was characterized by a sudden fall in auditory acuity. Not all features are expressed in all carriers of the gene, which raises some difficult questions for the involved families; the literature has been analyzed in an attempt to obtain some tentative answers for use in genetic counseling.

PRESENTATION OF CASES Case 1 (111-11)

The proband had a patent ductus arteriosus ligated at 6 weeks of age, and was noted t o have a right preauricular pit (Fig 2) and a discharging left-sided branchial fistula on the anterior border of the sternomastoid, about halfway between the mastoid and clavicle. The sinus, as well as stenosis of the lachrymal ducts and a convergent strabismus, were treated later. He developed normally until age 10 years when hearing loss was noted, and audiometry showed a mild conductive hearing loss averaging 25 dB (ISO) in the left ear, and 15 dB (ISO) in the right ear. Further tests at age 1 1 1/3 showed that hearing had deteriorated by about 20 dB in each ear. At 11 5/6 years, bone conduction thresholds, previously within normal limits, were slightly depressed and impedence measures indicated abnormal reduced mobility of the ossicular chain. He has protruding ears and a rather long narrow face (Fig 3). Radiological findings for this and the other cases are presented in the following section.

I

2

3

4

5

7

6

@

8

9

I O ~ I l 12

13 14

male. conductive deafness female. ienior#-neural deafness pre-.urlcu~or pltr

15

w

0‘

0

16

17

18

19

bronchial cysts or sinuiei lochryrnol duct stenow exommed

Fig 1. Pedigree of the family.

20

21

22

23

24 25 26

27

Deafness, Branchial Clefts, Renal Dysplasia

243

Fig 2. A preauricular pit (Case 4).

Case 2 (111-13)

The first born of twins, a female, had bilateral preauricular pits and discharging cervical fistulas, similar in location to those of her brother. Both ears were somewhat protuberant (Fig 4). There was stenosis of the tear ducts. At 3 months an acute otitis media was treated successfully with antibiotics. At 1 1 months her mother noticed that she was falling behind her twin sister verbally, and a low-frequency conductive hearing loss was demonstrated audiologically, but again she had bilateral otitis media, which was thought to account for at least part of the hearing impairment. Those concerned were aware that the mother had a hearing problem, but not of its significance in relation to the branchial fistulas and preauricular pits. The otitis media did not respond well to antibiotics and anti-histamine, and at 13 months she had bilateral myringotomies. While an inpatient she developed mumps, complicated by meningoencephalitis. Following this her hearing rapidly decreased and at discharge from hospital she had a severe bilateral mixed hearing loss of over 100 dB. Hearing aids were prescribed and aural rehabilitation treatment was begun. Developmental skills, measured by the Griffiths Scale, were normal except for communication skills; these were so low (2 months at 14 months of age) as to suggest that a hearing deficit had been present from the first few months of her life, perhaps precipitated by the first attack of otitis media in a genetically predisposed individual. At 3%years no low-frequency response could be obtained, but reliable responses were obtained at 100 dB for 1,000 Hz, and 90 dB for 2,000 Hz in the right ear only. Hearing levels at 5% years averaged 105 dB in both ears. Impedance tests indicated multiple middle-ear abnormalities.

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Fig 3. Case 1 at age 15 years.

Case 3 (111-14)

