Introduction
Osteogenesis imperfecta is a hereditary connective tissue disorder, with a prevalence of approximately 1 per 15 000 to 20 000 individuals, without gender or ethnic preponderance.Reference Van Dijk and Sillence1 The hallmark features of this clinically heterogeneous syndrome are bone fragility, growth deficiency and bone deformity. Other common characteristics are blue sclerae, hearing loss, dental abnormalities and joint hyperlaxity.Reference Forlino and Marini2
The classical Sillence osteogenesis imperfecta types (I–IV)Reference Sillence, Senn and Danks3 with autosomal dominant inheritance account for 85–90 per cent of the cases.Reference Forlino, Cabral, Barnes and Marini4 In type I, the most frequent type, the patients have blue sclerae, hearing problems and multiple fractures due to osseous fragility. Type II refers to perinatally lethal osteogenesis imperfecta, in which inferior skull ossification, long bone deformities, fractures of the ribs and pulmonary insufficiency are observed. Patients with the severe, non-lethal osteogenesis imperfecta type III suffer from progressive deformation of the skeleton, abnormal dentine, blue sclerae, short stature and scoliosis. Type IV, known as the moderate autosomal dominant form, is characterised by a variable short stature, long bone deformities and, sometimes, blue sclerae.Reference Sillence, Senn and Danks3 These four autosomal dominant osteogenesis imperfecta types are caused by a wide variety of mutations in the genes COL1A1 and COL1A2. Mutations affecting these genes induce abnormalities in the quantity or structure of type I collagen, which is an important protein in bone, skin, sclerae, ligaments and tendons.Reference Forlino, Cabral, Barnes and Marini4
In the last decade, mutations in other genes that contribute to the post-translational modification, folding and cross-linking, mineralisation, and osteoblast differentiation of type I collagen have been related to the more uncommon, autosomal recessive forms of osteogenesis imperfecta. Consequently, the classification as mentioned above has recently been extended with osteogenesis imperfecta types V to XVI, and even more types are expected to be recognised in the future.Reference Forlino and Marini2
Hearing loss is diagnosed in about half of the patients with autosomal dominant osteogenesis imperfecta types I, III and IV.Reference Sillence, Senn and Danks3, Reference Pedersen5–Reference Swinnen, Coucke, De Paepe, Symoens, Malfait and Gentile7 The hearing loss is heterogeneous in terms of onset, type, severity and progression. In addition, no correlation has been found between the presence, configuration, type or severity of hearing loss and the other clinical osteogenesis imperfecta characteristics, type of osteogenesis imperfecta or the mutation.Reference Kuurila, Kaitila, Johansson and Grenman6–Reference Hartikka, Kuurila, Korkko, Kaitila, Grenman and Pynnonen8 Typically, the hearing impairment associated with osteogenesis imperfecta begins as a conductive type, between the second to fourth decade of life, and evolves to a mixed hearing loss because of progressive inner-ear involvement.Reference Kuurila, Kaitila, Johansson and Grenman6, Reference Riedner, Levin and Holliday9–Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14 Occasionally, it manifests in childhood.Reference Kuurila, Grenman, Johansson and Kaitila15
The conductive impairment is caused by ossicular dysfunction associated with otospongiotic changes of the temporal bone structures that induce stapes footplate fixation, sometimes with microfractures or atrophy of the stapedial crura.Reference Pedersen5, Reference Stewart and O'Reilly11, Reference Pillion and Shapiro13, Reference Albahnasawy, Kishore and O'Reilly16 A concomitant sensorineural component arises when the otospongiotic changes proliferate to the retrofenestral labyrinthine bone.Reference Swinnen, Casselman, De Leenheer, Cremers and Dhooge17 Pure sensorineural hearing loss is observed in a minor proportion of osteogenesis imperfecta adults; this is generally less severe and less progressive in comparison with conductive or mixed hearing loss in osteogenesis imperfecta.Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14 Cranial fractures, inner-ear hair cell loss, perilymph haemorrhage, and tectorial membrane and stria vascularis abnormalities have been suggested to be the underlying pathologies of sensorineural hearing loss in osteogenesis imperfecta.Reference Shapiro, Pikus, Weiss and Rowe10, Reference Pillion and Shapiro13
