Syndromic Hearing Loss: an update

Abstract

Hearing impairment is one of the commonest clinical conditions. It has been estimated that approximately 1 in 10 persons has hearing concerns. Further epidemiological studies have found that the percentage of the general population with hearing loss greater than 45 dB HL and 65 dB HL is 1.3% and 0.3%, respectively, between 30 and 50 years of age; and 2.3% and 7.4% between 60 and 70 years of age. The prevalence of childhood and adolescent hearing loss is around 3%. At birth, between one and two out of 1000 newborns are affected by hearing loss of such a degree as to require treatment (auditory training and rehabilitation, hearing aids or cochlear implantation). To summarize, hearing impairment affects up to 30% of the international community and estimates indicate that 70 million persons are deaf. The causes of hearing loss differ and they can vary in severity and physiopathology. In many cases it is not possible to define a definite aetiology. Nevertheless, it is known that most are due to a genetic cause and among these the majority appear in a non-syndromic form. The aetiology of hearing loss in children is unknown in 40% of cases, genetic non-syndromic in 30%, and genetic syndromic in 3–5%. The two most common genes involved in hearing loss are GJB2 and SLC26A4. Mutations in these genes can be responsible for syndromic hearing loss, as keratitis ichthyosis deafness (KID) and Pendred syndromes, respectively, or non-syndromic hearing loss (as DFNB1 and DFNB4, respectively). DFNB1 with GJB2 mutations is the most common non-syndromic form and Pendred syndrome is the most common syndromic form. Neither of these last two is usually characterized by congenital macroscopic dysmorphic features, and affected children can be generally considered as well babies. Nonetheless, 2–4% of live births have congenital malformations, most commonly caused by multifactorial defects, followed by chromosomal disorders, single gene mutations and teratogens (alcohol, drugs).

Some of these conditions could directly affect the auditory system and be responsible for sensorineural, conductive or mixed hearing loss. The London Dysmorphology Database lists approximately 400 syndromes that include hearing loss among the clinical features. Other conditions such as cystic fibrosis are not usually responsible for hearing loss but they can indirectly affect the auditory system as a consequence of the management of the disease. Other systemic disorders can lead to hearing impairment when the disease involves a part of the auditory system from the external ear to the auditory cortex. From this standpoint there are a huge number of syndromes or conditions that can directly or indirectly cause hearing impairment. They can be responsible for congenital or prelingual, progressive and post-lingual hearing loss, with sensorineural, mixed or conductive deficits. In this updating research we have focused on syndromic forms that are known to be associated with hearing loss or that directly affect the auditory system. Some conditions of particular interest, or with high incidence, are also included.

Full text

Correspondence: A. Castiglione, Department of Neurosciences  Operative Unit of Otolaryngology and Otosurgery, 2 Giustiniani – Padua 35100, Italy. Fax:
 39 049 821 1994. E-mail: alessandro.castiglione@unipd.it
(Accepted 25 June 2013)
ORIGINAL ARTICLE
Syndromic hearing loss: An update
ALESSANDRO CASTIGLIONE
1
, MICOL BUSI
2
& ALESSANDRO MARTINI
1
1
Department of Neurosciences, C.O.U. of Otorhinolaryngology and Otosurgery, University Hospital of Padua, and
2
Department of Medical & Surgical Disciplines of Communication and Behavior, University of Ferrara, Italy
Abstract
Hearing impairment is one of the commonest clinical conditions. It has been estimated that approximately 1 in 10 persons
has hearing concerns. Further epidemiological studies have found that the percentage of the general population with hear-
ing loss greater than 45 dB HL and 65 dB HL is 1.3% and 0.3%, respectively, between 30 and 50 years of age; and 2.3%
and 7.4% between 60 and 70 years of age. The prevalence of childhood and adolescent hearing loss is around 3%. At birth,
between one and two out of 1000 newborns are affected by hearing loss of such a degree as to require treatment (auditory
training and rehabilitation, hearing aids or cochlear implantation). To summarize, hearing impairment affects up to 30%
of the international community and estimates indicate that 70 million persons are deaf. The causes of hearing loss differ
and they can vary in severity and physiopathology. In many cases it is not possible to defi ne a defi nite aetiology. Neverthe-
less, it is known that most are due to a genetic cause and among these the majority appear in a non-syndromic form. The
aetiology of hearing loss in children is unknown in 40% of cases, genetic non-syndromic in 30%, and genetic syndromic
in 3 – 5%. The two most common genes involved in hearing loss are GJB2 and SLC26A4 . Mutations in these genes can be
responsible for syndromic hearing loss, as keratitis ichthyosis deafness (KID) and Pendred syndromes, respectively, or non-
syndromic hearing loss (as DFNB1 and DFNB4, respectively). DFNB1 with GJB2 mutations is the most common non-
syndromic form and Pendred syndrome is the most common syndromic form. Neither of these last two is usually
characterized by congenital macroscopic dysmorphic features, and affected children can be generally considered as well
babies. Nonetheless, 2 – 4% of live births have congenital malformations, most commonly caused by multifactorial defects,
followed by chromosomal disorders, single gene mutations and teratogens (alcohol, drugs).
Some of these conditions could directly affect the auditory system and be responsible for sensorineural, conductive or
mixed hearing loss. The London Dysmorphology Database lists approximately 400 syndromes that include hearing loss
among the clinical features. Other conditions such as cystic fi brosis are not usually responsible for hearing loss but they
can indirectly affect the auditory system as a consequence of the management of the disease. Other systemic disorders can
lead to hearing impairment when the disease involves a part of the auditory system from the external ear to the auditory
cortex. From this standpoint there are a huge number of syndromes or conditions that can directly or indirectly cause
hearing impairment. They can be responsible for congenital or prelingual, progressive and post-lingual hearing loss, with
sensorineural, mixed or conductive defi cits. In this updating research we have focused on syndromic forms that are known
to be associated with hearing loss or that directly affect the auditory system. Some conditions of particular interest, or with
high incidence, are also included.
Keywords:
hearing impairment , syndrome , syndromic hearing loss , non-syndromic hearing loss
Introduction
The term ‘ syndrome ’ , from the Greek σ υ ν δ ρ μ η´
(course along with, together), defi nes an association
or concurrence of clinically recognizable signs
(objectives, that can be observed by someone
other than the patient) and symptoms (subjectives,
reported by the patient) with unknown, unclear or
various aetiology, that involves at least two different
organs, apparatus or systems. We also call ‘ syndrome ’
conditions caused by well-known pathophysiological
events or characterized by signs or symptoms affect-
ing the same organ: for example, some authors call
EVA syndrome the association between hearing loss
and enlarged vestibular aqueduct. This is accepted,
even if improper use of the meaning of ‘ syndrome ’
can generate some misunderstanding and certainly
makes the defi nition of syndromic hearing loss dif-
fi cult. Consequently, fi ltering out the prevalence of
Hearing, Balance and Communication, 2013; Early Online: 1–14
ISSN 2169-5717 print/ISSN 2169-5725 online © 2013 Informa Healthcare
DOI: 10.3109 /21695717.2013.820514
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2 A. Castiglione et al.
syndromic hearing loss among non-syndromic and
non-hereditary hearing loss is an imperfect task,
given also phenotypic variability, complicating med-
ical risk factors, and incomplete family histories. In
addition, epidemiological studies are complicated
when the same condition can lead at different times
(depending on symptoms and signs onset) to non-
syndromic or syndromic forms. For example,
DFNB4 could become Pendred syndrome when the
disease involves the thyroid gland with clinical man-
ifestations. This ‘ instability ’ in defi nitions makes
comprehensive research on syndromic hearing loss
quite diffi cult. An update could be that syndromic
hearing loss includes every condition, disorder, dis-
ease or syndrome that shows hearing impairment
associated with one other sign or symptom.
