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2 Hearing Disorders in Children
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
malformation of the temporal bone that is associated with early-onset hearing loss and vestibular disorders. Hearing loss is usually progressive, profound, and bilateral.23 Large vestibular aqueduct syndrome is often associated with Mondini malformation.
Another form of abnormality is that of semicircular canal
dehiscence,24 wherein the bone overlying the canal is abnormally
thinned or absent. This results in abnormal pressure transmission to the membranous labyrinth. When present in children,
it is assumed to be congenital in nature. Semicircular canal
dehiscence has been associated with sensorineural, mixed, and
conductive hearing loss, accompanied in some cases by vestibular
impairment.
Included in malformations limited to the membranous
labyrinth are complete membranous labyrinth dysplasia (BingSiebenmann) and two forms of partial dysplasia: cochleosaccular
dysplasia (Scheibe aplasia) and cochlear basal turn dysplasia
(Alexander aplasia). The Bing-Siebenmann malformation is a rare
malformation that results in complete lack of development of the
membranous labyrinth. Scheibe aplasia is a common inner ear
abnormality in which the organ of Corti fails to develop fully, the
cochlear duct collapses, the vestibular membrane adheres to the
limbus, and the stria vascularis degenerates. Alexander aplasia is
an abnormal development of the basal turn of the cochlea, with
typical development in the remainder of the cochlea, resulting in
low-frequency residual hearing.
In recent years, there has been greater success with cochlear
implantation in cases of deafness caused by these deformities,
despite the unusual anatomy.
Cytomegalovirus
Cytomegalovirus (CMV) is the largest known member of the
human herpesvirus family and causes the most common fetal
viral illness. Congenital infection is the result of transplacental
transmission of CMV and is known as cytomegalic inclusion
disease. Sensorineural hearing loss is the most common clinical
finding of congenital CMV. Other findings include microcephaly,
petechiae (small purple spots on a body surface), intrauterine
growth retardation, enlargement of the liver and spleen, and
chorioretinitis (inammation of the choroid and retina). Hearing
loss is of variable severity and can be bilateral or unilateral.
Threshold uctuations are common (more than 20% of cases), and
hearing loss is often progressive (more than 15%). Approximately
10 to 15% of congenitally infected infants are symptomatic at
birth. Children with symptomatic congenital CMV are at greater
risk for hearing impairment (22–65%) than those with asymptomatic infection (6–23%). Hearing loss tends to appear earlier
and with greater severity in these patients.
Recent studies suggest that certain antiviral medications or
hyperimmunoglobulin therapies may have a protective eect
against hearing loss if administered in the prenatal or neonatal
periods.
25
Congenital Syphilis
Congenita l syphilis is a bac terial infe ction that is t ransmitted f rom
mother to fetus in utero or through contact with a genital lesion
during delivery. The disease occurs in 11.2 cases per 100,000 live
birth s. Congenital syph ilis is categorize d by its time of occur rence
into early and late stages. In congenital syphilis occurring within
the first 2 years of life, severity can range from severe multiorgan involvement to minor symptoms. Although rarely observed
i
n the United States, late congenital syphilis includes the set of
symptoms known as the Hutchinson triad: small, notched teeth;
hearing loss; and interstitial keratitis. Typical hearing loss is a
rapid symmetric progression from high-frequency sensory loss
to complete bilateral deafness. Hearing loss can also involve
neural or conductive components. Vestibular function may also
be severely aected. The Hennebert sign, in which nystagmus is
observed as a result of pressure applied to the external auditory
canal, is often found in otosyphilis.
26
Maternal Rubella
Maternal rubella occurs when an infected mother transmits the
rubella virus to the fetus. Expression of symptoms of maternal
rubella infection, called congenital rubella syndrome or Gregg
syndrome, includes a wide variety of defects, usually aecting
hearing, vision, and heart function, and often involving mental
retardation and microcephaly. Subclinical infections are more
common than those that are symptomatic at birth. However, 70%
of infants who are asymptomatic at birth will develop symptoms
within the first 5 years of life.27 Hearing loss is the most common
manifestation of congenital rubella, occurring in up to 80% of
infected children. Hearing loss ranges from unilateral mild loss
to bilateral profound deafness; severe bilateral losses are more
common. Configuration of the hearing loss is usually at, and
hearing sensitivity may be asymmetric. Children with normal
pure tone thresholds may demonstrate abnormal auditory brainstem responses. Once transmission has occurred, fetal infection
is chronic. Infection tends to persist throughout fetal life and
after birth and to continue to cause pathology in the child.