As a gradually increasing hearing loss manifests both in osteogenesis imperfecta adults and children, audiological screening and monitoring in patients with osteogenesis imperfecta is recommended. Timely intervention with hearing aids or appropriate middle-ear surgery may prevent hearing-impaired children with osteogenesis imperfecta from experiencing psychosocial, learning and developmental difficulties. Consecutive audiological testing is also beneficial in adults because they often underestimate the degree of hearing loss.Reference Kuurila, Kaitila, Johansson and Grenman6
There is limited knowledge about the progression of the osteogenesis imperfecta related hearing loss. On the basis of a cross-sectional study in osteogenesis imperfecta type I patients, Garretsen et al. concluded that the gradual increase of osteogenesis imperfecta related hearing loss with age was significantly higher than the increase in hearing loss due to presbyacusis.Reference Garretsen, Cremers and Huygen18 Age-related threshold audiograms for both conductive or mixed hearing loss and sensorineural hearing loss in osteogenesis imperfecta have been developed, in another cross-sectional study.Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14 However, longitudinal research investigating the progression of hearing loss in osteogenesis imperfecta is lacking.
In contrast with cross-sectional surveys, longitudinal research avoids cohort effects, and may describe the progression of hearing loss in both individual osteogenesis imperfecta patients and a group of osteogenesis imperfecta patients. The current follow-up study aimed to longitudinally analyse the progression of osteogenesis imperfecta related hearing loss.
Materials and methods
Subjects
Eighty-four Belgian osteogenesis imperfecta patients who participated in a large study investigating the audiological phenotype of osteogenesis imperfecta were invited to participate in a follow-up study.Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14 Forty-two patients agreed to participate (a total of 84 ears). The study was approved by the Ethics Committee of Ghent University Hospital (‘UZ Ghent’). In accordance with the Declaration of Helsinki, informed consent was obtained from all patients prior to participation.
Ears with a history of stapes surgery or with a suspicion of hearing loss related to causes other than osteogenesis imperfecta were precluded from the analysis in order to reliably map the progression of the osteogenesis imperfecta related hearing loss. Six patients were excluded from the analysis because they had undergone bilateral stapes surgery. Of two patients who underwent unilateral stapes surgery, only the results of the non-operated ears were included in the analysis. There was no clinically relevant noise exposure history in this group of patients.
The audiometric follow-up evaluation comprised acoustic admittance and acoustic stapedial reflex measurements, pure tone audiometry, and transient evoked and distortion product otoacoustic emissions (TEOAEs and DPOAEs) testing. The same protocol was applied to both adult and paediatric osteogenesis imperfecta patients.
Audiological follow-up evaluation
Acoustic admittance and acoustic stapedial reflex measurements
Tympanograms were acquired bilaterally by means of a TympStar 226 Hz (85 dB SPL) probe tone (Grason Stadler, Eden Prairie, Minnesota, USA). The pressure in the ear canal fluctuated from −400 to +200 daPa. The tympanograms were classified into the following types: A, Ad, As, B and C, as defined by Jerger.Reference Jerger19
Ipsilateral acoustic stapedial reflex thresholds were obtained bilaterally for a stimulus at 1.0 kHz (TympStar). The acoustic reflex threshold was defined as normal within the range of 70–100 dB SPL, with an admittance deflection of more than 0.02 ml.Reference Fria, Leblanc, Kristensen and Alberti20
Pure tone audiometry
Auditory sensitivity was assessed bilaterally, applying the Hughson–Westlake method in a sound-isolated room with double walls, and using the Equinox 2.0 personal computer based audiometer (OtoAccess 1.2.1 software; Interacoustics, Assens, Denmark).
