Clin. Otolaryngol.

2003, 28, 112±120

The aetiology of otosclerosis: a review of the literature

D.J. MENGER & R.A. TANGE
Department of Otolaryngology ± Head and Neck Surgery, Academic Medical Centre, University of Amsterdam,
the Netherlands

Accepted for publication 29 October 2002

M E N G E R D . J . & TA N G E R . A .
(2003) Clin. Otolaryngol. 28, 112±120
The aetiology of otosclerosis: a review of the literature
During the last century, hundreds of studies have been performed to identify factors that are involved in
the aetiology of otosclerosis. These studies include a variety of aetiological factors and, although many
theories have been postulated, the process of the development of the disease remains unclear. A
historical overview and analysis of the literature dealing with the aetiology of otosclerosis is presented. The role
of collagen disorders, genetic linkage studies, associations with the HLA system and measles virus
infection as causal factors is discussed. From an epidemiological point of view, the disease has an autosomal
dominant mode of inheritance. Therefore, since the introduction of new genetic research techniques over
the last decades, more studies have been performed to ®nd evidence of a genetic factor that initiates the
development of otosclerosis. In this review, we tried to categorize the most prominent studies in
sections according to their subjects within the diversity of aetiological factors that have been studied.
Keywords otosclerosis aetiology genetics review

Otosclerosis is a term used to describe a localized disease of
the bone derived from the otic capsule and characterized by
alternating phases of bone resorption and formation. Mature
lamellar bone is removed by osteoclasts, and replaced by
osteoblasts with bone of greater thickness, cellularity and
vascularity. The characteristic lesion is a deposit of new bone
with a different ®brillar and cellular pattern which is laid down
at speci®c sites in the temporal bone. The site of predilection
of otosclerotic foci is the region of the otic capsule, between
the cochlea and the vestibule, and just anterior to the footplate
of the stapes. This region is associated with the globuli
interossei or so-called embryonic rests.1
The term `otosclerosis', introduced by Politzer2 in 1894,
refers to the ®nal inactive stage of the process where the bone
is sclerotic or hardened. The term `otospongiosis', ®rst used
by Siebenmann3 in 1912, refers to the active and vascular
stage of the process, and is more accurate from the patholo-
gical point of view as it indicates that an active lesion may be
present. The term `otospongiosis' was initially widely used in
Correspondence: D.J. Menger, MD, Department of Otolaryngology ±
Head and Neck Surgery, Academic Medical Centre, University of
Amsterdam, Meibergdreef 9, 1105 AZ, The Netherlands (e-mail:
d.j.menger@amc.uva.nl).
Europe. However, the term `otosclerosis' was used in the UK
and in North America, and is at present time adopted in the
English language world literature to de®ne the pathological
changes.
The disease is bilateral in 70±80% of patients, and usually
symmetrical in extension and distribution of the otosclerotic
foci. Symptoms occur depending on the site of the otosclerotic
focus. Clinical features are characterized by hearing loss,
tinnitus and vertigo, or combinations of these. The hearing
loss is of the conductive type but long-term follow-up studies
suggest that about 10% of these persons also develop a sen-
sorineural hearing loss.4,5 Clinical otosclerosis, as described
above, should be distinguished from histological otosclerosis,
a term used for the ®nding of abnormal capsular bone on
microscopic study. Histological otosclerosis is about 10 times
more common than clinical otosclerosis and is found in 10%
of the Caucasian population. In other races, the prevalence is
much lower. For example, among blacks, a prevalence of 1%
was reported by Guild et al.6 The age of onset is roughly
between the ages of 15±45 years.7±9 Several studies reported a
female to male ratio of clinical otosclerosis of approximately
2:1.7,10±13 Histological studies of the temporal bone do not
show this sex ratio difference.14,15 Altman et al.16 calculated
the collective ®ndings of several histological cadaver studies.

