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(autosomal recessive). This disorder is
characterized by craniofacial features
including midface hypoplasia, micrognathia and retrognathia, external ear malformations, and lower eyelid abnormalities.
Hearing loss can be mixed, conductive,
or sensorineural; however, 40% to 50%
of individuals present with a conductive
hearing loss (Katsanis & Jabs, 2018). This
is attributed to middle ear abnormalities
including malformation of the ossicles
and middle ear hypoplasia. Auricular
deformities are a key characteristic and
can include small, absent, or malformed
pinnas. Atresia of the external auditory
meatus is often observed, and the ossicular chain can be absent or malformed.
Stickler Syndrome. This syndrome is
caused by mutation in collagen genes.
Stickler syndrome is characterized by
auditory, ocular, orofacial, and skeletal
abnormalities (Baker et al., 2011). Because
of facial bone deformities, affected individuals can have difficulty breathing and
eating. It is estimated that 1 in 7,500 to 1 in
9,000 births may have Stickler syndrome
(Printzlau & Andersen, 2004). This disorder is inherited in an autosomal dominant
pattern. The diagnosis of Stickler syndrome is based on clinical findings including ocular involvement (myopia, cataracts, and retinal detachment), hearing
loss, midfacial underdevelopment, cleft
palate, mild spondyloepiphyseal dysplasia, and/or precocious arthritis (Robin,
Moran, & Ala-Kokko, 2017). There are several associated pathogenic gene variants
including COL2A1, COL11A1, COL11A2,
COL9A1, COL9A2, and COL9A3 (Robin,
Moran, & Ala-Kokko, 2017). The degree of
hearing loss can vary but typically affects
the high frequencies, and is sensorineural
in nature (Robin, Moran, & Ala-Kokko,
2017). Because this is a collagen mutation, the epithelium of the inner ear is at
risk; hence, sensorineural hearing loss is
common. However, in cases that present
with cleft palate and facial anomalies, it
stands to reason that conductive hearing
loss could also manifest. Of interest is
that Stickler syndrome is often associated
with Pierre Robin sequence. In fact, Stickler syndrome has been found to be the
most common genetic diagnosis of Pierre
Robin sequence (Izumi, Konczal, Mitchell,
& Jones, 2012).
Down Syndrome. In this genetic dis-
order, there is usually trisomy (an extra
chromosome) for chromosome 21. The
risk for having a child with this condition
increases with parental age. Translocation
of chromosomes can also be the basis for
Down syndrome, but this etiology is relatively rare. The occurrence of Down syndrome is related to maternal age with an
occurrence of 1 case of the syndrome in
800 newborns, with approximately 5,300
babies born each year with Down syndrome (U.S. National Library of Medicine,
2019c). Down syndrome manifests facial
features such as epicanthal folds, open
mouth, protruding tongue, flattened nose,
and rectangular-shaped ears. Affected
individuals can also suffer from severe
cognitive compromise, hypotonia, congenital heart disease, shortened hands,
and dermatologic problems.
There is a high prevalence of hearing
loss in individuals with Down syndrome.
It is estimated that permanent hearing
loss occurs in nearly 25% of children with
this condition (Nightengale, Yoon, WolterWarmerdam, Daniels, & Hickey, 2017).
The majority of these losses are bilateral
(75.4%) and conductive (33.3%) in nature.
However, not all hearing losses noted in
this population are permanent as 22% to
30% of individuals with Down syndrome
have transient hearing losses due to middle ear pathology. These particular hear-
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ing losses are conductive in nature and are
linked to a high incidence of upper respiratory and sinus infections in individuals
with Down syndrome. Sensorineural loss
by itself has been reported, but it is rare.
A curious finding in the early latency ABR
waves is often observed when testing
patients with this particular syndrome.
This unique finding is that the interwave
intervals of I–III and I–V are often shortened in their latencies. Even when compared to other populations with various
types of developmental disabilities, the
differences in interwave intervals remain
significantly shorter for the Down syndrome population (Kittler et al., 2009). As
reviewed by Kittler et al. (2009), there is
no firm agreement as to why ABR interwave intervals are shorter in the Down
syndrome population; however, smaller
brain volume and faster development
early in life (quicker myelination) have
been considered as potential causes.