Air conduction thresholds (dB HL) were measured at eight audiometric frequencies (0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0 and 8.0 kHz) with a TDH-39 headphone. Bone conduction thresholds (dB HL) were determined at five octave frequencies (0.25, 0.5, 1.0, 2.0 and 4.0 kHz). Contralateral narrow band masking noise was used to obtain masked air conduction thresholds when the inter-aural differences in air conduction or the differences between the air conduction thresholds and the contralateral bone conduction thresholds were larger than 40 dB. An air–bone gap beyond 10 dB required contralateral masking noise to determine masked bone conduction thresholds.
The pure tone average (PTA) was computed for air conduction and bone conduction for each ear by averaging the thresholds at 0.5, 1.0 and 2.0 kHz. The high-frequency PTA was calculated by averaging the air conduction thresholds at 4.0, 6.0 and 8.0 kHz. In addition, the average air–bone gap at 0.5, 1.0 and 2.0 kHz was computed.
Hearing was classified as: (1) normal hearing – PTA air conduction of less than 15 dB HL and average air–bone gap of less than 15 dB; (2) conductive hearing loss – PTA bone conduction of less than 15 dB HL and average air–bone gap of 15 dB or more; (3) pure sensorineural hearing loss – PTA air conduction of 15 dB HL or more and average air–bone gap of less than 15 dB; (4) high-frequency sensorineural hearing loss – high-frequency PTA of more than 30 dB HL; (5) mixed hearing loss – PTA bone conduction of 15 dB HL or more and average air–bone gap of 15 dB or more; or (6) undefined hearing loss – bone conduction thresholds are undefined because of a limited audiometer output.Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14
By comparing the pure tone thresholds with the 95th percentile value for sex- and age-related hearing thresholds (International Organization for Standardization (‘ISO’) 7029 standard),21 osteogenesis imperfecta related hearing loss could be distinguished from presbyacusis. If application of the abovementioned criteria pointed towards a conductive, sensorineural, high-frequency sensorineural or mixed hearing loss, and the air conduction thresholds at three or more frequencies exceeded the International Organization for Standardization 7029 values, the presence of osteogenesis imperfecta related hearing loss was confirmed. The diagnosis of hearing loss was discounted when the air conduction thresholds corresponded with the 95th percentile normal threshold values.
The severity of hearing loss was classified as: mild when the air conduction PTA was at least 15 dB HL and better than 40 dB HL; moderate when the air conduction PTA was at least 40 dB HL and better than 70 dB HL; severe when the air conduction PTA was at least 70 dB HL and better than 95 dB HL; or profound when the air conduction PTA was at least 95 dB HL.Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14
Otoacoustic emissions
The TEOAEs and DPOAEs were both examined in a sound-isolated room with double walls. The signal-to-noise ratio was used to determine the presence of TEOAEs and DPOAEs at each frequency from 1.0 to 4.0 kHz and from 1.0 to 8.0 kHz, respectively.
The TEOAE measurements were performed by using an acoustic click with a duration of 80 μs, and with an intensity of 80 dB peak equivalent sound pressure level, and by alternating polarity (Otoport Advanced ILOV6 software; Otodynamics, Hatfield, UK). In general, TEOAEs were considered present if at least three out of five frequency bands showed a signal-to-noise ratio of at least 3 dB.Reference Vinck, De Vel, Xu and Van Cauwenberge22
In DPOAE measurements, two pure tones were delivered with a frequency ratio of 1.22 (f2 / f1 = 1.22; f2 > f1) and an intensity (I) of 65 and 55 dB SPL (I1 > I2), resulting in the measurement of the combination tone (2f1-f2) (Otoport Advanced ILOV6 software). The DPOAEs were considered as present if at least five out of seven frequency bands showed a signal-to-noise ratio of at least 3 dB.Reference Keppler, Dhooge, Degeest and Vinck23, Reference Degeest, Clays, Corthals and Keppler24
Statistical analysis
Data were analysed with SPSS® statistical software, version 21.0. Descriptive statistics were performed to compare the prevalence of normal or aberrant results from the first and second evaluation for each audiological test. The Kolmogorov–Smirnov test and the Shapiro–Wilk test were applied to evaluate the normal distribution of continuous variables. The Wilcoxon matched-pairs signed rank test was used to compare thresholds averaged over three frequencies between both audiometric evaluation times, because normal distribution was not achieved in these variables. In all analyses, a significance level of 0.05 was applied.