A correct defi nition and classifi cation could help
in managing and organizing particular events with a
copious number of elements that are clinically diffi -
cult to consider or treat together. From this point of
view, a multidisciplinary approach in managing syn-
dromic hearing loss is mandatory. Conversely, the
term syndromic hearing loss could be strictly used
to name conditions that almost constantly affect
hearing and at least one other organ or system with
clinical manifestations, without a clear aetiology.
Other conditions could be called diseases or disor-
ders, even if accepting this will probably not change
the indications for treatment or therapy of the hear-
ing loss that essentially remains based on the avail-
able audiological data.
In waiting for a better defi nition of the fi eld of
syndromic hearing loss, the present study adopted
the following criteria for selection of conditions that
can be related to hearing loss: independently from
names, aetiology and entity of hearing loss, disorders
were selected based on their estimated prevalence, in
decreasing order and divided into different types, in
order to illustrate a few examples of various condi-
tions. Generally, among these syndromes there are
syndromes with a high prevalence and no constant
hearing concerns, as well as very rare syndromes that
could be characterized by a strong association with
severe to profound hearing loss. It should be noted
that not all syndromes are recognized as having a
genetic cause, e.g. cytomegalovirus and foetal-alcoholic
syndromes. Cases of particular interest are also des-
cribed and discussed herein, and reported in decreas-
ing order of estimated prevalence, if not otherwise
specifi ed (1 – 6).
Clinical aspects
Because abnormalities of virtually every organ sys-
tem have been associated with hearing loss, physi-
cians must become familiar with the constellation of
physical fi ndings that may help determine the diagno-
sis and aetiology of a patient’s hearing impairment
(Figures 1 – 4). As most hearing loss is recognized as
having a genetic cause, patients generally benefi t from
a genetic evaluation, particularly if they present syn-
dromic features. To date, more than 90 genes have
been identifi ed as being potentially or defi nitely related
to hearing loss (4,5); this is an increasing number
and it could be doubled in the coming years (http://
hereditaryhearingloss.org/). Approximately 400 syn-
dromes (of around 7000 described rare syndromes or
diseases of which approximately 1500 are known to
have a genetic aetiology) include hearing impairment
as a potential feature of the clinical picture. It could
therefore be deduced that around 6% of rare diseases
affect hearing. Even if this is an approximation, it indi-
cates that hearing is a hot spot for genetic syndromes
or rare diseases and disorders, probably due to its
specifi c function, anatomical structure and topo-
graphic position; additionally, auditory cells have a
lifespan different from that of cells of other sensory
organs. Gustatory cells survive for 14 – 21 days and
olfactory cells survive for 30 – 90 days. The ciliated
cells of the ear have an average life of 70 – 100 years,
but their number is fewer than 20,000, compared to
137 million cells in the retina. These aspects increase
the probability of the ear being involved in a lifetime
disease. In summary, it could be concluded that every
systemic condition, including genetic disorders,
requires an audiological investigation. Reviewing the
most common systemic disorders, such as auto-
immune and metabolic disorders, diabetes and
hypertension, reveals that they could be strongly
associated with hearing loss (5 – 8).
Recognizing a syndrome depends on many fac-
tors, and is essentially based on a multidisciplinary
approach. Nevertheless, it is often thought among
specialists that the diagnosis of a syndrome depends
on a kind of intuitive reaction when seeing a patient.
It could be noted that this preconception is quite
wrong and it could lead to misdiagnosis (1). Intuition
and inspection are very important, but a correct
approach to syndromes requires a specifi c, clear and
methodical approach. The physical examination
should incorporate an in-depth ear, nose, throat,
head, and neck evaluation, along with an overall
assessment of general physical and neurological sta-
tus. Children with syndromic features associated
with hearing loss should be screened early and rou-
tinely for hearing loss. Valid and reliable techniques
are available to determine the presence, degree,
and nature of hearing impairment and such tech-
niques include the following: auditory brainstem
response, speech and tonal audiometry, tympa-
nometry and acoustic refl ex threshold measurement
and otoacoustic emissions.
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Syndromic hearing loss 3
Congenital/Prelingual hearing loss 1-2:500-1000 newborns
Genetic 35-40%
Non Genetic 25-30%
Non syndromic hearing loss 70%
Syndromic hearing loss 30%
15-2% AD
DFN A
65-85% ar
DFN B
1-2% X-linked
DFN X
0-1% Y-linked
DFN Y
0-1% Auditory Neuropathies
AUN
15-30% AD
Treacher Collins
Waardenburg
BOR
30-60% ar
Pendred
Usher
Jervell & Lange-Nielsen
5-10% X-linked
Albinism (ar)
Alport (AD)
Norrie (ar)
0-1 % Mitochondrial DNA
DFN MT
0-1 % Modifier Genes
DFN M
2-5% mt DNA
MIDD, MELAS, MERRF
5-15% Multifactorial disorders
Goldenhar (non genetic?)
CHARGE (?)
Unknown/Idiopathic
35-40%
Mendelian inheritance
Non mendelian inheritance
1-3% Imprinting/uniparental disomy
Angelman/Prader Willi Syndromes (?)
Figure 1. Aetiology and epidemiology of congenital hearing loss. AD: autosomal dominant; ar: autosomal recessive.
Early identifi cation of hearing loss and appropri-
ate intervention provides the best opportunity for
counselling, habilitation, and development. Addi-
tionally, early enrolment in services for a child with
hearing impairment reduces health care, special
education, and other service costs. Even if initial
screening examinations indicate normal hearing, the
child remains at risk. During infancy and early
childhood, parents should be aware of, and ques-
tioned about, the child’s hearing and language mile-
stones. Some syndromes, such as Pendred, Alport,
Refsum, neurofi bromatosis type II, Usher, and
osteopetrosis, may place the patient at risk for pro-
gressive hearing loss. The morbidity of hearing loss
varies with the severity of involvement; however, it
is a signifi cant problem even for the most mildly
involved. Bilateral profound hearing loss has a great
potential for morbidity. Many studies support that
deafness signifi cantly affects quality of life; social,
educational, and earning potential are diminished.
Patients with unilateral hearing loss have diffi culty
hearing in background noise and diffi culty localizing
sound. Furthermore, some syndromes, such as
Usher syndrome, which accounts for a large per-
centage of the aetiology of deaf-blindness, could
affect more than one sensory system. The dual sen-
sory impairment has huge implications for commu-
nication and education.
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4 A. Castiglione et al.