Toxoplasmosis
Toxoplasmosis is an infection caused by the parasite Toxop lasma
gondii. The parasite can be transmitted to humans by ingestion
of raw or inadequately cooked infected meat or foods that have
come in contact with infected meat, ingestion of parasites that
cats have passed in their feces, or transplacental transmission of
the infection from a woman to her fetus. Despite increasing probability of infection with pregnancy progression, consequences
are more severe when fetal infection occurs in early stages of
pregnancy. Although most newborns (70 to 90%) infected with
congenital toxoplasmosis are asymptomatic at birth, up to 80% of
these children develop sequelae later in life. Those who are symptomatic often have a classic triad of chorioretinitis, intracranial
calcifications, and hydrocephalus. The disease course may also
include cognitive abnormalities of variable severity, seizures, or
learning disabilities with onset after several months or years.28
Auditory disorder can occur from mastoid and cochlear inammation and involvement of the auditory brainstem. The resulting
disorder is a sensory or neural hearing loss that may range from
mild unilateral loss to bilateral deafness.
29
21
I Hearing Loss: Essential Information
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
2.4.2 Acquired Perinatal and Postnatal
Sensory Disorders
Persistent Pulmonary Hypertension of
the Newborn/Extracorporeal Membrane
Oxygenation
Persistent pulmonary hypertension of the newborn (PPHN), also
known as persistent fetal circulation, is a condition wherein the
infant’s blood ow bypasses the lungs, thereby eliminating oxygen
supply to the organs of the body.30 PPHN is associated with perinatal respiratory problems such as meconium aspiration or pneumonia. Sensorineural hearing loss is a common complication of PPHN
and has been found in approximately 35% of surviving children.
Hearing loss ranges from high-frequency unilateral loss to severe
to profound bilateral loss and is progressive in many cases.
Pearl
Sensorineural hearing loss is a common complication of persistent pulmonary hypertension and has been found in approximately 35% of surviving children.
PPHN is treated by administration of oxygen or oxygen and
nitric oxide via a mechanical ventilator. Extracorporeal membrane oxygenation (ECMO) is a treatment for PPHN that involves
verting blood from the heart and lungs to an external bypass,
di
where oxygen and carbon dioxide are exchanged before the blood
reenters the body. When ECMO is applied as part of respiratory
management, it has been associated with hearing loss in up to 75%
of cases.31 Hearing loss is often progressive.
Meningitis
Meningitis is an inammation of the membranes that surround
the brain and spinal cord. There are three types of meningitis:
bacterial, aseptic, and viral. The greatest frequency of hearing
loss occurs in cases of bacterial meningitis; estimates range from
5 to 35% of cases. Other common signs and symptoms of bacterial
meningitis include fever, seizures, neck stiness, and altered
mental status.32 Vestibular function may be compromised as
well. Hearing disorder ranges from mild to profound sensitivity
loss or total deafness, may be unilateral or bilateral, and may
be progressive. Most involvement is thought to be cochlear, but
central auditory involvement may occur in some individuals.
Hearing loss is usually permanent, although there have been
reports of some recovery of hearing over time in some individuals. Cochlear osteoneogenesis, or bony growth in the cochlea,
may occur following meningitis, complicating possible cochlear
implantation. The use of MRI may have utility in predicting
hearing loss prior to onset and prior to ossification, which may
have a positive impact on treatment planning.34 There have been
reports of meningitis following cochlear implantation, especially
with use of a positioner during implantation.35 However, there is
a strong association between cochlear deformities, particularly
33
Michel deformity, and meningitis that may be independent of
cochlear implantation.
36
Pearl
Cochlear osteoneogenesis, or bony growth in the cochlea, may
occur following meningitis, complicating possible cochlear
implantation.
