Branchio-Oto-Renal Syndrome
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J Am Acad Audiol 6 : 103-110 (1995)
Branchio-Oto-Renal Syndrome
Kevin B . Coppage*
Richard J. H. Smitht
Abstract
Branch io-oto-renal syndrome is an autosomal-dominant disorder with branchial, otologic,
and renal manifestations . The branchial manifestations are usually inconsequential ; how-
ever, the hearing impairment and renal malformations can be significant. Appropriate evaluation
of affected persons is necessary to minimize disease morbidity.
Key Words: Branchial, otologic, renal, BOR
ranchio-oto-renal (BOR) syndrome is an and hearing impairment was reported by
autosomal-dominant form of inherited Heusinger in 1864 and by Paget in 1877 and
B hearing impairment characterized by: (1) 1878 . Under the Nazi regime, the disease pro-
a conductive sensorineural or mixed hearing voked a great deal of discussion by several Ger-
loss ; (2) preauricular pits ; (3) auricular malfor- man authors, notably Albrecht (1933), Schnei-
mations of the outer ear and structural defects der (1937), Loebell (1938), Steinberg (1938), and
of the middle and inner ear; (4) branchial fistu- Langenbeck (1938), because of the eugenic prob-
lae or cysts; and (5) renal anomalies, ranging lems it raised . BOR syndrome was referred to
from mild hypoplasia to a lethal condition of as Innenohrschwerhorigkeit, or "hereditary hard-
bilateral renal agenesis . Less common anomalies ness of hearing" (Fourman and Fourman, 1955).
that occur include lacrimal duct stenosis, preau- More frequent recognition of BOR syndrome
ricular tags, facial nerve paralysis, palate defects, followed the 1955 publication by Fourman and
a narrow face with a high-arched palate, and a Fourman of a large family with preauricular
deep overbite . In spite of this broad constellation pits, bilateral branchial fistulae, and progressive
of findings, variable expressivity of the BOR sensorineural hearing loss . Twenty years later,
gene can, at times, make the diagnosis very dif- Melnick et al (1975) recognized the possibility
ficult . Gene penetrance is high, however, and of associated renal anomalies and suggested
most known carriers display some aspects of the term branchio-oto-renal syndrome, under-
the disease phenotype if carefully examined scoring the phenotypic anomalies of the
(Fraser et al, 1978 ; Cremers and Fikkers-Van branchial arches, otocysts, and renal primor-
Noord, 1980). dia. The nomenclature for BOR syndrome, how-
ever, has varied . Terms applied to the disease
Historical Perspective reflect observation and author bias and include
ear pits-deafness syndrome ; preauricular pits,
Early reports of BOR syndrome can be cervical fistulae, hearing loss syndrome ; bran-
traced to the nineteenth century. Aucherson chio-oto-dysplasia syndrome ; branchio-oto-
(1832) was the first to recognize the familial ureteral syndrome ; branchio-oto-renal dysplasia;
occurrence of branchial anomalies . The combi- and Melnick-Fraser syndrome (Cremers and
nation of preauricular pits, branchial fistulae, Fikkers-Van Noord, 1980 ; Fraser et al, 1983).
Prevalence
`Department of Pediatrics, University of Iowa ; and
tDepartment of Otolaryngology-Head and Neck Surgery, Congenital deafness affects 1 of every 1000
University of Iowa Hospitals and Clinics, Iowa City, Iowa children, and an estimated 50 percent of these
Reprint requests : Richard J . H . Smith, Department
affected children have inherited hearing impair-
of Otolaryngology - Head and Neck Surgery, University
of Iowa, Hospitals and Clinics, 200 Hawkins Dr., E230 GH, ment (Fraser, 1976). The precise prevalence of
Iowa City, IA 52242-1078 BOR syndrome is unknown; however, two esti-Journal of the American Academy of Audiology/ Volume 6, Number 1, January 1995
mates have been made by Fraser. In 1976, he Table 1 Characteristic Findings
surveyed 3460 children with profound hearing in Branchio-Oto-Renal Syndrome
loss and found only 5 (0 .15%) with a family his-
tory of branchial fistulae and preauricular pits Feature Percentage
(1 :700,000) (Fraser, 1976 ; Fraser et al, 1978).