Hearing loss in the general population 1-3:10
Congenital/Prelingual Hearing Loss
1-2/500-1000 newborns
Non-Congenital/Peri/Post-lingual Hearing Loss
Genetic
(35-55%)
Acquired
(20-45%)
0 within 1 year of life 18 65
Age in months Age in years
GJB2 mutations
OTOF mutations
Waardenburg
Usher 1 Usher 2 Usher 3
Treacher-Collins
Alport
BOR
DFNB4 Pendred
Otosclerosis/Menière
Trauma
PresbiacusisNoise
Idiopathic/Unknown
(10-25%)
Infections
Iatrogenic
Norrie
Neurofibromatosis type 2
Mitochondrial DNA mutations
Stickler/Marshall
Wolfram
Pre-natal and peri-natal
suffering
Prematurity
Drugs
Acoustic Schwannoma
Figure 2. Aetiology and epidemiology of hearing loss in the general population with age of symptom onset.
Upon identifi cation of hearing loss, a complete
history should include gestational, perinatal, postna-
tal, and family histories. Other conditions could be
characterized by comorbidities or mortality. Glom-
erulonephritis associated with Alport syndrome can
end in kidney failure and necessitate kidney trans-
plantation. Children with Jervell and Lange-Nielsen
syndromes are at risk for syncope, arrhythmias, and
sudden death (1 – 8).
Even if clinical testing for many genes or param-
eters associated with hearing loss is available, a rou-
tine series of laboratory tests is not recommended in
the evaluation of patients with hearing impairment.
A rational assessment of the cost-benefi t ratio and
the clinician’s index of suspicion dictate the selection
of laboratory studies to be performed for each indi-
vidual patient. Studies may include the following:
genetic testing, including GJB2 , GJB6 and SCL26A4
(in the presence of dilated vestibular aqueduct) gene
mutation testing, blood routine testing with CBC
count with differential, glycaemic levels, BUN/
creatinine and urinalysis (to investigate renal func-
tion), thyroid function studies, fl uorescent trepone-
mal antibody absorption (FTA-ABS) and specifi c
immunoglobulin M (IgM) assays for toxoplasmosis,
rubella, cytomegalovirus, herpes virus, and autoim-
mune panel, e.g. erythrocyte sedimentation rate
(ESR), antinuclear antibody (ANA), rheumatoid
factor (RF), ENA and circulating immune complexes
(http://emedicine.medscape.com/).
CT scanning offers very high-resolution images
with  1 mm slices, allowing good visualization of
the anatomy of the bones, ossicles, and inner ear.
CT scanning may be used to identify potential surgi-
cally reparable causes of SNHL and may also be
used to identify the less dysplastic, and presumably
better hearing, ear, when considering auditory habil-
itation. CT abnormalities are found in up to 30% of
individuals with hearing loss and thus are an impor-
tant component of the evaluation of a patient. For
example, an enlarged vestibular aqueduct and Mon-
dini malformation are common fi ndings in Pendred
syndrome. New techniques such as the CONE
BEAM TC allow better quality images with a reduced
ray exposure. Magnetic resonance imaging com-
pletes the neuroradiological investigations. High
soft-tissue contrast makes MRI ideal for evaluation
of the inner ear, internal auditory canal, and cerebel-
lopontine angle. In addition it could be considered
with thyroid and renal ultrasonography when abnor-
malities are suspected. Other radiological investiga-
tions can help in the diagnosis of achondroplasia and
Goldenhar syndrome (http://emedicine.medscape.
com/) (7 – 11).
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Syndromic hearing loss 5
Specifi c tests could be performed in certain
conditions when an appropriate degree of clinical
suspicion is present. ECG reveals cardiac conduc-
tion anomalies and echocardiography allows the
identifi cation of heart defects. Electro-oculography
can identify retinitis pigmentosa earlier than a
physical examination. Vestibular testing allows the
identifi cation of vestibular disorders that could be
associated with hearing loss, in particular condi-
tions such as Pendred, Usher, CHARGE and
Alagille syndromes (1 – 8).
Hearing evaluation in most common genetic
disorders
Down syndrome or trisomy 21 (1:600 newborns)
Trisomy 21, or Down syndrome, is the most com-
mon chromosomal disorder characterized by dys-
morphic features, macroglossia, abnormal teeth,
epicanthal folds, broad short trunk, muscular hypo-
tonia, congenital heart disease, thyroid dysfunction,
transverse palmar crease and neurological abnor-
malities including mental retardation of a variable
degree. Hearing loss occurs in up to 80% of cases
and it can be conductive (the majority), secondary
to external ear stenosis, chronic middle ear diseases
(otitis media with effusion or cholesteatoma) or
ossicular chain anomalies, sensorineural or mixed.
The risk of this syndrome in the offspring increases
with maternal age at pregnancy (1,2,6 – 8,10).
Fragile X or Martin-Bell syndrome (1:750 newborns)
Fragile X syndrome is associated with the most com-
mon types of inherited developmental delay and men-
tal retardation. The delay and cognitive diffi culties
can range from very mild to severe and are sometimes
100%
PendredJervell Lange-Nielsen
0%
Down
Crouzon
BORUsher
Airport
CHARGE
Angelman
Martin Bell
Prader Willi
TreacherCollins
Noonan
Sensorineural ConductiveMixed
Type of hearing loss
% of patients who develop hearing loss
Goldenhar
Noonan
Patau (?)
Edwards (?)
Klinefelter
Turner
Turner
Kartagener
Achodroplasia
Sickle Cell Disease
Waardenburg I
Waardenburg II
Waardenburg IV
Waardenburg III
Norrie
Figure 3. Types of hearing loss and percentage of hearing impaired
patients in different genetic conditions.
Figure 4. Schematic representation of the entity and distribution in the frequency range of the hearing loss in different genetic
conditions.
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6 A. Castiglione et al.
associated with autism. Even if there are reported
cases of hearing loss in patients with fragile X syn-
drome, they do not have an increased incidence of
hearing loss. Nevertheless, 85% of patients develop
recurrent episodes of otitis media, which could lead
to transient or permanent hearing impairment (1,2).
Klinefelter syndrome (1:500 newborn males)
Klinefelter syndrome (KS) is the most common sex
chromosomal aberration (47, XXY) in males. It is
characterized by neurodevelopmental problems of
variable degree, tall stature with abnormal body pro-
portions, infertility, hypergonadotropic hypogonadism
with increased urinary excretion of FSH, azoospermia
and gynaecomastia. While the association between KS
and infertility has been well documented, hearing loss
has been poorly investigated in these patients. The
external and middle ear are not generally affected and
they usually appear normal; consequently no conduc-
tive hearing loss is reported among these patients.
Sensorineural hearing loss was found in approxi-
mately 20% of cases; nevertheless, further studies are
needed to confi rm these data (9).
Noonan syndrome (40:100,000)
Noonan syndrome (NS) is a common autosomal
dominant condition characterized by short stature,
congenital heart defects, developmental delay, cryp-
torchidism, broad or webbed neck and chest deformi-
ties. The incidence of NS is estimated to be 1 – 2 cases
per 2500 live births. Mutations in PTPN11 , SOS1 ,
RAF1 and KRAS are known to be responsible for NS.
Even if NS is usually included among syndromes with
associated hearing impairment, this is not a constant
feature and its degree and type are extremely variable.