112 # 2003 Blackwell Publishing Ltd


In this study, no statistically signi®cant evidence of sex ratio
differences was found for histological or clinical otosclerosis,
the latter de®ned as stapedial ankylosis.
Many theories about the aetiology have been postulated.
However, despite the intensive research, the true nature about
the origin of otosclerosis remains unclear. The theories that
are currently considered as relevant are concerned with more
than one cause but it is not fully understood how they are
related to each other. Over the last decades, new ®elds of
research were encountered in order to obtain a better under-
standing of the true nature of the disease. Some of these
studies were based on older concepts. The goal of this paper is
to provide a systematical synopsis of the literature concerning
the aetiology of otosclerosis.
Literature study
In the past, a variety of different theories have been postulated
to explain the development of otosclerotic foci. Today how-
ever, these studies are not considered as relevant in the
aetiology of otosclerosis. Nevertheless, we would like to give
a minor synopsis of some of these theories to demonstrate the
diversity of hypothesis in the past.
stresses and str a ins
Stresses and strains in the temporal bone, as a result of the
upright posture during evolution, were postulated by Sercer.17
Today, however, this concept has little support because of the
occurrence of primary otosclerosis in the stapes.
e n d o c r i n e fac t o r s
Endocrine factors have been cited as a cause for the onset or
progression of symptoms during pregnancy. In addition, oes-
trogens are well-known stimulators of osteocytic activity and
may play a role during ossi®cation of otosclerotic foci. Many
scientists noted a progression of symptoms or the onset of the
disease in 30±60% of otosclerotic woman with a history of at
least one pregnancy.9,18,19 Gristwood and Venables20 studied
479 otosclerotic women. They found that in bilateral cases,
pregnancy aggravated the progression of the symptoms and
this incidence ranged from 33% after one pregnancy to 63%
after six pregnancies. It was found that the prevalence of a
unilateral pregnancy-related deterioration of hearing was
lower.
pa r at h y r o i d f u n c t i o n
Abnormal parathyroid function, resulting in altered levels of
calcium and phosphorus, has been postulated as a causative
factor of otosclerosis. This hypothesis suggests that otosclero-
sis is a generalized disease of the bony skeleton. Jensen et al.21
# 2003 Blackwell Publishing Ltd, Clinical Otolaryngology, 28, 112±120
Aetiology of otosclerosis 113
studied this hypothesis by measuring the mineral content of
skeletal bone and the serum levels of calcium and phosphorus
in 63 patients with otosclerosis and in 206 control subjects
matched for age and sex. The serum levels of calcium,
phosphorus and alkaline phosphatase were found to be nor-
mal, as was the mineral content of the skeletal bones. These
®ndings are in agreement with the view that otosclerosis is a
localized disease of the otic capsule. In a more recent study,
Lolov et al.22 also observed the level of total serum alkaline
phosphatase activity. The concentration of alkaline phospha-
tase was signi®cantly higher only when patients had a disease
duration of between 3 and 5 years compared with other
otosclerotic patients.
a etiolo gy of s e n s ori n eu r al h ea ri ng lo s s
Apart from concepts primarily concerning the development of
otosclerotic foci, theories have been postulated to explain the
sensorineural hearing loss in otosclerotic patients. The ®rst
was postulated by Politzer2 that sensorineural hearing loss
would be the result of bony invasion of the scala tympani of
the cochlea. Secondly, Mayer23 and Ruedi24 suggested circu-
latory changes in the cochlea as a result of abnormal bony foci.
The third theory was ®rst described by Siebenmann3 in
1912 and Witmaack25 in 1919, and held toxic metabolites,
released from an otosclerotic focus, responsible for cochlear
damage. Chevance et al.26 postulated that this would be the
result of the toxic actions of enzymes released from oto-
sclerotic foci as will be described later in this paper. Another
explanation suggests that hyalization of the spiral ligament
due to otosclerotic foci is associated with sensorineural hear-
ing loss.27±29
e n z y m at i c t h e o ry
Enzymes have been associated with the aetiology of oto-
sclerosis by many researchers. However, it remains unclear
if enzymes are the initiating factor of the disease process.
Some believe that they are the result of an already started
process of bone remodelling on which they might have an
agonistic effect.
The involvement of enzymes was ®rst postulated by Che-
vance, Causse and their co-workers.30 These researchers
developed a concept that explains the long, slow and variable
progress of the disease. They suggested that the trigger of the
disease process is an autoimmune reaction of the endochon-
dral otic capsule to the globuli interossei. Histiocytes and
genetically inferior osteocytes within the primary focus
release hydrolytic enzymes and proteases to the different
areas of the cochlea causing cellular destruction. If these
enzymes reach the oval window niche, a process of bone
rebuilding takes place leading to stapedial ®xation, causing a
conductive hearing loss. Sensorineural hearing loss develops
114 D.J. Menger & R.A. Tange
when the proteolytic enzymes damage the inner ear. The
severity of the sensorineural hearing loss depends on the equili-
brium between trypsin and alpha-1-anti-trypsin in the peri-
lymph of otosclerotic patients. The toxic action of various