The second-born twin, sister of Case 2, also had preauricular pits, draining lateral cervical sinuses, and stenosis of the tear ducts. The pinna of the right ear was thin and flat, lacking a helix superiorly. The left ear was slightly protuberant (Fig 5). Audiological tests were normal at 13 months of age, and development (Griffiths Scale) was that of a bright child with normal hearing. The first evidence of hearing loss was found at 3% years when threshold levels in the right ear averaged 15 dB and were normal in the left ear. Within one month further deterioration had occurred; air conduction loss fluctuated on repeated tests from averages of 25 to 35 dB in each ear. When the child was 4 516 years old, the mother noted marked hearing problems, and audiometry showed mixed hearing loss averaging 50 dB in the right ear and 35 dB in the left. Hearing remained stable at these levels over the next six months. At 5 5/12 years of age there was further rapid deterioration of hearing in the right ear. Within one week hearing loss in this ear increased from an average of 50 dB to an average of 80 dB. Otological examination and impedance measurements indicated the presence of fluid in both ears, and treatment with antibiotics and antihistamines was begun. The mother said that the child then seemed t o hear better on some days than others, but by audiometry the hearing loss appeared relatively stable over the next six months. Results of tests at 5 11/12 years of age confirmed average hearing levels of 40 dB in the left ear and 80 dB in the right. At this age her expressive skills were within normal limits, but speech reception skills were slightly impaired. Although the twins were quite similar in appearance, the presence of minor differences in iris pigmentation and facial appearance suggested that they might not be monozygotic. However, on the basis of the blood groups of the twins and their parents (A, Rh, MNS, P, Le,k, Lu, Fy, Ki), and dermatoglyphic analysis, the probability of monozygosity was calculated as 0.97.

Deafness, Branchial Clefts, Renal Dysplasia

Fig 4. Case 2 at age 9 years.

245

Fig 5. Case 3 at age 9 years.

Case 4 (11-9)

The mother of the proband and twins (Fig 6) became aware of her hearing problems at 14 years of age. She has mixed hearing loss, preauricular pits, and pinhole-sized sinuses in her neck, o f which she only became aware when that of the proband started to discharge. Her lachrymal ducts were operated on when she was a child. Her average hearing levels at 35 years of age were 70 dB in the left ear and 35 dB in the right. Differences between air- and bone-conduction thresholds in her left ear were approximately 30 dB and in her right ear, 15 dB. Four unsuccessful attempts were made to improve hearing in the left ear through surgery (stapedectomy), in the course of which otosclerosis involving the footplate of the stapes was found, but no abnormalities affecting other middle-ear structures were observed. The left ear was protuberant (Fig 6).

Case 5 (11-8)

The proband’s maternal aunt first noticed her hearing loss at age 21. She has a bilateral mixed hearing loss averaging about 25 dB, which tends to fluctuate slightly. She has a cervical sinus opening close to the right sternomastoid near the clavicle.

Case 6 (1-2)

The proband’s maternal grandfather first had hearing problems at about 40 years of age. Audiological tests at 65 years of age revealed hearing loss primarily of conductive origin averaging 40 dB in both ears. Responses at 4,000 Hz for bone conduction suggested onset of presbycusis. He has no pits or cervical sinuses.

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Fig 6 . Case 4.

Case 7 (1-3)

The maternal grandfather’s sister has been deaf as long as she can remember. Her hearing loss, averaging 30 dB in the left ear, and 60 dB in the right, is entirely sensorineural. She has no pits or cervical sinuses. The maternal grandmother (I-9), who died at the age of 64, had no overt hearing loss, pits, or clefts. One of her sisters (1-6) had sensorineural hearing loss from an early age but no pits or clefts. RADIOLOGICAL FINDINGS Ears

Radiographic examination of the mastoids, including tomograms, were done in the proband, his twin sisters, and mother. The proband and one twin had repeated radiological examinations from early infancy. All four patients had asymmetrical development of the petrous processes; the mastoid process on the right was smaller and had fewer aerated air cells than that on the left. In Gzse 2 there was bilateral hypoplasia and displacement of the ossicles, with only fragments of the ossicles demonstrated on the left. The semicircular canals were asymmetrical and the canals and cochlea were hypoplastic on both sides. In the other three patients the abnormalitites were similar, though not so marked. In Case 4 radiographic examination of the petrous bone including tomograms was done after multiple surgical interventions on the left side, but abnormalities are shown on the nonoperated side as well. Two of these patients (Cases 1 and 2) had documented middle-ear infections in infancy but neither had developed cholesteatomas or bony destruction. In the two patients (Cases 1 and 3), where the mastoids were examined in the first few months of life, the radiological abnormalities have become more obvious with time.

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Urinary Tract

Intravenous pyelograms were done at ages 3 and 4 months, and at 15 years in Case I ; at ages 1 and 10 years in Cmes 2 and 3,and at age 38 years in Case 4.

