International Journal of Pediatric Otorhinolaryngology (2005) 69, 449—455

www.elsevier.com/locate/ijporl

Etiological diagnosis of bilateral, sensorineural

hearing impairment in a pediatric
Greek population
M. Rigaa,*, I. Psarommatisa, Ch. Lyraa, D. Douniadakisa,
M. Tsakanikosa, P. Neoub, N. Apostolopoulosa

a
ENT Department, ‘‘P&A Kyriakou’’ Children’s Hospital of Athens, Athens, Greece
b
Pediatric Department, ‘‘P&A Kyriakou’’ Children’s Hospital of Athens, Athens, Greece

Received 12 May 2004; received in revised form 21 October 2004; accepted 8 November 2004

KEYWORDS Summary Early diagnosis, evaluation and treatment of childhood deafness are
Sensorineural; essential for a child’s normal growth. Etiological diagnosis of hearing loss makes
Hearing loss; prevention, family scheduling and more effective therapy feasible goals. Etiological
Etiology; assessment of sensorineural deafness still remains difficult although recently with the
Connexin 26; progress of genetics it has become more efficient. In this retrospective study, the
Children etiology of bilateral, sensorineural hearing loss with indication for hearing aids has
been studied in 153 hearing impaired children. Etiological diagnosis was based on
family and patient record, physical, audiological and laboratory examinations. Among
the 94 children who completed the diagnostic protocol etiological groups revealed the
following distribution: non-hereditary acquired hearing impairment was present in 36
children (38%) and hereditary was present in 44 (47%) children. The etiology remained
unknown in 14 (15%) children. Non-syndromic autosomal dominant type accounted for
13 (29% of hereditary hearing loss) children, non-syndromic autosomal recessive type
for 21 (48%) children and syndromic deafness for 10 (23%) children. Modern diagnostic
methods, such as genetic testing, help diminish the number of cases with hearing
impairment of unknown etiology, for the benefit of children who receive early and
appropriate medical, audiologic, genetic and educational counseling based on the
etiology of their hearing loss.
# 2004 Elsevier Ireland Ltd. All rights reserved.

* Corresponding author at: 11 Messatidos str, 26331 Patras,
Greece.
E-mail address: mariariga@hotmail.com (M. Riga).
1. Introduction
Auditory deprivation if undiagnosed or poorly trea-
ted permanently affects development and emo-
tional maturation, limits the acquisition of
occupational and creative skills, aural rehabilita-
tion, professional opportunities and generally low-

0165-5876/$ — see front matter # 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijporl.2004.11.007
450 M. Riga et al.

Table 1 Etiology of acquired hearing loss

Prenatal Rubella, measles, toxoplasmosis, poliomyelitis, viral pneumonia,
herpes zoster, hepatitis, syphilis, CMV, alcohol, aminoglycosides,
diabetes mellitus, X-rays, thalidomide, nephropathy, hypoxia,
drug addiction
Perinatal Asphyxia, rhesus incompatibility, congenital heart failure, herpes,
prematurity, trauma during birth, hyperbilirubinemia,
low birth weight (<1500 g), meconium aspiration
Postnatal Sepsis, amiglycosides, measles, herpes zoster, bacterial meningitis,
radiation, noise trauma, posterior fossa tumor or cyst