Hearing Loss 86 (191/223)
Four years later, however, he presented evi-
Branchial Fistulae/Cysts 69 (142/206)
dence to suggest that the prevalence of BOR is Preauricular Pits 68 (168/246)
much greater (Fraser et al, 1980). In a study of Malformed Ears 48(30/62)
421 white children in the Montreal schools for Renal Anomalies (by IVP)
the deaf, he diagnosed BOR syndrome in 2 per- Mild 40(51/127)
Severe 20(25/127)
cent of the profoundly deaf students . Fraser,
Lethal 10(13/127)
therefore, roughly estimated disease prevalence
Data pooled from Cremers and Fikkers-Van Noord (1980), Fraser
at 1 :40,000. The true value is probably some- et al (1980), Cote and O'Regan (1982), Carmi et al (1983), Fraser
where between these extremes . et al (1983), Smith et al (1984), Preisch et al (1985), Gimsing and
Dyrmose (1986), Heimler and Leiber (1986), Greenberg et al (1988),
Legius et al (1990), Ostri et al (1991), Chitayat et al (1992) .
Characteristic Findings
Hearing impairment is the most common ing loss in the other ear have been reported
feature of BOR syndrome and affects approxi- (Karmody, 1974).
mately 80 percent of carriers (Fraser et al, 1978 ; The otologic aspects of the external ear are
Cremers and Fikkers-Van Noord, 1980) (Table often the most striking feature of BOR syn-
1) . The impairment may be congenital or late- drome . Most commonly, the antihelix of the
in-onset and is either nonprogressive or pro- pinna is malformed, and the result is a lop-ear
gressive in nature . It is sensorineural (20%), deformity (Fig. 2) . This type of abnormality is
conductive (30%), or mixed (50%) and ranges in reported in about 40 percent of affected indi-
severity from mild to profound (Fraser et al, viduals (Fraser et a1,1978; Cremers and Fikkers-
1980) (Fig. 1) . Interestingly, all three types of Van Noord,1980), although in our experience this
hearing loss can be observed in individuals number is underestimated . Severe microtia also
within the same pedigree, and the type of hear- occurs .
ing loss may even differ in each ear within an Anterior to the pinna, preauricular carti-
individual . For example, carriers with a sen- laginous appendages may be found. A more sub-
sorineural loss in one ear and a conductive hear- tle finding is the presence of preauricular pits .
Right Ear I Pure Tone Audiometry Left Ear
.26K AK lK 2H 4K SK .29{ .s¢ ILK 2H 4K 6K
dB
0
20
40
60
s0
100
Unmasked Masked
No
.
Reap
BC 0
Acoustic
Reflex
uncrossed
crossed
0
Figure 1 Audiogram of a patient with BOR syndrome. There is a sensorineural
loss in the right ear and a mixed loss in the left ear.
104Branchio-Oto-Renal Syndrome/Coppage and Smith
Figure 2 Two unrelated persons with BOR syndrome . Facial features appear similar, primarily due to the lop-ear
deformity created by absence of the antihelical folds of the pinnae .
This hallmark feature is typically noted as a Abranchial fistula or cyst occurs in approx-
shallow, pinhead-sized depression near the supe- imately 63 percent of carriers (Fig . 4) . This hall-
rior attachment of the helix. Approximately 1 per- mark feature may be either unilateral or bilat-
cent of the general population of newborns has
preauricular pits (Fraser et al, 1980 ; Melnick,
1980), and it is estimated that 1 child in 500 with
pits has BOR syndrome (Fraser et al, 1980).
There may be substantial malformations of
the middle ear (Fitch and Srolovitz, 1976). Abnor-
malities have been observed by computerized
tomography and surgical exploration. The ossi-
cles can be malformed, displaced, fixed, fused,
enlarged, hypoplastic, or even absent (Ostri et
al, 1991). Specific findings include interruption
of the ossicular chain, footplate fixation, short-
ening of the lenticular process of the incus, and
aberrant fixation of the incus and stapes . These
types of ossicular abnormalities result in a con-
ductive hearing loss .