The percentage of affected individuals that develop
hearing problems is approximately 50%; the degree
of hearing loss is mild to moderate and secondary to
serous otitis media, therefore of conductive type. Sen-
sorineural hearing loss is less common and is generally
mild (10%). Severe to profound sensorineural hearing
loss is uncommon (3 – 5%) (1,2).
Turner syndrome (20:100,000; 1:2000 newborn
females)
Described for the fi rst time in 1938 by Henry Turner,
this syndrome is caused by monosomy (45, X) or
structural abnormalities of the X chromosome. Turner
syndrome (TS) is characterized by short stature, lym-
phoedema, gonadal insuffi ciency, cardiac defects and
learning disabilities. Absent pubertal development
and primary amenorrhoea occur in most individuals
due to an accelerated loss of oocytes in the 45,X
ovary, leaving few follicles in a fi brous strike by birth.
Nevertheless, approximately one-third of girls with
TS may undergo spontaneous puberty, particularly in
milder phenotypes (12). Although in TS there is not
a clear genotype/phenotype correlation, girls with
mosaic TS who have a normal cell line, or an extra X
chromosome, exhibit a better prognosis (1 – 3).
Up to 80% of cases suffer from conductive hear-
ing loss probably due to more horizontally oriented
Eustachian tubes. In addition, or as a consequence
of chronic otitis media, they could show progressive
sensorineural hearing loss in the high frequencies. In
approximately 10% of patients, hearing loss requires
hearing aid amplifi cation before 20 years of age.
Sickle cell disease (15:100,000)
Sickle cell disease (SCD) is a hereditary haemoglobin
disorder characterized by intermittent episodes of
vascular occlusion and end-organ damage. Mutations
in the HBB gene cause sickle cell disease. Reviewing
the literature revealed a signifi cant incidence (up to
40%) of sensorineural hearing loss (more severe at
the higher frequencies) in SCD patients (13).
Cystic fi brosis (12.6:100,000)
Cystic fi brosis (CF) is an autosomal recessive genetic
disorder caused by mutations in the CFTR gene. CF
is the second most common life-shortening, inherited
disorder occurring in childhood in the United States,
after sickle cell anaemia. The incidence of cystic fi bro-
sis is estimated to be 1 – 2 cases per 2500 live births.
Patients with CF do not seem to have a higher
incidence of hearing impairment than healthy people.
Nevertheless, recurrent treatment with aminoglyco-
sides increases the risk of sensorineural hearing loss.
Prader Willi (10.7:100,000) and Angelman syndrome
(7.5:100,000)
These two different conditions derive from a ‘ specu-
lar ’ genomic or imprinting disorder: Prader-Willi
syndrome is due to the lack of paternal contribution
in a critical region on 15q; in contrast, Angelman
syndrome is due to the lack of maternal contribution
in the same region. Such conditions are primarily
related to microdeletions of the critical region 15q
or to uniparental disomy of chromosome 15. Less
than 5% of cases could be related to the involvement
of genes located on the proximal region of the long
arm of chromosome 15 (15q11).
Interestingly, patients affected by Angelman syn-
drome generally have normal vision and hearing;
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Syndromic hearing loss 7
even if there is mild to moderate hearing loss it is
rarely reported. Despite their hearing level, most
show severe language retardation (none or few
words). In Prader Willi syndrome, hearing is gener-
ally normal and language development is delayed;
nevertheless, verbal skills are not markedly affected
even if speech is poorly articulated. Both syndromes
are characterized by neurological defects, mental
retardation and cognitive impairment that infl uence
audiological assessment and rehabilitation (2).
Edwards syndrome or trisomy 18 (1:5000 newborns)
Edwards syndrome is named after John Hilton
Edwards, who fi rst described the syndrome in 1960.
Clinical features include malformed pinna, micro-
gnathia, prominent occiput, intestinal defects, heart
abnormalities, kidney malformations and mental
retardation. It is the second most common autosomal
trisomy, after Down syndrome and around 80% of
those affected are female. Most affected infants do
not survive past their third month of life, although
up to 13% live past the age of one year. The risk of
this syndrome increases with maternal age at preg-
nancy. Temporal bone studies have revealed severe
abnormalities in the middle and inner ear; therefore
it is thought that babies with Edwards syndrome are
deaf or at least severely hearing impaired.
Patau syndrome or trisomy 13 (1:6000)
Trisomy 13 occurs in approximately 1 per 6000
births. Congenital malformations are so severe that
most affected infants do not survive beyond the fi rst
year of life. Clinical features include microcephaly,
cleft lip and palate, polydactyly, rocker-bottom feet,
low-set malformed pinna, cardiac dextroposition,
scalp defects, and mental retardation. Temporal bone
analysis reveals cystic changes within the stria vascu-
laris, a shortened cochlea, saccular degeneration, and
anomalies of the semicircular canals. The risk of this
syndrome in the offspring increases with maternal
age at pregnancy. Temporal bone fi ndings in these
patients suggest that they are likely to be deaf or at
least severely hearing impaired.
Kartagener syndrome (1 – 2:32,000 newborns)
In 1930, a physician from Switzerland, Kartagener,
described a familial form of bronchiectasis, situs
inversus and rhino-sinusitis with nasal polyps.
Kartagener syndrome is a genetically heterogenous
disorder that prevalently shows an autosomal reces-
sive inheritance pattern. To date mutations have been
identifi ed in eight genes, reported in decreasing order
of involvement as follows: DNAH5 , DNAI1 , RSPH4A ,
DNAI2 , DNAH11 , RSPH9 , KTU , TXNDC3 . KS is
characterized by malfunction of the cilia (primary
ciliary dyskinesia) within organs, such as the nose,
ears and lungs, resulting in ineffective clearance of
mucus and bacteria. This condition leads to recur-
rent infections of the lungs, ears and nose which, if
left untreated, results in long-term organ damage. It
also affects the fl agella of sperm with consequent
sterility. It should be noted that the outer and inner
hair cells are not affected by Kartagener syndrome
because the cilia are different in structure. Karta-
gener syndrome specifi cally affects microtubules
constituted of alpha and beta tubulins. In contrast,
stereocilia of the inner and outer cells are made of
actin. Other ciliopathologies that are reported to be
responsible for retinopathy and sensorineural
hearing loss, affect cilia constituted mainly of actin.
Kartagener syndrome can cause chronic glue ear,
rhinitis and sinusitis, with the prevalence of conduc-
tive hearing loss (14 – 19).
