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Auditory Dysfunction in Stickler Syndrome
Yvonne M. Szymko-Bennett, PhD;
Mary A. Mastroianni, MS;
Lawrence I. Shotland, PhD;
Joie Davis, CPNP, MSN;
Frank G. Ondrey, MD, PhD;
Joan Z. Balog, RN, MSN;
Susan F. Rudy, MSN, CRNP, CORLN;
Linda McCullagh, MSN;
Howard P. Levy, MD;
Ruth M. Liberfarb, MD, PhD;
Clair A. Francomano, MD;
Andrew J. Griffith, MD, PhD
Arch Otolaryngol Head Neck Surg. 2001;127:1061-1068.
ABSTRACT
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Objectives To characterize the natural history and possible mechanisms of hearing
loss in Stickler syndrome (OMIM 108300; or hereditary progressive arthro-ophthalmopathy)
and to determine if the auditory phenotype is a useful discriminating feature
for the differential diagnosis of this group of disorders.
Design Multifamily study.
Setting Outpatient audiology and otolaryngology clinics at the Warren Grant
Magnuson Clinical Center of the National Institutes of Health, Rockville,
Md.
Subjects Forty-six affected individuals from 29 different families segregating
Stickler syndrome.
Interventions Clinical audiologic and otolaryngological examinations were performed
on all individuals, including pure-tone audiometry, speech audiometry, and
middle ear immittance testing. Otoacoustic emissions, auditory brainstem response,
infrared video electronystagmography, and temporal bone computed tomography
were performed on a subset of participants.
Results The hearing loss was most often sensorineural in adults, and approximately
28 (60%) of the 46 adult patients had 2 or more thresholds greater than the
corresponding 95th percentile values for an age-matched, otologically normal
population. The hearing loss most often affected high frequencies (4000-8000
Hz) and was generally no more progressive than that due to age-related hearing
loss. Type AD tympanograms (classification using the Jerger model),
indicating hypermobile middle ear systems, were observed in 21 (46%) of the
46 affected individuals. Computed tomography of the temporal bones revealed
no inner ear malformations in 19 affected individuals.
Conclusions The hypermobile middle ear systems observed in ears with normal-appearing
tympanic membranes represent a novel finding for Stickler syndrome and are
likely to be a useful diagnostic feature for this disorder. The overall sensorineural
hearing loss in type I Stickler syndrome is typically mild and not significantly
progressive. It is less severe than that reported for types II and III Stickler
syndrome linked to COL11A2 (OMIM 120290) and COL11A1 (OMIM 120280) mutations, respectively, or the closely
related Marshall syndrome. This difference will be a useful discriminatory
feature in the differential diagnosis of this group of disorders.
INTRODUCTION
STICKLER SYNDROME is an autosomal dominant disorder characterized by
vitreoretinal anomalies, joint laxity, palatal clefting, facial dysmorphism,
and hearing loss.1 Stickler syndrome is phenotypically
similar to Marshall syndrome, which has led to extensive debate about their
nosologic relationship. Marshall syndrome has been proposed to differ from
Stickler syndrome based on the persistence of distinctive craniofacial dysmorphic
features into adulthood. The hearing loss in Stickler syndrome has been reported
to be variable and can be sensorineural, conductive, or mixed.2
The hearing loss has not been well characterized owing to this variability
and the few patients studied in any one series.3-8
Stickler syndrome is genetically heterogeneous and may be associated
with mutations in any 1 of at least 3 collagen genes: COL2A1, COL11A2, or COL11A1.