ers the quality of life. Etiological diagnosis is crucial
for prognosis, cancellation of etiological or dete-
riorating factors, choice of appropriate therapy,
genetic counseling and prevention. It may also help
public health services to undertake effective pre-
ventive measures [1—4].
Etiology of sensorineural hearing loss is classified
in acquired, hereditary and unknown. Environmen-
tal factors which may cause acquired hearing
impairment are characterized as prenatal, perinatal
or postnatal and are presented in Table 1 [1,3,4].
Hereditary hearing loss may be syndromal or non-
syndromal (hearing loss alone). To date nearly 400
multiple anomaly syndromes have been identified in
which hearing impairment is a significant compo-
nent [3].
Etiological assessment of sensorineural hearing
loss is a complicated and difficult procedure. Con-
sequently, the percentages of cases of unidentified
etiology reported in recent studies are still high
(12.8—67%) [4,5]. Isolated cases (negative medical
history for the three last generations) and recessive
non-syndromic hearing loss are the most likely to
escape early diagnosis, as suspicion usually arises
after speech delay is observed [1].
Autosomal recessive non-syndromic deafness
(DFNB) (DFN for deafness; B indicates recessive)
[6] accounts for approximately 40—85% of all child-
hood hearing loss [7—10]. To date, 30 chromosomal
loci have been reported responsible for non-syndro-
mal autosomal recessive sensorineural hearing
impairment, but a single locus on chromosome 13
DFNB1 (numerical suffix is the sequential numbering
reflecting date of discovery) [6], accounts for at
least 50% of this type of hearing loss [11—16].
Localized to DFNB1 is the gene which encodes the
gap junction protein connexin 26 (Cx26 or the gap
junction protein B2 gene [GJB2]) [6,12,17]. A single
mutation variably known as 30 or 35delG, resulting
from the deletion (del) of a single guanine (G)
residue in a stretch of 6 G’s at nucleotide position
30—35, is responsible for 80% of DFNB1 in European
and American populations [13,17—19].
Connexins are a family of six proteins which form
gap junctions. Gap junctions are plasma membrane
channels. The formation of intracellular channels is
possible through interaction of adjacent cells with
connexins in the plasma membrane. Gap junctions
are found in the stria vascularis, basement mem-
brane, limbus and the spiral prominence of the
cochlea. Ion channels and gap junctions are critical
for the movement of potassium ions from the hair
cells to the endolymph such that the correct elec-
trical signal is sent to the auditory nerve [20,21].
Testing for DFNB1 as the first step in etiologic
diagnosis for sensorineural hearing loss seems pro-
mising. It may enlighten etiology of hearing impair-
ment early in the diagnostic procedure and limit the
need for time consuming and expensive tests (such
as CT, perchlorate washout studies for Pendred
syndrome, MRI, virological tests etc.) many of which
require deep sedation or general anesthesia [17,22].
The purpose of this study is to report the epide-
miological data of bilateral, educationally signifi-
cant, sensorineural hearing loss in a pediatric Greek
cohort, as it has been modified by the latest screen-
ing protocols and genetic studies.
2. Patients and methods
The present study was undertaken by the ENT
department of ‘‘P&A Kyriakou’’ Children’s Hospital
of Athens. Child care clinics, speech—language
pathologists and logopedists, ENT specialists and
pediatric departments of southern Greece all refer
a great percentage of high-risk neonates, children
suffering from syndromes associated with hearing
loss and children with speech delay to our hospital.
High-risk neonates were characterized as such
according to the well-known indicators associated
with sensorineural hearing loss (Position Statement
of the Joint Committee on Infant Hearing 1994) [23].
We studied retrospectively the medical records
of all 153 children (87 boys/66 girls), aged from 30
days to 13 years (average age 3 years), in whom we
Etiological diagnosis of bilateral, sensorineural hearing impairment in a Greek population
Fig. 1 Flow chart of the protocol.
have recommended amplification during the years
2000—2003. Children with unilateral or mild hearing
loss were excluded from the study since hearing aids
have rarely–—if even–—been recommended to them.
All children were subjected to medical history tak-
ing and physical examination. Clinical history