All patients had normal excretion and concentration of the contrast medium at the time of each examination. Case I was followed by repeated intravenous pyelogram (IVP) since he had a narrow pelviureteric junction bilaterally with a full and partially distorted pelvicalyceal system. However, no evidence of pelvirureteric junction obstruction appeared. Unexplained calyceal distortion was demonstrated in three family members (Cases 1, 3 , 4 ) , with one kidney being somewhat small. These variations were minor and would have been interpreted as normal variations on routine inspection. The renal function by intravenous urography remained excellent in those examined on several occasions and no progressive renal abnormality or renal failure was documented. The most obvious renal anomaly was seen in the mother (Case 4), consisting of a smaller than normal, wellfunctioning right kidney, with an obviously distorted, and rounded, minor calyceal pattern, without radiologically recognizable focal scarring of the renal parenchyma. She had no history of urinary tract infection. Thus there appears to be some type of renal anomaly in three of the four members investigated. This probably represents dysplasia, though it has not been histologically documented, and urographic diagnosis of renal dysplasia in an older child or an adult with normal renal function is considered inconclu sive.

DISCUSSION

The pedigree (Fig 1) is compatible with autosomal dominant inheritance of mixed hearing loss, frequently associated with preauricular pits, branchial cleft sinuses, stenosis of the tear ducts, and renal anomalies. All these features were expressed in the proband, his twin sisters, his mother, and (except for the tear-duct anomaly) his mother’s sister. The maternal grandfather probably carried the gene, since he had conductive, and his sister sensorineural, hearing loss, though neither had pits or sinuses. Alternatively, one might assume that the gene was transmitted by the maternal grandmother without being manifested, but did cause her sister’s “life-long” sensorineural deafness, without clefts or pits. This seems less likely. Preauricular pits are typically shallow, pin-head sized blind depressions in the helix of the ear near its upper attachment; they may be situated in the skin anterior to this [ 11 ; cartilaginous preauricular appendages may occur as well, or instead, in some individuals. They are well described by Konigsmark and Gorlin [ 171 . They occur in about 1% of the general population [8, 14,331 . In a number of families they show autosomal dominant inheritance [6, 16, 1 9 , 2 8 , 3 4 ] . The penetrance in the familial cases has been estimated as 85% [ 141 . It is difficult to ascertain the proportion that have a positive family history; this has been reported as 1 out o f 3 1 in British naval recruits by Ewing [ 8 ] , but since only one-third of the affected individuals were aware that they themselves had it, this is likely to be an underestimate. In Italian school children, 74% of 93 cases were familial 1141. Branchial cleft fistulas, or “collar sinuses”, open externally in the lower third of the neck, usually on the median border of the stemomastoid muscle [ 17,26,30,313 . The opening is usually quite inconspicuous, but the sinus may ooze fluid or become infected. There may be an internal opening in the tonsillar fossa. The developmental defect may