Type I Stickler syndrome is caused by premature termination mutations in the
fibrillar collagen gene COL2A1. Type II, also called
"nonocular Stickler syndrome," "Weissenbach-Zweymueller syndrome," or "heterozygous
otospondylomegaepiphyseal dysplasia" (OSMED), is associated with missense
or in-frame deletion mutations in COL11A2 and is
not associated with ocular abnormalities, which makes it readily distinguishable
from types I and III.9-12
Type III is caused by mutations in COL11A1 and may
be distinguished from types I and II based on the appearance of the ocular
vitreous in slitlamp examination.13-14
However, at least some cases of Stickler syndrome are not linked to these
3 fibrillar collagen genes.15
Marshall syndrome is caused by splice-site mutations or genomic deletions
in 54–base pair (bp) exons in the C-terminal region of COL11A1,16 whereas other types of COL11A1 mutations cause type III Stickler syndrome.16-17 Annunen et al17
in 1999 reported that the hearing loss associated with type III Stickler syndrome
or Marshall syndrome seemed to be more severe than that associated with type
I Stickler syndrome. Although this genotype-phenotype correlation may provide
a useful discriminating clinical feature for the differential diagnosis of
these disorders, audiometric data were not shown or reported to support the
authors' conclusion.17
The pathogenesis of hearing loss in these disorders is unknown, as there
are currently no published reports of radiological or histopathologic studies
of temporal bones of individuals with Stickler syndrome. A previous report
of a single kindred segregating the closely related Marshall syndrome indicated
that the hearing loss was not associated with gross dysmorphogenesis of the
osseous labyrinth.18 We have studied a series
of individuals with Stickler syndrome to characterize the natural history
and possible mechanisms of hearing loss in this disorder and to determine
if the auditory phenotype is a useful discriminating feature for the differential
diagnosis of this group of disorders.
SUBJECTS, MATERIALS, AND METHODS
SUBJECTS
Forty-six individuals from 29 families segregating Stickler syndrome
composed the study group. The diagnosis of Stickler syndrome was based on
family history and clinical evaluation by a medical geneticist (H.P.L., R.M.L.,
or C.A.F.). Nineteen males and 27 females, ranging in age from 9 months to
70 years (average age, 22.8 years for males and 38.8 years for females), participated
in this study after receiving informed consent. This study was approved by
the institutional review board of the National Human Genome Research Institute,
National Institutes of Health, Rockville, Md.
CLINICAL EVALUATIONS
Otolaryngological histories were obtained and physical examinations,
including pneumatic otoscopy, were performed on each subject. Audiologic evaluations
consisted of pure-tone air and bone conduction audiometry, speech audiometry,
and middle-ear immittance testing (tympanometry and acoustic reflex testing)
in American National Standards Institute (ANSI)–approved conditions.19-20 Young children were evaluated by
play or visual reinforcement audiometry according to their age. Some patients
also underwent transient-evoked or distortion product otoacoustic emissions
testing (model ILO96 Otodynamic Analyzer; Otodynamics, London, England) or
auditory brainstem response testing (Nicolet Spirit; Nicolet Biomedical Inc,
Madison, Wis). Six of the patients underwent video electronystagmography testing
(House IR/Video ENG System, Torrance, Calif, Copyright Eye Dynamics, 1997).
Nineteen of the 46 patients underwent computed tomography of the temporal
bones with 1-mm axial and coronal sections.
CLINICAL DATA ANALYSIS
The type of hearing loss was classified as sensorineural, conductive,
or mixed according to the European Working Group on Genetics of Hearing Impairment.21 Conductive hearing loss was defined as normal bone
conduction thresholds (<20 dB) and an averaged air-bone gap of 15 dB or
more for 500, 1000, and 2000 Hz. Mixed hearing loss was defined as a bone
conduction threshold greater than 20 dB in combination with an averaged air-bone
gap 15 dB or more for 500, 1000, and 2000 Hz. Sensorineural hearing loss was
defined as an averaged air-bone gap of less than 15 dB for 500, 1000, and
2000 Hz.
The degree of hearing loss was categorized in 2 different ways: employment
of commonly used age-independent clinical guidelines,22
and comparison of thresholds to age-dependent percentiles.23-24
The age-independent analysis defined degree of hearing loss as the greatest
observed degree of impairment at any threshold according to the age-independent
guidelines established by the World Health Organization.22
Impairment was audiometrically classified using the following pure-tone threshold
ranges: normal, 0 to 25 dB; mild, 26 to 40 dB; moderate, 41 to 55 dB; moderately
severe, 56 to 70 dB; severe, 71 to 90 dB; and profound, 91 to 110 dB.