Autoimmune Inner Ear Disease
Autoimmune inner ear disease (AIED) is a syndrome of potentially reversible, bilateral, rapidly progressive, and often uctuating sensor y hearing loss that may be associated with vestibular
symptoms mimicking Ménière disease.37 Symptoms are thought
to be consequences of immune-mediated inammation in the
inner ear. The disorder may be specific to the ear or may occur as
a manifestation of a systemic immune-mediated inammatory
disorder, such as rheumatoid arthritis, systemic lupus erythe-
matosus, inammatory bowel disease, polyarteritis nodosa, or
Cogan syndrome. Hearing sensitivity is generally responsive to
immunosuppressive drugs such as steroids.38 AIED is associated
with sensory hearing loss that is generally bilateral, asymmetric,
and rapidly progressive.
Viral Infections
Mumps is a viral infection that attacks a variety of organs, especially the salivary glands. Although the incidence in the United
States of hearing loss associated with mumps is low because of
vaccination, it continues to occur in other areas of the world.
Mumps has historically been the most common cause associated
with unilateral acquired sensorineural hearing loss in children.
The typical pattern of sensory hearing loss is unilateral and
profound, with sudden onset. Endolymphatic hydrops (Ménière
disease) is also a common manifestation of mumps virus.
Measles is a highly contagious viral illness whose symptoms
characteristically include rash, cough, fever, conjunctivitis,
photophobia, and Koplik spots (white spots on the membranous
surfaces of the mouth). Hearing loss is a common complication
of measles. Before vaccination in the United States became wide-
spread, measles accounted for 5 to 10% of all cases of profound,
bilateral sensorineural hearing loss. Measles is still a significant
cause of hearing loss and deafness in other parts of the world
and appears to be re-emerging in the United States and other
countries.39 Sensory hearing loss from measles virus is typically
severe, permanent, and bilateral, although milder hearing loss
can occur. Conductive hearing loss from otitis media is also a
common complication of measles that may be due to immunosuppression following viral infection. Localized measles virus in
the otic capsule is also hypothesized to be a causative factor in
later development of otosclerosis.
Other viruses, such as Lassa, Ebola, and Zika, are increasingly
associated with significant sensorineural hearing loss, presumably secondary to the hemorrhagic fever resulting from the viral
40
22
2 Hearing Disorders in Children
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
infection.41 Hearing loss has been identified as a sequela of the
infection and also as part of congenital syndromes associated with
maternal infection.
Pearl
Viruses such as Lassa, Ebola, and Zika are increasingly associated
with signicant sensorineural hearing loss, presumably secondary to the hemorrhagic fever resulting from the viral infection.
Ototoxicity
Ototoxicity is hearing loss from the toxic eects of drugs on the
inner ear. Aminoglycoside antibiotics (streptomycin, gentamicin,
dihydrostreptomycin, neomycin, kanamycin, erythromycin, and
vancomycin), loop diuretics (furosemide), antineoplastic agents
(cisplatin), salicylates, and antimalarial drugs (quinine) can all
damage the cochlea. Eects relate to the level of the drug in the
system, synergistic eects of these drugs in combination, potentiation of eect caused by coexisting renal disease, and heredi-
tary susceptibility in the case of aminoglycosides.42 Children and
neonates are considered to be at lower risk for ototoxicity than
adults in most cases. One exception is cisplatin-induced hearing
loss, which has a higher incidence and increased severity in chil-
dren, causing hearing loss in ~ 60% of pediatric cases.43 Cisplatin
ototoxicity may also have additional risk factors, including sex,
age, and genetic susceptibility. Hearing loss from ototoxicity is
generally symmetric sensory loss that progresses from higher
to lower frequencies with increased drug exposure. Because of
this pattern, monitoring for ototoxicity via distortion-product
otoacoustic emissions (OAEs) may be particularly valuable for
children. Some hearing loss also involves neural components
with certain drug classes.
2.5 Neural Hearing Disorders
Causes of neural hearing disorders are summarized in Table 2.3.
2.5.1 Auditory Neuropathy Spectrum
Disorder
Auditory neuropathy spectrum disorder (ANSD) is a term that is
used to describe disorders that are operationally defined based on
a constellation of clinical findings. That constellation varies neces-
sarily as a function of age. In older children, auditory neuropathy
is defined by an absent auditory brainstem response (ABR), poor
Table 2.3 Some causes of neural hearing disorder
Causes of neural disorders
Neoplasms
Hydrocephalus
Hypoxia
speech perception, varying levels of hearing sensitivity loss,
absence of acoustic reexes, and a preservation of some cochlear
function as evidenced by the preservation of OAEs or cochlear
microphonics. In infants, auditory neuropathy is defined by absent
ABR and preserved OAEs or cochlear microphonics.