Inner ear abnormalities also occur. The hor-
izontal semicircular canals can be asymmetri-
cal, dysplastic, or absent. The cochlea can be
hypoplastic or dysplastic, and the internal audi- Figure 3 Computed tomogram of left ear. The internal
auditory canal is dilated and the vestibular aqueduct
tory canal can be widened (Fig. 3) . These abnor-
and vestibule are enlarged . A dilated internal auditory
malities may result in vestibular hypoactivity canal can lead to a stapes gusher if stapedectomy is
and a sensorineural hearing loss (Fraser et al, done ; an enlarged endolymphatic duct is associated with
1978 ; Gimsing and Dyrmose, 1986). sensorineural hearing impairment.Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995
ity and proteinuria, or reduced creatine clearance
and diminished glomerular filtration rate . His-
tologically, prominent glomerular lesions have
been noted, causing segmental and focal hyal-
ization with dense immunoglobin deposits of
IgG, IgM, IgA, and C3 along the basement mem-
brane and into the mesangium (Dumas, 1982).
Several other abnormalities are less fre-
quent aspects of BOR syndrome . Nasolacrimal
duct stenosis is noted in up to 9 percent of car-
riers; however, because the stenosis may resolve
spontaneously, this number may be an under-
estimate (Fraser et al, 1978 ; Melnick et al,
Figure 4 Branchial fistula in a neck skin crease . These
small openings lie anterior to the sternocleidomastoid 1978 ; Cremers and Fikker-Van Noord, 1980) .
muscle and may track internally to open in the tonsillar Preisch et al (1985) has also described gusta-
fossa . tory lacrimination with absent reflex tearing in
affected persons. Several authors have noted
eral . Fistulae are located in the mid-to-lower facial abnormalities, such as a long, narrow
third of the neck as small openings anterior to face with a constricted or high-arched palate,
the sternocleidomastoid muscle . The openings retrognathia, an overriding bite, and a bifid
may be inconspicuous or may ooze fluid and uvula or cleft palate (Melnick et al, 1976 ; Cre-
become infected . Cysts are usually palpable mers and Fikkers-Van Noord, 1980 ; Cote and
deep to the sternocleidomastoid muscle and may O'Regan, 1982) . There may be facial or
present with a cutaneous opening. In the absence mandibular asymmetry (Muckle, 1961 ; Rollnick
of a cutaneous opening, diagnosing a branchial and Kaye, 1985 ; Heimler and Lieber, 1986),
cyst is more difficult. Approximately 0.02 percent and it has even been hypothesized that hemi-
of the pediatric population have branchial fis- facial microsomia constitutes severe pheno-
tulae as an isolated finding and do not have typic expression of BOR (Heimler and Lieber,
BOR syndrome (Smith et al, 1984) . 1986). Congenital seventh nerve palsy also
The spectrum of renal malformations in occurs (Cremers and Fikkers-Van Noord, 1980).
BOR syndrome ranges from mild to severe . The Ocular manifestations include a few reports
majority of renal anomalies are minor and often of strabismus (Cote and O'Regan, 1982) and a
remain asymptomatic . In fact, many renal anom- single report of BOR syndrome associated with
alies are subtle and can be missed on routine an epibulbar dermoid (Gimsing and Dyrmose,
intravenous pyelography (IVP) (Fraser et al,
1978). With close scrutiny, however, IVP demon-
strates some structural anomaly of the renal
system in two-thirds of persons with BOR syn-
drome (Cremers and Fikkers-Van Noord, 1980).
Ten percent of affected persons have clinically
significant renal involvement. Severe renal
anomalies include bilateral renal agenesis, poly-
cystic kidneys, and enlarged, blunted kidneys.
Other anomalies of the renal system include
unilateral renal agenesis, vesiculo-ureteral
reflux, crossed renal ectopia, bilateral bifid renal
pelvis, ureteropelvic junction obstruction, dupli-
cation of the ureter and collecting system,
extrarenal pelvis, fetal lobulation, abnormal
rotation of the kidney, calyceal diverticuli or
distorted calyceal system, abnormal renal
parenchymal thickness, and tapered superior
pole of the kidney (Fig. 5) . Renal function stud-
ies have shown normal urinary sediment in all
patients (Wildervanck, 1962). A small number Figure 5 Right renal agenesis in a person with BOR
of patients have a disturbed concentration capac- syndrome demonstrated by renal scanning .