The age-dependent analysis of the degree of hearing loss plotted pure-tone
air conduction thresholds at 500, 1000, 2000, and 4000 Hz, and pure-tone averages
(PTAs) for 500, 1000, and 2000 Hz, against corresponding 95th percentiles.23 Similarly, pure-tone air conduction thresholds at
8000 Hz were plotted against corresponding 90th percentile values.24 Ninety-fifth percentile values for 500, 1000, 2000,
and 4000 Hz were obtained from a uniformly otologically screened population,23 and 90th percentile values for 8000 Hz were obtained
from the 1990 International Organization for Standardization standards.24 Ninetieth percentile values were chosen for 8000
Hz owing to a lack of established 95th percentile data for this frequency.
The percentage of study subjects with pure-tone thresholds above the
95th percentile was calculated separately for men and women 25 years and older.
Air conduction thresholds were used for the analysis at frequencies with no
air-bone gap, whereas bone conduction thresholds were used at frequencies
with air-bone gaps of 15 dB or more. Only data from subjects with complete
sets of bone conduction thresholds were included. Subjects with a history
of trauma, otologic surgery, ototoxic reactions, noise exposure, or concurrent
medical conditions known to cause hearing loss were excluded from the analysis.
Configuration of hearing loss was classified according to the European
Working Group on Genetics of Hearing Impairment.21
Audiometric configurations were defined as midfrequency U-shaped, 15-dB or
more difference between the poorest thresholds in the midfrequencies and those
at higher frequencies; low-frequency ascending, 15-dB or more from the poorer
thresholds to the higher frequencies; flat, less than 15-dB difference between
250 and 8000 Hz; high frequency, 15-dB or more difference between the mean
thresholds at 500 and 1000 Hz and the mean thresholds at 4000 and 8000 Hz.
High-frequency hearing loss was further described as either gently or steeply
sloping.21 Tympanometric results were categorized
according to standardized values for static compliance and tympanometric peak
pressure.25-27
 2 Analysis was used to assess a possible correlation
between a history of otitis media and sensorineural hearing loss. A positive
history of otitis media was categorized as either more than 6, 12, or 20 lifetime
episodes. The presence of sensorineural hearing loss was defined as 2 or more
thresholds in 1 or both ears above the 95th percentile value (for 500, 1000,
2000, or 4000 Hz) or the 90th percentile value for 8000 Hz.23-24
Cross-sectional analysis of hearing loss progression was carried out
in a similar manner to that of Kunst et al.28
Fiftieth percentile thresholds were subtracted from observed thresholds and
plotted vs age to determine the degree of progression relative to that in
a normal population. Fiftieth percentile thresholds for 500 Hz to 4000 Hz
were obtained from Morrell et al23 and 50th
percentile thresholds for 250, 6000, and 8000 Hz were derived from International
Organization for Standardization 1990 standards.24
Linear regression analysis was performed on all normally distributed adjusted
threshold data (see "Clinical Data Analysis" subsection herein). Slopes of
the regression lines were calculated to determine the rate of progression
of hearing loss and were compared with those calculated for the uniformly
otologically screened population.23
Serial audiograms were available for 8 subjects and were analyzed for
linear hearing loss progression according to the European Working Group on
Genetics of Hearing Impairment21: progression
was defined as a deterioration of 15 dB or more in the PTA or in 2 or more
frequencies within a 10-year period.
Pure-tone averages for the subjects with Stickler syndrome were compared
with those for affected individuals of a previously described Marshall syndrome
kindred16 and 5 affected members of a previously
unreported kindred that was ascertained as part of our study. The Shapiro-Wilk
test for normality was performed on both PTA distributions, and a t test was performed to determine if a statistically significant difference
existed between the 2 distributions. Parametric and nonparametric statistical
analyses were performed using JMP software (SAS Institute Inc, Cary, NC).
