Download Branchio-Oto-Renal Syndrome

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 ; however, 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
autosomal-dominant form of inherited
B hearing impairment characterized by: (1)
a conductive sensorineural or mixed hearing
loss ; (2) preauricular pits ; (3) auricular malformations of the outer ear and structural defects
of the middle and inner ear; (4) branchial fistulae or cysts; and (5) renal anomalies, ranging
from mild hypoplasia to a lethal condition of
bilateral renal agenesis . Less common anomalies
that occur include lacrimal duct stenosis, preauricular tags, facial nerve paralysis, palate defects,
a narrow face with a high-arched palate, and a
deep overbite . In spite of this broad constellation
of findings, variable expressivity of the BOR
gene can, at times, make the diagnosis very difficult . Gene penetrance is high, however, and
most known carriers display some aspects of
the disease phenotype if carefully examined
(Fraser et al, 1978 ; Cremers and Fikkers-Van
Noord, 1980).
Historical Perspective
Early reports of BOR syndrome can be
traced to the nineteenth century. Aucherson
(1832) was the first to recognize the familial
occurrence of branchial anomalies . The combination of preauricular pits, branchial fistulae,
`Department of Pediatrics, University of Iowa ; and
tDepartment of Otolaryngology-Head and Neck Surgery,
University of Iowa Hospitals and Clinics, Iowa City, Iowa
Reprint requests : Richard J . H . Smith, Department
of Otolaryngology - Head and Neck Surgery, University
of Iowa, Hospitals and Clinics, 200 Hawkins Dr., E230 GH,
Iowa City, IA 52242-1078
and hearing impairment was reported by
Heusinger in 1864 and by Paget in 1877 and
1878 . Under the Nazi regime, the disease provoked a great deal of discussion by several German authors, notably Albrecht (1933), Schneider (1937), Loebell (1938), Steinberg (1938), and
Langenbeck (1938), because of the eugenic problems it raised . BOR syndrome was referred to
as Innenohrschwerhorigkeit, or "hereditary hardness of hearing" (Fourman and Fourman, 1955).
More frequent recognition of BOR syndrome
followed the 1955 publication by Fourman and
Fourman of a large family with preauricular
pits, bilateral branchial fistulae, and progressive
sensorineural hearing loss . Twenty years later,
Melnick et al (1975) recognized the possibility
of associated renal anomalies and suggested
the term branchio-oto-renal syndrome, underscoring the phenotypic anomalies of the
branchial arches, otocysts, and renal primordia. The nomenclature for BOR syndrome, however, has varied . Terms applied to the disease
reflect observation and author bias and include
ear pits-deafness syndrome ; preauricular pits,
cervical fistulae, hearing loss syndrome ; branchio-oto-dysplasia syndrome ; branchio-otoureteral syndrome ; branchio-oto-renal dysplasia;
and Melnick-Fraser syndrome (Cremers and
Fikkers-Van Noord, 1980 ; Fraser et al, 1983).
Prevalence
Congenital deafness affects 1 of every 1000
children, and an estimated 50 percent of these
affected children have inherited hearing impairment (Fraser, 1976). The precise prevalence of
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
surveyed 3460 children with profound hearing
loss and found only 5 (0 .15%) with a family history of branchial fistulae and preauricular pits
(1 :700,000) (Fraser, 1976 ; Fraser et al, 1978).
Four years later, however, he presented evidence to suggest that the prevalence of BOR is
much greater (Fraser et al, 1980). In a study of
421 white children in the Montreal schools for
the deaf, he diagnosed BOR syndrome in 2 percent of the profoundly deaf students . Fraser,
therefore, roughly estimated disease prevalence
at 1 :40,000. The true value is probably somewhere between these extremes .
Table 1 Characteristic Findings
in Branchio-Oto-Renal Syndrome
Feature
Percentage
Hearing Loss
Branchial Fistulae/Cysts
Preauricular Pits
Malformed Ears
Renal Anomalies (by IVP)
Mild
Severe
Lethal
86 (191/223)
69 (142/206)
68 (168/246)
48(30/62)
Data pooled from Cremers and Fikkers-Van Noord (1980), Fraser
et al (1980), Cote and O'Regan (1982), Carmi et al (1983), Fraser
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
feature of BOR syndrome and affects approximately 80 percent of carriers (Fraser et al, 1978 ;
Cremers and Fikkers-Van Noord, 1980) (Table
1) . The impairment may be congenital or latein-onset and is either nonprogressive or progressive in nature . It is sensorineural (20%),
conductive (30%), or mixed (50%) and ranges in
severity from mild to profound (Fraser et al,
1980) (Fig. 1) . Interestingly, all three types of
hearing loss can be observed in individuals
within the same pedigree, and the type of hearing loss may even differ in each ear within an
individual . For example, carriers with a sensorineural loss in one ear and a conductive hear-
ing loss in the other ear have been reported
(Karmody, 1974).
