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Inner Ear Anomalies Are Frequent but Nonobligatory Features of the Branchio-oto-renal Syndrome
Martijn H. Kemperman, MD;
Sacha M. P. Koch, MD;
Frank B. M. Joosten, PhD;
Shrawan Kumar, PhD;
Patrick L. M. Huygen, PhD;
Cor W. R. J. Cremers, PhD
Arch Otolaryngol Head Neck Surg. 2002;128:1033-1038.
ABSTRACT
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Objective To summarize the syndromic features and evaluate the presence of inner
ear anomalies in 35 patients with branchio-oto-renal (BOR) syndrome from 6
families.
Design Retrospective evaluation of magnetic resonance imaging of the temporal
bones and clinical features in patients with BOR syndrome.
Setting Tertiary referral center.
Patients The study population comprised 35 clinically affected patients with
BOR syndrome from 6 families. Most of these families were followed for over
25 years.
Main Outcome Measures Twenty-four patients underwent high-resolution, heavily T2-weighted
3-dimensional magnetic resonance imaging of the temporal bones for evaluation
of inner ear anomalies. Special attention was paid to the endolymphatic duct
and sac.
Results A total of 7 enlarged endolymphatic ducts and sacs (3 bilaterally and
4 unilaterally) and 5 enlarged endolymphatic ducts only (2 bilaterally and
3 unilaterally) were observed. Eight hypoplastic cochleas and 6 hypoplastic
labyrinths were seen bilaterally. Seven family members had normal inner ears.
Conclusion These findings suggest that inner ear anomalies are frequent but nonobligatory
features of BOR syndrome.
INTRODUCTION
THE BRANCHIO-OTO-RENAL (BOR) syndrome is defined as an autosomal dominant
inherited disorder characterized by the following 3 essential clinical features:
(1) hearing loss with structural defects of the external (including earpits),
middle, and/or inner ear; (2) second branchial arch defects; and (3) renal
anomalies, ranging from mild hypoplasia to aplasia, which can lead to varying
degrees of renal failure. Accompanying features such as lacrimal duct stenosis
or a high-arched palate can also be present in these patients.1-4
One gene underlying the BOR syndrome, EYA1 (chromosome
8q13.3), has been identified.5-8
Recent linkage analysis provided evidence for a second gene on chromosome
1q31.9 This disorder has a high penetrance
but variable clinical expression. The major clinical findings associated with
BOR syndrome are branchial clefts, hearing loss, and renal failure.1-4,10-11
The general prevalence of BOR syndrome is 1 in 40 000 people, and it
occurs in 2% of profoundly deaf children.12
Radiological and histological investigations have demonstrated the presence
of congenital inner ear anomalies in patients with BOR syndrome.4, 13
Enlarged vestibular aqueduct and cochlear hypoplasia have been identified
and may be important findings in BOR syndrome.
The syndromic features of 35 patients with BOR syndrome from 6 families
are described in the present article. Magnetic resonance imaging (MRI) of
the temporal bones was performed in most of the patients to evaluate inner
ear anomalies. Special attention was paid to a large endolymphatic duct and
sac.
PATIENTS AND METHODS
We investigated 6 families with BOR syndrome (families A-F) with 35
affected family members. The family members who participated in this study
were seen at the outpatient clinic of the Department of Otorhinolaryngology,
University Medical Center St Radboud, Nijmegen, the Netherlands. Most of these
BOR syndrome families were followed for over 25 years.3, 10-11,14-17
Renal function tests, intravenous pyelography, and/or ultrasonography of the
kidneys have been performed to record any renal involvement in most patients.11 Pedigrees were updated (Figure 1), and the results of the otorhinolaryngological examination
were evaluated (Table 1).
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Figure 1. Overview of the pedigrees of the
6 participating families with branchio-oto-renal (BOR) syndrome (families
A-F). The clinical features of the persons affected by BOR syndrome are presented
in more detail in Table 1. Open
symbols represent unaffected cases, whereas filled symbols are cases affected
by BOR syndrome. Probands are indicated by a black arrow; magnetic resonance
imaging of the petrosal bones was performed in patients indicated by a plus
sign; possible affected cases are indicated by a question mark. Slashed symbols
represent deceased, and double slashes, separated or divorced relationships.
SB indicates still birth; SA, spontaneous abortion.
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Table 1. Clinical Features in Families A Through F*
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Twenty-four patients underwent high-resolution, heavily T2-weighted
3-dimensional MRI of the temporal bones (Siemens Magnetom Vision, 1.5 T; Siemens,
Erlangen, Germany). This MRI technique enables 3-dimensional reconstruction
in any desirable plane to study abnormalities of the inner ear structures.