RESULTS
PURE-TONE AUDIOMETRIC FINDINGS
Table 1 gives the mean PTAs
and air conduction thresholds and their corresponding SDs vs the age of the
affected subjects. Two study subjects were infants whose hearing was evaluated
by sound field audiometry and, therefore, their data could not be included
in Table 1. Table 1 indicates that the mean hearing thresholds are in the normal
to mild range in the frequencies critical for speech (500, 1000, and 2000
Hz). Mean thresholds increased with age and ranged from mild to severe in
the higher frequencies.
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Mean Pure-Tone Averages (PTAs) and Average Air Conduction Thresholds
From 250 to 8000 Hz as a Function of Age for Affected Individuals*
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Figure 1A illustrates the
degree of hearing loss as a function of age of affected subjects. Although
at lower frequency among the oldest age groups, mild impairment was prevalent
among all age groups. A lesser percentage of subjects had hearing loss in
the moderate to profound categories. Profound impairment was most prevalent
in the oldest age group, although these profound losses were only observed
in the highest frequencies. Figure 1B shows the type of hearing loss as a function of age of affected subjects.
Hearing loss in children was most commonly conductive. Normal hearing was
most common in the 21- to 30-year age group, whereas sensorineural hearing
loss becomes more common in the older age groups. Mixed hearing losses were
present in 4 of the 7 age groups. The pure-tone audiometric configuration
was classified into 1 or more of the following categories: high frequency,
midfrequency U-shaped, low-frequency ascending, or flat. Figure 1C shows that high frequencies were most commonly affected,
with increasing prevalence of this configuration in age groups older than
10 years. Low-frequency and midfrequency thresholds were most commonly affected
in the youngest age groups. High-frequency configurations in young children
were gently sloping, whereas older subjects had steeply sloping high-frequency
configurations.
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Figure 1. A, The degree of hearing loss
as a function of age. B, The type of hearing loss vs age of affected individuals.
C, The configuration of hearing loss as a function of age of affected individuals.
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To identify the contribution of the underlying gene mutations to the
observed sensorineural hearing loss, audiometric thresholds at 500, 1000,
2000, 4000, and 8000 Hz, as well as PTAs, were compared with those reported
for an otologically screened population 25 years and older.23-24
Subjects with a history of otologic surgery were excluded from our analysis.
Fourteen had undergone prior placement of 1 or more sets of tympanostomy tubes
and 2 had undergone tympanoplasties (no subjects reported a history of mastoidectomy).
As shown in Figure 2, approximately
60% (14 of the 24 subjects) of all affected adults with complete bone conduction
data had at least 2 thresholds above the 95th percentile or, in the case of
8000 Hz, above the 90th percentile.
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Figure 2. Comparison of thresholds for female
and male subjects 25 years old and older (squares) with 95th percentile data
(diamonds)23 or, for 8000 Hz, the 90th percentile
from International Organization for Standardization 1990 standards24 as follows: A-G, 500 Hz; B-H, 1000 Hz; C-I, 2000
Hz; D-J, 4000 Hz; E-K, 8000 Hz; and F-L, pure-tone average right ear (squares),
and left ear (triangles), respectively. dB HL indicates decibel hearing level.
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2 Analysis revealed no statistically significant correlation
between the number of episodes of otitis media with sensorineural hearing
loss at 500, 1000, 2000, and 4000 Hz (P = .59, .75,
and .75, for  6 [n = 9], 12 [n = 4], and 20 [n = 4] episodes of
otitis media per lifetime, respectively). Six of 32 adults were excluded from
this analysis because of incomplete data, and 2 were excluded because of a
history of otologic surgery (tympanoplasty). There was also no correlation
between the number of episodes of otitis media with sensorineural hearing
loss at 8000 Hz (P = .47, .24, and .24, for 6, 12,
and 20 episodes per lifetime, respectively).