trypsin concentrations on the hair cells of the Corti organ
in the guinea pig were studied. The intensity and extension of
the Corti hair cell alterations were related to the trypsin
concentration. Therefore, these researchers believe that the
mechanism of otosclerosis is provoked by a disturbance of the
balance between trypsin and anti-trypsin in the otosclerotic
focus.31
In more recent studies, other enzymes have been associated
with the pathogenesis of otosclerosis as well. Ribari32 mea-
sured elevated levels of cathepsin B in otosclerotic foci
compared with normal temporal cortical bone and the stapes
superstructure. Besides this enzyme, elevated levels of cathe-
psin D and collagenase-like peptidase were detected in oto-
sclerotic foci.33 These enzymes are produced by osteoblasts,
which would suggest that these cells not only induce bone
formation but are also involved in the resorption process.
Ribari et al.34 also measured the levels of cathepsin D in the
perilymph and found signi®cantly higher levels in otosclerotic
subjects compared with control subjects.
Sziklai and co-workers35 studied the role of a speci®c
enzyme in the perilymph of patients with otosclerosis. This
0.3±5 kilo Dalton protein inhibits myosin light-chain kinase
activity in the Corti organ of the guinea pig, suggesting that
this substance induces sensorineural hearing loss. Recently,
the same group studied the effect of an otosclerotic peptide
derived from the perilymph of otosclerotic patients on the
electromotility of isolated outer hair cells of the guinea pig,
in vitro. The peptide decreased the electromotile performance
of the outer hair cells.36
t h e rol e of s o di u m flu or i d e a s a n e nz y m e
inhibitor
Chevance, Causse and their co-workers believe that sodium
¯uoride has an anti-enzymatic effect. Moderate doses of
sodium ¯uoride would inhibit proteolytic enzymes. Conse-
quently, a decrease of the disease progress will take place.37
Moderate doses of sodium ¯uoride indeed can change active
otosclerotic lesions to more dense inactive lesions with sta-
bilization of sensorineural hearing loss, reduction of tinnitus
and recalci®cation of otosclerotic foci as was shown radio-
graphically.38
Epidemiological studies also indicated that clinical oto-
sclerosis is associated with areas that have low ¯uoride
contents in the drinking water.20,39,40 Although several treat-
ment protocols, indications and contraindications have been
suggested over the last decades, inconsistent results with this
hypothesis have also been reported.41,42 Besides ¯uoride,
other agents like cytokine antagonists43 and biphosphonates44
# 2003 Blackwell Publishing Ltd, Clinical Otolaryngology, 28, 112±120
would have an inhibitory effect on the progression of oto-
sclerosis but they are not widely used.
g e n e t i c fac t o r s
As otosclerosis occurs more often in certain families, than in
the general population, a genetic component in the aetiology
of otosclerosis has been considered for a long time.
Several types of inheritance are described. For example, X-
linked and recessive modes with different percentages of
penetrance have been postulated in the literature over the last
century.7,10,45 Also chromosomal abnormalities, by observing
an increased frequency of trisomy and tetrasomy mosaics of
chromosomes 13 and 15, were reported in the literature.46
Furthermore, recently again, a new mode of inheritance was
suggested in a Tunisian study of 65 pedigrees. This study
suggests that otosclerosis is primarily heterogenic and that in
13% of the clinical cases studied the affected individuals carry
a dominant gene with nearly complete penetrance.47 However,
despite these ®ndings, there exists nowadays more or less
consensus about the way otosclerosis is inherited: autosomal
dominant with incomplete penetrance. The penetrance is
estimated to be 40% by several epidemiological-based studies.
Most studies in the past were performed to identify an
otosclerosis gene by examining an association with a known
gene complex or with a speci®c clinical factor like eye colour.
Jannuzzis48 published the ®rst essay that described linkage
with otosclerosis; it was linkage with the ABO blood groups.
This ®nding suggested that the ABO blood groups and an
otosclerosis gene are situated close together and tend to
segregate together. Years later, Morrison18 noted that in
Jannuzzis's study probably only two of ®ve probands actually
had otosclerosis and that the ABO genotyping was incomplete
in all ®ve families. Morrison found no evidence for linkage
between otosclerosis and the ABO blood groups or an asso-
ciation with Rh, Mn, and secretor status or haptoglobin
genotype. However, the association that was observed
between otosclerosis and the ability to taste phenylthiocarba-
mide was surprising. Later, Morrison and Bundey49 found no
association with hair colour or the colour of the iris and
otosclerosis.
Tomek et al.50 screened the human genome systematically
in order to ®nd a gene on which otosclerosis was located. Short
tandem repeat polymorphism (STRP) was used in a multi-
generation family to complete genetic linkage analysis over
the entire genome. This is an indirect method where STRP is
used as a marker to identify an abnormal chromosome within
families. Multipoint linkage showed lod scores >2 on chro-
mosome 15q. Additional STRP in this region resulted in a lod
score of 3.5 in 15q25-q26, a 14.5-cM region. This indicates
strong evidence of linkage between this region and clinical
otosclerosis which suggests that this region could harbour an
otosclerosis gene. Recently, evidence of a second otosclerosis