106Branchio-Oto-Renal Syndrome/Coppage and Smith
1986). Anomalies of the fourth and sixth Treacher Collins Syndrome
branchial arch vessels have been noted, includ- (Mandibulofacial Dysostosis)
ing a right aortic arch with an anomalous left
subclavian artery (Legius et al, 1990), an aber- Like OAV and BOR syndromes, Treacher
rant right subclavian artery (Melnick et al, Collins syndrome also results from abnormal
1978), and preductal coarctation of the aorta development of the first and second branchial
(Chitayat et al, 1992). arches . The characteristic phenotype includes
antimongoloid slanting palpebral fissures, malar
Differential Diagnosis bone hypoplasia, mandibular hypoplasia, and
lower lid coloboma . Auricular malformations,
In general, the diagnosis of BOR syndrome including microtia, hypoplasia, cupping, preau-
is straightforward. Individuals exhibit the char- ricular tags and pits, and external auditory canal
acteristic disease phenotype, and an autosomal- defects occur in 77 percent of patients . The mid-
dominant line of transmission is evident. Fam- dle ear ossicles also are often malformed, and 40
ily histories, however, can be obscure, new muta- percent of patients have a conductive hearing loss .
tions do occur, and phenotypic expression varies, Inheritance is autosomal dominant, and, like
making it helpful to have some knowledge of BOR syndrome, expression is highly variable .
other syndromes considered in the differential Affected individuals may exhibit only a few char-
diagnosis. acteristics of the disease spectrum (Smith, 1986).
See Jahrsdoerfer and Jacobson (1995) in this
Oculo-Auriculo-Vertebral (OAV) volume for a detailed account of Treacher Collins
Dysplasia (Hemi facial Microsomia, syndrome .
Goldenhar Syndrome)
Otomandibular Dysostosis
The OAV dysplasia spectrum is a disease
phenotype in which the predominant malfor- This syndrome, questionably distinct from
mations reflect abnormalities in morphogenesis Treacher Collins syndrome, includes prominent
of the first and second branchial arches, verte- lop ears, long thin nares, micrognathia, and
brae, and eyes. OAV dysplasia usually occurs spo- bilateral fixation of the stapes foot plate. Only one
radically and, in general, only about 2 percent family has been reported; inheritance is autoso-
of first-degree relatives of carriers are affected mal dominant (Konigsmark and Gorlin, 1976).
by major or minor phenotypic features of the dis-
ease (Cohen et al, 1989). Towns-Brocks Syndrome
Included in the OAV spectrum are malfor-
mations of the auricle, preauricular tags any- This syndrome consists of lop ears, ear tags,
where along an imaginary line from the tragus sensorineural deafness, renal anomalies, thumb
to the oral commissure, preauricular pits, and, malformations, imperforate anus, and skeletal
in over 50 percent of carriers, varying degrees anomalies . Inheritance is autosomal dominant
of hearing impairment . Renal anomalies are (Walpole and Hockey, 1982).
also reported and include absent kidneys, dou-
ble ureters, crossed renal ectopia, hydronephro- Branchio-oculo-facial (BOF) Syndrome
sis, hydroureter, and an anomalous blood sup-
ply to the kidneys (Cohen et al, 1989). BOF syndrome consists of bilateral branchial
The feature distinguishing BOR syndrome cleft sinuses, congenital strabismus, obstructed
from the OAV spectrum is the facial abnormal- nasolacrimal ducts, a broad nasal bridge, a pro-
ities. The OAV spectrum is characterized by truding upper lip, a pseudocleft of the upper
hypoplasia of the malar, maxillary, and mandibu- lip, hemangiomatous branchial clefts, malformed
lar regions, especially the ramus and condyle, and ears, and linear skin lesions behind the ears .
ocular findings such as narrowed palpebral fis- Other associated anomalies include colobomas,
sures on the affected side, epibulbar dermoids, microphthalmia, auricular pits, lip pits, high-
colobomas, lipodermoids, notched upper lids, arched palate, dental anomalies, subcutaneous
strabismus and, rarely, microphthalmia or anoph- cysts of the scalp, premature graying, and poor
thalmia. Often, there is an obvious facial asym- growth . Legius et al (1990) described a father and
metry in OAV dysplasia, with one side being son with overlapping features of both BOR and
more severely affected than the other. In contrast, BOF syndromes. Inheritance is autosomal dom-
in BOR syndrome, the facial skeleton is normal. inant (Legius et al, 1990).