Owing to the presence of endolymph, these structures have a high-signal intensity
on T2-weighted images. Thin-section MRI technique enables us to visualize
the often invisible endolymphatic duct and sac, especially if they are enlarged.19 The endolymphatic duct is considered to be dilated
when its diameter, at the midpoint between the common crus and its external
aperture, is 1.5 mm or more on thin-section images.20
Linkage analysis and/or mutation analysis of the EYA1
gene was performed in all 6 families.
RESULTS
The pedigrees of the families A through F are shown in Figure 1, and relevant clinical information is presented in Table 1 for each affected family member
separately. The number of affected individuals in each generation conformed
to an autosomal dominant pattern of inheritance with close to 100% penetrance
in almost each family, including the ones indicated as "affected by history,"
whose children were affected. The only possible exception was the second generation
of family E (P = .04 in binomial distribution). Male-to-male
transmission was documented in families A, C, and D.
Clinical features, present in about 32 cases (95%) of cases, were malformed
auricles, preauricular sinus and/or pit, second branchial arch fistula, and
hearing impairment. Renal malformation was fairly common (13 patients [37%]),
whereas preauricular tags and lip pits (6 patients [17%]) were less common.
The penetrance of these features did not differ significantly in any of the
separate families from the average penetrance calculated for the combined
families.
Most patients had had their second branchial arch fistulas surgically
removed. Preauricular sinus and/or pits or tags had only been removed incidentally.
Surgical intervention is often indicated because of recurrent infection of
these anatomical variations. Aesthetic surgical correction of malformed auricles
has been performed in a few cases (Table
1). Nine patients (38%) required middle ear surgery. Cremers et
al10, 14, 16 and Kemperman
et al17 described the results and details of
these interventions and, based on these data, discussed the impact of syndromic
diagnosis, including BOR syndrome, on the outcome of reconstructive ear surgery.21
The MRI findings in the 6 BOR syndrome families are given in detail
in Table 2, together with the
findings of serial audiometry, and the relative frequency of anomalous MRI
findings by structure are summarized below:
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Table 2. Findings From MRI of the Temporal Bones and Serial Audiometry
in 6 Families With Branchio-oto-renal Syndrome*
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In 7 patients, a large endolymphatic duct and sac (3 bilaterally and
4 unilaterally) and in 5 others a large endolymphatic duct (2 bilaterally
and 3 unilaterally) were observed. Nine hypoplastic cochleae and 6 bilateral
hypoplastic labyrinths were present (Table
2). We did not find any congenital defects in 8 affected BOR syndrome
patients (Figure 2, Figure 3, and Figure 4).
In most cases the type of hearing loss was mixed. Long-term audiometric follow-up
analysis (threshold data not shown) demonstrated that progressive, fluctuant
sensorineural hearing loss is not uncommon in BOR syndrome (Table 2); we were unable to confirm this feature in all BOR syndrome
patients.17, 22 Although a considerable
proportion of cases exhibited anomalous findings, we were unable to find a
clear relationship between these and any of the features of hearing impairment
(progressive and/or fluctuant).
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Figure 2. A, Magnetic resonance image of
the temporal bones of case B/III:6 (see Figure 1) showing a bilaterally enlarged
endolymphatic duct; B, magnetic resonance image of the temporal bones of case
B/III:6 showing a bilaterally enlarged endolymphatic sac.
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Figure 3. Magnetic resonance image of the
temporal bones of case B/IV:2 (see Figure 1) showing a bilaterally plump internal
acoustic canal, bilateral hypoplastic cochleas, and vestibules with an enlarged
endolymphatic duct on both sides. The endolymphatic sac is also bilaterally
enlarged (not shown).
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Figure 4. A, Magnetic resonance image of
the right temporal bone showing the normal configuration of the cochlea, vestibule,
and lateral semicircular canal; B, magnetic resonance image of the left temporal
bone of case F/II:2 (see Figure 1), showing a hypoplastic cochlea.
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Linkage to the EYA1 locus was found in family
A22 and family B; however, no mutations were
detected by mutation analysis (S.K., unpublished data, 1999). In family C,
a mutation (IVS-9 + G>C at -1) (S.K., unpublished data, 1999) was found,
which probably results in aberrant splicing of the gene. Mutation analysis
in family D showed the presence of a missense mutation (T-to-C transition
at position 1360) in exon 13, resulting in a Ser454Pro substitution in the
EYA1 protein.6 Family E has a delC at position
1592 of exon 15 causing a frameshift mutation.7
No mutation has been detected in family F yet.