involved obstetric, perinatal and personal history
of the patient, as well as family history, which
included the last three generations. Physical exam-
ination involved identification of malformations
associated with syndromes known to include sensor-
ineural hearing loss, abnormalities of the external
and or middle ear (including otitis media with effu-
sion), ophthalmologic examination by a pediatric
ophthalmologist and developmental evaluation
by a specialized pediatrician. All children were
subjected to laboratory examinations such as elec-
trocardiogram, blood counts, serum tests for con-
genital infections, TSH, T3, T4, urea, creatinine,
blood gases, electrolytes, serum glucose, choles-
terol, sickling test and urine analysis [24—26].
Detection of 35delG mutation in Connexin 26 by
polymerase chain reaction (PCR) was performed
for autosomal recessive and isolated cases. Audio-
logical examination consisted of tympanogram, sta-
pedial muscle reflex, free field audiometry, auditory
brainstem response (ABR) measures and otoacoustic
emissions depending on the diagnostic needs of each
case. Whenever cooperation of the child was
granted, a pure tone audiogram was obtained. Chil-
dren suffering from otitis media with effusion were
reevaluated one or more months later, after effu-
sion was resolved. If effusion persisted for more
451
than 2 months, audiologic examination was per-
formed taking into consideration the changes
brought by otits media with effusion on audiometric
measurements [27—29]. A flow chat of the protocol
is presented in Fig. 1.
After diagnosis of hearing loss has been con-
firmed, it has been suggested that these patients
should be examined by the department of clinical
genetics for etiological diagnosis.
In general, if one or both parents present pro-
nounced sensorineural hearing impairment, the
child is considered to suffer from a dominantly
inherited hearing loss. If one or more siblings of
normal hearing parents suffer from hearing loss or if
the parents are known to be blood related, the child
is considered to suffer from an autosomal recessive
hearing disorder [30]. To all children with family
history indicative of non-syndromic hearing impair-
ment inherited by the autosomal recessive type and
isolated cases, detection of 35delG mutation in
Connexin 26 by polymerace chain reaction was
recommended. Children with hearing loss acquired,
syndromic or hereditary by the autosomal dominant
type were excluded from this test.
3. Results
A clear male predominance (87 boys versus 66 girls)
was observed in our cohort. The average age of
diagnosis of hearing impairment was found to be
3 years of age. Only 24 children (16%) were aged less
than 1 year.
452
Table 2 Etiological classification of hearing loss
(n = 94)
Number Percentage
Hereditary 44 47
Acquired 36 38
Unknown 14 15
Total 94 100
Hearing impairment was symmetric in 135 chil-
dren (88%) and asymmetric in 18 children (12%).
Based on audiologic test battery a moderate hearing
loss was diagnosed in 16 children, severe in 28 and
profound to total in 109 children.
Though recommended 59 children of the total
cohort of 153 children (38.5%) did not come for
etiological diagnosis.
Etiology of sensorineural hearing loss in a cohort
of 94 children presented the following distribution:
hereditary in 44 children (47%), acquired in 36
(38%), unknown in 14 (15%) (Table 2). The etiology
of hearing loss remained unknown for isolated cases
in whom blood examination for the 35delG mutation
was negative. Among the 44 children with heredi-
tary hearing loss syndromic deafness was identified
in 10 children (23%) and non-syndromic (implying
the absence of coinherited phenotypic features) in
34 (77%) children. Specifically 4 children suffered
from Klippel—Feil syndrome, 1 from LEOPARD syn-
drome and in five children the syndrome was meta-
bolic. In these children hearing loss was either
sensorineural or mixed. Sex-linked inheritance
was not found in any of the examined children.
Autosomal dominant type non-syndromic hereditary
hearing loss was identified in 13 children (29% of
diagnosed hereditary deafness) and autosomal
recessive in 21 (48%). The autosomal recessive group
finally consisted of those children in whom such a
diagnosis was made by their medical history and of
those children who revealed biallelic 35del G muta-
tion (Table 3).
Table 3 Hereditary hearing loss (n = 44)
Non-syndromic
Autosomal recessive (AR) homozygous
AR heterozygous
