ARTICLE

Etiologic and Audiologic Evaluations After Universal

Neonatal Hearing Screening: Analysis of 170
Referred Neonates
Frank Declau, MD, PhDa, An Boudewyns, MD, PhDa, Jenneke Van den Ende, MDb, Anouk Peeters, MDa, Paul van den Heyning, MD, PhDa

Departments of aOtorhinolaryngology, Head and Neck Surgery, and Communication Disorders and bMedical Genetics, University of Antwerp, Anwerp, Belgium

The authors have indicated they have no financial relationships relevant to this article to disclose.

What’s Known on This Subject What This Study Adds

Hearing loss is one of the most common congenital anomalies. Hearing impairment in To the best of our knowledge, this is the first report in the literature that provides data on
infants can negatively affect speech and language acquisition, academic achievement, both audiologic confirmation and etiologic assessment in a large sample of newborns
and social and emotional development. These negative effects can be diminished referred after failed screening.
through early intervention.

ABSTRACT
OBJECTIVE. The goal was to clarify the audiologic aspects and causes of congenital
hearing loss in children who failed universal neonatal hearing screening.
www.pediatrics.org/cgi/doi/10.1542/
METHODS. A prospective analysis of 170 consecutive records of neonates referred to a peds.2007-1479
tertiary center after universal neonatal hearing screening failure, between 1998 and doi:10.1542/peds.2007-1479
2006, was performed. The data presented here represent the equivalent of ⬃87 000 Key Words
screened newborns. The screening results were validated with a clinical ear, nose, congenital sensorineural hearing loss,
and throat examination and electrophysiological testing, including diagnostic audi- cytomegalovirus, genetics, hearing
screening, newborn
tory brainstem response, automated steady state response, and/or behavioral testing.
A diagnostic evaluation protocol for identification of the cause of the hearing loss was Abbreviations
UNHS— universal neonatal hearing
also implemented, in collaboration with the departments of genetics and pediatrics. screening
ABR—auditory brainstem response
RESULTS. Permanent hearing loss was confirmed in 116 children (68.2%). Bilateral AABR—automated auditory brainstem
hearing loss was diagnosed in 68 infants (58.6%) and unilateral hearing loss in 48 response
infants (41.4%). Median thresholds for the neonates with confirmed hearing loss PCR—polymerase chain reaction
CMV— cytomegalovirus
were severe in both unilateral and bilateral cases, at 70 dB nHL and 80 dB nHL, WS—Waardenburg syndrome
respectively. In 55.8% of those cases, no risk factors for hearing loss were found. In Accepted for publication Sep 27, 2007
60.4%, the initial automated auditory brainstem response diagnosis was totally in Address correspondence to Frank Declau, MD,
agreement with the audiologic evaluation results. In 8.3% of the cases, however, a PhD, Department of Otorhinolaryngology,
unilateral refer result was finally classified as bilateral hearing loss. An etiologic factor Head and Neck Surgery, and Communication
Disorders, University Hospital Antwerp,
could be identified in 55.2% of the cases. Of the causes identified, a genetic mech- Wilrijkstraat 10, B-2650 Edegem, Belgium.
anism was present in 60.4% of the cases, peripartal problems in 20.8%, and con- E-mail: nko@telenet.be
genital cytomegalovirus infection in 18.8%. PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2008 by the
CONCLUSIONS. An etiologic factor could be identified for nearly one half of the children American Academy of Pediatrics
with confirmed congenital hearing loss referred through a universal hearing screen-
ing program. Pediatrics 2008;121:1119–1126

H EARING LOSS IS one of the most common congenital anomalies, occurring in ⬃1 to 2 infants per 1000.1 The
prevalence of hearing loss has been shown to be greater than that of most other diseases and syndromes
screened for at birth (eg, phenylketonuria and sickle cell disease). The incidence of hearing loss is considerably higher
in infants in the NICU (1–2 cases per 200 infants; 1.9% bilateral and 0.6% unilateral.2 Left undetected, hearing
impairment in infants can negatively affect speech and language acquisition, academic achievement, and social and
emotional development. These negative effects can be diminished and even eliminated through early intervention at
or before 6 months of age.3 Reliable screening tests that minimize referral rates and maximize sensitivity and
specificity are available. The goal of universal neonatal hearing screening (UNHS) is to maximize linguistic and
communicative competence and literacy development for children who are hard of hearing or deaf.
In Flanders, a community-based screening program was successfully implemented by the federal health care
agency in 1998. The hearing screening program is performed with automated auditory brainstem response (AABR)
testing and aims to identify all children with a permanent unilateral or bilateral hearing impairment of ⱖ35 dB nHL.
The AABR testing is performed at the age of ⬃4 weeks. If the infant fails the initial test, then it is repeated within