Genetic syndromes with hearing loss as a
characteristic feature
Autosomal recessive syndromes (60 – 70% of congenital
and genetic hearing loss)
Pendred syndrome (5.5:100,000). First described in
1896 by Vaughan Pendred, the Pendred syndrome is
responsible for approximately 1 – 8% of congenital
hearing loss and mutations in the SLC26A4 gene are
the second commonest cause of genetic hearing loss
(after GJB2 mutations). There are two clinical forms
related to these mutations: syndromic and non-
syndromic deafness; the former is called Pendred
syndrome (PS) when deafness is associated with a
thyroid goitre; the latter is called DFNB4, when no
other symptoms are present. PS and DFNB4 can be
associated with inner ear malformations. In most
cases (around 80%), these consist of an enlarged ves-
tibular aqueduct (EVA). PS and DFNB4 are trans-
mitted as an autosomal recessive trait, but simple
heterozygotes can develop both forms of deafness,
which is probably due to mutations in unidentifi ed
genes. The FOXI1 (5q34) gene encodes a transcrip-
tional activator that is required in order to develop
normal hearing, sense of balance and kidney func-
tion. This activator allows the transcription of the
SLC26A4 gene. Furthermore, mutations in the
inwardly rectifying K(  ) channel gene KCNJ10
(1q23.2) are also associated with non-syndromic
hearing loss in carriers of SLC26A4 mutations with
an EVA/PS phenotype. It is thought that Pendred
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8 A. Castiglione et al.
syndrome occurs when both alleles of SLC26A4 gene
are mutated; DFNB4 (or non-syndromic EVA) seems
to be due to monoallelic mutations.
Some patients with hearing loss and EVA do not
have mutations in the SLC26A4 gene. This condition
is known as ‘ hearing loss associated with EVA ’ or
‘ EVA syndrome ’ . EVA can also be associated with
other syndromes, such as BOR syndrome or
Waardenburg syndrome, but in these syndromes
other genes are considered to be involved. EVA is
diagnosed by neuroimaging (CT and MRI): the ves-
tibular aqueduct is defi ned as enlarged if its diameter
is greater than 1.2 – 1.5 mm at the midpoint. Hearing
loss is sensorineural or mixed with a conductive
component in the low frequencies. Generally, hear-
ing impairment is congenital or prelingual, but pro-
gressive and post-lingual worsening is also possible
(10,11).
Usher syndrome (3.5:100,000). Children with Usher
syndrome develop hearing loss, vestibular and visual
impairment. It has been estimated that Usher syn-
drome accounts for approximately 3 – 5% of hearing
loss among children. The disorder is responsible for
up to 8% of cases of congenital deafness and it is
inherited in an autosomal recessive pattern. Usher
syndrome is characterized by progressive blindness
due to retinitis pigmentosa, along with moderate to
severe sensorineural hearing loss, and accounts for
about 50% of the deaf-blind in the United States.
Funduscopic examination before the age of 10 years
is limited. Electroretinography can reveal early retinal
abnormalities in young children but is not routinely
available. Night blindness and visual fi eld defi cits
may mark developing retinitis pigmentosa. Loss of
vision is progressive and 50% of individuals develop
complete blindness before the age of 50 years.
Hearing loss is generally present at birth, and
85% of affected individuals eventually become totally
deaf. Usher syndrome is classifi ed in three types, as
follows:
Type I is characterized by bilateral congenital •
severe to profound hearing loss and poor or
absent vestibular function with retinitis pigmen-
tosa diagnosed by age 10 years.
Type II is characterized by mild to moderate •
hearing loss at birth and normal vestibular func-
tion with onset of retinitis pigmentosa before
the age of 20 years.
Type III Usher syndrome is characterized by pro- •
gressive hearing loss and vestibular dysfunction
with a variable degree of retinitis pigmentosa.
The genetic basis of Usher syndrome is complex
with mutations at 13 loci (USH1 previously called
USH1A does not in fact exist) and 10 genes
identifi ed including MYO7A , USH1C , CDH23 ,
PCDH15, SANS, USH2A, VLGR1, WHRN, USH3A,
PDZD7 .
Jervell and Lange-Nielsen syndrome (0.3:100,000).
Although prolongation of the QT interval has the
higher prevalence, this condition is only called Jervell
and Lange-Nielsen syndrome when it is accompa-
nied by hearing loss; thus, by defi nition, 100% of
patients have severe to profound hearing loss. Jervell
and Lange-Nielsen syndrome is thought to be the
third most common cause of autosomal syndromic
hearing loss and accounts for 1% of all cases of reces-
sive hearing loss. This disorder is characterized by
electrocardiographic changes of a prolonged QT
interval, Stokes-Adams attacks, congenital bilateral
severe hearing loss, and sudden death. Syncopal
attacks begin in early childhood, with sudden death
often occurring in later years. The genetic basis of
Jervell and Lange-Nielsen syndrome is thought to be
mutations in the KCNQ1 , and less commonly, the
KCNE1 gene, which are responsible for coding pro-
teins that form potassium transport channels. These
channels are critical in the function of the inner ear
and heart muscle.
Alstr ö m syndrome (0.14:100,000). Alstr ö m syndrome
is an autosomal recessive disorder caused by muta-
tions in the ALMS1 gene. Alstr ö m syndrome is char-
acterized by features such as retinitis pigmentosa,
diabetes mellitus, cardiomyopathy, short stature,
obesity, and progressive hearing loss. It is important
to distinguish this condition from Usher syndrome
because of a marked difference in prognosis. Alstr ö
m
syndrome can lead to liver failure, kidney failure and
pulmonary problems, although the presentation is
variable. Hearing loss, generally of the sensorineural
variety, typically occurs by age 10 years.
Autosomal dominant syndromes (20 – 30% of
congenital and genetic hearing loss)
These are less frequent causes of hearing loss than
autosomal recessive disorders. Examples include
Stickler syndrome, achondroplasia, Waardenburg,
neurofi bromatosis, Crouzon, and branchio-oto-renal
syndromes.
Stickler syndrome (13.5:100,000). Stickler syn-
drome, also named hereditary progressive arthro-
ophthalmopathy, is a genetically Heterogeneous
condition with involvement of the connective tissue
and showing an autosomal dominant pattern. It is
characterized by high phenotypic variability essen-
tially based on disorders of the ocular, auditory,
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Syndromic hearing loss 9
in the EYA1 gene. To date it is uncertain that BOR,
BO and OFC syndromes are different entities; over-
lapping features have suggested that they could be
considered as three different clinical pictures of the
same disorder. BOR and BO syndromes are so sim-
ilar that researchers often consider them together. In
contrast, Oto-Facio-Cervical (OFC) syndrome is
still not universally accepted as an allelic variant,
because of additional features (hypoplasia of the cer-
vical musculature, pronounced sloping shoulders
and short stature) that are usually not present in BO/
BOR syndrome. Branchio-Oculo-Facial (BOF) syn-
drome presents overlapping features with BO/BOR/
OFC disorders, with or without kidney anomalies. It
is now clear that it is caused by mutations in the
TFAP2A gene and BOF syndrome is generally
considered a different entity. To date, BOR, BOS,
OFC and even Branchio-oto-ureteral (BOU) syn-
dromes should be considered in the light of molecu-
lar genetics: affected persons in families segregating
EYA1 mutations have clinical fi ndings consistent
with the diagnosis of BOR, BOS, OFC or BOU syn-
drome. These syndromes are best considered as
branchio-oto-renal spectrum disorders or EYA1-
related disorders. These similar conditions require a
multidisciplinary approach in diagnosis, management
and treatment: an otorhinolaryngologist, audiologist,
neuroradiologist, nephrologist, ophthalmologist and
geneticist are involved in a comprehensive evaluation.
Branchio-oto-renal (BOR) syndrome (MIM#
113650), also known as Melnick-Fraser syndrome
(because fi rst described by Melnick and Fraser in
1972), is an autosomal dominant disorder that
consists of external, middle and inner ear malforma-
tions, branchial cleft sinuses, cervical fi stulae, mixed
or conductive hearing loss and renal anomalies.