Biotinidase Deficiency. Biotinidase defi-
ciency is an autosomal recessive metabolic
disorder defined by the lack of adequate
levels of biotin, the B-complex vitamin
(Wolf, 2016). The mutation occurs in the
BTD gene. The lack of the enzyme biotinidase can affect certain kinds of protein synthesis, which in turn can result in
abnormalities of the auditory system, as
well as other medical manifestations (e.g.,
seizures, hypertonia). In some cases, however, symptoms may not manifest until
several years after birth. The symptoms
can be treated with biotin if early identification of the genetic condition is achieved,
but once symptoms occur, they are difficult to reverse. Currently, screening for
biotinidase deficiency is carried out in all
states, so future occurrences of this condition can and should be managed effectively. Both hearing loss and vestibular
problems have been reported in individu-
als with biotinidase deficiency. It has been
estimated that 76% of untreated symptomatic children with significant biotinidase deficiency will have sensorineural
hearing loss (Wolf, Spencer, & Gleason,
2002). This disorder has also been shown
to affect myelin in the central nervous system. Therefore, both central and peripheral auditory and vestibular involvement
should be considered. Profound or partial
biotinidase deficiency has an incidence of
approximately 1 in 60,000 newborns (U.S.
National Library of Medicine, 2019a).
Refsum Disease. Refsum disease is in-
herited as a recessive trait and presents as a
disorder of lipid metabolism due to mutations in the PEX7 and PHYH genes. It has
been associated with severe peripheral
neuropathies (it is possible that the inefficient lipid metabolism could influence the
development of myelin, resulting in poor
nerve conduction) (Wanders, Waterham,
& Leroy, 2015). Poor coordination, muscle
weakness, retinitis pigmentosa, and hearing loss are among its symptoms. The hearing loss is progressive, bilateral, and sensorineural in nature. It ranges from mild to
profound and typically affects the mid- to
high frequencies (Wanders et al., 2015). Subtle auditory nerve involvement has been
found in some cases (Bamiou, Spraggs,
Gibberd, Sidey, & Luxon, 2003). The gene
for Refsum disease has been linked with
mutations in the PHYH gene in 90% of
cases, and the remaining 10% are caused
by mutations in PEX7 (U.S. National
Library of Medicine, 2019h), but the incidence of Refsum disease is unknown.
Norrie Disease. Norrie disease is a rare,
X-linked recessive genetic disorder with
an unknown incidence (U.S. National
Library of Medicine, 2019d). It primarily manifests as a progressive, severe eye
disorder that results in blindness at birth
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or early in life due to mutations of the
NDP gene. The retina does not develop
normally. About one-third of those with
Norrie disease will develop progressive,
bilaterally symmetric sensorineural hearing loss; however, the onset of the hearing
loss can be late. Developmental motor
delays and intellectual disability are common. Males are affected with this disorder
much more often than females.
CHARGE Syndrome. CHARGE syn-
drome is a disorder that involves multiple systems. CHARGE is an acronym
that stands for the following conditions/
disorders (note: the letters that appear in
this acronym identify the specific areas
of the body that are compromised in this
particular genetic disorder): C = coloboma
(missing segment or tear of the eye), H =
heart (cardiac involvement), A = atresia
of the nasal choanae (blocked nasal passages), R = retardation (of growth and
development), G = genitourinary (genital,
urinary problems), and E = ear (otologic,
audiologic problems). The occurrence of
CHARGE syndrome is somewhere in the
range of 1 in 8,500 to 1 in 10,000 persons
(Lalani Hefner, Belmont, & Davenport,
2012). CHARGE syndrome is a result of a
defect in the CHD7 gene, which was discovered in 2004 (see Hartshorne, Hefner,
Davenport, & Thelin, 2011). Hartshorne
and colleagues (2011) provide a comprehensive review of CHARGE syndrome,
which is the basis for much of our discussion here. The CHD7 gene plays a
key role in the development of the neural
crest embryologically. The neural crest is
responsible for the development of the 12
cranial nerves; hence, dysfunction related
to these important structures is a main factor contributing to the problems related to
CHARGE syndrome.
It is useful to modestly elaborate on
the dysfunctions related to CHARGE syn-
drome as listed previously. Eye anomalies
such as coloboma of the iris, optic disks,
retina, and choroids have been shown to
occur at a high frequency (80% to 90%).
Blocked or maldeveloped nasal passages
(choanal atresias) in the back of the nose
are also present, but not as often as eye
disorders. There can also be anomalies
of cranial nerves I, VII, VIII, IX, and X.
Hearing loss is one of the primary features of CHARGE syndrome. In addition,
the pinnae are often short and wide, protrude, and are asymmetric, with reduced
amounts of cartilage being observed.