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also lead to a cyst, with no opening, or a cartilaginous mass. They are much less frequent than preauricular pits, and affected persons often have preauricular pits as well. In a minority of cases of branchial clefts the condition is familial, 1 of 16 families, according to Sedgwick and Walsh [31], with an autosomal dominant mode of inheritance and somewhat reduced penetrance. Several families have been reported in which the combination of preauricular pits and branchial fistulas is dominantly inherited without mention of hearing loss [3, 1 8 , 2 3 , 2 4 , 3 1 ] ,though this was not ruled out audiometrically. In other families there appears to be autosomal dominant inheritance of a syndrome that involves various combinations of preauricular pits, cervical cysts, or fistulas, and hearing loss; less frequently’preauricular appendages, abnormally shaped external ears, malformed ossicles, and lachrymal duct stenosis are reported. In some of these families renal anomalies are described. Melnick, Bider, Silk et a1 [21, 221 have suggested a distinction between those families in which the pits, fistulas, and hearing loss occur without renal anomalies, branchio-oto-dysplasia (the BO syndrome), and those with renal anomalies, branchio-oto-renal dysplasia (the BOR syndrome). Since the distinction is not entirely clear, the following paragraphs will consider them together. The only available estimate of the frequency of the syndrome(s) is provided by Fraser [ 131 , who, in a survey of 3,460 children with profound hearing loss, found 11 proposiii with a syndrome of profound hearing loss, branchial fistulas, and preauricular pits, of whom five had affected relatives. Renal anomalies were not searched for. Hearing loss in families showing dominant inheritance of the syndrome may be sensorineural, conductive, o r (most frequently) mixed. It may be sensorineural in one ear and conductive in the other ear of the same individual [15] . It seems unjustified, therefore, to classify families into those with sensorineural and those with mixed hearing loss, as suggested by Konigsmark and Gorlin [ 171 . Age of onset varies from early childhood to young adult. It is usually not described as progressive, but one report [4] tells of two cases in which there was sudden loss of hearing after intense exertion or trauma. Several other reports of the syndrome describe malformations of the middle ear, vestibular system and cochlea [20-22,25, 29,321, and the pathological anatomy has been described in detail in an infant with the syndrome who had renal agenesis [ l o ] . The ossicles may be displaced and malformed [4, 151 ; the stapes and incus may be fused [32] , unconnected [20,29] ,or normal [ 101 . Families showing dominant inheritance of hearing loss associated with malformed unconnected stapes and incus, and no pits or branchial clefts, have also been reported [ 7 , 3 6 ] , with deformity of the pinna in one of them [36]. These probably do not represent the present syndrome. Defects of the external ear also seem to occur frequently in families with the syndrome [4, 11, 15,20-22,25,29,32,35] .These may range from severe microtia, to minor anomalies of the pinna, variously described as cup, flap, lop, flattened, or hypoplastic. The external canal may be narrow, “malformed”, or slanted upwards, making otoscopic examination difficult. In those families in which the combination of preauricular pits and branchial fistulas occur without hearing loss, no abnormalities of the external ear are described [3, 1 8 , 2 3 , 2 4 , 3 2 ] ;in almost all those families in which hearing loss occurs in some members, external ear anomalies occur in some affected individuals [ 2 , 4 , 5,9, 1 1 , 15,20-22,25,29,32,35] . In the one exception [12] such auricular anomalies were not mentioned, but their absence cannot be assumed. In the five families with preauricular pits and branchial cleft fistulas without hearing loss, 83% of 28 affected individuals had both pits and fistulas, and 17%had pits only. None had fistulas only. There were no examples of transmission by unaffected carriers,

Deafness, Branchial Clefts, Renal Dysplasia

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but not many opportunities to observe it. In the 14 families with hearing loss, the corresponding figures are 57%, 32%, and 11%. If this trend is confirmed by further and more reliable data, it would seem that pits occur without fistulas more often in the latter than the former group. These findings suggest that hereditary preauricular pits and branchial fistulas may be an entity separate from hereditary preauricular pits, branchial fistulas, and hearing loss, and that external ear anomalies are characteristic of the latter, but not of the former, which therefore have been excluded from the following analysis. In the 14 families with pits, fistulas, and hearing loss, segregation of the trait was compatible with autosomal dominant inheritance, in spite of the deficiencies in reporting of the family histories in several reports. Excluding one proband per family, there were 130 offspring of affected individuals of which 67 or 5 1%were affected. There were 91 affected individuals [ 2 , 4 , 5 , 9 , 11, 12, 15,20,22,25,29,32,35], including the cases presented here, with reasonably adequate descriptions of their phenotypes with respect to pits, fistulas, and hearing loss (Table I). Of these, 43 had pits, fistulas, and hearing loss, 16 had pits and hearing loss, 7 had fistulas and hearing loss, 5 had pits and fistulas, 11 had pits alone (but about half of these were quite young), 2 had fistulas alone, and 5 had hearing loss alone. Of 71 carriers of the gene who were hard of hearing, 93%had pits, fistulas, or both (22%, lo%, and 61%, respectively). There was no obvious tendency for the external ear anomalies to occur preferentially with any one of the other features. These figures are not to be regarded as an accurate representation of the frequencies of various combinations of features, as there are probably ascertainment biases, and under-reporting, particularly of hearing loss in the younger age groups. There were two examples [ 12, 291 of transmission by an apparently unaffected carrier of the gene, and in one family [ 3 5 ] ,“flapped” ears seems to be the only manifestation of the gene in two members. In both these groups of families those carriers of the gene who had branchial fistulas almost always had preauricular pits and/or deafness as well (79 out of 81). However, in one family [26], dominant inheritance of deafness and branchial fistulas or cysts is described, with no mention of pits. One wonders because pits are often so insignificant, whether they might have been overlooked, or whether this represents another genotype.