COMMENT
Inner ear abnormalities can be regarded as common findings in patients
with BOR syndrome. Recently, the presence of such abnormalities in combination
with progressive hearing loss has been demonstrated in Pendred syndrome. In
particular, the presence of an enlarged vestibular aqueduct was an almost
obligatory finding in these patients.23-24
The autosomal recessively inherited large vestibular aqueduct syndrome is
a distinct clinical entity, although mutation analysis has shown that the
large vestibular aqueduct syndrome and the Pendred syndrome both share mutations
in the pendrin gene (PDS).25
The present study shows that inner ear anomalies, such as cochlear hypoplasia
and large endolymphatic duct and sac, are frequent features of BOR syndrome.
This syndrome shares these features as well as progressive, fluctuant hearing
loss with the Pendred syndrome. However, although such features were nonobligatory
but frequently present in our BOR syndrome patients, they were not clearly
correlated to one another. The latter result was obtained by testing on possible
correlations of the pooled data of all families. This procedure is, obviously,
not permitted if there is genetic heterogeneity between the present families.
Unfortunately, we have insufficient information on form (MRI), impaired function
(progressive and/or fluctuant hearing impairment), and linkage/mutation analysis
to test for such a correlation in each family, even the largest ones, separately.
Because of the pathognomic presence of an enlarged vestibular aqueduct,
computed tomographic scanning of the temporal bones can function as a diagnostic
procedure in Pendred syndrome. We know from our experience that the branchiogenic
origin of BOR syndrome can cause a wide range of anatomic malformations of
the outer, middle, and inner ear structures. Indeed, many different forms
of inner ear anomalies were present in our patients; however, none of them
seems to be pathognomic for BOR syndrome. Nevertheless, MRI remains a useful
additional tool that can visualize the neuronal tissues and the endolymphatic-
and perilymphatic-filled structures, such as the cochlea and endolymphatic
duct. It is clear that this technique refines our knowledge of the inner ear
anatomy in general and specifically in BOR syndrome patients.
Until now many mutations in the EYA1 gene have
been described,5-7
and recent linkage analysis provided evidence of involvement of another gene
underlying the BOR syndrome.9 No mutations
are detected in the coding sequence of EYA1 in approximately
70% of families with the BOR phenotype. It would be interesting to perform
further linkage analysis in such families. This would enable us to study the
possible correlations between imaging findings, audiometrical follow-up results,
and linkage results.
AUTHOR INFORMATION
Accepted for publication March 4, 2002.
This study was financially supported by the Dutch Organization for Scientific
Research, counsel for medical and health research (project No. 920-03-100).
The BOR research work in the United States was supported by grant 1R01 DE14090-01
from the National Institute on Dental and Cranial-Facial Research, National
Institutes of Health (Dr Kumar).
We would like to thank the family members who participated in this study.
Corresponding author and reprints: Martijn H. Kemperman, MD, Department
of Otorhinolaryngology, University Medical Center St Radboud, PO Box 9101,
6500 HB Nijmegen, the Netherlands (e-mail: M.Kemperman{at}kno.azn.nl).
From the Departments of Otorhinolaryngology (Drs Kemperman, Koch, Huygen,
and Cremers) and Radiology (Dr Joosten), University Medical Center St Radboud,
Nijmegen, the Netherlands; and the Department of Genetics, Center for Hereditary
and Communication Disorders, Boys Town National Research Hospital, Omaha,
Neb (Dr Kumar).
REFERENCES
| |
1. Melnick M, Bixler D, Nance WE, Silk K, Yune H. Familial branchio-oto-renal dysplasia: a new addition to the branchial
arch syndromes. Clin Genet. 1976;9:25-34.
ISI
| PUBMED
2. Fraser FC, Ling D, Clogg D, Nogrady B. Genetic aspects of the BOR syndrome—branchial fistulas, ear pits,
hearing loss, and renal anomalies. Am J Med Genet. 1978;2:241-252.
FULL TEXT
|
ISI
| PUBMED
3. Cremers CW, Fikkers Van Noord M. The earpits-deafness syndrome: clinical and genetic aspects. Int J Pediatr Otorhinolaryngol. 1980;2:309-322.
PUBMED
4. Chen A, Francis M, Ni L, et al. Phenotypic manifestations of branchio-oto-renal syndrome. Am J Med Genet. 1995;58:365-370.
FULL TEXT
|
ISI
| PUBMED
5. Abdelhak S, Kalatzis V, Heilig R, et al. A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel
gene family. Nat Genet. 1997;15:157-164.
FULL TEXT
|
ISI
| PUBMED
6. Kumar S, Deffenbacher K, Cremers CW, Van Camp G, Kimberling WJ. Branchio-oto-renal syndrome: identification of novel mutations, molecular
characterization, mutation distribution, and prospects for genetic testing. Genet Test. 1997-98;1:243-251.