Although in CHARGE syndrome the pinnae are often malformed in some way, this
condition in and of itself seldom leads to
any hearing loss. In the middle ear, ossicular malformations can result in maximal
conductive losses, and these malformations appear to be the primary cause of
hearing loss in this particular syndrome.
Dysfunction of the Eustachian tube is the
second most common cause of conductive hearing loss in CHARGE syndrome.
Mondini defects in the cochlea result in
various degrees of sensorineural hearing
loss, and, when combined with conductive loss, can yield a considerable degree
of mixed hearing loss. Like the cochlea,
the peripheral vestibular apparatus can
be maldeveloped or incompletely developed. Auditory and vestibular nerves
in CHARGE syndrome can be absent or
reduced in size. Maldevelopment of the
central auditory system can also exist in
CHARGE syndrome, but it is difficult to
assess because the peripheral system is
often compromised to the degree that testing of the central auditory nervous system
is not possible (Thelin, 2011).
The incidence and degree of hearing loss in CHARGE syndrome has been
reviewed by Thelin (2011), who reports
that 15% have normal hearing, 38% have
mild to moderate loss, and 47% have
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severe to profound loss. Given these findings, it is clear that hearing loss is a major
factor in the overall well-being of individuals with this syndrome.
There are other physical anomalies
associated with CHARGE syndrome,
such as genital hypoplasia and delayed
puberty. Cardiovascular problems as well
as growth deficiency and cleft lip and/or
palate are routinely observed in CHARGE
syndrome. Tracheal and esophageal fistulas and renal anomalies are also relatively
common in this syndrome (see Hartshorne et al., 2011).
Neurofibromatosis. Special mention
of neurofibromatosis type II (NF2) is in
order when discussing hereditary hearing loss. NF2 is an autosomal dominant
disease that can result in bilateral acoustic neuromas, meningiomas, and ependymomas. However, bilateral tumors are not
necessary for the diagnosis of NF2. NF2
is estimated to have a birth incidence of 1
in 33,000 with an estimated overall prevalence of 1:60,000 (Evans, 2018). Interestingly, 50% to 60% of individuals with NF2
do not have a family history of the disease,
which is due to the “de novo” (new) gene
mutation of the NF2 gene. In addition, 25%
to 33% of the cases are specifically due to
truncating gene mutations. About 70% of
individuals with this disease have skin
tumors and a large proportion of patients
may develop visual problems secondary
to cataracts. According to Evans (2018),
there are a variety of reported symptoms
in individuals with NF2, including hearing loss (9% bilateral, 35% unilateral),
tinnitus (10%), balance problems (8%),
focal weakness (12%), seizures (8%), and
blindness (1%). These symptoms usually
appear during adolescence or early adulthood (but they can begin at any age), and
by the age of 30 years, bilateral tumors
will be present in most patients with NF2.
Interestingly, 11% of individuals who are
at risk for NF2 are asymptomatic. In these
cases, a diagnosis was confirmed because
screening for NF2 was recommended due
to a parent being affected and not because
of any symptoms. By the age of 60 years,
practically all individuals with the disease have manifested symptoms (Gareth
& Evans, 2009).
The hearing loss associated with NF2
is most often consistent with what is usually observed in patients with acoustic
tumors (i.e., a high-frequency sensorineural hearing loss). This topic was covered in
Chapter 6, “Auditory Nerve Disorders.”
However, tumors can also appear in the
brainstem and/or cerebrum, and in these
cases, hearing difficulties similar to those
noted in other central auditory disorders
are commonly observed (see Chapter 7,
“Disorders of the Central Auditory Nervous System”).
Auditory Neuropathy Spectrum Disorder. Auditory Neuropathy Spectrum
Disorder (ANSD) (also referred to by some
professionals as Auditory Neuropathy/
Auditory Dys-synchrony) has recently
received attention for a possible genetic
basis. Studies on the genetic link to ANSD
are difficult because many etiologies can
contribute to the manifestation of the disorder. For example, Charcot-Marie-Tooth
disease often manifests as ANSD and
this disease has long been known to be
inherited. However, in other cases where
otoacoustic emissions have been present
but hearing loss and abnormal ABRs have
been demonstrated, no identifiable genetic
syndrome or disease was observed (Varga
et al., 2003). ANSD may be a result of both
syndromic and nonsyndromic autosomal
dominant, autosomal recessive, X-linked,
and/or mitochondrial mutations. A number of genes have reportedly been linked
to ANSD including OTOF, CACNAID,
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GABP2, SLC17A8, DIAPH3, OPA1, ROR1,
ATP1A3, TIMM8A, AIFM1, NARS2, MPZ,
PMP22, and PJVK (Carvalho, Ramos,
Castilho, Guimarães, & Sartorato, 2016;
Shearer & Hansen, 2019).