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48 hours. Children who twice the test fail or for whom
unreliable test results are obtained are referred for re-
testing and diagnostic evaluation. The coverage of the
screening with AABR testing in Flanders has been
⬃96% since its introduction, with a false-positive rate of
only 0.06% (specificity: 99.94%).4 In many UNHS pro-
grams, the screening/therapy coordination is the weak-
est point of the pathway, with lost to follow-up moni-
toring (and treatment) rates as high as 2% to 52%.5
METHODS
In Flanders, a community-based screening program was
successfully implemented by the federal health care
agency (Kind & Gezin). The agency coordinates the pre-
ventive care and wellness of children in Flanders and is
well organized, with 620 nurses working at 330 consul-
tation bureaus in 62 Flemish regions.6 All neonates
(NICU and non-NICU) referred after UNHS between
March 1998 and April 2006 were included in the present
study. Referral was initiated after 2 consecutive failures
of the AABR testing. The pattern of referral to the ter-
tiary centers by the federal health care agency was based
on the geographical areas in which the children resided.
Most children came from a suburban area around Ant-
werp, Belgium.
The standard method for validation of UNHS results is
a combination of ear, nose, and throat and audiologic
evaluations performed with electrophysiological testing,
such as diagnostic auditory brainstem response (ABR),
automated steady state response, and/or behavioral test-
ing. The medical evaluation was performed by an oto-
rhinolaryngologist, in close collaboration with a medical
geneticist and a pediatrician. The purpose of this evalu-
ation was not only to determine the pathogenesis of
hearing loss but also to identify related medical condi-
tions and to provide recommendations for medical treat-
ment, as well as referral to other services.6
The evaluation included a detailed pedigree analysis
for congenital hearing loss, medical history, and risk
factors, as identified by the Joint Committee on Infant
Hearing 2000 position statement.7 The clinical examina-
tion included tympanoscopy and an examination of the
head and face to search for outer ear anomalies, preau-
ricular pits or tags, and syndromic features.
The audiologic assessment in this study was per-
formed according to guidelines published by the Royal
Ear Nose Throat Society.6 The examinations included
click-evoked ABR testing, measurement of auditory
steady state responses, and acoustic immittance audiom-
etry with high-frequency tones (678 Hz) and transient
evoked otoacoustic emissions. This testing was per-
formed by audiologists with technical expertise and
training for testing in infants, and results were obtained
for an ear-specific estimate of the type, degree, and
configuration of the hearing loss.
The infant then was examined at the department of
pediatrics and ophthalmology, where additional standard
examinations were conducted (Table 1). Mutation analysis
of connexin 26 (GJB2) was performed for every child. For
GJB2, denaturing high performance liquid chromatogra-
phy analysis was performed for the complete coding region
1120 DECLAU et al
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TABLE 1 Diagnostic Protocols
Standard diagnostic protocol for children with congenital hearing loss
General pediatric examination (dysmorphic signs)
Urine sample (viral culture isolation, measurement of electrolyte levels)
Neurologic examination
Ophthalmologic examination
Electrocardiography
High-resolution computed tomography or MRI
Complementary examinations for children with congenital hearing loss
Electroretinography, slit-lamp examination
Renal ultrasonography
Heart ultrasonography, Holter monitoring
Radiography of thorax and spine
Karyotyping
Perchlorate testing
DNA isolation for specific syndromes (eg, pendrin, otoferlin, and connexin 30)
(exon 1 and 2). If a mutation in GJB2 was found, then
polymerase chain reaction (PCR) was performed to detect
the most frequent deletion in connexin 30 (GJB6-
D13S1830). Also, a toxoplasmosis, rubella, cytomegalovirus
(CMV), herpes, and syphilis serologic screen was per-
formed for every child (toxoplasmosis, IgM and IgG; ru-
bella, IgM; CMV, IgG and IgM; herpes simplex, IgM and
IgG; Treponema pallidum, rapid plasma reagin and T palli-
dum hemagglutination tests). These results were discussed
by the multidisciplinary team and, depending on the type
of hearing loss, familial history, risk factors, and associated
features, complementary examinations were performed
(Table 1).6
The imaging modalities used consisted of computed
tomography and MRI, and imaging was requested for all
children with confirmed unilateral and/or bilateral hear-
ing loss of ⱖ60 dB nHL or craniofacial malformations.
The cutoff value was set according to the report by
Bamiou et al.8 They found that profound or progressive
hearing loss and craniofacial abnormalities were signifi-
cant predictors of abnormal computed tomographic find-
ings. The radiologic imaging was usually performed at
⬃6 months of age. After the initial diagnostic evaluation
and confirmation of the hearing loss, children were
scheduled for early intervention programs (including
hearing aids and rehabilitation) and auditory follow-up
evaluation was performed with visual reinforcement au-
diometry or conditioned play audiometry according to
the child’s age and cooperation.
All data obtained were stored in a database system
(Excel; Microsoft, Redmond, WA); for each child, a com-
plete report was sent to the federal health care agency.
Statistical analysis was performed with SPSS 13.0 (SPSS,
Chicago, IL). The results were summarized as means,
medians, and percentages. Subgroups within the study
population were compared with Mann-Whitney and
Kruskal-Wallis tests. A P value of ⱕ.05 was accepted as
indicating statistically significant results.
RESULTS
Audiologic Assessment
In Flanders, ⬃120 infants each year are referred to a
tertiary center after failed newborn hearing screening
 25
TABLE 3 Results From Diagnostic Audiologic Workup Versus
unilateral
Screening Results Obtained Through AABR Screening
bilateral
AABR Finding ABR Result, n (%)