107Journal of the American Academy of Audiology/ Volume 6, Number 1, January 1995
Branchial Arch Syndrome (X-Linked) surgical intervention should be recommended
only when the hearing loss is confined to the lat-
There is one report of this syndrome, which eral ossicular chain.
consists of microcephaly, downslanting palpebral Renal anomalies can be severe and even
fissures, high-arched palate, low-set protrud- incompatible with life . Fatal malformations are
ing ears, bilateral sensorineural hearing loss, not typically diagnosed in utero, and the peri-
slightly webbed neck, short stature, and learn- natal care of newborns with BOR syndrome has
ing disability. It may occur with cryptorchidism, received only minimal attention. There are at
subvalvular pulmonic stenosis, and body asym- least nine documented deaths in neonates with
metry (Toriello et al, 1985). confirmed BOR syndrome (Fitch and Srolovitz,
1976 ; Melnick et al, 1978; Carmi et al, 1983 ;
Other Syndromes Greenberg et al, 1988 ; Chitayat et al, 1992). In
each instance, the neonate was born with renal
Other syndromes in the differential diag- agenesis or dysplasia . Death occurred within
nosis include Wildervanck's syndrome, frontal hours of delivery from respiratory distress sec-
nasal dysplasia sequence, Bixler's syndrome, ondary to pulmonary hypoplasia. It was not pos-
VACTERL association, CHARGE association sible to predict, based on the phenotype of the
(see Toriello [19951 in this volume), MURCS affected parent, whether the neonate would
association, otofaciocervical syndrome, deaf- exhibit a severe form of BOR syndrome . Even
ness-craniofacial syndrome, Ladd's syndrome, parents with asymptomatic or radiologically
otocephaly anomaly, Mengel's syndrome, undetectable renal anomalies were at risk for
congenital conductive or mixed deafness- progeny with renal agenesis . If one child had
preauricular sinus-external ear anomaly and severe renal malformation, couples were at
commissural lip pit syndrome, PHEP syn- increased risk for having other similarly affected
drome, and Nager syndrome . children.
Based on these reports, we recommend care-
Management ful monitoring of any pregnancy in which either
parent has BOR syndrome . Special attention
The medical management of BOR syn- should be given to fundal height, and serial
drome requires special emphasis on hearing ultrasounds should be done to detect the pres-
impairment, renal abnormalities, perinatal ence of oligohydramnios (Carmi et al, 1983).
complications, and genetic counseling . The The presence of renal tissue and an estimate of
prompt recognition of hearing impairment is lung volume should be established. If severe
important, and children with the phenotypic abnormalities are present, the child should be
characteristics of BOR syndrome should delivered in a hospital with a level III neonatal
undergo thorough audiologic testing as early as intensive care nursery, so that neonatologists
possible . We would also recommend auditory skilled in the management of respiratory distress
screening for children with only preauricular can provide optimal care .
pits or tags . If hearing loss is documented, We also would recommend an IVP to eval-
appropriate aural habilitation should be initi- uate renal structure and function in affected
ated . Infants who experience otitis media should individuals. This procedure is superior to a renal
be maintained on chemoprophylactic antibi- ultrasound or abdominal X-ray in delineating
otics to prevent fluctuations in hearing, and if structural abnormalities and variations found in
a middle ear effusion is present for longer than BOR syndrome . The potential complications
3 months, pressure-equalizing tubes are indi- from reflux, impaired renal function, and a pre-
cated. An annual audiologic evaluation is essen- disposition for urinary tract infections cannot be
tial, as hearing loss can be progressive. dismissed. Furthermore, prior knowledge of an
The role of surgery in correcting fixed losses affected individual's renal anatomy and function
has not been established. Cremers et al (1981) are invaluable in an emergency situation involv-
have noted that stapedectomy in carriers with ing an accident or trauma to the kidneys . If a
a mixed loss is generally followed by a poor out- renal abnormality is detected on IVP, referral to
come . If stapedectomy is to be considered, com- a nephrologist is in order.