Central Auditory Disorders. Although
there are a number of inherited disorders
of the central nervous system, there is a
paucity of information on these kinds of
disorders that are linked to central auditory dysfunction. With regard to syndromic hearing loss specifically, there is
some evidence that PAX6 mutations may
result in central auditory involvement.
The work of Bamiou and colleagues (2007)
yields some interesting information in this
regard. The PAX6 gene mutation has been
associated with panocular maldevelopment with aniridia (absence of the iris)
and structural brain abnormalities. These
structural brain abnormalities often seem
to manifest in the region of the corpus callosum. This could indicate that interhemispheric auditory transfer may be affected
in patients with PAX6 mutations. Bamiou
et al. (2007) tested 11 children with mutations of the PAX6 gene, all of whom had
aniridia. Ten of the 11 children in this
study with the PAX6 gene mutation demonstrated auditory processing deficits.
Specifically, left ear deficits in dichotic
listening and depressed pattern recognition scores were among the deficits dem-
onstrated in this patient population — a
finding that is consistent with interhemispheric transfer problems. Based upon the
results of this study, it appears that central auditory involvement may be associated with this particular gene mutation.
However, additional research with larger
sample sizes is needed to provide information regarding the incidence and/or
prevalence of central auditory system
deficits in this population.
More recently, evidence has unfolded
regarding genetic manifestations of 22q11.2
deletion syndrome and its relationship
to auditory function and dysfunction.
22q11.2 deletion syndrome is estimated to
affect 1 in 4,000 individuals (U.S. National
Library of Medicine, 2019i). This syndrome can involve multiple systems and
has been found to result in heart abnormalities, cleft palate, kidney abnormalities, low calcium levels, and hearing loss.
It is a result of a missing gene sequence
on chromosome 22. It is hypothesized that
compromise of the TBX1 gene is responsible for a number of the characteristics
associated with 22q11.2 deletion syn-
drome (Hacihamdiog˘ lu, Hacihamdiog˘lu,
& Delil, 2015), including those that are
auditory in nature. Behavioral and mental health issues, which were not mentioned earlier, are also associated with
this syndrome and are believed to occur
due to mutations of the COMT gene (Bertrán, Tagle, & Irarrázaval, 2018). Some
of the evidence to support central auditory involvement in those with this syndrome includes the work by Cantonas
and colleagues (2019). These researchers
identified abnormal auditory development in individuals with 22q11.2 deletion syndrome as compared to controls.
Specifically, they found reduced amplitudes on the auditory mismatch negativity response. Individuals with this deletion syndrome have also been found to
demonstrate significant musical auditory
processing deficits (Gao et al., 2018). Interestingly, the 22q11.2 deletion syndrome
has been identified as the most common
genetic risk factor for schizophrenia. It
has been well established that individuals with schizophrenia often present with
abnormal auditory function that typically
is manifested as auditory hallucinations
(see Chapter 8 for review).
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congenital
malfoRmations
Congenital malformations can exist for
the external, middle, or inner ears, as well
as for the auditory nerve and/or the IAM
and the brain. These malformations may
have a hereditary link in that they may
be part of an inherited syndrome or they
can be associated with embryonic maldevelopment (which may or may not be
genetically linked). Definitive information
in regard to a genetic or other embryologic cause or insult is difficult to determine in many cases with congenital ear
malformations.
External and Middle
Ear Malformations
Aplasias and Atresias
External ear malformations are usually
related to abnormal embryologic development of the first and second branchial
arches (Hartzell & Chinnadurai, 2018).
These malformations can be viewed as
aplasias or atresias and are estimated to
occur in 5% of the population (Ma et al.,
2019). Aplasia usually indicates that the
pinna is deformed, but that an ear canal
opening remains that allows an acoustic
pathway to the middle ear. Atresia usually refers to an absence or abnormal narrowing of the ear canal. One of the best
known conditions that can involve aplasia
or atresia is the microtic ear. The severity
of microtia ranges from mild abnormalities of only the pinna to the total absence
of the pinna and complete atresia of the
external ear canal (Liess & Kinney, 2007).
This condition can be bilateral, but it is
more commonly a unilateral condition.