20 No Hearing Loss Unilateral Bilateral

(n ⫽ 44) (n ⫽ 44) (n ⫽ 56)
Unilateral (n ⫽ 87) 36 (41.9) 41 (47.7) 10 (11.6)
Number of cases

Bilateral (n ⫽ 57) 8 (14.0) 3 (5.3) 46 (80.7)

15

screening population were found to have normal hear-

10
5
0 116) with confirmed hearing loss (⬎35 dB nHL), the
30 40 45 50 55 60 65 70 75 80 90 100110 120
ABR thresholds
dB nHL
FIGURE 1
Hearing loss distribution.
(mean birth rate: 61 673 births per year during the years
1998 –20059). The data presented here represent the
equivalent of ⬃87 000 screened newborns.
The referral population after failed screening (n ⫽
170) consisted of 91 boys and 79 girls (gender ratio:
1.15), with a median age at first presentation in the
referral center of 50 days (range: 36-86 days). A total of
157 infants (92.4%) were referred as non–NICU infants;
148 infants were referred directly from the UNHS pro-
gram, and 9 were sent by referral hospitals for a second
opinion. In addition, 13 infants (7.6%) came from a
NICU. Indications for further audiologic evaluation after
AABR screening (n ⫽ 148) were unilateral refer results
(n ⫽ 87), bilateral refer results (n ⫽ 57), and failed tests
(n ⫽ 4). The median period between referral by the
federal health care agency and the first visit at the au-
diologic center was 8 days. A total of 96.5% (n ⫽ 164) of
the referral population was of white origin and 3.5%
(n ⫽ 6) black.
Audiologic evaluation after screening confirmed the
presence of hearing loss in 121 children. Five children
(2.9%) initially had secretory otitis media, which re-
solved during the testing period. Consequently, 116
(68.2%) of the referred children had permanent hearing
loss of ⱖ35 dB nHL; 31.8% of the children from the
ing. The male/female ratio remained almost constant at
1.11.
Bilateral hearing loss was diagnosed in 68 infants
(58.6%) and unilateral hearing loss in 48 infants
(41.4%). Bilateral involvement was more frequently
seen in boys. The bilateral/unilateral ratio was 1.54 for
boys and 1.29 for girls. Considering only the infants (n ⫽
median thresholds were 70 dB nHL in unilateral cases
and 80 dB nHL in bilateral cases. The distribution of
hearing loss in the 184 ears (116 infants) involved is
presented in Fig 1. There was no statistical difference
between the hearing loss levels in the unilateral and
bilateral hearing impairment populations (Mann-Whit-
ney test, P ⫽ .098). However, patients with bilateral
hearing loss were more apt to have profound hearing
loss than were those with unilateral hearing loss (41.0%
vs 20.8%) (Table 2).
The relationship between the initial AABR screening
results from the federal health care agency (n ⫽ 144)
and the final audiologic diagnoses is shown in Table 3. In
60.4%, the initial AABR screening diagnosis was totally
in agreement with the audiologic evaluation. However,
11.6% of neonates with a unilateral refer result revealed
a permanent bilateral hearing loss. Children with a uni-
lateral refer result were more likely to have normal
hearing than were those with a bilateral refer result
(41.9% vs 14.0%). For children with bilateral refer re-
sults at screening, this diagnosis was confirmed in 80.7%
of cases.
At first presentation at the referral center, risk factors
for hearing loss were identified by using the guidelines of
the Joint Committee on Infant Hearing 2000 position
statement.7 Ninety-six children (57.8%) had no risk fac-
tors, there were 4 children for whom risk factors were
unknown because of unavailable questionnaires, and 70
children (42.2%) had 1 (n ⫽ 58) or more (n ⫽ 12) risk
factors. The relationship between the presence or ab-
sence of risk factors and the hearing status after audio-
metric evaluation is presented in Table 4. A total of
65.6% of children without risk factors were found to