The otologic aspects of the external ear are
often the most striking feature of BOR syndrome . Most commonly, the antihelix of the
pinna is malformed, and the result is a lop-ear
deformity (Fig. 2) . This type of abnormality is
reported in about 40 percent of affected individuals (Fraser et a1,1978; Cremers and FikkersVan Noord,1980), although in our experience this
number is underestimated . Severe microtia also
occurs .
Anterior to the pinna, preauricular cartilaginous appendages may be found. A more subtle finding is the presence of preauricular pits .
Right Ear I Pure Tone Audiometry
.26K AK
lK
2H
4K
40(51/127)
20(25/127)
10(13/127)
SK
dB
Left Ear
.29{ .s¢ ILK 2H
4K
6K
0
20
40
60
s0
100
No
.
Reap
Acoustic
Reflex
Unmasked
BC
uncrossed
crossed
Masked
0
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.
104
Branchio-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
shallow, pinhead-sized depression near the superior attachment of the helix. Approximately 1 percent 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). Abnormalities have been observed by computerized
tomography and surgical exploration. The ossicles 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, shortening of the lenticular process of the incus, and
aberrant fixation of the incus and stapes . These
types of ossicular abnormalities result in a conductive hearing loss .
Inner ear abnormalities also occur. The horizontal semicircular canals can be asymmetrical, dysplastic, or absent. The cochlea can be
hypoplastic or dysplastic, and the internal auditory canal can be widened (Fig. 3) . These abnormalities may result in vestibular hypoactivity
and a sensorineural hearing loss (Fraser et al,
1978 ; Gimsing and Dyrmose, 1986).
Abranchial fistula or cyst occurs in approximately 63 percent of carriers (Fig . 4) . This hallmark feature may be either unilateral or bilat-
Figure 3 Computed tomogram of left ear. The internal
auditory canal is dilated and the vestibular aqueduct
and vestibule are enlarged . A dilated internal auditory
canal can lead to a stapes gusher if stapedectomy is
done ; an enlarged endolymphatic duct is associated with
sensorineural hearing impairment.
Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995
Figure 4 Branchial fistula in a neck skin crease . These
small openings lie anterior to the sternocleidomastoid
muscle and may track internally to open in the tonsillar
fossa .
eral . Fistulae are located in the mid-to-lower
third of the neck as small openings anterior to
the sternocleidomastoid muscle . The openings
may be inconspicuous or may ooze fluid and
become infected . Cysts are usually palpable
deep to the sternocleidomastoid muscle and may
present with a cutaneous opening. In the absence
of a cutaneous opening, diagnosing a branchial
cyst is more difficult. Approximately 0.02 percent
of the pediatric population have branchial fistulae as an isolated finding and do not have
BOR syndrome (Smith et al, 1984) .
The spectrum of renal malformations in
BOR syndrome ranges from mild to severe . The
majority of renal anomalies are minor and often
remain asymptomatic . In fact, many renal anomalies are subtle and can be missed on routine
intravenous pyelography (IVP) (Fraser et al,
1978). With close scrutiny, however, IVP demonstrates some structural anomaly of the renal
system in two-thirds of persons with BOR syndrome (Cremers and Fikkers-Van Noord, 1980).
Ten percent of affected persons have clinically
significant renal involvement. Severe renal
anomalies include bilateral renal agenesis, polycystic 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, duplication 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 studies have shown normal urinary sediment in all
patients (Wildervanck, 1962). A small number
of patients have a disturbed concentration capac106
ity and proteinuria, or reduced creatine clearance
and diminished glomerular filtration rate . Histologically, prominent glomerular lesions have
been noted, causing segmental and focal hyalization with dense immunoglobin deposits of
IgG, IgM, IgA, and C3 along the basement membrane and into the mesangium (Dumas, 1982).