It is becoming apparent that the term auditory neuropathy, as it
is defined clinically, may represent at least two fairly distinct disorders, one preneural or sensory and the other neural. The auditory
neuropathy of preneural origin is probably a sensory hearing
disorder that represents a transduction problem, with the failure
of the cochlea to transmit signals to the auditory nerve. The most
likely origin is absent inner hair cells or disordered inner hair cell
neurotransmitter release. Preservation of the OAEs and cochlear
microphonics represents normal function of outer hair cells without any inner hair cell function to sensitize. In cases of preneural
ANSD, the absence of an ABR is a reection of the sensitivity loss
of the system and accurately predicts substantial hearing loss.
Hearing loss from preneural ANSD acts like any other sensitivity
loss in terms of its inuence on speech and language acquisition
and its amenability to hearing aids and cochlear implants.
44
Pearl
It is becoming apparent that the term auditory neuropathy, as
it is dened clinically, may represent at least two fairly distinct
disorders, one preneural or sensory and the other neural.
Auditory neuropathy of neural origin was first described as
a specific disorder of the auditory nerve that results in a loss of
synchrony of neural firing.
it has also been referred to as auditory dyssynchrony. The cause
of auditory neuropathy is often unknown, although it may be
observed in cases of syndromic peripheral pathologies (e.g.,
Friedreich ataxia, Charcot-Marie-Tooth syndrome) and auditory
nerve atresia. The age of onset is usually before 10 years. Hearing
sensitivity loss ranges from normal to profound and is most
often at or reverse-sloped in configuration. Hearing loss often
uctuates and is progressive in some children. Speech perception
is often substantially poorer than what would be expected from
the audiogram.46 Neural ANSD may not be as amenable to con-
ventional amplification and implant treatment as preneural ANSD
is. See Chapter 33 for more information about management of
infants and children with ANSD.
2.5.2 Other Neural Hearing Disorders
Neoplasm
Unlike those in adults, tumors of the posterior fossa in children
are less likely to be acoustic schwannoma and more likely to be
intrinsic tumors, such as gliomas and ependymomas.47 These
benign tumors of the cerebellopontine angle aect the auditory
system when they impinge on the eighth cranial nerve. The
most common form of acoustic tumor in children is that found
in association with neurofibromatosis type 2 (NF2). NF2 is
45
Because of the nature of the disorder,
23
I Hearing Loss: Essential Information
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
characterized by bilateral cochleovestibular schwannomas that
are faster-growing and more virulent than the unilateral type.
This is an autosomal dominant disease and is associated with
other intracranial tumors. Hearing loss in NF2 is not particularly
dierent from that due to a unilateral type of schwannoma,
except that it is bilateral and often progresses more rapidly.
Hydrocephalus
The cause of neural hearing disorders in children has also been
attributed to more diuse sources, including hydrocephalus,
hypoxia, and hyperbilirubinemia. In hydrocephalus, the most
common finding is one of neuromaturational delay of the
auditory system as measured on the ABR. This is usually due
to enlarged ventricles and is not associated with permanent
changes in auditory function.
Hypoxia
Hypoxia is a deficiency in the amount of oxygen in the body.
Hearing disorder is often associated with hypoxia, although the
eects of respiratory distress in neonates are dicult to separate from other possible factors, such as kernicterus, treatment
with ototoxic medications, and low birth weight.48 Disorders of
auditory neural function are often diuse, although progressive
sensorineural hearing loss can occur as a result.
Hyperbilirubinemia
Hyperbilirubinemia is an excess of bilirubin in the blood that can
be caused by m any factors. Hyperbi lirubinemia is associated with
auditory neuropathy and other neural hearing disorders. The
clinical spectrum of bilirubin-induced auditory toxicity ranges
from transient auditory dysfunction to permanent sensory hearing loss when bilirubin levels are high.49 Audiometric findings
include predominantly high-frequency bilateral and symmetric
hearing loss with recruitment and abnormal loudness growth.
Auditory nerve and generalized auditory brainstem dysfunction
may occur.50 Other, more diuse APDs have also been associated
with hyperbilirubinemia.