TABLE 2 Patients Categorized According to Maximal Hearing Loss

Hearing n TABLE 4 Relationship Between Risk Factors and Hearing Status
Loss Risk Factor ABR, n
40–70 dB 71–95 dB ⬎95 dB
nHL nHL nHL Hearing Loss Normal Hearing
Bilateral 25 15 28 (n ⫽ 113) (n ⫽ 53)
Unilateral 27 11 10 Present (n ⫽ 70) 50 20
Total 52 26 38 Absent (n ⫽ 96) 63 33

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 Familial deafness
10.6%
In utero infections
6.7%
Craniofacial anomalies
5.0%
Hyperbilirubinemia
4.5%
FIGURE 2
No risk factor
Distribution of risk factors according the guidelines of the Joint Weight < 1500 g
53.6%
Committee on Infant Hearing 2000 position statement. 6.1%

Low Apgar score

2.2%

Ototoxic medication
2.8%
Artificial breathing > 5
Deafness syndromes days
3.9% 4.5%

have a hearing loss, whereas 28.6% of the children with
risk factors had normal hearing. The distribution of the
different risk factors is presented in Fig 2.
Familial history of deafness was the most frequently
encountered risk factor for congenital hearing loss in our
population. Risk factors were not statistically different
between the normal hearing and hearing loss groups
(Kruskal-Wallis test, P ⫽ .44).
The screening population of NICU infants demon-
strated a permanent hearing loss in 61.5% of cases. The
male/female ratio was 3.0. The median hearing loss of
the hearing-impaired children was 60 dB nHL. The
most-prevalent risk factors were mechanical ventilation,
low birth weight, and hyperbilirubinemia.
Etiologic Evaluation
Additional diagnostic testing for the permanently hear-
ing-impaired infants (n ⫽ 116) could be performed in 87
cases. Dropout of 29 (25.0%) of 116 children was ob-
served, in which case the complete diagnostic protocol
could not be conducted. A specific etiologic diagnosis
was established for 48 (55.2%) of the 87 children for
whom a permanent hearing loss was confirmed. For the
remaining 39 children (44.8%), the cause underlying
the congenital hearing loss remained unknown. The
distribution of the etiologic diagnoses is presented in Fig
3. Of the causes identified, a genetic cause was present in
60.4% of cases, peripartal problems in 20.8%, and con-
genital CMV infection in 18.8%. With respect to the
genetic causes of hearing loss in our population, muta-
tions in the GJB2 gene accounted for 37.9% of the cases,
chromosomal aberrations were found in 13.8% (n ⫽ 4),
specific syndromic deafness for which the underlying
molecular basis was known was proven in 6.9% (n ⫽ 2),
and a yet unknown genetic factor was involved in
41.4% (n ⫽ 12). The last category was based on pedigree

Asphyxia Cerebral bleeding

Bacterial meningitis 3.4% 3.4%
1.1%
ABO incompatibility
2.3%

Syndromic deafness
2.3%
CMV
FIGURE 3 No diagnosis 10.3%
Etiologic diagnoses for children with congenital permanent 44.8%
hearing loss.
CX 26
12.6%