Results
Population characteristics
Measurements corresponding to 70 ears from 36 different patients aged 6–79 years (including both ears of 34 patients and one ear of 2 patients with unilateral stapes surgery) at the first and second audiological evaluations were analysed to map the progression of osteogenesis imperfecta related hearing loss. The population characteristics are summarised in Table I. The mean time interval between the first and second evaluations was four years and one month (standard deviation = 8 months).
Population characteristics
* Total n = 31 (86.1%); †total n = 5 (13.9%). SD = standard deviation
Audiometric evaluation
The air conduction PTA, bone conduction PTA, high-frequency PTA and average air–bone gap of all 70 ears were compared between both evaluation times. A significant increase of air conduction PTA (p < 0.001, Wilcoxon signed rank test), bone conduction PTA (p < 0.001, Wilcoxon signed rank test) and high-frequency PTA (p < 0.001, Wilcoxon signed rank test) was found at the second audiological evaluation, in comparison with the first evaluation. In contrast, the average air–bone gap did not significantly differ between both evaluations (Wilcoxon signed rank test).
In order to discount the possibility that the significant increases of air conduction PTA and high-frequency PTA at the second audiological evaluation were caused by increased age, air conduction PTAs and high-frequency PTAs at both the first and second evaluations were subtracted from the averaged 95th percentile values for sex- and age-related hearing thresholds (International Organization for Standardization 7029 standard).21 The difference between air conduction PTA and sex- and age-related thresholds was significantly larger at the first evaluation compared to the second evaluation (p < 0.05, Wilcoxon signed rank test). In contrast, no significant differences were found between the age- and sex-corrected high-frequency PTAs at the first versus the second audiological evaluation (Wilcoxon signed rank test).
Hearing was impaired in 22 out of 60 adult ears (36.7 per cent) at the first audiological evaluation, and in 24 out of 60 adult ears (40.0 per cent) at the second evaluation. No hearing loss was identified in the 10 evaluated children's ears. The different types of hearing loss are shown in Figure 1. Occurrence and type of hearing loss were not associated with the clinically diagnosed osteogenesis imperfecta type (Table II). The severity of hearing loss is represented in Figure 2. The severity and type of hearing loss were compared between the first and second audiological evaluations. Ten hearing-impaired ears showed an alteration in severity and/or type of hearing loss from the first to the second audiological evaluation, all of which are listed in Table III.
Occurrence and types of hearing loss in 70 ears with osteogenesis imperfecta at first and second audiometric evaluations, with a mean time interval of 4 years and 1 month. SN = sensorineural; HF = high-frequency
Severity of hearing loss in the hearing-impaired ears of osteogenesis imperfecta patients at the first (n = 22) and second (n = 24) audiometric evaluations, with a mean time interval of four years and one month. Classification of severity is based on pure tone averages of air conduction thresholds at 0.5, 1.0 and 2.0 kHz, as described in the main text.
Hearing loss occurrence and type as a function of clinical osteogenesis imperfecta type*
Data represent numbers of ears.
* Total ears n = 70. SNHL = sensorineural hearing loss
Overview of hearing-impaired ears with changes in hearing loss severity and/or type between first and second audiometric evaluation
* Note that ‘+’ indicates present and ‘−’ represents absent. Pt no. = patient number; y = years; ASR = acoustic stapedius reflex; TEOAE = transient evoked otoacoustic emissions; DPOAE = distortion product otoacoustic emissions; L = left ear; F = female; mth = months; SNHL = sensorineural hearing loss; R = right ear; N/A = not available
Acoustic admittance measurements
Acoustic admittance measurements were performed in 69 out of 70 ears (98.6 per cent) at the first audiological evaluation and in 65 out of 70 ears (92.9 per cent) at the second evaluation. Measurements were missing in one ear with a moderate mixed hearing loss at the first and second audiological evaluation because stapes surgery was performed in the other ear before the first evaluation and the patient was fearful of undergoing the test. In addition, acoustic admittance measurements were not performed in both ears of a 79-year-old patient with severe and profound undefined hearing loss at the second audiological evaluation to limit the test time for this individual. Acoustic admittance measurements were also not available at the second audiological evaluation in another patient fearful of this test, who had bilateral high-frequency sensorineural hearing loss.