puterized tomography is essential to delineate Genetic counseling is invaluable for per-
malformations of the inner ear that may pre- sons with BOR syndrome . Counseling assures
dispose to a stapedial gusher (Gimsing and Dyr- that the pattern of disease inheritance is under-
mose, 1986 ; Ng et al, 1989) (Fig . 3) . In general, stood by affected persons. Phenotypic variabil-
108Branchio-Oto-Renal Syndrome/Coppage and Smith
ity also can be explained, stressing the need for Cohen MM, Kaye CI, Rollnick BR. (1989) . Oculauriculo-
vertebral spectrum : an updated critique . Cleft Palate J
appropriate medical and audiologic evaluation
26(4) :276-286 .
and care. Counseling is especially important in
instances where BOR syndrome has been asso- Cote A, O'Regan S . (1982) . The branchio-oto-renal syn-
ciated with severe renal anomalies. drome . Am J Nephrol 2 :144-146 .
Cremers CWRJ, Fikkers-Van Noord M . (1980) . The ear-
Pathogenesis pits-deafness syndrome . Clinical and genetic aspects . Int
J Ped Otorhinolaryngol 2 :309-322 .
The pathogenesis of BOR syndrome is not Cremers CWRJ, Kenyon JB, Kimberling WJ, Kumar S,
known. Malformations Marres HAM, Smith RJH . (1992) . Autosomal dominant
branchio-oto-renal syndrome - localization of a disease
in BOR syndrome are the result of the gene to chromosome 8q by linkage in a Dutch family.
simultaneous occurrence of aberrant differen- Hum Mol Genet 1(7):491-496 .
tiation of three separate embryologic forma-
Cremers CWRJ, Thijssen HOM, Fischer AJEM, Marres
tions: the branchial apparatus, the otocyst, and
EHMA . (1981) . Otological aspects of the earpit-deafness
the renal primordia. Genetic studies (Haan et al, syndrome . ORL 43 :223-239.
1989 ; Kumar et al, 1992; Smith et al, 1992) sug-
gest that a single gene defect results in the BOR Dumas R. (1982) . Glomerular lesions in the branchio-
oto-renal (BOR) syndrome . Int J Ped Nephrol 3 :67-70.
phenotype. The gene defect may result in alter-
ations in cell-to-cell recognition surface proteins Fitch N, Srolovitz H . (1976) . Severe renal dysgenesis
or enzyme receptors, alterations in directed cell produced by a dominant gene . Am J Dis Child
130 :1356-1357 .
movement, alterations in cellular division, or a
deficiency of mesodermal cellular components in Fraser FC, Ayme S, Halal F, Sproule J. (1983) . Autosomal
the branchial arch and metanephros. To answer dominant duplication of the renal collecting system, hear-
these questions and increase our understanding ing loss, and external ear anomalies : a new syndrome?
Am J Med Genet 14 :473-478 .
of auditory and renal development, research
efforts are underway to clone the BOR gene . Fraser FC, Ling D, Clogg D, Nogrady B . (1978) . Genetic
aspects of the BOR syndrome - branchial fistulas, ear
pits, hearing loss, and renal anomalies . Am J Med Genet
Conclusion 2 :241-252 .
Most individuals with BOR syndrome do Fraser FC, Sproule JR, Halal F. (1980). Frequency of the
branchio-oto-renal (BOR) syndrome in children with pro-
not have a life-threatening condition, and, in found hearing loss . Am J Med Genet 7 :341-349 .
many families, it is not uncommon for the dis-
ease to go undiagnosed until the birth of a child Fraser GR. (1976) . The Causes of Profound Deafness in
Childhood . Baltimore : Johns Hopkins University Press .
with severe manifestations of the BOR pheno-
type . This is unfortunate, as recognition of the Fourman P, Fourman J. (1955) . Hereditary deafness in
hallmark features of BOR syndrome could ensure family with ear-pits (fistula auris congenital). Br Med J
that affected persons receive appropriate med- December 3:1354-1356 .
ical information and care . Integral elements of Gimsing S, Dyrmose J. (1986) . Branchio-oto-renal dys-
medical care include audiologic, otologic, head plasia in three families . Ann Otol Rhinol Laryngol
and neck, urologic, and genetic evaluation . 95 :421-426 .
Greenberg CR, Trevenen CL, Evans JA . (1988). The BOR
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