AR undetermined (Mutation not detected or patient not examined)
Autosomal dominant
Syndromic
Klippel—Feil
Leopards
Metabolic
Total
M. Riga et al.
Blood examination for the detection of the muta-
tion 35delG in Connexin 26 by PCR amplification was
recommended in 35 cases. It was performed in 18
children and revealed 7 homozygous cases and 1
heterozygote. The mutation was not present in 10 of
the examined children. Consequently, blood exam-
ination for the detection of the mutation 35delG set
a detailed etiological diagnosis for the hearing loss
of 7 out of 18 patients tested. Only 2 of the 735delG
homozygous children were old enough to cooperate
for pure tone audiogram. Both of these children
presented a flat audiogram in both ears. All 7 chil-
dren with biallelic mutation had profound to total
hearing loss.
In the majority of the children who have been
treated in neonatal intensive care units acquired
sensorineural deafness has been attributed to
one or more of the following factors, without
being able to assess separately the contribution of
each one to the resulting hearing impairment:
cytomegalovirus (CMV) was involved in 3 cases,
rubella in 1, perinatal asphyxia in 2, intracerebral
hemorrhage in 3, hyperbilirubinemia in 11, low birth
weight (<1500 g) in 23, sepsis in 3 and amiglycosides
in 14.
Acquired hearing loss in older children was attrib-
uted to bacterial meningitis and treatment with
aminoglycosides at the age of 3 years in one child
and in another child to mumps at the age of 4 years.
One child with chronic renal failure presented mod-
erate hearing loss to the left and mild hearing loss to
the right at the age of 13 years.
4. Discussion
In our cohort boys outnumbered girls (87 boys to 66
girls), as it has been reported in most other studies
[1,31]. The etiology of this difference remains
unknown, but it does not seem to stem from a
genetic factor [32].
Number Percentage
7 16
1 2
13 30
13 30
4 9
1 2
5 11
44 100
Etiological diagnosis of bilateral, sensorineural hearing impairment in a Greek population
Table 4
Country Great Britain Finland
(cohort) (n = 339) [1] (n = 98) [5]
Year 1995 1997
Acquired (%) 43 29
Hereditary (%) 23 41
Unknown (%) 34 30
Maturation of the auditory pathways is depen-
dent on adequate acoustic stimulation [2,3,33,34].
In order that hearing impaired children receive this
stimulation, definite diagnosis of hearing impair-
ment and optimal therapy by means of hearing
aid or cochlear implant should be made until the
sixth month of life [17,33]. The high average age of
diagnosis of congenital or early-onset hearing loss
worldwide, which has been confirmed by this study
(3 years), emphasizes the poor results of the present
screening arrangements for the hearing impaired
children.
Percentages of acquired and hereditary hearing
impairment, as well as percentages for hearing loss
of unknown etiology reported in contemporary lit-
erature are reviewed in Table 4 [1,4,30,35]. Our
results on acquired hearing loss are similar to those
reported by Walch et al. [4] and by Das et al. [1] and
have been modulated during the last few years by
systematic application of screening and vaccination
projects, as well as by higher survival percentages
for premature neonates.
Acquired sensorineural hearing loss attributed to
autoimmune mechanisms, maternal diabetes melli-
tus, head trauma, blood diseases, diseases of the
nervous system, Wegener and other granulomatoses,
Ménière’s disease and perilymphatic fistula are rather
rare in childhood and have not been diagnosed in any
of the children we have studied [24,26].
Hearing impairment is reported to be syndromal
in approximately one-third of the cases of heredi-
tary hearing loss, while in two thirds it is non-
syndromal [1,37,38,39]. There have been described
more than 400 syndromes in which hearing loss is a
significant component [39]. In our study, syndromal
hearing loss was found in 23% of cases.
In our study hereditary deafness was diagnosed
more often than in the studies mentioned in Table 4,
because etiological diagnosis was performed by
specialists who had at their disposal the test for
detecting the mutation 35delG in Connexin 26.
Recessive non-syndromic hearing impairment was
found to account for approximately 22% of the
cases. This is of great clinical importance because
it indicates that focusing only on the high-risk groups
leaves a high percentage of the hearing impaired
children undiagnosed and poorly treated [17].
453
Austria USA Greece