MIDDLE-EAR IMMITTANCE RESULTS
Type A tympanograms, representing normal middle ear mobility and pressure,
were observed in 18 (39%) of the 46 ears (Figure 3). Type B tympanograms, representing hypomobile middle ear
systems, were observed in 5 (12%) of the 46 ears and could be attributed to
patent tympanostomy tubes, middle ear effusions, or tympanic membrane perforations.
Type C tympanograms, with negative tympanometric peak pressures, were observed
in 2 (4%) of the 46 ears, and type AD tympanograms were found in
21 (46%) of the 46 ears. The average ages of the subjects with types A, B,
C, and AD tympanograms were 37, 5, 11, and 33 years, respectively.
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Figure 3. Percentage of ears with indicated
tympanometric findings. The Jerger model of classification was used.
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The type AD tympanogram, representing hypermobile middle
ear systems, was the most common tympanometric type seen in our patients (Figure 3). The mean (±SD) static compliance
was 2.9 ± 1.3 mmho for adults and 2.2 ± 0.6 mmho for 13 children
with demonstrated hypermobile middle ear systems in at least 1 ear. Approximately
14 (31%) of 46 ears had type AD tympanograms with normal-appearing
tympanic membranes examined by pneumatic otoscopy. Seven (15%) of 46 ears
with type AD tympanograms had tympanic membranes that were abnormally
flaccid and thin in at least one portion or all of the membrane; pneumatic
otoscopy revealed that the amplitude of motion of these latter membranes was
disproportionately greater than that of the long process of the malleus.
ANALYSIS OF HEARING LOSS PROGRESSION
There were several anamnestic reports of progression of hearing loss
among the study subjects. Longitudinal analysis revealed that 4 of 8 subjects
with serial audiograms had progressive hearing loss according to the criterion
proposed by the European Working Group on Genetics of Hearing Impairment21 (data not shown).
A strong ascertainment bias would be present in an analysis restricted
to this small subset of study subjects who had previously undergone audiometric
testing. Therefore a cross-sectional analysis of age-adjusted binaural hearing
thresholds was performed for subjects aged from 25 to 65 years (Figure 4). The Shapiro-Wilk test for normality revealed that the
500- and 2000-Hz adjusted threshold data were not normally distributed, thus
prohibiting linear regression analysis of these data. Moreover, most of the
hearing losses primarily affected high frequencies (Figure 1C). Linear regression analysis was performed only on the
4000-, 6000-, and 8000-Hz thresholds. Figure
4 shows the regression analysis of pure-tone air conduction audiometric
thresholds from 4000 to 8000 Hz. Slopes of the regression lines in the cross-sectional
analysis of hearing thresholds in this study were: -0.03 dB per year
at 4000 Hz, 0.16 dB per year at 6000 Hz, and 0.25 dB per year at 8000 Hz,
with the absolute mean value slope of 0.12 dB per year. Data of Morrell et
al23 revealed a maximum slope of approximately
2 dB per year at all of the frequencies they analyzed. Therefore, there was
little, if any, progression of thresholds above that expected from normal
aging from 25 to 65 years in our study.
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Figure 4. Cross-sectional analysis of hearing
threshold as a function of age. Linear regression lines and their corresponding
equations are shown for the 3 sets of data at 4000, 6000, and 8000 kHz. dB
HL indicates decibels hearing level.
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Figure 5 shows the PTAs of
subjects with Marshall16 and Stickler syndromes
as a function of age. A Shapiro-Wilk test revealed normal distributions for
both the Marshall syndrome–affected and Stickler syndrome–affected
groups, with the median PTAs for the Marshall syndrome cohort being a 50-dB
hearing level, and for the Stickler syndrome cohort being a 17-dB hearing
level. A t test revealed that these medians were
significantly different (P<.00). Linear regression
analysis demonstrated that the slope of the regression line for the Marshall
syndrome PTAs was significantly greater than that for the Stickler syndrome
PTAs (0.61 dB and 0.13 dB, respectively). Although there is considerable variability
in the Stickler syndrome PTAs, these data are consistent with the observation
of Annunen et al17 that individuals with Marshall
syndrome have a more severe auditory phenotype than individuals with Stickler
syndrome.