Discussion Questions
1. What are the dierences in expectations for suprathreshold
hearing among conductive, sensory, and neural hearing losses?
2. What are some possible eects on speech and language
development from acquired conductive hearing losses, such
as otitis media with eusion?
3. What diseases and disorders may cause progressive hearing
loss in childhood? How might knowledge about the possi-
bility of a progressive hearing loss inuence assessment and
follow-up decisions?
4. What types of drugs cause ototoxicity? How might monitoring of hearing during treatment with ototoxic medication
contribute to preservation of hearing?
5. How are the two types of neural hearing disorders—retroco-
chlear disorders and auditory processing disorders—dierent
from one another?
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Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
3 Genetics of Hearing Loss
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
Kristin E. Gravel, Aparna Rao, Joan Steyermark, and Lisa A. Schimmenti
3 Genetics of Hearing Loss
Summary
Genetics contribute to more than 50% of prelingual hearing loss.
The Joint Committee on Infant Hearing recommends a genetics
evaluation for every child with hearing loss, and audiologists
are called upon to share information about the significance of
a genetics referral following hearing loss identification. Over
400 genetic syndromes are associated with hearing loss, and
it is important for audiologists to have an awareness of these
conditions and how they aect the individual with hearing loss.
Traditionally, individual genes were tested one at a time. Today,
nearly all confirmed hearing loss genes are sequenced simultaneously through a process called next-generation sequencing (NGS).
Even for individuals who previously tested negative for individual
genes associated with hearing loss, audiologists can suggest additional follow-up with genetics professionals to further investigate
the etiology of hearing loss as new hearing loss genes are identified.
Audiologists are vital members of the multidisciplinary team,
which may include a medical geneticist, genetic counselor, and oto-
laryngologist. In fact, the audiologist may be the first provider on
the team to see a patient or family and may be the point of referral
for the individual as he or she begins the process of genetic testing.
This chapter will provide a review of basic genetics and will inform
audiology students, clinicians, and allied health professionals about
the current state of understanding in the field of genetics and a
glimpse into the future for genetic medicine and hearing loss.
Keywords
genetic testing, hearing loss, deafness, phenotype, genotype,
syndrome, DNA, connexins, nonsyndromic hearing loss,
next-generation sequencing
Key Points
All children identied with permanent hearing loss can bene-
•
t from genetics evaluation and testing, although most cases
will not present with a family history of hearing loss.
Today, over 100 hearing loss genes can be tested at one time
•
using NGS.
A negative result does not rule out a genetic cause. As more
•
genes are discovered and added to the testing panel, the
genetic basis may become known.
Interprofessional collaboration between audiologists, genet-
•
icists, and genetic counselors is key to providing this service
to families with a child with hearing loss.
3.1 Introduction to Genetics of
Hearing Loss
With the advent of universal newborn hearing screening in
the late 1990s in the United States, the incidence of congenital
hearing loss is now better understood than ever before. The
most recent data released by the Centers for Disease Control and
Prevention (CDC) indicated that 97.2% of the US birth cohort was
screened for hearing loss. Of these, 1.5 per thousand newborns
were found to have some form of hearing loss.
More than 95% of all infants with hearing loss are born to
parents with normal hearing, making it seem counterintuitive to
many families that a hearing loss could potentially be hereditary.
However, more than 50% of children born into families where
they are the only aected individuals will have an identifiable
genetic reason for being deaf/hard of hearing. Knowing the cause
of hearing loss will aid in the immediate medical care of the child,
facilitate the long-term management of the child’s hearing loss,
and inform development and communication.
1
Pearl
More than 50% of childhood hearing loss is genetic.
3.2 Genetics and Universal
Newborn Hearing Screening
Audiologists are often the first point of entry into the world of
hearing loss for families whose infant did not pass a newborn
hearing screening, and they are called on to share informa-
tion about the significance of a genetics referral. With an
understanding of the goal of genetic evaluation and testing,
audiologists should become comfortable with providing valid
information about what will happen when a family meets with
genetics professionals. Audiologists also provide the connection
to genetics professionals who specialize in hearing loss when
genetic evaluations are not readily available in the family’s
local health system. Achieving these connections requires a
thorough understanding of the roles of a genetic counselor and
geneticist and the goals of a clinical genetic evaluation, genetic
counseling, and testing.