(n = 106) [2] (n = 168) [4] (n = 153)
2000 2000 2003
38 13 38
18 40 47
44 36 15
Sex linked and mitochondrial hearing impairment
[40,41,42] were not diagnosed in any of the children
of our cohort.
Advances in genomics have been catalytic in
clarifying the genetic heterogeneity of non-syndro-
mic hearing impairment. Allele variants of the gene
that encodes the protein connexin 26 cause half of
moderate-to-profound non-syndromic autosomal
recessive deafness in many world populations
[13—15,43]. Many different loci cause hearing
impairment and the etiology may be different even
among family members. As well as locus heteroge-
neity, allelic heterogeneity is a common finding
[21]. During the last 10 years, there has been a
virtual explosion in the number of genes that have
been localized or even cloned. Elucidating the func-
tional biology of these genes may facilitate our
efforts in hearing habilitation.
Eighty-four loci have been identified by linkage
analysis as loci involved in non-syndromic hereditary
hearing impairment. There have been mapped 41
non-syndromic loci responsible for autosomal domi-
nant hearing loss, 30 for autosomal recessive, 3 for
either dominant or recessive, 8 for sex linked and 2
for mitochondrial [44].
Around 60% of autosomal recessive families and
up to 40% of sporadic cases of non-syndromal sen-
sorineural hearing loss are caused by mutations in
the Cx26 gene [12—17,45]. According to other stu-
dies a deaf child born to normal hearing parents
would have an approximately 15—33% chance of
having a Cx26 gene mutation detected [46]. A prob-
able explanation for this variation in the prevalence
of Cx26 mutations is the fact that populations with
different genetic profiles were studied. The percen-
tage in our study, which was limited to the 35delG
mutation, was 7/18 children (38%) in accordance to
the reported high prevalence of the mutation in
Greek populations [47].
More than 60 mutations have been described for
the Cx26 gene. A deletion of a single guanine (G)
residue in a stretch of 6 G’s at nucleotide position
30—35 (variably known as 30 or 35delG) is respon-
sible for the most common type of non-syndromic
recessive deafness among white populations
[7,13,16,45]. The mutation 35delG has been found
to account for 60% or more of Cx26 mutations in
454
families with autosomal recessive non-syndromal
sensorineural hearing loss from the mediterranean
area [14]. The high prevalence of detection of the
mutation in healthy cohort (2.5% in Caucasian and
even higher, 3.5 in Greek cohorts) has to be men-
tioned [15,47,48]. Hearing loss associated with
35delG is more likely symmetrical, of early onset
(during the first year of age) and exhibits a slopping
or flat audiogram configuration and only rarely
ascending or U-shaped. As far as progression is
concerned some studies report a stable hearing
threshold while others report deterioration of hear-
ing impairment in 1/3 of the cohort [8,12,13,15,16].
Although the genotype does not predict the hearing
of the examined child, as even intrafamilial varia-
tions of the severity of hearing loss are common,
30—57% of these children are expected to have a
profound and another 26—30% severe hearing loss
[12,17]. In our study, all 7 children with biallelic
mutation had severe to profound hearing loss,
although our cohort is rather small to come to any
definitive conclusion.
From the practical point of view screening for
connexin mutations is simple. Mutation 35delG can
be detected by an amplification-resistant mutation
screen (ARMS), a simple polymerase chain reaction-
based reaction resolved on an agarose gel. Most of
the other mutations can be identified as single-
stranded conformational polymorphisms (SSCP)
[6,47,49,50].
The fact that many parents did not respond to our
suggestion for etiological diagnosis reveals the need
for more effective protocols and better information
of the parents of the value of etiological diagnosis of
their children’s hearing impairment.
In conclusion, the progress of genetics during the
last decade has changed the medical evaluation of
the deaf child. A thorough medical and genetic
history, completed by mutation screening for con-
nexin 26 have now been added in the battery of tests
that are routinely ordered contributing significantly
to early diagnosis and prospective treatment of
hearing impaired children as well as to efficient
genetic counseling to their parents.
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