gene on a 16-cM interval on chromosome 7q34±36 was
found.51 This study was also performed using genetic linkage
in a multi-generational family. In both linkage studies, the loci
are large and additional studies will be necessary to identify
the genes in these regions. Other genetic studies, like studies
of the human leucocyte antigen (HLA) system, will be dis-
cussed in speci®c sections such as Disorders of the immune
system.
di s or de rs of th e i m m u n e syst em
Auto-antibodies
Yoo et al. noted elevated antibody levels to type II collagen in
patients with otosclerosis and in otosclerosis-like lesions of
rats induced by type II collagen immunization.52 These anti-
bodies are not only detected in sera and otosclerotic foci but
also in the perilymph. This led to the hypothesis that an
autoimmune reaction to type II collagen could be a causative
factor in the aetiology of otosclerosis.52
They hypothesized that otosclerosis is a disease caused by
an autoimmune response to embryonic cartilaginous remnants
of the otic capsule. Bujia53 also reported higher levels of type
II collagen antibodies and of the minor type IX collagen in
sera of patients with otosclerosis. Involvement of perilymph
was reported by Reshetnikov et al.54 by measuring elevated
antibody levels to type II collagen and to double-stranded
DNA in the perilymph of otosclerotic patients.
In contrast with this hypothesis, Sùrensen et al.55 found no
difference in antibody titre in patients with otosclerosis and in
control subjects. Animal studies did not show histological
evidence of otosclerotic-like lesions in temporal bones for
type II collagen autoimmunity.55,56
Lolov et al.22 found elevated antibody levels to human type
II collagen, and to double- and single-stranded DNA in sera.
A peak level of these antibodies was found when patients
had disease durations between 3 and 5 years compared with
patients with a longer or shorter disease duration. The level
of total serum alkaline phosphatase activity showed the
same disease duration association. They postulated that these
observations suggested that enzymatic bone resorption is the
driving force in human otosclerosis. Elevated serum autoan-
tibodies during tissue reparation, like antibodies to type II
collagen, during the active stage of the disease would be a
transient response to sustained excess antigen turnover in the
primary lesion. This process is fundamentally no different
from the response to a foreign antigen.57
Otosclerosis and the association with the HLA system
The human leucocyte antigen (HLA) is the international
designation for the region consisting of the major histocom-
patibility complex (MHC). This region is located on chromo-
some 6 and consists of the polymorphic genetic system that
plays a role in immunological response. The analysis of HLA
# 2003 Blackwell Publishing Ltd, Clinical Otolaryngology, 28, 112±120
Aetiology of otosclerosis 115
antigenic determinants of the MHC shows that there exists an
association between speci®c HLA genotypes and several
autoimmune diseases. These diseases occur more commonly
than expected in subjects with particular HLA phenotypes
which implies that certain HLA determinants may affect
disease susceptibility. The most common example is the
association that exists between ankylosing spondylitis and
the W27 antigen at the HLA-B locus.
Gregoriadis et al.58 studied 68 patients with otosclerosis
with and without a positive family history. In patients with a
positive family history, they found a highly signi®cant
increase in the antigens A11, Bw35 and B14. These ®ndings
indicated for the ®rst time that HLA antigens might play a role
in the aetiology of otosclerosis. A summary of statistically
signi®cant associations that are reported in the literature is
presented in Table 1.
Signi®cantly lower frequencies of the B40 antigen were
detected in patients with otosclerosis compared with blood
donors by Dahlqvist et al.59 No difference was found between
men and women, or between patients with and patients with-
out a family history of otosclerosis. A lower frequency of the
B40 antigen in patients with otosclerosis versus those without
otosclerosis was also found by Svatko et al.60 For patients with
otosclerosis, a tendency was established to a more frequent
occurrence of antigens A2 and B12, and a lower frequency of
B27 and Cw1 than control subjects.
A higher frequency of the Aw33 antigen in patients with
otosclerosis compared with control subjects (24.2% versus
9.5%) was observed by Miyazawa et al.61 In the same year,
Bernstein and others62 demonstrated the relative risk of
various haplotypes in 49 patients with otosclerosis. The
relative risk of developing otosclerosis was 4.9 in patients
who had the B8/DR3 antigens and 7.1 in patients with A1/B8/
DR3 antigens. On the contrary, the presence of a DR2 antigen
was negatively correlated with the relative risk of developing
otosclerosis. In a preliminary study of 27 individuals with
various hearing maladies (three with otosclerosis), Bernstein
found that 44% of these patients (two with otosclerosis)
expressed an extended MHC haplotype which contained a
C4A gene deletion, in contrast to only 8±13% of the general
population, suggesting that this haplotype appears to be
disease associated. Recently, Singhal63 found signi®cantly
higher levels of the antigens A9, A11 and B13 in patients
with otosclerosis compared with normal individuals, suggest-
ing a HLA-related component in the development of oto-
sclerosis. Singhal also found signi®cantly higher levels of A9
and A11 in patients with a positive family history, indicating
genetic heterogenicity between isolated cases and familial
otosclerosis.
Despite these ®ndings, Pedersen et al.64 did not ®nd a
signi®cant association with HLA-A, -B or -C antigens in
100 randomly chosen subjects with otosclerosis. Corres-
pondingly, no signi®cant association between HLA antigens
116 D.J. Menger & R.A. Tange