Fetal Alcohol syndrome

1.1%

Chromosomal
aberrations
Familial hearing loss 4.6%
13.8%

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 TABLE 5 Genotype-Phenotype Correlation in Children With GJB2 ABO incompatibility (n ⫽ 2), bacterial meningitis (n ⫽
Mutations 1), and fetal alcohol syndrome (n ⫽ 1). The other labo-
ratory tests demonstrated various findings in a number
Patient GJB2 Mutation Hearing Threshold, dB nHL
of cases, without any contribution to the final etiologic
Right Ear Left Ear diagnosis. Ophthalmologic examination revealed 5 in-
1 35delG homozygote ⬎100 ⬎100 fants with eye abnormalities, including astigmatism (n ⫽
2 35delG homozygote ⬎100 ⬎100 2), eye ptosis, pseudofakia, and strabismus. In the
3 35delG/1VS1 ⫹ 1G⬎A 70 90 present population, ophthalmologic evaluations were of
4 35delG/1VS1 ⫹ 1G⬎A 50 65 only limited importance for the diagnosis of deafness.
5 35delG homozygote ⬎100 ⬎100
Radiologic imaging was performed for 37 patients
6 35delG homozygote ⬎100 20
7 35delG homozygote 60 80
(38.5%) exhibiting sensorineural hearing loss of ⱖ60 dB
8 35delG homozygote ⬎100 90 nHL (n ⫽ 96). Of those patients, 11 (29.7%) showed
9 71G⬎A homozygote ⬎120 ⬎120 positive radiologic findings. Computed tomography had
10 C101T⬎C ⫹ C71G⬎A 50 70 a slightly higher rate of abnormality detection (n ⫽ 33;
11 35delG ⫹ 35dupG 120 120 27%) than did MRI (n ⫽ 23; 21%).
In aural atresia, the classical malformations of the
external and middle ear were found. Minor inner ear
malformations at the semicircular canals were described
characteristics demonstrating a mendelian type of inher-
in 3 cases, but no Mondini-like defects were observed.
itance or specific phenotypes for which the gene or the
Electrocardiographic findings were abnormal in only 1
sequence is not yet known.
patient, with Jervell and Lange-Nielsen syndrome.
For 11 children, hearing loss was attributed to muta-
tions in the GJB2 gene. A detailed description of the
DISCUSSION
different GBJ2 mutations and the resulting hearing loss is
Hearing loss is one of the most common congenital
shown in Table 5. All of these children were either
anomalies, occurring in ⬃1 to 2 infants per 1000. Left
homozygous or compound heterozygous. Homozygotic
undetected, hearing impairment in infants can nega-
carriage of the 35delG mutation was the most common
tively affect speech and language acquisition, academic
pattern but demonstrated variable clinical expression.
achievement, and social and emotional development.
Apart from GBJ2 mutations, the following specific
These negative effects can be diminished and even elim-
genetic phenotypes were found: trisomy 21 (n ⫽ 2),
inated through early intervention at or before 6 months
partial trisomy 19p (n ⫽ 1), trisomy 18 (n ⫽ 1), Jervell
of age.3 To the best of our knowledge, this is the first
and Lange-Nielsen syndrome (n ⫽ 1), Waardenburg
report in the literature that provides data on audiologic
syndrome (WS) (n ⫽ 1), and craniofacial malformations
confirmation and etiologic assessment in a large sample
(n ⫽ 6). The last category included 4 cases of aural
of newborns referred after failed UNHS.
atresia.
Many UNHS programs are experiencing difficulty get-
For 9 children, a diagnosis of congenital CMV infec-
ting all or most of the infants referred from the screening
tion was made. CMV was detected through PCR assays
program to complete the diagnostic process and to be
with the blood spots on Guthrie cards, viral cultures, or
enrolled in intervention programs. Attrition rates as high
blood serologic tests. A detailed description of these chil-
as 60% between the initial referral and diagnostic con-
dren and their hearing thresholds at birth and at fol-
firmation are not unusual.10 Moreover, an important
low-up evaluations is presented in Table 6.
deficiency of virtually all UNHS programs is that they
Perinatal causes of hearing loss were cerebral bleeding
lack information on diagnostic evaluations.6 The current
(n ⫽ 3), asphyxia (n ⫽ 3), kernicterus attributable to
tracking system organized by the federal health care
agency seems to be very effective, because virtually all
patients sent by the organization were actually seen for
TABLE 6 Hearing Thresholds at Time of Diagnosis and Evolution in follow-up audiologic confirmation. In addition, organiz-
Children With Hearing Loss Attributable to Congenital ing the etiologic evaluation was quite efficient, with a
CMV Infection dropout rate of only 25.0%. The search for an underly-
Patient Hearing Threshold, Age at Last Follow-up Evolution ing cause must be undertaken through a multidisci-
dB nHL Evaluation, y plinary approach involving an ear, nose, and throat sur-
Right Ear Left Ear geon, a pediatrician, a geneticist, an ophthalmologist, a
radiologist, and other specialists when indicated by the
1 40 80 3.0 Stable
2 ⬎100 40 2.5 Stable
clinical findings. An efficiently managed diagnostic pro-
3 55 45 Lost to follow-up ? tocol decreases the burden for the parents and child and
monitoring limits the risk of noncompliance.
4 ⬎100 ⬎100 1.2 Stable The presence of hearing loss (either unilateral or bi-
5 70 60 2.4 Progressive lateral) was confirmed in 68.2% of the referrals. In
6 120 120 1.8 Stable 31.8%, hearing was found to be normal after a thorough
7 50 70 0.9 Stable audiometric evaluation. In 60.4% of the cases, exactly
8 40 120 1.1 Progressive analogous results were found in screening and diagnos-
9 60 100 0.8 Stable tic testing. Our results suggest that the accuracy of new-