Type A tympanograms were the most prevalent, being found in 75.4 per cent (52 out of 69) of the ears at the first audiological evaluation and 73.8 per cent (48 out of 65) of the ears at the second evaluation. Type Ad tympanograms were found in 18.8 per cent (13 out of 69) of the ears at the first audiological evaluation and in 18.5 per cent (12 out of 65 ears) of the ears at the second evaluation. No association was found between the type of tympanogram and the occurrence or type of hearing loss. Of the remaining ears, type As tympanograms were found in 1.4 per cent (1 out of 69) at the first audiological evaluation and 7.7 per cent (5 out of 65) at the second evaluation; type B tympanograms were found in 2.9 per cent (2 out of 69) at the first evaluation; and type C tympanograms were found in 1.4 per cent (1 out of 69) at the first evaluation.
Acoustic admittance measurements were performed in 65 ears at both evaluation times. In 11 of these ears (16.9 per cent), the type of tympanogram was different at the first audiological evaluation compared to the second evaluation. All ears with an altered tympanometric shape had an unaltered type of hearing loss. Two of these ears (case number 20 (right and left ears); Table III) showed a change in hearing loss severity.
Ipsilateral acoustic stapedial reflex measurements
Acoustic stapedial reflexes were measured in 67 out of 70 ears (95.7 per cent) at the first audiological evaluation and in 65 out of 69 ears (92.9 per cent) at the second evaluation. However, no measurements were obtained for the ears already described in the Acoustic admittance measurements section above. In addition, acoustic stapedial reflex measurements were missing in both ears of a six-year-old boy (case number 5) at the first audiological evaluation.
In the majority of the ears with normal hearing, acoustic stapedial reflexes were elicited at both measurement times: in 91.3 per cent and 84.8 per cent of normal-hearing ears at the first and second audiological evaluations, respectively. At both evaluations, acoustic stapedial reflexes were absent in all ears with a conductive hearing loss component, and in most of the ears with a sensorineural or high-frequency sensorineural hearing loss.
In 63 ears, acoustic stapedial reflexes were tested at both evaluations. In 10 ears, a change in the presence of acoustic stapedial reflexes between both measurements took place. In four normal-hearing ears and one ear with a mild high-frequency sensorineural hearing loss, acoustic stapedial reflexes were registered at the first audiological evaluation but were absent at the second evaluation, without an alteration in the presence or type of hearing loss. However, high-frequency PTA increased in one of these normal-hearing ears from 6.7 dB HL at the first audiological evaluation to 18.3 dB HL at the second evaluation, and in another ear from 8.3 dB HL to 16.7 dB HL. In one ear with a mild mixed hearing loss at both measurements, acoustic stapedial reflexes were absent at the first audiological evaluation, but present with an acoustic reflex threshold of 100 dB SPL at the second evaluation. The average air–bone gap in this ear changed from 30 dB at the first audiological evaluation to 15 dB at the second evaluation. One normal-hearing child had bilaterally absent acoustic stapedial reflexes at the first audiological evaluation, but acoustic stapedial reflexes were present at the second evaluation. The average air–bone gap in this individual decreased from 6.7 dB (right ear) and 11.7 dB (left ear) at the first audiological evaluation to 0.0 dB in both ears at the second evaluation, and the tympanogram changed from type B to type As bilaterally. The hearing changed in one ear (case number 16 (left ear); Table III) from normal hearing with a present acoustic stapedial reflex to high-frequency sensorineural hearing loss with an absent acoustic stapedial reflex. In another patient, both ears (case number 28; Table III) changed from normal hearing with a present acoustic stapedial reflex to mild sensorineural hearing loss with an absent acoustic stapedial reflex.