Several other abnormalities are less frequent aspects of BOR syndrome . Nasolacrimal
duct stenosis is noted in up to 9 percent of carriers; however, because the stenosis may resolve
spontaneously, this number may be an underestimate (Fraser et al, 1978 ; Melnick et al,
1978 ; Cremers and Fikker-Van Noord, 1980) .
Preisch et al (1985) has also described gustatory lacrimination with absent reflex tearing in
affected persons. Several authors have noted
facial abnormalities, such as a long, narrow
face with a constricted or high-arched palate,
retrognathia, an overriding bite, and a bifid
uvula or cleft palate (Melnick et al, 1976 ; Cremers and Fikkers-Van Noord, 1980 ; Cote and
O'Regan, 1982) . There may be facial or
mandibular asymmetry (Muckle, 1961 ; Rollnick
and Kaye, 1985 ; Heimler and Lieber, 1986),
and it has even been hypothesized that hemifacial microsomia constitutes severe phenotypic expression of BOR (Heimler and Lieber,
1986). Congenital seventh nerve palsy also
occurs (Cremers and Fikkers-Van Noord, 1980).
Ocular manifestations include a few reports
of strabismus (Cote and O'Regan, 1982) and a
single report of BOR syndrome associated with
an epibulbar dermoid (Gimsing and Dyrmose,
Figure 5 Right renal agenesis in a person with BOR
syndrome demonstrated by renal scanning .
Branchio-Oto-Renal Syndrome/Coppage and Smith
1986). Anomalies of the fourth and sixth
branchial arch vessels have been noted, including a right aortic arch with an anomalous left
subclavian artery (Legius et al, 1990), an aberrant right subclavian artery (Melnick et al,
1978), and preductal coarctation of the aorta
(Chitayat et al, 1992).
Differential Diagnosis
In general, the diagnosis of BOR syndrome
is straightforward. Individuals exhibit the characteristic disease phenotype, and an autosomaldominant line of transmission is evident. Family histories, however, can be obscure, new mutations do occur, and phenotypic expression varies,
making it helpful to have some knowledge of
other syndromes considered in the differential
diagnosis.
Oculo-Auriculo-Vertebral (OAV)
Dysplasia (Hemi facial Microsomia,
Goldenhar Syndrome)
The OAV dysplasia spectrum is a disease
phenotype in which the predominant malformations reflect abnormalities in morphogenesis
of the first and second branchial arches, vertebrae, and eyes. OAV dysplasia usually occurs sporadically and, in general, only about 2 percent
of first-degree relatives of carriers are affected
by major or minor phenotypic features of the disease (Cohen et al, 1989).
Included in the OAV spectrum are malformations of the auricle, preauricular tags anywhere along an imaginary line from the tragus
to the oral commissure, preauricular pits, and,
in over 50 percent of carriers, varying degrees
of hearing impairment . Renal anomalies are
also reported and include absent kidneys, double ureters, crossed renal ectopia, hydronephrosis, hydroureter, and an anomalous blood supply to the kidneys (Cohen et al, 1989).
The feature distinguishing BOR syndrome
from the OAV spectrum is the facial abnormalities. The OAV spectrum is characterized by
hypoplasia of the malar, maxillary, and mandibular regions, especially the ramus and condyle, and
ocular findings such as narrowed palpebral fissures on the affected side, epibulbar dermoids,
colobomas, lipodermoids, notched upper lids,
strabismus and, rarely, microphthalmia or anophthalmia. Often, there is an obvious facial asymmetry in OAV dysplasia, with one side being
more severely affected than the other. In contrast,
in BOR syndrome, the facial skeleton is normal.
Treacher Collins Syndrome
(Mandibulofacial Dysostosis)
Like OAV and BOR syndromes, Treacher
Collins syndrome also results from abnormal
development of the first and second branchial
arches . The characteristic phenotype includes
antimongoloid slanting palpebral fissures, malar
bone hypoplasia, mandibular hypoplasia, and
lower lid coloboma . Auricular malformations,
including microtia, hypoplasia, cupping, preauricular tags and pits, and external auditory canal
defects occur in 77 percent of patients . The middle ear ossicles also are often malformed, and 40
percent of patients have a conductive hearing loss .
Inheritance is autosomal dominant, and, like
BOR syndrome, expression is highly variable .
Affected individuals may exhibit only a few characteristics of the disease spectrum (Smith, 1986).
See Jahrsdoerfer and Jacobson (1995) in this
volume for a detailed account of Treacher Collins
syndrome .