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born hearing screening remains an issue, even if the
positive predictive value for the UNHS program orga-
nized by the federal health care agency in Belgium has
been reported to be as high as 32%.6
Children with unilateral refer results were more likely
to have normal hearing, but 11.6% of those children
were diagnosed as having bilateral hearing loss. These
findings underscore the need for a comprehensive au-
diometric evaluation in both unilateral and bilateral re-
ferral cases. Limiting the audiometric protocol to bilat-
eral referral cases cannot be justified, because unilateral
referral cases with bilateral hearing loss (and the need
for rehabilitation) would go undetected.
The same holds true for limiting screening to new-
borns with risk factors for congenital hearing loss. A total
of 55.8% of children with hearing loss had no risk fac-
tors at all. The presence of ⬎1 risk factor does not
necessarily imply a cumulative risk for hearing loss, be-
cause 4 children with multiple risk factors had normal
hearing.
In some European countries, such as the United King-
dom, an etiologic investigation is usually conducted only
for children with bilateral hearing loss of ⬎35 dB nHL
identified through the National Newborn Hearing
Screening Program.11 Interestingly, in both the GJB2 and
congenital CMV groups, some children had only 1 af-
fected ear. If an etiologic diagnosis had been sought only
for children with bilateral hearing loss, then those chil-
dren would have been missed.
According to the literature, prelingual hearing loss is
attributed to genetic causes in 50% of cases and to
environmental causes in the other 50%.12 In the present
study, an etiologic diagnosis could be established in
55.2% of the cases. Of the causes identified, a genetic
cause was present in 60.4% of the cases and environ-
mental problems in 39.6%.
Among the genetic causes, ⬃30% were reported pre-
viously to be syndromic and 70% nonsyndromic.12
Within the prelingual, nonsyndromic, hearing loss
group, inheritance is reported to be 75% to 80% auto-
somal recessive, 20% to 25% autosomal dominant, and
15 to 1.5% X-linked. Although nonsyndromic sensori-
neural hearing loss is very heterogeneous, mutations in
the GJB2 gene account for nearly 50% of cases of con-
genital, autosomal recessive, nonsyndromic, sensorineu-
ral hearing loss in the white population.13
Looking specifically at the genetic causes of hearing
loss in our population (n ⫽ 29), syndromic sensorineural
hearing loss accounted for 31.0% and nonsyndromic
phenotypes for 69.0%. Mutations in the GJB2 gene ac-
counted for 38% of the genetic cases, specific syndromic
deafness for 7%, and chromosomal aberrations for 14%;
in 41% of cases, a mendelian phenotype without known
gene and/or sequence was involved. This finding is in
agreement with the finding that GJB2 mutations account
for 30% to 40% of genetic causes of prelingual hearing
loss throughout the world.
Hearing impairment in subjects in the biallellic non-
truncating GJB2 mutations ranges from mild to profound
and is usually nonprogressive.14,15 The c35delG (35delG
mutation) variant is the most common in children of
1124 DECLAU et al
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northern European ancestry and has a carrier frequency
of ⬃2.5% in the general population. It was also the most
common allele variant of GJB2 in our population. As
illustrated in Table 5, there was a variable genotype-
phenotype correlation even among children homozy-
gous for 35delG, which is known to be associated with
profound hearing loss. Our data are in accordance with
those from a large multicenter study reported by Sno-
eckx et al.16 Those authors found that the degree of
hearing loss associated with biallellic truncating muta-
tions (such as 35delG) was more severe than that asso-
ciated with biallellic nontruncating mutations. A diag-
nosis of GJB2 mutations has important implications for
parental counseling. Hearing loss attributable to GJB2
mutations is usually nonprogressive, and prenatal diag-
nosis is possible in the case of future children.14–16
WS is the most common type of autosomal dominant