The prevalence of BOR syndrome is approximately
1:40,000 newborns, and it has been reported to
occur in about 2% of deaf children (1 – 4). Branchio-
otic (BO) and Oto-Facio-Cervical (OFC) syndromes
are much less common disorders that show clinically
overlapping features of BOR syndrome without kid-
ney involvement (5,6). Branchio-oto-ureteral (BOU)
syndrome defi nes similar conditions characterized by
constant duplication of the ureters.
The EYA1 (eyes absent homologue 1) gene is the
human homologue of Drosophila eyes absent gene,
which is essential for eye development in that species.
In humans, it consists of 16 coding exons and has
been localized to chromosome 8q13.3 (1 – 4). To date,
at least four different isoforms are known ( EYA1A ,
EYA1B , EYA1C , EYA1D ), respectively, constituted
by 559 amino acids (AA), 592 AA, 592 AA and 557
AA; furthermore, many transcriptional variants or
polymorphisms have been reported. Mutations in the
EYA1 gene are associated with both sporadic and
orofacial and musculoskeletal systems. There are
three types of Stickler syndrome: type I is caused by
mutations of the gene COL2A1 (12q13.11-q13.2);
type II by mutations of the gene COL11A1 (1p21)
and type III (non-ocular type) by mutations of the
gene COL11A2 (6p21.3). Also recorded are muta-
tions in the gene COL9A1 causing autosomal reces-
sive inheritance. Marshall and Stickler syndromes
are similar conditions and it is not yet clear whether
Marshall syndrome should be considered a variant of
Stickler syndrome (type II) or rather an entity in
itself. The hearing loss is of mixed type or sensorineu-
ral, and more serious in Marshall syndrome and
types II (progressive hearing loss) and III (non pro-
gressive hearing loss).
Treacher Collins or Franceschetti syndrome (6:100,000).
Treacher Collins or Franceschetti syndrome is a mal-
formation condition with high penetrance and vari-
able expressivity that is caused by mutations in the
gene TCOF1 , located in the region 5q31.3 . The
TCOF1 gene encodes a protein (treacle) involved in
nucleolar function. Around 60% of cases are ‘ de
novo ’ . The typical clinical picture is due to faults in
the development of the fi rst two branchial arches,
bilateral and symmetrical  oblique eyelid sloping
downwards and laterally, lower eyelid coloboma,
hypoplasia cheekbones, micrognatia, mouth wide
and thin, dental faults. There may be cleft palate and
nasal spread with nostrils narrow, and sometimes
choanal atresia. Faults of the roof are constant (ano-
tia, hypoplasia, cup), which is associated with the
presence of fi stulae or pre-auricular appendages, fre-
quent atresia or stenosis of the external auditory
meatus. In the middle ear, hypoplasia of the mastoid
bone, frequent anomalies of the ossicular chain
(undescended testes of the incus, malformation or
ankylosis or absence of the bracket, lack of the oval
window) are common. Impairment of the vestibular
apparatus (dysplasia of the semicircular canal) is fre-
quent, while the cochlea is normal. The hearing loss
is generally conductive or mixed, rarely sensorineu-
ral, and is bilateral and symmetrical in 55% of cases
(1,2,10).
BOR syndrome and other EYA1-related disorders (2.5:
100,000). Branchio-oto-renal (BOR), Branchiootic
(BO) and Oto-Facio-Cervical (OFC) syndromes are
dominant disorders characterized by variable hearing
impairment (HI) and branchial defects. BOR syn-
drome includes additional kidney malformations. BOR/
BO/OFC syndromes are genetically Heterogeneous
and caused by mutations in EYA1 , SIX1 , and SIX5
genes. Nevertheless, mutations in the same gene can
lead to different syndromes. About 40% of people
with BO, BOR or OFC syndromes have a mutation
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10 A. Castiglione et al.
discrimination. The hearing loss can be bilateral and
asymmetrical in case of bilateral schwannomas, lead-
ing to deafness within 5 – 10 years.
CHARGE association (0.14:100,000). CHARGE (iris
coloboma, heart defects, choanal atresia, growth and
development delay and retardation, genitourinary
hypoplasia, ear abnormalities and deafness) associa-
tion is a recognizable (genetic) pattern of birth defects
due to mutations in the CHD7 gene in approximately
60 – 70% of cases. Up to 90% of patients present with
sensorineural hearing loss. Generally, there is no his-
tory of CHARGE association or any other similar
condition in the family. Babies with CHARGE syn-
drome are often born with life-threatening birth
defects, including complex heart defects and breath-
ing problems.
Hypoplastic cranial nerves and external or inner
ear malformations are usually present and these can
be responsible for facial paresis or hearing loss with
consequent diffi culties in cochlear implantation
(20,21).
FGFR2-related disorders and craniosynostosis (1:3000):
Crouzon (2:100,000), Apert (1.25:100,000), and
Pfeiffer syndromes (1:100,000). Mutations in the
FGFR2 gene can be responsible for Crouzon, Apert
and Pfeiffer syndromes, the most common cranio-
synostosis syndromes. They follow an autosomal
dominant pattern, even if sporadic cases are quite
common. The FGFR1 gene can also be involved in
Pfeiffer syndrome. Craniosynostosis is the premature
fusion of the cranial sutures and Crouzon, Apert and
Pfeiffer syndromes are bi-coronal craniosynostosis.
All these syndromes can be associated with a hyp-
oplastic middle ear and conductive hearing loss
(1,2,7 – 10,22).
X-linked recessive syndromes: Norrie disease
Norrie disease or syndrome is caused by mutations
in the NDP gene (Xp11.3) that encodes a protein
(norrin) of 133 amino acids. The norrin protein is
essential to the development of blood vessels and
retinal cells; furthermore, it seems to be involved in
inter- and intra-cellular communications.
The clinical picture is characterized by a degen-
erative process causing blindness in childhood. Dur-
ing the fi rst days of life the retinal dysplasia manifests
with sickle creases of the retina and progressively
results in retinal detachment. At birth the corneas
are usually clear but during the pre-school years
become opaque and also develop a secondary cata-
ract. About 35% of subjects have a sensorineural
hearing loss, progressive in the high frequencies after
10 years of age. Approximately 35% of patients show
familial cases. There are over 160 reported mutations
in EYA1 to date (http://www.healthcare.uiowa.edu/
labs/pendredandbor/), even if in some cases muta-
tions in different isoforms are deduced by bioinfor-
matics analysis. EYA1 mutations were found in
31% of families fi tting established clinical criteria for
BOR and 7% of families with questionable BOR
phenotype. SIX1 (1 – 2%) and SIX5 (approximately
2 – 5%) mutations are much less common. EYA1
mutations produce a wide range of clinical manifes-
tations even within the same family, from mild to
severe clinical phenotypes associated with hearing
and renal anomalies (penetrance appears to be
around 100% although expressivity is highly variable).