Table 1. Statistically significant associa-

Higher (‡) or Patients versus Positive versus tions of HLA antigens and otosclerosis
Lower (±) control subjects Negativey

Gregoriadis et al. (1982)58 ‡ A11

Dahlqvist et al. (1985)59
Svatko et al. (1994)60
Miyazawa et al. (1996)61
Bernstein et al. (1996)62
Singal et al. (1999)63

Higher or lower frequency of a specific HLA antigen.
yFamily history.
‡ Bw35
‡ B14
± B40
± B40
± B27
± Cw1
‡ A2
‡ B12
‡ Aw33
‡ A1
‡ B8
‡ DR3
± DR2
‡ A9 A9
‡ A11 A11
‡ B13

and clinical otosclerosis was found in several other
studies.65±67
v i r a l i n v o lv e m e n t i n t h e a e t i o l o g y o f
ot o scl e ro s i s
Viral participation in the aetiology of otosclerosis was con-
sidered when both respiratory syncytial virus and measles
antigens were demonstrated in the osteoclasts of patients with
Paget's disease.68±70 This disease has several similarities with
otosclerosis. Among patients with otosclerosis, antigenic
expression in otosclerotic foci was ®rst demonstrated with
the use of immunohistochemical techniques. Mumps, rubella
and, most dominantly, measles viruses in otosclerotic foci were
detected by Arnold et al.71 Subsequently, McKenna72,73 demon-
strated measles virus antigens with several different monoclonal
antibodies in active otosclerotic foci. In spite of these ®ndings,
Roald et al.74 failed to demonstrate any viral antibodies, with
the use of the same technique, in a study of 24 subjects.
Since the introduction of the polymerase chain reaction
(PCR) technique, studies became more sensitive. With the use
of PCR, it was possible to detect viral RNA sequences.
Niedermeyer and Arnold75 demonstrated measles RNA
sequences in active otosclerotic foci, while other tissues from
these subjects and from a negative control group lacked such
sequences. Moreover, IgG anti-measles virus antibodies were
detected in the perilymph of otosclerotic subjects, supporting
the hypothesis that these viruses could provoke a local
immune response within the inner ear. Based on these reports,
it was suggested that the middle ear mucosa becomes infected
via the Eustachian tube. When the viral particles invade the
bone of the labyrinth, via either lymphatic or pericapillary
spaces, otosclerotic foci develop.76 In contrast to this hypoth-
esis, Grayeli et al.77 did not ®nd evidence of measles virus in
stapes samples or bone cell cultures.
As women suffer from severe measles virus infections more
often than men, it has been suggested that women have higher
susceptibility of their cochleo-vestibular tissues to these
viruses.78 Differences in ethnic epidemiological data do not
support a primary viral aetiology.79±82 Consequently, viral parti-
cipation could have a secondary pathophysiological role in the
aetiology of otosclerosis. By considering a hereditary predis-
position and a secondary infection of the measles virus causing
the bone remodelling of the otosclerotic lesions, it can, however,
explain both the sporadic and the familial cases as well as the
observed incomplete penetrance of the phenotype.
Nevertheless, like Shea83 mentioned in his `Personal His-
tory of Stapedectomy': with the near-universal administration
of the measles virus to children, there will be less hearing loss
from otosclerosis. Vaccination against measles eventually will
even eliminate the hearing loss of otosclerosis completely.
Theoretically, this could be true even if this virus plays a
secondary role in the aetiology of otosclerosis. Accordingly,
Niedermeyer et al.84 found an increase in the average age of
otosclerosis patients who underwent surgery between 1978
and 1999.
oto scle ro s i s a n d di s o r d e r s of t h e
connective tissue
Several studies have been performed to determine whether
otosclerosis is related to connective tissue disorders. Although