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Figure 5. Pure-tone averages as a function
of age for individuals with Marshall (solid circles and solid triangles) and
Stickler syndromes (open circles and triangles). dB HL indicates decibels
hearing level.
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OTHER FINDINGS
Results of infrared videovestibular testing were incomplete in 6 subjects
and confounded by concurrent ocular pathologic abnormality. Vestibular symptoms
and signs were infrequent and consistent with imbalance rather than true vertigo.
These findings were usually attributable to the typical rheumatologic and
ocular abnormalities of Stickler syndrome.
Otoacoustic emissions testing in 7 subjects revealed responses that
were consistent with the degree of hearing loss.29-30
Specifically, distortion product otoacoustic emissions and transient-evoked
otoacoustic emissions accurately identified auditory status between 2000 and
4000 Hz, with the most robust emissions obtained when audiometric thresholds
were lower than the 30-dB hearing level. As expected, emissions were absent
in subjects with thresholds above 30 dB in the range of 1000 to 4000 Hz. Temporal
bone computed tomographic scans of 19 affected subjects revealed no malformations
of the inner or middle ears.
COMMENT
We have observed that the hearing loss in Stickler syndrome is typically
mild overall and sensorineural with a steeply sloping, high-frequency configuration
in adults, whereas it is most commonly conductive in children. The observed
conductive hearing loss in children may be due to chronic otitis media or
its sequelae, which commonly occurs in this population. Approximately 26 (60%)
of our 44 adult subjects with Stickler syndrome had 2 or more thresholds above
the 95th percentile, indicating that the sensorineural hearing loss in this
disorder is an incompletely penetrant trait. These results are consistent
with those of previous reports of smaller series of patients.3-7
Type AD tympanograms were a common immittance finding in
our subjects and have not been previously reported for Stickler syndrome.
This tympanometric finding was not significantly associated with conductive
hearing loss at any frequency in our study (not shown). Hypermobility was
sometimes associated with thin, visibly hyperflaccid tympanic membranes, which
is a common and otoscopically detectable sequela of chronic or recurrent otitis
media and/or previous tympanostomy tubes. However, 6 (21%) of 28 affected
subjects with hypermobility had completely normal-appearing tympanic membranes
and no history of otitis media or previous tympanostomy tube insertions. Type
II collagen is known to be present in the tympanic membrane and the ossicular
joints31 and, therefore, hypermobility may
be a sequela of otitis media, a direct result of the primary collagen defect,
or a combination of both of these factors. We postulate that the type AD tympanograms asssociated with normal-appearing tympanic membranes
may be due to ossicular joint hypermobility, since hypermobility is also commonly
observed in other articular joints in patients with Stickler syndrome. Ossicular
joint hypermobility may be a useful diagnostic feature for Stickler syndrome.
Although 4 (50%) of the 8 subjects with serial audiograms had progressive
hearing loss, this ratio is likely to be an artificially high estimate due
to ascertainment bias. Subjects with the most severe or progressive hearing
loss were more likely to have had serial audiograms prior to their participation
in our study. Our regression analysis of cross-sectional, age-adjusted hearing
thresholds indicates that there is minimal progression beyond that associated
with normal aging in individuals with Stickler syndrome. Therefore, the sensorineural
component of the hearing loss caused by most Stickler syndrome mutations seems
to be stable over long periods.
Nonprogressive hearing loss has also been reported in families with
nonsyndromic deafness DFNA13 and Stickler syndrome mutations in COL11A2, although the sensorineural hearing loss associated with these
mutations is more severe and appears to affect the middle and lower frequencies
to a greater degree than we observed in our study subjects.3, 32
In contrast, the hearing loss caused by type III Stickler syndrome and Marshall
syndrome mutations in COL11A1 is much more severe
and progressive than that observed in our patients.3, 16
Since none of our families with Stickler syndrome had ocular or craniofacial
phenotypic features that were suggestive of linkage to COL11A2 or COL11A1,14, 17
it is likely that most, if not all, of our subjects segregate type I Stickler
syndrome (ie, mutations in COL2A1). The mild, nonprogressive
sensorineural hearing loss we observed in our subjects may be used to clinically
distinguish these patients from those with hearing loss linked to COL11A1 mutations17 (Figure 1A), or to the more severe, nonprogressive sensorineural
hearing loss associated with COL11A2 mutations. This
hypothesis is being addressed by ongoing genotypic analyses of our study subjects.