3.3 Clinical Management:
Collaborating with Geneticists
and Genetic Counselors
A team approach is required for accurate diagnosis and management of hearing loss. This interprofessional team consists
of audiologists, otolaryngologists, pediatricians, speechlanguage pathologists, clinical geneticists, and genetic counsel-
ors. Board-certified clinical geneticists and genetic counselors
are trained to interpret the significance and limitations of new
tests and to convey the current status of knowledge during
27
I Hearing Loss: Essential Information
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
genetic counseling.
the degree, type, configuration, and onset of hearing loss is considered a phenotype. The genetic makeup that contributes to the
hearing loss is a genotype.
Genetic testing is best accomplished through both clinical
geneticists and genetic counselors. A clinical geneticist (physician)
provides a detailed clinical evaluation of the deaf/hard of hearing
patient, recommends diagnostic genetic testing based on phenotypic and family history information, and develops a plan for
medical care. A genetic counselor provides information regarding
the benefits and limitations of testing, instructs patients and
families so that they may understand their genetic testing results,
and conveys the impact of genetic testing results on the deaf/hard
of hearing individual and the family. In the pediatric population,
this process is meant to educate and empower parents to make
the best decisions regarding genetic testing for their child and for
themselves. This, in turn, can help ensure appropriate follow-up
and maximize individual outcomes.
Molecular, or deoxyribonucleic acid (DNA)–based, testing has
become standard practice in evaluating the genetic basis for
hearing loss. With current genetic testing capabilities, dozens of
genes can be assessed at the same time. Despite these advances,
there are limitations to genetic tests. The results can be complex
and require interpretation, particularly when test results provide ambiguous information. The clinical geneticist’s or genetic
counselor’s review and explanation of genetic test results are
vital in the process of genetic evaluation of hearing loss.
2,3
In the study of genetics related to hearing,
importance of diagnosis management, Jervell and Lange-Nielsen
syndrome is characterized by hearing loss, long QT syndrome,
and heart arrhythmia that may lead to sudden death. If identified
early, children can be treated with β-blockers and, if required,
implantable defibrillators. In the case of Usher syndrome, which
carries a risk of vision loss, parents may consider enhanced
opportunities for spoken language rather than manual communication, which relies solely on vision.
3.4.2 Understanding the Chance of
Recurrence
Many families are interested in knowing the chances of having
another child with hearing loss in the future. Identifying a
genetic cause of hearing loss may allow families to prepare for
another child with hearing loss, emotionally, financially, and
socially. For those families whose genetic testing comes back
negative, it is even more important to note that a genetic cause
may still be at play, even though testing was not able to identify
the specific cause.
Parents of children with hearing loss perceive genetic testing
as beneficial and do not typically perceive it as harmful.4 When
positive test results are received, and genetic counseling is performed, parents demonstrate better understanding of causation
of their child’s hearing loss and their recurrence risk for future
pregnancies/children.
Pearl
All newborns and children diagnosed with sensorineural hearing
loss should be referred for a genetic evaluation.
Pearl
Case history information typically gathered by the audiologist
can assist the clinical geneticist and genetic counselor tremendously, as it may bring to light a suspected genetic etiology.
3.4 Benets of Evaluating the
Genetic Cause of Hearing Loss
3.4.1 Medical Plan Management
Beyond initial identification of the etiology of a hearing loss, professionals can use genetic testing results to tailor an individual’s
plan of care, an application of precision medicine. As part of this
process, parents of deaf/hard of hearing children are counseled
about the prognosis of the hearing loss and associated conditions, and early management can allow preventative therapy to
begin for potentially life-threatening conditions. To illustrate the
3.5 Basics of Genetics
Humans, like all organisms, are made of millions of cells. The
nucleus of each cell contains DNA. A DNA molecule consists of
a long strand made of alternating deoxyribose sugar molecules
and phosphate groups, with one of four dierent base molecules
bonded to each sugar molecule. Each base can pair up with
only one of the other bases: adenine (A) with thymine (T) and
guanine (G) with cytosine (C). Most of the time, two strands with
matching bases coil around each other in the familiar image of
the double helix. The sequence of the bases makes it possible
for DNA to carry information, and the specific pairing between
bases makes it possible for this information to be copied and
transcribed.