# 2003 Blackwell Publishing Ltd, Clinical Otolaryngology, 28, 112±120


not all these studies are very recent, some subjects are still
being studied. Studies concerning the connective tissue can be
categorized in the following areas:
1. general disorders of connective tissue;
2. type I collagen and osteogenesis imperfecta;
3. the collagenase system.
General disorders of connective tissue
The suggestion that otosclerosis is related to a general disorder
of connective tissue came from histological85 and histochem-
ical86 studies of patients with otosclerosis. Several studies
demonstrated connective tissue abnormalities, separate from
the local manifestations in the cochleo vestibular region.
Penderson87 found reduction of dermal thickness and minor
degenerative changes of elastic ®bers in otosclerotic patients.
Mann88 reported morphological changes in the extra- and
intracellular space, indicating `a complex metabolic distur-
bance of all tissue components'. Despite these ®ndings,
Oxlund et al.89 did not observe differences in structure or
composition of skin biopsies taken from patients with oto-
sclerotis and those from a control group without otosclerosis.
Type I collagen and osteogenesis imperfecta
Much has been reported on the possible relationship between
otosclerosis and osteogenesis imperfecta. Although osteogen-
esis imperfecta is a generalized disease, the otosclerotic-like
lesions in the temporal bone sometimes appear similar to foci
in patients with clinical otosclerosis.90 Similarities between
both diseases were reported by Ogilvie and Hall.91 Both have
an autosomal dominant mode of inheritance. Otosclerosis and
the type of osteogenesis imperfecta found in combination with
blue sclerae are more frequent in women, whereas most other
hereditary diseases are more frequent in men. Furthermore,
both are characterized by phases of osteoblastic and osteo-
clastic activity. It has been hypothesized that both may be the
result of an identical genetic anomaly with otosclerosis not
only being a less severe form but also being a local manifesta-
tion of osteogenesis imperfecta.
Defects in the genes for type I collagen, COL1A1 and
COL1A2, are associated with osteogenesis imperfecta. Dif-
ferent mutations result in different degrees of structural
aberration in type I collagen and have different degrees of
severity of clinical manifestations.92 These defects, in com-
bination with the close relation with otosclerosis, made
COL1A1 and COL1A2 candidate genes for otosclerosis.
McKenna et al.93 analyzed these two genes and found a
signi®cant association of three polymorphic markers within
the COL1A1 gene and clinical otosclerosis, both sporadic and
familial. No association was observed with COL1A2 or
COL2A1, a gene encoding for type II collagen. This ®nding
suggests that the COL1A1 gene might play a role in the
aetiology of otosclerosis. Correspondingly, in patients with
very mild osteogenesis imperfecta (type I), several different
# 2003 Blackwell Publishing Ltd, Clinical Otolaryngology, 28, 112±120
Aetiology of otosclerosis 117
mutations occur strictly within the COL1A1 gene without
defects in COL1A2. These mutations within the COL1A1
gene result in a null expression because of an unstable
RNA.94,95 These ®ndings suggest that very mild osteogenesis
imperfecta and some cases of otosclerosis might be closely
related with both having mutations within the COL1A1 gene.
Despite the similarities between osteogenesis imperfecta
and clinical otosclerosis, enzymatic and histological differ-
ences have been reported in the past. Osteogenesis imperfecta
has an earlier onset, a more severe middle ear involvement and
a higher incidence of perceptive hearing loss.96 Furthermore,