7. Kumar S, Kimberling WJ, Weston MD, et al. Identification of three novel mutations in human EYA1 protein associated with branchio-oto-renal syndrome. Hum Mutat. 1998;11:443-449.
FULL TEXT
|
ISI
| PUBMED
8. Van Camp G, Smith RJ. Hereditary Hearing Loss Web site. Available at: http://dnalab-www.uia.ac.be/dnalab/hhh/.
Accessed December 2001.
9. Kumar S, Deffenbacher K, Marres HA, Cremers CW, Kimberling WJ. Genomewide search and genetic localization of a second gene associated
with autosomal dominant branchio-oto-renal syndrome: clinical and genetic
implications. Am J Hum Genet. 2000;66:1715-1720.
FULL TEXT
|
ISI
| PUBMED
10. Cremers CW, Thijssen HO, Fischer AJ, Marres EH. Otological aspects of the earpit-deafness syndrome. ORL J Otorhinolaryngol Relat Spec. 1981;43:223-239.
PUBMED
11. Widdershoven J, Monnens L, Assmann K, Cremers CW. Renal disorders in the branchio-oto-renal syndrome. Helv Paediatr Acta. 1983;38:513-522.
ISI
| PUBMED
12. Fraser FC, Sproule JR, Halal F. Frequency of the branchio-oto-renal (BOR) syndrome in children with
profound hearing loss. Am J Med Genet. 1980;7:341-349.
FULL TEXT
|
ISI
| PUBMED
13. O'Neill G, Frosh AC, Jayaraj SM. Systematic errors in bone conduction audiometry. Clin Otolaryngol. 2000;25:468-470.
PUBMED
14. Cremers CW, Marres EH. Deafness and hypacusis combined with branchiogenic and sometimes renal
congenital abnormalities. Ned Tijdschr Geneeskd. 1977;121:1676-1679.
PUBMED
15. Cremers CW. Congenital pre-auricular fistula communicating with the tympanic cavity. J Laryngol Otol. 1983;97:749-753.
PUBMED
16. Cremers CW, Marres HA, Brunner HG. Neo-oval window technique and myringo-chorda-vestibulopexy in the BOR
syndrome. Laryngoscope. 1993;103:1186-1189.
PUBMED
17. Kemperman MH, Stinckens C, Kumar S, Huygen PL, Joosten FB, Cremers CW. Progressive fluctuant hearing loss, enlarged vestibular aqueduct, and
cochlear hypoplasia in branchio-oto-renal syndrome. Otol Neurotol. 2001;22:637-643.
PUBMED
18. Kumar S, Kimberling WJ, Lanyi A, et al. Narrowing the genetic interval and yeast artificial chromosome map
in the branchio-oto-renal region on chromosome 8q. Genomics. 1996;31:71-79.
FULL TEXT
|
ISI
| PUBMED
19. Okamoto K, Ito J, Furusawa T, Sakai K, Horikawa S, Tokiguchi S. MRI of enlarged endolymphatic sacs in the large vestibular aqueduct
syndrome. Neuroradiology. 1998;40:167-172.
FULL TEXT
|
ISI
| PUBMED
20. Harnsberger HR, Dahlen RT, Shelton C, Gray SD, Parkin JL. Advanced techniques in magnetic resonance imaging in the evaluation
of the large endolymphatic duct and sac syndrome. Laryngoscope. 1995;105:1037-1042.
ISI
| PUBMED
21. Cremers CW, Teunissen E. The impact of a syndromal diagnosis on surgery for congenital minor
ear anomalies. Int J Pediatr Otorhinolaryngol. 1991;22:59-74.
PUBMED
22. Stinckens C, Standaert L, Casselman JW, et al. The presence of a widened vestibular aqueduct and progressive sensorineural
hearing loss in the branchio-oto-renal syndrome a family study. Int J Pediatr Otorhinolaryngol. 2001;59:163-172.
PUBMED
23. Cremers CW, Admiraal RJ, Huygen PL, et al. Progressive hearing loss, hypoplasia of the cochlea and widened vestibular
aqueducts are very common features in Pendred syndrome. Int J Pediatr Otorhinolaryngol. 1998;45:113-123.
FULL TEXT
|
ISI
| PUBMED
24. Fukuda S, Kuroda T, Chida E, et al. A family affected by branchio-oto syndrome with EYA1 mutations. Auris Nasus Larynx. 2001;28(suppl):S7-S11.
25. Usami S, Abe S, Weston MD, Shinkawa H, Van Camp G, Kimberling WJ. Non-syndromic hearing loss associated with enlarged vestibular aqueduct
is caused by PDS mutations. Hum Genet. 1999;104:188-192.
FULL TEXT
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ISI
| PUBMED
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