Waardenburg syndrome (2.4:100,000). Waardenburg
syndrome (WS) is one of the most common causes
of autosomal dominant syndromic hearing loss and
it is estimated to account for 2 – 5% of all cases of
congenital hearing loss. Mutations in the PAX3 gene
cause WS type I and WS type III with an autosomal
dominant inheritance pattern. WS type II is caused
by mutations in the MITF or SNAI2 (also called
SLUG ) genes. WS type IV has been linked to muta-
tions in EDNRB , EDN3 and SOX10 . Phenotypes are
inherited with a recessive pattern when the genes
SNAI2 , EDNRB and EDN3
are involved. WS type I
is characterized by: 1) dystopia canthorum (lateral
displacement of the medial canthi); 2) hyperplastic,
high and large nasal root; 3) hyperplasia of the medial
portion of the eyebrows that can be confl uent; 4) skin
or iris pigmentary anomalies (iris heterochromia);
5) circumscribed albinism of the frontal head hair or
white forelock; 6) sensorineural deafness (20 – 25% of
cases), unilateral or bilateral. Type I and type II are
distinguished on the basis of the presence of the dys-
topia canthorum, which is absent in type II. The pres-
ence of abnormalities of the upper limb identifi es
type III, which is also called Klein-Waardenburg syn-
drome. Finally, the association of autosomal recessive
inheritance and Hirshprung disease is defi ned as type
IV or Waardenburg-Shah syndrome (1,2,8 – 10).
Neurofi bromatosis type 2 (0.5:100,000). Neurofi bro-
matosis 2 is caused by mutations in the NF2 gene
and is characterized by the development of multiple
tumours, including vestibular schwannomas (bilateral
in 95% of cases), meningiomas, gliomas, and
ependymomas that could manifest as early as 8 – 12
years of age. The hearing loss caused by a vestibular
schwannoma in neurofi bromatosis 2 is approximately
the same as a single-sided acoustic neuroma. About
half of patients present with sudden onset of unilateral
sensorineural hearing loss, that is characterized by
slow pure-tone change (more marked at high
frequencies) and progressive impairment in speech
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Syndromic hearing loss 11
OTOF gene, which are currently considered as
responsible for an auditory neuropathy, are classifi ed
as DFNB9 (non-syndromic recessive hearing loss).
OPA1 mutations have been associated with optic
atrophy type 1, which is a dominantly inherited optic
neuropathy resulting in progressive loss of visual
acuity, leading in many cases to legal blindness. It
could be accompanied by involvement of different
cranial nerves such as the eighth nerve, with conse-
quent hearing impairment (25 – 29).
Biotinidase defi ciency (1 – 2:100,000). Biotinidase
defi ciency is inherited as an autosomal recessive trait;
as expected, the vast majority of mutations are
homozygous or compound heterozygous. Biotinidase
defi ciency usually manifests in children from one
week of age to adolescence, with most exhibiting
symptoms between three and six months of age. If
untreated, children with profound biotinidase defi -
ciency usually develop one or more of the following:
neurological disorders (myoclonic seizures, hypoto-
nia, ataxia), developmental delay, visual problems,
hearing loss and dermatological disorders (alopecia,
eczema, and/or candidiasis). In a few cases, individu-
als with profound biotinidase defi ciency may remain
asymptomatic or develop symptoms after adoles-
cence. All symptomatic-affected individuals improve
with oral pharmacological doses of the vitamin, bio-
tin. Biotin treatment prevents the development of
symptoms in affected children identifi ed before they
have clinical fi ndings or are identifi ed by newborn
screening. Biotin therapy is lifelong (30).
Modifi er genes
Modifi er genes can modify the expression of other
genes. Mutations in these genes can be responsible
for non-syndromic hearing loss or infl uence the
clinical picture in the syndromic forms. These condi-
tions do not appear to follow traditional Mendelian
expression patterns. For example, cadherin 23 pro-
duces a spectrum of phenotypic traits, including
presbycusis, non-syndromic prelingual hearing loss
(DFNB12), and syndromic hearing loss as part of
Usher syndrome (Usher 1D). Missense mutations in
CDH23 have been associated with presbycusis and
DFNB12, whereas null alleles cause the majority of
Usher 1D. Modifi er gene products that interact with
cadherin 23 also affect the phenotypic spectrum. In
addition, the phenotypic spectrum of Wolfram syn-
drome is also hypothesized to be infl uenced by mod-
ifi er gene products. Further studies are needed to
provide more evidence for the importance of modi-
fi er genes. Characterizing modifi er genes may result
in better treatment options for patients with hearing
progressive mental retardation and 25% of cases are
affected by psychosis.
X-linked dominant syndromes: Alport syndrome
Alport syndrome is characterized by progressive sen-
sorineural hearing loss in addition to renal disorders
(such as renal insuffi ciency, glomerulonephritis or
haematuria) and ocular anomalies. Mutations in the
COL4A5 gene are responsible for the dominant
inheritance of the syndrome and they account for
approximately 80% of all affected patients (23). The
autosomal forms are caused by mutations in the
COL4A3 and COL4A4 genes.
Sensorineural hearing loss develops in 80 – 90% of
males with Alport syndrome by the age of 40 years.
Generally, hearing loss is not congenital. In its early
stages the hearing defi cit is detectable only by audi-
ometry, with bilateral reduction in sensitivity in the
high frequencies. In affected males, the hearing loss
is progressive and eventually extends to other fre-
quencies, including those of conversational speech.
Hearing loss is frequently identifi able by formal
assessment of hearing in late childhood, but in some
families is not detectable until relatively late in life
(http://www.ncbi.nlm.nih.gov/books).
Y-linked syndromes
To date, there are no recognized syndromic forms of
hearing loss related to anomalies on chromosome Y.
Nevertheless, a review of the literature suggests a
potential role for chromosome Y in syndromic hear-
ing loss (24).
Auditory neuropathies
Hearing loss due to auditory neuropathy is currently
divided in two main groups: the fi rst, called Auditory
Neuropathy Spectrum Disorders (ANSD), includes
all diseases or conditions or syndromes characterized
by neuropathy that can affect the auditory system.
The second group is strictly related to specifi c genes,
which, if mutated, can lead to hearing loss due to
auditory neuropathy. It should be noted that some
authors prefer to consider the second group as part
of the fi rst. The acronym AUN could be used exclu-
sively to indicate conditions mainly characterized by
auditory neuropathy (non-syndromic) and caused by
mutations in specifi c genes for which loci are defi ned
as AUNA in the case of autosomal dominant inheri-
tance, followed by identifi cation numbers in chrono-
logical order. To date, there is only one recognized
gene responsible for non-syndromic auditory neu-
ropathy, i.e. DIAPH3 (AUNA1). Mutations in the
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12 A. Castiglione et al.
in children with craniofacial anomalies such as cleft
lip/palate (70%) and Down syndrome (62%). A
small percentage of FAS children have also been
shown to display mild to moderate sensorineural
hearing loss (33 – 38).
Cytomegalovirus syndrome (40:100,000)
Cytomegalovirus (CMV) is one of the most frequently
transmitted intrauterine infections, detectable in
an estimated 0.64 – 0.70% of live births worldwide.