TABLE I. Frequencies o f Traits and Their Associations in 9 1 Affected Members o f 14 Families Segregating for Preauricular Pits (F’), Branchial Fistulas (F), and Hearing Loss (D) Associations of traits

N

%

P F D P F P D F D P F D

43 5 16

41

5

Total

2

18 8 12 2 5 2

91

99

7 11 2

5

N

%

P

75

F D anomalous pinna lachrymal duct block renal anomaly

51 71

82.4 62.6 78.0

31

40.7

8 11

... ...

Individual traits

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We have recently seen a family in which a girl with mixed hearing loss (with a very small conduction component) has a left preauricular pit and a hypoplastic left ossicular mass, and her sister has pits, hypoplastic displaced ossicles, but no hearing loss by audiogram. Neither has branchial clefts or renal anomalies. Possibly the hearing loss is coincidental in this case, or perhaps this represents still another variant. Only recently has it become apparent that individuals with the syndrome o f hearing loss with pits and fistulas may also have renal anomalies. A family in which four affected members had renal dysplasia was described by Melnick et al [21,22] . A fifth child, who died in infancy, was said to have had branchial cleft fistulas and bilateral polycystic kidney disease. In that family there were no signs of renal dysfunction in the living members, but an IVP revealed anomalies ranging from sharply tapered superior poles with blunting of the calyces t o marked hypoplasia. Three members of the present family show mild features of the same type. Possibly the family reported by Martins [ 181 falls into this group as well; one member had a hypoplastic kidney w h c h was discovered because he had a facies “vaguely reminiscent of the facies in renal agenesis” (external ear anomalies). Deafness was not mentioned. Bailleul [2] reported a family in which one affected member, a young girl, had a renal anomaly requiring hospitalization, but did not give further details, and Brusis [S] described repeated renal colic and inflammation in an affected man. The renal defect, however, can be much more severe. In a family reported by Fara [9], one affected member had unilateral renal agenesis. The classification of this family as having a separate syndrome, the otofaciocervical syndrome [17] seems premature, In another family [l 11 , a woman with the syndrome had a child with pits, fistulas, and renal hypoplasia and another with renal agenesis. The mother had a normal intravenous pyelogram. Stenosis of the lachrymal ducts has been mentioned often enough (8 out of 91 cases) to suggest that this is also a feature of the syndrome [ l o , 13, 21, 22, the present family] but, since it cannot be assumed to be absent when not mentioned, its frequency is difficult to assess. Furthermore, there may be associated facial features including a long narrow face, “constricted” palate, and deep overbite [21, 221. Several other reports describe or portray patients with similar facies [ 1 5 , 2 0 , 2 9 ] , but the kidneys were not investigated. If these families d o represent the same syndrome, one could add paralysis of certain facial muscles as an additional inconstant feature. Our proband and his mother show some facial features like those described in Melnick‘s family, but the twins d o not. The question arises of whether the renal anomalies are simply an inconstant feature of the syndrome of deafness with preauricular pits and branchial fistulas,pr whether deafness, pits, and fistulas can be caused by two different mutant genes, either allelic or at separate loci, with one causing renal anomalies as well. Since the IVPs in our case were routinely read as normal, one cannot assume that the renal features were not there in other cases unless they have been specifically looked for. On the other hand, the NP of the mother in Fitch‘s family [ 113 was normal, after being reviewed in this context (Fitch, 1977, personal communication), as was that of the present Case 2,so a radiologically demonstrable renal anomaly is not a constant feature. Further data are required to clarify this point; a t present any individual with preauricular pits and branchial clefts deserves both otologic and renal investigation. Our present knowledge may be summarized in terms of the information available for counseling of family members with one or more of the cardinal features of preauricular pits, branchial fistulas, or cysts, and deafness: a) A person who has preauricular pits