The DNA molecules in the nucleus of each cell are stored in the
form of structures called chromosomes. Humans have 23 pairs of
chromosomes, making a total of 46 chromosomes. Each parent
normally contributes one member of each pair of chromosomes.
Of these 23 pairs, one pair consists of the sex chromosomes,
usually XX for females and XY for males. The chromosomes in the
remaining 22 pairs are known as autosomes. The length of DNA
that makes up each chromosome comprises numerous genes, the
functional units of heredity, which encode the proteins responsible for structure, function, and regulation of tissues and organs.
There are an estimated 18,000 genes on human chromosomes.
5
Pearl
Hundreds of genes contribute to cochlear function.
28
3 Genetics of Hearing Loss
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
An individual’s mother and father each normally contribute one
chromosome to each chromosome pair. Therefore, each parent
provides one copy of each gene, also known as an allele, to a child.
If an individual’s two alleles are of same sequence, the person is
homozygous for that allele. If the alleles in a pair are of dierent
sequence, the person is heterozygous for that allele.
Chromosomes in cells are best visualized at the moments
leading up to cell division. When a cell is caught at this stage,
special stains are applied and the chromosomes can be observed
under the microscope. Each of the 23 pairs of chromosomes in
a cell can be distinguished by characteristic staining patterns,
called banding, and the presence of a short arm, called the p arm,
and a long arm, called the q arm. Karyotyping is the process of
identifying all 46 chromosomes and interpreting whether each
chromosome has the correct size and maintains an appropriate
banding pattern. Large structural chromosome abnormalities
visible by karyotype include deletions, duplications, inversions,
and translocations.6 Certain genetic conditions, such as trisomy
21 (the cause of Down syndrome), can be easily identified by
karyotyping.
While obvious chromosomal dierences are identified by
karyotype, small variants in chromosome regions and single-gene
dierences are too small to be seen by microscope. With the development of chromosomal microarrays (CMAs) in the mid-2000s,
the human genome can be probed for deletions and duplications
in the genome that were not previously detectable.7 For example,
the chromosome deletion on the long arm of chromosome 7 that
causes Williams syndrome, a condition with a high prevalence
of hearing loss,8 would be detectable by microarray but not by
standard karyotyping. CMA is now the standard of care and is
performed as a first-line test, typically in children who have other
birth defects or other conditions in addition to being deaf or hard
of hearing.
Pearl
Specic chromosome deletions or duplications identied by CMA
are named based on their location in terms of chromosome, arm,
band, and subband. For example, 22q11.2 deletion syndrome
(also known as DiGeorge or velocardiofacial syndrome) occurs at
the second subband of the 11th band on the q arm of chromosome 22.
the cytoplasm, where protein synthesis, known as translation,
occurs. Structures called ribosomes move along the mRNA
strand, assembling proteins based on the precise sequence of
the string of bases. Each set of three bases, known as a codon,
encodes one of 20 dierent amino acids, the building blocks
of protein, to be added to the growing protein chain. One
of the codon sequences serves as a signal to stop assembling
amino acids and release the protein chain from the ribosome.
The chemical properties of the various amino acids cause the
released protein molecule to fold up in a particular way that
enables it to do its job.
If a variation occurs within the sequence of bases in a gene (the
genotype), an altered protein will be produced. Sometimes this
variation may change the production or function of the protein in
a seemingly insignificant way, such as a substitution of one amino
acid for another, but a single amino acid change can have a dra-
matic eect. For example, a genetic variation may produce a stop
codon earlier than typically expected, resulting in an incomplete
protein. When evaluating the genetic cause of hearing loss, the
clinical geneticist’s role is to determine the impact of the variation
upon the cells of the hearing system (the phenotype).
9
3.5.2 Inheritance Patterns
Inheritance of genetic material from one generation to the next
can be categorized in the following modes: autosomal recessive
(AR), autosomal dominant (AD), X-linked, and mitochondrial.
Fig. 3.1 shows how each inheritance type contributes to the
occurrence of genetic hearing loss. During a genetic evaluation,
a geneticist or genetic counselor will typically compile a pedi-
gree, the diagram that outlines familial inheritance of specific
traits, to determine how a particular genetic dierence is passed
through a family.