Otoacoustic emissions
Transient evoked and distortion product otoacoustic emissions (TEOAEs and DPOAEs) were only measured at the second audiological evaluation in 68 out of 70 ears.
Transient evoked otoacoustic emissions
The TEOAEs were absent in 22 out of 68 ears (32.4 per cent): 3 normal-hearing ears, 2 ears with mild conductive hearing loss, 2 ears with mild sensorineural hearing loss, 10 ears with mixed hearing loss, 2 ears with profound hearing loss and 3 ears with high-frequency sensorineural hearing loss (of which, 2 had mild severity and 1 had moderate severity).
Conversely, TEOAEs with a signal-to-noise ratio of at least 3 dB at three or more frequency bands were found in 43 normal-hearing ears and in 3 ears with sensorineural hearing loss. In these 43 normal-hearing ears, TEOAEs at 1.0 and 4.0 kHz were more often absent in comparison with TEOAEs at 1.4, 2.0 and 2.8 kHz (Table IV). The TEOAEs at 2.0, 2.8 and 4.0 kHz were present in all three ears with mild sensorineural hearing loss. In one of these ears, TEOAEs were present at all frequencies. In the lower frequencies (1.0 and 1.4 Hz), TEOAEs were absent in two ears with sensorineural hearing loss (Table IV).
Ears with present TEOAEs at each frequency band*
Data represent percentages of ears, unless indicated otherwise.
* Signal-to-noise ratio of more than 3 dB. TEOAEs = transient evoked otoacoustic emissions; SNHL = sensorineural hearing loss
Distortion product otoacoustic emissions
In 18 out of 46 normal-hearing ears (39.1 per cent), DPOAEs were present at all seven frequencies. In 16 normal-hearing ears (34.8 per cent), DPOAEs were present at six frequencies. Nevertheless, DPOAEs were present at less than five frequencies in six normal-hearing ears (13 per cent). The DPOAEs at 8.0 kHz were present in less than 50 per cent of the normal-hearing ears, whereas DPOAEs at all other frequencies (1.0, 1.4, 2.0, 2.8, 4.0 and 6.0 kHz) were present in about 80–90 per cent of these ears (Table V).
Ears with present DEOAEs at each frequency band*
Data represent percentages of ears, unless indicated otherwise. Absence of any distortion product otoacoustic emissions (DPOAEs) at a certain frequency band is indicated by ‘−’.
* Signal-to-noise ratio of more than 3 dB. SNHL = sensorineural hearing loss
Discussion
Hearing loss has been reported to affect about half of osteogenesis imperfecta patients.Reference Pedersen5–Reference Kuurila, Kaitila, Johansson and Grenman6, Reference Riedner, Levin and Holliday9, Reference Stewart and O'Reilly11, Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14 The present study is the first attempt to longitudinally map the progression of osteogenesis imperfecta related hearing loss. The audiological results of a comprehensive audiometric evaluation in 36 osteogenesis imperfecta patients were compared with those of a second audiometric evaluation, with an average test time interval of 4 years.