Lastly, while the hearing loss attributable to the collagen mutations may
be mild and nonprogressive, there will still be age-related changes that will
make individuals with Stickler syndrome at risk for severe or profound hearing
loss, especially in the high frequencies.
The sensorineural component of the hearing loss may be directly due
to recurrent or chronic otitis media in these patients. However, there was
no correlation between sensorineural hearing loss and the number of episodes
of otitis media in our subjects. Moreover, the hearing loss is not associated
with malformations of the osseous labyrinth as detected by temporal bone computed
tomographic scans. It is possible that there are subtle structural malformations
of the osseous or membranous labyrinths that may be detectable with more sensitive
imaging techniques such as magnetic resonance imaging. We hypothesize that
Stickler syndrome mutations affect sound transmission within the cochlea by
altering mechanical properties of the cochlear partition. Collagen fibrils
are thought to contribute tensile strength33-34
to the tissues in which they are expressed. Mutations affecting fibril morphology
may alter their tensile strength, resulting in a range of disease phenotypes
that can include osteogenesis imperfecta33
and Stickler syndrome. These observations are consistent with the observation
of expression of Col2A1, Col11A1, and Col11A2 messenger RNA in soft tissue
elements of the mouse cochlea35 and in earlier
studies demonstrating expression of type II collagen within the cochlea.36-37 Differing effects of Marshall and
Stickler syndrome mutations on auditory function may reflect differing contributions
of these collagen genes to the synthesis, structure, and function of the extracellular
matrix within the cochlea. These alterations could directly affect sound mechanotransduction,
or they may also cause abnormal mechanical stress forces leading to hair cell
degeneration and sensorineural hearing loss.
We are analyzing the correlation of hearing loss with extra-auditory
phenotypic features such as palatal clefting, as well as the underlying fibrillar
collagen genotypes in these patients. Our results and those of future studies
should extend our understanding of how the extracellular matrix and its fibrillar
collagens contribute to normal auditory function. They will also facilitate
the diagnosis and care of patients with Stickler syndrome and its related
disorders.
AUTHOR INFORMATION
Accepted for publication May 16, 2001.
This work was supported by intramural funds Z01 DC 00054-01 and Z01
DC 00055-01 from the National Institute on Deafness and Other Communication
Disorders, National Institutes of Health (NIH).
Presented at the Association for Research in Otolaryngology Midwinter
Meeting, St Petersburg Beach, Fla, February 23, 2000.
We thank all of the families who participated in this study. We gratefully
acknowledge the NIH Center for Information Technology for their help in the
statistical analysis. We also thank Carter Van Waes, MD, PhD, and Jeff Kim,
MD, for their assistance in the clinical otolaryngological evaluations and
manuscript review, and Thomas Friedman, PhD, for reviewing the manuscript.
Corresponding author and reprints: Andrew J. Griffith, MD, PhD, National
Institute on Deafness and Other Communication Disorders, National Institutes
of Health, 5 Research Ct, Room 2A-02, Rockville, MD 20850 (e-mail:
griffita{at}nidcd.nih.gov).
From the Hearing Section, Neuro-Otology Branch (Drs Szymko-Bennett,
Shotland, and Griffith and Mss Mastroianni, Rudy, and McCullagh), Head and
Neck Surgery Branch (Dr Ondrey), Laboratory of Molecular Genetics, National
Institute on Deafness and Other Communication Disorders (Dr Griffith), and
the National Human Genome Research Institute, National Institutes of Health
(Mss Davis and Balog and Drs Levy, Liberfarb, and Francomano), Bethesda, Md.
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