Traditionally, “mutation” has been a widely used term to
describe genetic dierences. Genetic mutations can be dis-
ease-causing (i.e., pathogenic) as well as non-disease-causing (i.e.,
benign), and the use of the word “mutation” can lead to confusion
about genetic findings. It has, therefore, been recommended that
the term “variant” be used to describe genetic dierences, followed by one of following five terms to describe the nature of the
variation: pathogenic, likely pathogenic, uncertain significance,
likely benign, or benign.10 A pathogenic variant describes a DNA
sequence change that is likely to cause a harmful condition. The
phrase “pathogenic variant” is the preferred description for the
older term “mutation.”
3.5.1 Protein Synthesis
The central dogma of molecular biology is that DNA is transcribed to ribonucleic acid (RNA), and RNA is translated to
sequences of amino acids that make up proteins. Proteins are
the fundamental workhorses of cellular function, and DNA
sequence establishes the proteins that will be created. During
the process of transcription, the two DNA strands are separated,
creating a template for exact replication of the sequence using
the corresponding bases of messenger RNA (mRNA). The mRNA
carries the transcribed information out of the cell nucleus to
Pearl
The term “variant” is now used to describe a DNA sequence
change with its appropriate designator.
Autosomal Recessive Inheritance
Autosomal recessive inheritance is the most commonly observed
inheritance pattern for genetic hearing loss. In this pattern, the
29
I Hearing Loss: Essential Information
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
75-85%
Autosomal
Recessive
66 genes
~ 25% have two
GJB2/GJB6 alleles
20%
Environmental
• Trauma
• Inf ns: CMV
• Ototoxic drugs
Autosomal
Dominant
36 genes
60%
Gene c
70%
20%
Cause
Undetermined
30%
Syndromic Non-Syndromic
15-24%
1-2%
X-Linked
5 genes
<1%
Mitochondrial
6 genes or
large deletions
> 400 syndromes, including Usher,
Lange-Nielsen, Pendred
BOR, Jervell and
Fig. 3.1 Etiologies of childhood hearing loss. Abbreviations: BOR, branchio-oto-renal; CMV, cytomegalovirus.
gene involved is located on one of the 22 autosome pairs. As illustrated in Fig. 3.2a , the child inherits one variant f rom each parent.
If the condition only occurs when both of the chromosomes in
the pair have the pathogenic variant, the condition is recessive.
Thus, autosomal recessive hearing loss occurs when the child
has inherited the pathogenic variant from both parents. If the
parents of a child with an autosomal recessive hearing loss are
carriers of the variant (that is, they have it on only one member
of the chromosome pair), they are unaected themselves. With
every pregnancy, carrier parents have a 25% chance of having
another aected child. Two-thirds of their unaected children
will be carriers. A child with autosomal recessive hearing loss is
typically the only person in the family to have hearing loss, and
thus a “negative” family history can still produce a genetic condition. Autosomal recessive hearing loss tends to be congenital,
prelingual, or early-onset and greater in severity than autosomal
dominant conditions.
Parents who share a common ancestor have an increased
chance of having children with an autosomal recessive condition.
If parents are related to one another (called a consanguineous
pairing), the likelihood that a child has a recessive form of hearing
loss is increased.
The GJB2 gene, which encodes for the connexin 26 protein,
is the cause of the most common form of autosomal recessive
hearing loss in East Asian and Caucasian populations.11 Common
examples of autosomal recessive syndromes include Jervell and
Lange-Nielsen, Pendred, and Usher syndromes.
Autosomal Dominant Inheritance
An autosomal dominant hearing loss is caused by a pathogenic
variant in a single copy of the gene. A person with autosomal
dominant hearing loss may have inherited the variant from an
aected parent. The pedigree of an individual with autosomal
dominant hearing loss might include a number of individuals
with hearing loss in successive generations. Fig. 3.2b shows that
with every pregnancy, there is a 50% chance an individual with
autosomal dominant hearing loss will pass the variant gene on
and have a child with hearing loss. Some autosomal dominant
hearing loss is due to new genetic variants in a sperm or egg cell,
and individuals with these de novo variants are born to hearing
parents with no family history of hearing loss.
Autosomal dominant conditions may exhibit variable expression, in which the severity and onset of hearing loss can be
30
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