Otomandibular Dysostosis
This syndrome, questionably distinct from
Treacher Collins syndrome, includes prominent
lop ears, long thin nares, micrognathia, and
bilateral fixation of the stapes foot plate. Only one
family has been reported; inheritance is autosomal dominant (Konigsmark and Gorlin, 1976).
Towns-Brocks Syndrome
This syndrome consists of lop ears, ear tags,
sensorineural deafness, renal anomalies, thumb
malformations, imperforate anus, and skeletal
anomalies . Inheritance is autosomal dominant
(Walpole and Hockey, 1982).
Branchio-oculo-facial (BOF) Syndrome
BOF syndrome consists of bilateral branchial
cleft sinuses, congenital strabismus, obstructed
nasolacrimal ducts, a broad nasal bridge, a protruding upper lip, a pseudocleft of the upper
lip, hemangiomatous branchial clefts, malformed
ears, and linear skin lesions behind the ears .
Other associated anomalies include colobomas,
microphthalmia, auricular pits, lip pits, higharched palate, dental anomalies, subcutaneous
cysts of the scalp, premature graying, and poor
growth . Legius et al (1990) described a father and
son with overlapping features of both BOR and
BOF syndromes. Inheritance is autosomal dominant (Legius et al, 1990).
107
Journal of the American Academy of Audiology/ Volume 6, Number 1, January 1995
Branchial Arch Syndrome (X-Linked)
There is one report of this syndrome, which
consists of microcephaly, downslanting palpebral
fissures, high-arched palate, low-set protruding ears, bilateral sensorineural hearing loss,
slightly webbed neck, short stature, and learning disability. It may occur with cryptorchidism,
subvalvular pulmonic stenosis, and body asymmetry (Toriello et al, 1985).
Other Syndromes
Other syndromes in the differential diagnosis include Wildervanck's syndrome, frontal
nasal dysplasia sequence, Bixler's syndrome,
VACTERL association, CHARGE association
(see Toriello [19951 in this volume), MURCS
association, otofaciocervical syndrome, deafness-craniofacial syndrome, Ladd's syndrome,
otocephaly anomaly, Mengel's syndrome,
congenital conductive or mixed deafnesspreauricular sinus-external ear anomaly and
commissural lip pit syndrome, PHEP syndrome, and Nager syndrome .
Management
The medical management of BOR syndrome requires special emphasis on hearing
impairment, renal abnormalities, perinatal
complications, and genetic counseling . The
prompt recognition of hearing impairment is
important, and children with the phenotypic
characteristics of BOR syndrome should
undergo thorough audiologic testing as early as
possible . We would also recommend auditory
screening for children with only preauricular
pits or tags . If hearing loss is documented,
appropriate aural habilitation should be initiated . Infants who experience otitis media should
be maintained on chemoprophylactic antibiotics to prevent fluctuations in hearing, and if
a middle ear effusion is present for longer than
3 months, pressure-equalizing tubes are indicated. An annual audiologic evaluation is essential, as hearing loss can be progressive.
The role of surgery in correcting fixed losses
has not been established. Cremers et al (1981)
have noted that stapedectomy in carriers with
a mixed loss is generally followed by a poor outcome . If stapedectomy is to be considered, computerized tomography is essential to delineate
malformations of the inner ear that may predispose to a stapedial gusher (Gimsing and Dyrmose, 1986 ; Ng et al, 1989) (Fig . 3) . In general,
108
surgical intervention should be recommended
only when the hearing loss is confined to the lateral ossicular chain.
Renal anomalies can be severe and even
incompatible with life . Fatal malformations are
not typically diagnosed in utero, and the perinatal care of newborns with BOR syndrome has
received only minimal attention. There are at
least nine documented deaths in neonates with
confirmed BOR syndrome (Fitch and Srolovitz,
1976 ; Melnick et al, 1978; Carmi et al, 1983 ;
Greenberg et al, 1988 ; Chitayat et al, 1992). In
each instance, the neonate was born with renal
agenesis or dysplasia . Death occurred within
hours of delivery from respiratory distress secondary to pulmonary hypoplasia. It was not possible to predict, based on the phenotype of the
affected parent, whether the neonate would
exhibit a severe form of BOR syndrome . Even
parents with asymptomatic or radiologically
undetectable renal anomalies were at risk for
progeny with renal agenesis . If one child had
severe renal malformation, couples were at
increased risk for having other similarly affected
children.