Overall, statistically significant increases in average air conduction PTA and bone conduction PTA were found at the second compared to the first audiological evaluation. This progression of hearing loss could not be explained by physiological age-related hearing deterioration, as there was a significantly higher difference between air conduction PTA and the 95th percentile of sex- and age-related thresholds (International Organization for Standardization 7029 standard)21 at the second audiological evaluation in comparison with the first evaluation. However, no significant difference was found for the average air–bone gap between the first versus the second audiological evaluation. Therefore, the increase of hearing thresholds in osteogenesis imperfecta is predominantly determined by the progression of the sensorineural component, which has already been suggested by cross-sectional research on osteogenesis imperfecta.Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14, Reference Garretsen, Cremers and Huygen18
Pure tone audiometry demonstrated that hearing was impaired in 31.4 per cent (i.e. 22 out of 70) and 34.3 per cent (i.e. 24 out of 70) of the ears at the first and second audiological evaluations, respectively. The increasing prevalence of hearing loss after a four-year interval, as demonstrated in the present study, is in line with the reported increase in prevalence of hearing loss with advancing age in other studies.Reference Shapiro, Pikus, Weiss and Rowe10, Reference Stewart and O'Reilly11, Reference Pillion and Shapiro13, Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14
Osteogenesis imperfecta related hearing loss typically starts with a conductive loss before the age of 40 years, most often due to stapes footplate fixation, and evolves to mixed hearing loss over time.Reference Kuurila, Kaitila, Johansson and Grenman6, Reference Riedner, Levin and Holliday9–Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14 However, at the second audiological evaluation, we noted the onset of a mild sensorineural hearing loss in three ears, corresponding to two subjects aged younger than 40 years. In another ear, mild sensorineural hearing loss at the first audiological evaluation changed to a conductive hearing loss at the second evaluation. Given the criteria used to define hearing loss, early conductive loss with a small air–bone gap might have been classified as mild sensorineural hearing loss.
Measurement of acoustic stapedial reflexes and otoacoustic emissions (OAEs) in addition to pure tone audiometry is recommended in the osteogenesis imperfecta population in order to make a differential diagnosis between early conductive and sensorineural hearing loss. Absent acoustic stapedial reflexes and absent OAEs in ears classified as having mild sensorineural loss on the basis of the audiogram suggest a conductive component, as acoustic stapedial reflexes and OAEs can usually still be elicited in sensorineural loss cases with audiometric thresholds better than 50–60 dB HL. Other changes in the type of hearing loss in the present study also demonstrate variability in audiometric threshold measurement accuracy; in one ear, sensorineural hearing loss across all frequencies evolved to sensorineural hearing loss at high frequencies only, and, in another ear, a mild sensorineural hearing loss disappeared. The importance of a test battery comprising audiometry, admittance measurements and OAE registration is emphasised in order to detect early changes in hearing sensitivity and to more accurately determine the lesion site.
Similar to other studies reporting on hearing loss in osteogenesis imperfecta, the hearing loss severity ranged from mild to profound. Between the first and the second audiological evaluations, little difference was observed in the numbers of ears corresponding to the different categories of hearing loss severity, which may be attributed to the relatively short test time interval. In addition, this longitudinal study could not offer a reliable estimation of the average annual threshold deterioration in hearing-impaired osteogenesis imperfecta patients, as the obtained thresholds deviated from the normal distribution and because of the small amounts of patients in some categories of hearing loss types. A cross-sectional study in hearing-impaired osteogenesis imperfecta patients with conductive or mixed hearing loss revealed annual increases of 0.6 dB/year and 0.4 dB/year for air conduction PTA and bone conduction PTA, respectively.Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14 Similar to the present study, the average air–bone gap remained relatively stable over time.Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14 In osteogenesis imperfecta patients with sensorineural hearing loss, annual threshold deteriorations of 0.2 dB/year for air conduction PTA to 1.2 dB/year at 8.0 kHz were demonstrated.Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14
Abnormal acoustic admittance results were obtained in 24.6 per cent and 26.2 per cent of the evaluated ears at the first and second audiological evaluations, respectively. However, normal type A tympanograms were observed in osteogenesis imperfecta ears with normal hearing and with different types of hearing loss. It has already been noted in other studies that tympanometric shape is not a good indicator of the different types of hearing loss related to osteogenesis imperfecta.Reference Stewart and O'Reilly11, Reference Pillion and Shapiro13, Reference Swinnen, Dhooge, Coucke, D'Eufemia, Zardo and Garretsen14 This is because of the often thin, hypermobile tympanic membranes inherent to the affected type I collagen that characterises osteogenesis imperfecta. In light of the connective tissue abnormalities affecting both the ear drum and middle-ear components, the interpretation of admittance results in osteogenesis imperfecta patients may be complicated. Therefore, the registration of OAEs in addition to admittance measurements might be helpful in the diagnosis of early conductive hearing loss caused by stapes footplate fixation, which is the major problem in osteogenesis imperfecta related hearing loss.