Sensorineural hearing loss is the most common
sequel following congenital CMV infection. CMV is
estimated to be the leading environmental cause
of childhood hearing loss, accounting for approxi-
mately 15 – 21% of all hearing loss at birth in the
United States. In addition, CMV-related hearing
losses may also be progressive or late onset, requiring
more frequent audiological monitoring of infants and
young children who have been diagnosed with con-
genital CMV infection (39 – 46).
Autoimmune disorders
Cogan syndrome. Cogan syndrome is a rare disorder
characterized by recurrent infl ammation of the front of
the eye (the cornea) and often fever, fatigue, and weight
loss, episodes of dizziness, and hearing loss. It can
lead to deafness or blindness if untreated. The classic
form of the disease was fi rst described by Cogan in
1945. In 60% of patients with Cogan syndrome,
cochlear implantation remains the only treatment
option for the auditory rehabilitation. Literature data
agree that once the electrode array is properly inserted,
functional outcomes are very good. Nevertheless,
results may deteriorate due to progressive cochlear
ossifi cation (47,48).
Goodpasture syndrome. Goodpasture syndrome, a
rare human autoimmune disorder, is characterized
by the presence of pathogenic autoantibodies that
react with the components of the glomerular base-
ment membrane. The clinical condition of Good-
pasture syndrome is characterized by an acute
necrotizing glomerulonephritis, often with accom-
panying pulmonary haemorrhage. Notably, the
Goodpasture antigen has been localized to the non-
collagenous domain of the α 3 chain of type IV col-
lagen. Goodpasture syndrome is an uncommon
disease, having an incidence of 0.5 to 1 cases per
million of the population with a slight preponder-
ance of males to females (49). Type IV collagen, the
major structural component of basement mem-
branes, is a multimeric protein composed of three
alpha subunits. These subunits are encoded by six
loss and defi ne new diagnostic and therapeutic tar-
gets (31,32).
Mitochondrial diseases: MELAS syndrome
(16:100,000), MERRF syndrome (1:100,000)
and MIDD (0.1:100,000)
Mitochondrial encephalopathy, lactic acidosis and
stroke-like episodes (MELAS) is a childhood disor-
der characterized by intermittent vomiting, proximal
limb weakness and recurrent cerebral insults resem-
bling strokes and causing hemiparesis and cortical
blindness. MELAS is frequently associated with
short stature. The wide range of clinical signs and
symptoms include hearing loss in approximately
30% of affected persons.
Myoclonic epilepsy and ragged red fi bres
(MERRF) is characterized by myoclonus, epilepsy
and ataxia, although dementia, optic atrophy and
deafness frequently occur. The degree of hearing loss
is variable.
In maternally inherited diabetes and deafness
(MIDD), several families have been described with
diabetes mellitus and sensorineural hearing loss, in
which mitochondrial mutations have been found.
The most frequently found mutation is the 3243A-  G
mutation, also found in MELAS. In population stud-
ies of diabetics, the 3243A-  G mutation has been
found in a small percentage of patients (1,2,8,10).
Non-genetic syndromes
Foetal alcohol syndrome (1:1000 newborns)
Foetal alcohol syndrome (FAS) is induced by exces-
sive maternal alcohol intake during pregnancy. FAS
is characterized by: facial dysmorphisms such as
smooth philtrum, thin vermillion border and small
palpebral fi ssures (at or below the 10th percentile),
central nervous system abnormalities, growth prob-
lems and maternal alcohol exposure. Diagnostic cri-
teria for FAS are all three of the following fi ndings:
1) all three facial abnormalities; 2) growth defi cits;
and 3) central nervous system abnormalities. Growth
defi cits are diagnosed when prenatal or postnatal
height or weight, or both, are at or below the 10th
percentile, documented at any one point in time
(adjusted for age, gender, gestational age, and race
or ethnicity). Central nervous system anomalies
include structural, neurological and functional
abnormalities. In multiple studies, children with FAS
have been reported to show much higher rates of
intermittent hearing loss due to recurrent middle ear
infections (75 – 93%) compared to the general paedi-
atric population (12%). The FAS fi ndings are more
consistent with middle ear disorder prevalence rates
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Syndromic hearing loss 13
different genes, alpha 1 through alpha 6, each of
which can form a triple helix structure with two
other subunits to form type IV collagen. This gene
encodes alpha 3 ( COL4A3 on 2q36-q37). In Good-
pasture syndrome, autoantibodies bind to the col-
lagen molecules in the basement membranes of
alveoli and glomeruli. The epitopes that elicit these
autoantibodies are localized largely to the non-
collagenous C-terminal domain of the protein. A
specifi c kinase phosphorylates amino acids in this
same C-terminal region and the expression of this
kinase is up-regulated during pathogenesis. This gene
is also linked to an autosomal recessive form of
Alport syndrome. The mutations contributing to this
syndrome are also located within the exons that
encode this C-terminal region. Like other members
of the type IV collagen gene family, this gene is orga-
nized in a head-to-head conformation with another
type IV collagen gene so that each gene pair shares
a common promoter (http://www.genecards.org).
Discussion and Conclusions
The defi nition of syndromic hearing loss still remains
an open fi eld that requires constant updating. Clas-
sifi cation, aetiology, clinical and epidemiological
data undergo continuous change, therefore it is
quite diffi cult to obtain a comprehensive assessment
on the prevalence and management of complex and
heterogeneous conditions. The multidisciplinary
approach is certainly the most correct and continu-
ous monitoring is essential. The diagnosis of syndro-
mic hearing loss requires a careful history and
objective examination, MRI and CT scanning and
laboratory testing (including genetic testing), tests
that are ever more sophisticated. The role of genet-
ics is constantly growing and giving us important
information on diagnosis and treatment. The most
common mutations that are responsible for hearing
loss involve the GJB2 gene; SLC26A4 mutations are
the second most common cause of genetic hearing
loss and the fi rst among syndromic deafness. The
SLC26A4 (PDS) gene mutations result in abnor-
malities of the endolymphatic system, which lead to
the dilation of the vestibular aqueduct as seen in
Pendred syndrome. Nonetheless, other genes can be
involved. Normal expression of the PAX2 and PAX3
genes is necessary for the normal development of
the cochlea. The FGF3 gene appears to be necessary
for differentiation within the otic vesicle (22). The
EYA1 gene has an important role in encoding
transcription factors and mutations of EYA1
are responsible for EYA1 -related disorders that
include BOR (branchio-oto-renal) syndrome, BO
(Branchio-otic) syndrome and OFC (Oto-Facio-
Cervical) syndrome. Nevertheless, it should be
noted that the aetiology remains unknown in most
cases and an indiscriminate use of testing does
not always change the prognosis or therapy. In
addition, it should be remembered that not all syn-
dromes have a genetic cause and there are several
heterogeneous conditions for which the aetiology
and pathophysiology is still unclear (50,51).
Non-syndromic and syndromic hearing losses
demand early evaluation and rehabilitation to reduce
the auditory deprivation that could affect perceptual,
verbal and linguistic skills. To date, hearing aids and
cochlear implantation are the most reliable and effec-
tive interventions for auditory rehabilitation. Although
further studies are necessary, the results of the pres-
ent work have confi rmed the need to carry out diag-
nostic, therapeutic and rehabilitation processes in
specialized centres with extensive and proven
experience.
Declaration of interest: The authors have no
confl icts of interest to disclose.
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