in osteogenesis imperfecta a more pronounced structural
disorganization and larger areas occupied by avascular ®brotic
resorption spaces were reported by Altman and Korn®eld,97
and Brosnan et al.98 Concentrations of lactate dehydrogenase
(LDH), phosphohydrolase and phosphofructokinase are all
high in the sera of patients with osteogenesis imperfecta. In
otosclerotic subjects, only the phosphohydrolase level is high
while the LDH level is abnormally low.99 It should, however,
be noted that all these differences were reported between
otosclerosis and more severe forms of osteogenesis imper-
fecta.
The collagenase system
In addition to abnormalities of type I collagen, changes in the
turnover of collagens have been reported in relation with
otosclerosis.
Thalmann et al.100 found signi®cantly increased collage-
nase levels in the tissue ¯uid of the media from human skin
®broblast cultures taken from patients with otosclerosis com-
pared with normal subjects. Nevertheless, they did not ®nd
differences in in vivo collagenase assays.
Gordon et al.101 attempted to con®rm and characterize
abnormalities of the procollagenase system. They studied
the in vivo messenger RNA (mRNA) transcription for pro-
collagenase, as well as for stromelysin and tissue inhibitor of
metalloprotease (TIMP), an activator and a speci®c inhibitor
of tissue collagenase activity respectively (Fig. 1). They found
lower levels of mRNA production for stromelysin among
patients with otosclerosis, and decreased mRNA amounts
of both TIMP and procollagenase, although these were not
found to be signi®cant. They hypothesized that a TIMP
Figure 1. The role of stomelysin and TIMP on the collagenase
activity.
118 D.J. Menger & R.A. Tange
transcription de®ciency would result in longer collagenase
activity causing a response mechanism to produce less pro-
collagenase, thereby producing normal levels of collagen in
the connective tissue. Gordon et al. concluded that abnormal
stromelysin mRNA expression might serve as a genetic
marker for otosclerosis.
Conclusions
Despite intensive research, the aetiology of otosclerosis is still
not fully understood. Epidemiological studies suggest auto-
somal dominant inheritance with incomplete penetrance of
approximately 40%. Candidate genes are found in multi-
generational families using linkage analysis; they are located
on chromosomes 15q25±26 and 7q34±36. Nevertheless, these
loci are large and follow-up studies will be necessary to
identify the relevant genes. Another candidate gene is
COL1A1, one of the genes that codes for type I collagen.
Association has been revealed in an association analysis
between COL1A1 and clinical otosclerosis, both familial
and sporadic. This suggests a similar underlying aetiology
of mild forms of osteogenesis imperfecta (type I) and some
cases of clinical otosclerosis. A local measles virus infection
has been suggested as an environmental stimulus on the
development of otosclerotic foci. However, based on epide-
miological data, it can only have a secondary role in the
pathophysiology. Associations between HLA antigens and
otosclerosis have been postulated but the reported antigens
vary in different studies. Other HLA association studies did
not ®nd associations. Auto-antibody levels to type II collagen
were found to be higher in patients with otosclerosis. Never-
theless, other studies did not ®nd a difference between oto-
sclerotic patients and control subjects. Con¯icting results
concerning autoimmunity to type II collagen are also found
in animal studies. Taken altogether, to determine the genetics
of otosclerosis, follow-up research should be considered for
loci 15q25±26 and 7q34±36 as well as for gene COL1A1.
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