Deafness, Branchial Clefts, Ren al Dysplasia

25 1

only, and no affected relatives is likely to have a non-genetic defect or occasionally may represent a fresh mutation of the normal allele of the gene for preauricular pits. There is a very small chance that (s)he carries a gene for the preauricular pits-branchial cleftshearing loss triad; b) A person with the pits-clefts-hearing loss triad is very likely to be a carrier of the mutant gene for this syndrome, and definitely if (s)he has affected near relatives. Each of the children would therefore have a 50:50 chance of inheriting the gene; c) In families in which t h e pits-clefts-hearing loss triad is segregating, those offspring of affected persons who have pits, fistulas, or both have a high chance o f hearing loss (66 out of 84 in the present analysis, or 79%) (see Table I), with an onset anywhere from infancy to about 20 years of age. There is an appreciable chance of having a renal anomaly, and a chance (not yet well estimated) that this will be severe enough to be medically significant, or even lethal (bilateral renal agenesis). Renal investigation is therefore indicated; d) For those offspring of a carrier who do not have pits o r fistulas at birth there is a chance (about 8%in the present series) that they are carriers and that deafness will be expressed. If they have anomalies of the external ears, lachrymal ducts, or kidneys, the chance will be much higher. Offspring with n o manifestations by age 20 are probably not carriers of the gene. As further information accumulates it will be possible t o assess more accurately the significance of the associated anomalies, and refine the above estimates.

ACKNOWLEDGMENTS

This research was supported by a Medical Research Council Group grant in Medical Genetics. The generous and extensive cooperation of the family members is gratefully acknowledged. REFERENCES 1. Aird I: Ear-pit (congenital aural and pre-auricular fistula). Edinburgh Med J 53:498-507, 1946. 2. Bailleul J, Libersa C, Laude M; Surdit6 et fistules auriculaires congknitales familiales. Pkdiatrie 27:739-747, 1972. 3. Binns PM, Lord OC: Five cases of bilateral branchial fistulae in three generations of a family. J Laryngol Otol79:455-456, 1965. 4. Bourguet J, Mazeas R, LeHu6rou Y: De l'atteinte des deux premisres fentes et des deux premiers arcs branchiaux. Rkv Otoneuro-ophtal38:162-175, 1966. 5. Brusis T : Gleichzeitiges Vorkommen von degenerativer InnenohrschwerhCkigkeit, Vestibularistarung, beiderseitigen Ohr-und lateralen Halsfisteln bei mehreren Mitgliedern einer Familie. Laryng Rhinol 53:131-139, 1974. 6. Connon FE: Inheritance of ear pits in six generations of a family. J Hered 32:413-414, 1941. 7 . Escher F, Hirt H: Dominant hereditary conductive deafness through lack of incus-stapes junction. Acta Oto Laryngol65 :25-32, 1968. 8. Ewing MR: Congenital sinuses of the external ear. J Laryngol61:18-32, 1946. 9. Fara M, Chlupackova V, Hrivnakova J: Dismorphia oto-faciocervicalis familiaris. Acta Chir Plast 9:255-268,1967. 10. Fitch N, Lindsay JR, Srolovitz H: The temporal bone in the preauricular pit, cervical fistula, hearing loss syndrome. Ann Otol Rhinol Laryngol85 :268-275,1976. 11. Fitch N,Srolovitz H: Severe renal dysgenesis produced by a dominant gene. Am J Dis Child 130: 1356-1357,1976. 12. Fourman F, Fourman J: Hereditary deafness in family with ear pits (fistula auris congenita). Br Med J 2:1354-1356, 1955.