syndromic hearing loss, in association with minor de-
fects in structures arising from the neural crest and pig-
mentation anomalies.17 It consists of variable degrees of
sensorineural hearing loss and pigmentary abnormalities
of the skin, hair (white forelock), and eyes (heterochro-
mia iridis). Four types are recognized (ie, WS I, WS II,
WS III, and WS IV), on the basis of the presence of other
abnormalities. WS I and WS II share many features but
have an important phenotypic difference; WS I is char-
acterized by the presence of dystopia canthorum,
whereas WS II is characterized by its absence. In WS III,
upper-limb abnormalities are present. In WS IV, Hirsch-
sprung disease is present. Mutations in PAX3 cause WS I
and WS III. Mutations in MITF cause some cases of WS
II. Mutations in EDNRB, EDN3, and SOX10 cause WS IV.
Jervell and Lange-Nielsen syndrome is an autosomal
recessive form of profound bilateral congenital deafness
associated with prolongation of the QT interval, as de-
tected through electrocardiography (the abnormal QTc is
⬎440 milliseconds). It is caused specifically by mutation
of the KCNE1 and KCNQ1 genes. Among untreated indi-
viduals with Jervell and Lange-Nielsen syndrome,
⬃50% die by the age of 15 years, as a result of ventric-
ular arrhythmias.18
Fetal alcohol spectrum disorder describes a spectrum
of permanent and often devastating birth defect syn-
dromes caused by maternal consumption of alcohol dur-
ing pregnancy. The main effect of fetal alcohol exposure
is brain damage. Church and Abel19 observed that fetal
alcohol spectrum disorder is associated with 4 kinds of
hearing disorders, that is, (1) developmentally delayed
speech and language development, (2) sensorineural
hearing loss, (3) intermittent conductive hearing loss
attributable to recurrent serous otitis media, and (4)
central hearing loss. As is the case with other syndromes
associated with craniofacial anomalies and hearing im-
pairments, speech and language pathologic conditions
also are common in patients with fetal alcohol spectrum
disorder. In our population, 1 child demonstrated clini-
cal signs of fetal alcohol spectrum disorder.
Craniofacial malformations were observed in 12.5%
of cases (n ⫽ 6). In 4 cases, aural atresia was determined.
According to Das,20 chromosomal aberrations may
account for 3.8% of congenital hearing loss. In our pop-
ulation, trisomies 18, 21, and 19p accounted for 8.3%
(n ⫽ 4) of the identified causes of prelingual hearing loss.
In the literature, the most important environmental
factors responsible for prelingual hearing loss are con-
genital infections (mainly rubella in nonvaccinated areas
and CMV), ototoxicity, prematurity, and asphyxiation.12
In our study group, 39.6% of the cases of permanent
hearing loss were attributable to environmental causes.
Congenital CMV infection was recognized as the most
frequent cause of acquired hearing loss in neonates. In
our population, congenital CMV infection was present
in 18.8% of cases. A diagnosis of congenital CMV infec-
tion was based on PCR assays with dried blood spots on
Guthrie cards, viral cultures from urine or saliva sam-
ples, and the presence of specific IgM antibodies. Con-
genital CMV infection is a challenging diagnosis.21 Once
children are older than 2 to 3 weeks, the diagnosis
becomes sometimes difficult, because viral excretion in
the urine might be intermittent and a postnatal infection
cannot be ruled out. In more-recent years, implementa-
tion of PCR analysis of viral DNA in dried blood spots has
significantly improved the diagnostic power for congen-
ital CMV infection.22,23 An early diagnosis of congenital
CMV has important implications from a therapeutic
point of view. Clinical studies with treatment protocols
based on ganciclovir are underway and promising, al-
though not applied in the present study.24,25 Hearing loss
attributable to congenital CMV may be progressive in
⬎50% of cases,26 and regular audiometric follow-up
monitoring is required until the age of 6 years. Both
aspects underscore the need for correct early diagnosis
and appropriate counseling of the parents.
According to Fortnum and Davis,27 bacterial menin-
gitis accounts for 6% of sensorineural hearing loss in