Based on these reports, we recommend careful monitoring of any pregnancy in which either
parent has BOR syndrome . Special attention
should be given to fundal height, and serial
ultrasounds should be done to detect the presence of oligohydramnios (Carmi et al, 1983).
The presence of renal tissue and an estimate of
lung volume should be established. If severe
abnormalities are present, the child should be
delivered in a hospital with a level III neonatal
intensive care nursery, so that neonatologists
skilled in the management of respiratory distress
can provide optimal care .
We also would recommend an IVP to evaluate renal structure and function in affected
individuals. This procedure is superior to a renal
ultrasound or abdominal X-ray in delineating
structural abnormalities and variations found in
BOR syndrome . The potential complications
from reflux, impaired renal function, and a predisposition for urinary tract infections cannot be
dismissed. Furthermore, prior knowledge of an
affected individual's renal anatomy and function
are invaluable in an emergency situation involving an accident or trauma to the kidneys . If a
renal abnormality is detected on IVP, referral to
a nephrologist is in order.
Genetic counseling is invaluable for persons with BOR syndrome . Counseling assures
that the pattern of disease inheritance is understood by affected persons. Phenotypic variabil-
Branchio-Oto-Renal Syndrome/Coppage and Smith
ity also can be explained, stressing the need for
appropriate medical and audiologic evaluation
and care. Counseling is especially important in
instances where BOR syndrome has been associated with severe renal anomalies.
Cohen MM, Kaye CI, Rollnick BR. (1989) . Oculauriculovertebral spectrum : an updated critique . Cleft Palate J
26(4) :276-286 .
Cote A, O'Regan S . (1982) . The branchio-oto-renal syndrome . Am J Nephrol 2 :144-146 .
Cremers CWRJ, Fikkers-Van Noord M . (1980) . The earpits-deafness syndrome . Clinical and genetic aspects . Int
J Ped Otorhinolaryngol 2 :309-322 .
Pathogenesis
The pathogenesis of BOR syndrome is not
known. Malformations
in BOR syndrome are the result of the
simultaneous occurrence of aberrant differentiation of three separate embryologic formations: the branchial apparatus, the otocyst, and
the renal primordia. Genetic studies (Haan et al,
1989 ; Kumar et al, 1992; Smith et al, 1992) suggest that a single gene defect results in the BOR
phenotype. The gene defect may result in alterations in cell-to-cell recognition surface proteins
or enzyme receptors, alterations in directed cell
movement, alterations in cellular division, or a
deficiency of mesodermal cellular components in
the branchial arch and metanephros. To answer
these questions and increase our understanding
of auditory and renal development, research
efforts are underway to clone the BOR gene .
Conclusion
Cremers CWRJ, Kenyon JB, Kimberling WJ, Kumar S,
Marres HAM, Smith RJH . (1992) . Autosomal dominant
branchio-oto-renal syndrome - localization of a disease
gene to chromosome 8q by linkage in a Dutch family.
Hum Mol Genet 1(7):491-496 .
Cremers CWRJ, Thijssen HOM, Fischer AJEM, Marres
EHMA . (1981) . Otological aspects of the earpit-deafness
syndrome . ORL 43 :223-239.
Dumas R. (1982) . Glomerular lesions in the branchiooto-renal (BOR) syndrome . Int J Ped Nephrol 3 :67-70.
Fitch N, Srolovitz H . (1976) . Severe renal dysgenesis
produced by a dominant gene . Am J Dis Child
130 :1356-1357 .
Fraser FC, Ayme S, Halal F, Sproule J. (1983) . Autosomal
dominant duplication of the renal collecting system, hearing loss, and external ear anomalies : a new syndrome?
Am J Med Genet 14 :473-478 .
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
2 :241-252 .
Most individuals with BOR syndrome do
not have a life-threatening condition, and, in
many families, it is not uncommon for the disease to go undiagnosed until the birth of a child
with severe manifestations of the BOR phenotype . This is unfortunate, as recognition of the
hallmark features of BOR syndrome could ensure
that affected persons receive appropriate medical information and care . Integral elements of
medical care include audiologic, otologic, head
and neck, urologic, and genetic evaluation .
Fraser FC, Sproule JR, Halal F. (1980). Frequency of the
branchio-oto-renal (BOR) syndrome in children with profound hearing loss . Am J Med Genet 7 :341-349 .
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