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13. Fraser GR: “The causes of profound deafness in childhood.” Baltimore: The Johns Hopkins Press, 1976. 14. Gualandri V: Ricerche genetiche sulla fistula auris congenita. Acta Genet Med Gemellol 18:5 168,1969. 15. Karmody CS: Autosomal dominant first and second branchial arch syndrome. A new inherited syndrome? In Bergsma D (ed): “Malformation Syndromes.” Miami: Symposia Specialists for The National Foundation-March of Dimes, BD:OAS X(7):3 1-40, 1974. 16. Kindred JE: Inheritance of a pit in the skin of the left ear. J Hered 12:366-367, 1921. 17. Konigsmark BW, Gorlin RJ: “Genetic and metabolic deafness.” Philadelphia: WB Saunders, 1976. 18. Martins AG: Lateral cervical and preauricular sinuses: their transmission as dominant characters. Br Med J 1:255-256, 1961. 19. McDonough ES: On the inheritance of ear pit. J Hered 32:169-171,1941. 20. McLaurin JW,Kloepfer HW, Laguaite JK, Stallcup TA: Hereditary branchial anomalies and associated hearing impairment. Laryngoscope 76: 1277-1288, 1966. 21. Melnick M, Bixler D, Silk KS, Yune H, Nance W: Autosomal dominance of branchiorenal dysplasia. In “New chromosomal and Malformation Syndromes (1974 Birth Defects Conference).” Miami: Symposia Specialists for The National Foundation-March of Dimes, BD:OAS XI(5): 121-128,1975. 22. Melnick M, Bixler D, Nance WE, Silk K, Yune H: Familial branchio*to-renal dysplasia: A new addition to the branchial arch syndromes. Clin Genet 9:25-34, 1976. 23. Miller JB: Branchial cleft cysts, fistulae and appendages. Laryngoscope 67:1123-1193, 1957. 24. Muckle TJ: Hereditary branchialdefects in a Hampshire family. Br Med J 1:1297-1299, 1961. 25. Nance W, Sweeney A: Genetic factors in deafness in early life. Otolaryngol Clin N Am 8:19-48, 1975. 26. Precechtel A: Pedigree of anomalies in the first and second branchial cleft. Acta Otolaryngol 11: 23-30, 1927. 27. Procter B: Lateral vestigial cysts and fistulas of the neck. Laryngoscope 65:355-401, 1955. 28. Quelprud T: Ear pit and its inheritance. J Hered 21:379-384, 1940. 29. Rowley PT: Familial hearing loss associated with branchial fistulas. Pediatrics 44 :978-985, 1969. 30. Schull WJ, Furuta M: Persistent gill slits. . . a dominant trait? Jpn J Genet 2:33-34, 1957. 31. Sedgwick CE, Walsh JF: Branchial cysts and fistulas - a study of seventy-five cases relative to clinical aspects and treatment. Am J Surg 83:3-8, 1952. 32. Shenoi PM: Wildervanck‘s syndrome. Hereditary malformations of the ear in three generations. J Laryngol Otol86:1121-1135, 1972. 33. Stewart AL, Keay AJ, Smith PG: Congenital malformations; a detailed study of 2,500 liveborn infants. Ann Hum Genet 32:353-360, 1969. 34. Whitney DD: Three generations of ear pits. J Hered 30:323-324, 1939. 35. Wildewanck LS: Hereditary malformations of the ear in three generations. Acta Oto-Laryng 54 : 553-560,1962. 36. Wilmot TJ: Hereditary conductive deafness due to incus-stapes abnormalities and associated with pinna deformity. J Laryngol84:469-479, 1970.

Edited by Robert J. Gorlin

Genetic aspects of the BOR syndrome--branchial fistulas, ear pits, hearing loss, and renal anomalies.

American Journal of Medical Genetics 2:241-252 (1978) Genetic Aspects of the BOR SyndromGBranchial Fistulas, Ear Pits, Hearing Loss, and Renal Anomal...
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