Otoacoustic emissions were recorded at the second audiological evaluation to determine the functioning of the outer hair cells in patients with osteogenesis imperfecta. Transient evoked otoacoustic emissions (TEOAEs) were absent in 32.4 per cent of ears. In general, TEOAEs were present in 93.5 per cent of normal-hearing ears and in 50.0 per cent of ears with mild sensorineural hearing loss. These results were within expectations, as TEOAEs are absent in endocochlear sensorineural hearing loss higher than 30 dB HL and in ears with a conductive hearing loss component. In contrast, Pillion and Shapiro concluded a moderate association between the presence of abnormal TEOAEs and the presence of hearing loss in osteogenesis imperfecta; they found absent TEOAEs in 13 per cent of normal-hearing ears, in 71 per cent of ears with conductive hearing loss, in 73 per cent of ears with mixed hearing loss and in 40 per cent of ears with sensorineural hearing loss.Reference Pillion and Shapiro13 Nevertheless, their criteria used to define absent TEOAEs were different to those of our study: signal-to-noise ratio was not taken into account, but TEOAEs were judged as absent when reproducibility at two or more frequency bands was less than 70 per cent.Reference Pillion and Shapiro13 In addition, TEOAEs are supposed to be absent in ears with a conductive component, which was confirmed by our results.
This is the first study to report on the results of distortion product otoacoustic emissions (DPOAEs) in osteogenesis imperfecta patients. The DPOAEs are expected to be absent in endocochlear sensorineural hearing loss above 55 dB HL and in hearing loss with a conductive component. In the present study, DPOAEs were absent in two ears with severe and profound undefined hearing loss, and in all ears with conductive or mixed hearing loss. Additionally, DPOAEs were also considered as absent in four out of five ears with mild sensorineural hearing loss, and in all ears with mild or moderate high-frequency sensorineural hearing loss. As mentioned before, early conductive hearing loss might, at least in some ears, have been classified as mild (high-frequency) sensorineural hearing loss, particularly in the ears with mild sensorineural loss on the basis of the audiogram and in combination with absent DPOAEs and acoustic stapedial reflexes. In two ears with sensorineural loss, TEOAEs were present while DPOAEs were absent, which might be explained by a higher sensitivity of DPOAEs to the higher frequencies compared to TEOAEs. Given that OAE measurements may be used as an additional test to detect early conductive hearing loss, as well as outer hair cell dysfunction, their inclusion is recommended in an audiological follow-up protocol for osteogenesis imperfecta patients.
This paper describes the first attempt to conduct a prospective, longitudinal follow-up study of osteogenesis imperfecta related to hearing loss. Presence, type and/or severity of hearing loss changed in 14.3 per cent of the ears after an average time interval of four years, and significant changes in median hearing thresholds were found between both evaluations. Although the percentage of altered hearing in this study is relatively low, which is partially a result of the limited number of patients, we encourage audiological follow up every three to four years in the osteogenesis imperfecta population. This follow up should comprise pure tone audiometry, tympanometry, and acoustic stapedial reflex and OAE measurements. A combination of these tests may help the clinician to detect early changes in hearing sensitivity or middle-ear compliance. In addition, further follow up is needed to map the audiological progression in osteogenesis imperfecta with more accuracy.
• Hearing loss affects about half of osteogenesis imperfecta patients
• Hearing loss in osteogenesis imperfecta usually appears as conductive hearing loss, in 20–40 year olds, and evolves to mixed hearing loss
• Sensorineural hearing loss occurs in a few osteogenesis imperfecta patients, of any age, and is less progressive
• This follow-up study found progression of hearing thresholds within an average of four years in osteogenesis imperfecta patients
• This significant progression exceeded the normal age- and sex-related physiological hearing deterioration
Competing interests
None declared