children. In a study by Koomen et al, 75% of patients
were ⬍2 years of age.28 Bacterial meningitis was a cause
of acquired neonatal hearing loss in 1 child (2.1%) in
our population.
A diagnosis of auditory dyssynchrony was estab-
lished for 2 children (4.2%). This disorder is charac-
terized by a dysfunction in neural/brainstem transmis-
sion of auditory stimuli in the presence of normal
outer hair cell function. This condition translates into
absent or abnormal ABR responses and normal oto-
acoustic emissions. The clinical significance is that this
may result in impaired development of normal audi-
tory behavior or oral language, often leading to co-
chlear implantation. According to Foerst et al,29 a
prevalence of 0.94% was found within the group at
risk for hearing loss, compared with 8.44% among
profoundly hearing-impaired children. Protocols that
use otoacoustic emission screening should refer in-
fants with hyperbilirubinemia for ABR testing, be-
cause there is mounting evidence in the literature
showing linkage between auditory dyssynchrony and
hyperbilirubinemia.30 In the present study, every child
who needed at least phototherapy was considered at
risk for hearing loss.
Mutations in the gene encoding otoferlin (OTOF),
known as DFNB9, also may cause a pattern of auditory
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dyssynchrony.31 In this particular case, the disorder is
attributed to functional alterations in the inner hair cells.
In 1 child, auditory dyssynchrony was caused by hy-
perbilirubinemia attributable to Rh factor incompatibil-
ity. The child was treated with exchange transfusion
during the newborn period, and later she received a
cochlear implant. For the other child, no risk factors
were present and mutations in the OTOF gene were
excluded.
It is obvious that identification of the cause of the
hearing loss provides new information relevant to hear-
ing loss management, coexisting medical problems, and
the prognosis for the child and family. In addition, these
investigations clarify the epidemiological features of con-
genital deafness, which may facilitate the planning of
effective hearing loss prevention and surveillance pro-
grams.
CONCLUSIONS
A diagnosis of congenital hearing loss (either unilateral
or bilateral) was made for 68.2% of neonates referred for
audiometric evaluation after failed UNHS. For 55.2% of
those children, an etiologic diagnosis could be made after
a comprehensive etiologic evaluation. This evaluation
allows for appropriate, individually tailored rehabilita-
tion, audiometric follow-up monitoring, and parental
counseling. Our diagnostic abilities are likely to improve
in the near future, with advances in molecular genetics
and the rapidly expanding knowledge concerning genes
involved in nonsyndromic sensorineural hearing loss.
This would significantly improve the strength of UNHS
programs and allow for the rapid identification of pre-
lingual hearing loss.
ACKNOWLEDGMENT
We thank the audiologists in our department for their
outstanding professional help and diligence in screening
newborns.
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Etiologic and Audiologic Evaluations After Universal Neonatal Hearing Screening:
Analysis of 170 Referred Neonates
Frank Declau, An Boudewyns, Jenneke Van den Ende, Anouk Peeters and Paul van den
Heyning
Pediatrics 2008;121;1119
DOI: 10.1542/peds.2007-1479
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by
the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2008 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
0031-4005. Online ISSN: 1098-4275.

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Etiologic and Audiologic Evaluations After Universal Neonatal Hearing Screening:
Analysis of 170 Referred Neonates
Frank Declau, An Boudewyns, Jenneke Van den Ende, Anouk Peeters and Paul van den
Heyning
Pediatrics 2008;121;1119
DOI: 10.1542/peds.2007-1479

The online version of this article, along with updated information and services, is located
on the World Wide Web at:
/content/121/6/1119.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2008 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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