This outer ear anomaly occurs more often
in males than females. If the middle and
inner ears are intact, surgical intervention
in cases with significant ear canal atresia
can provide a pathway for sound to travel
to the middle ear. Surgical reconstruction
of the pinna, however, is extremely challenging, and what is deemed a “successful” surgery is debatable.
Middle ear malformations are typically also related to problems with the
embryologic development of the first and
second branchial arches (Georgakopoulos & Zafar Gondal, 2019). Absence of the
ossicles, either partial or complete, is possible. In addition, fusion of the ossicles
may be observed and absence of the oval
and/or round windows may occur.
External and middle ear problems
require teamwork from the surgeon and
the audiologist, as well as other professionals depending on the nature of the
deficits. Proper audiologic diagnosis as
to the degree of conductive loss and any
secondary sensorineural involvement, if
present, is essential. Utilization of both airand bone-conduction ABR is an important
consideration in these diagnoses. In some
cases, surgical intervention may correct
most of the hearing deficit; in other cases,
little can be done surgically to improve
hearing. As conductive loss is usually the
primary deficit, bone-conduction hearing aids may be a useful approach for
those cases where surgical intervention is
unsuccessful or contraindicated. In these
cases, careful, long-term monitoring of
hearing status in both aided and unaided
conditions is required for good audiologic
management. Counseling as to audiologic
expectations, educational implications,
and social challenges that may be experienced, as well as the coordination of necessary referrals are important to the care
of the patient.
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Inner Ear Malformations
Aplasias
Cochlear malformations have a variety
of presentations and varying degrees of
hearing loss depending on the extent of
involvement. Given the wide range of presentations, there have been several classification systems proposed with respect to
categorizing inner ear aplasias (see Jackler,
Luxford, & House, 1987; Joshi, Navlekar,
Kishore, Reddy, & Kumar, 2012; Sennaroglu & Saatci, 2002), although there does
not appear to be large differences among
the systems. The following discussion is
based upon the classification system outlined by Joshi and his colleagues (2012).
The rarest of the congenital aplasias are complete labyrinthine aplasia
(also referred to as Michel aplasia) and
cochlear aplasia. These are estimated to
affect 1% to 3% of patients with congenital inner ear abnormalities, respectively.
Complete labyrinthine aplasia occurs in
the 3rd gestational week and results in
the total absence of all inner ear structures and a profound hearing loss. This is
slightly different than cochlear aplasia in
which the cochlea is absent but the vestibular apparatus is intact. Cochlear aplasias also occur in the 3rd gestational week
(late). Cochlear hypoplasias are fairly rare
(15% of congenital malformations of the
inner ear). This malformation occurs in
the 6th gestational week and results in a
“small cochlear bud” with less than one
turn. The vestibular apparatus may be
normal or may have some deformities.
A common cavity malformation occurs
when there is an absence of the normal
division between the vestibule and the
cochlea. This is a congenital condition
that typically results in profound hearing
loss (Brotto et al., 2019). It typically occurs
in the 4th week of gestation and affects
25% of patients with congenital malformations of the inner ear. There are two
types of incomplete cochlear partitions:
Type I and Type II. Type I incomplete
partitions occur in approximately 6% of
patients with congenital malformation of
the inner ear around the 5th gestational
week. These involve a cystic cochleovestibular malformation with absence of the
modiolus or a cystic vestibule that is present but is separated from the cochlea. The
most common malformation is the Type II
malformation (also referred to as Mondini aplasia), which accounts for 50% of
affected patients. This often manifests as a
partially developed cochlea that has a flattened appearance. According to Joshi and
colleagues, this occurs in the 7th week of
development and is often associated with
an enlarged vestibular aqueduct. Both the
membranous and bony cochlear structures are typically involved, with only
part of the cochlea (often the basal turn)
intact. The auditory nerve and vestibular
canal may also be compromised. Involvement may be unilateral or bilateral and
residual hearing can be present.
Vestibular and Cochlear
Aqueduct Malformations
Vestibular and cochlear aqueduct malformations have become diagnostically
popular in recent history. Jackler’s review
(1998) highlights key points of interest,
which are discussed here. In many cases,
an enlarged vestibular aqueduct accompanies other congenital abnormalities of
the cochlea or the vestibular apparatus. It
also can exist alone as a probable cause
of sensorineural hearing loss. Arrested
embryologic development is believed to
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result in a shortened but broad-shaped
vestibular aqueduct. The common term
for this condition is enlarged vestibular
aqueduct syndrome, which is diagnosed
when the width of the vestibular aqueduct measured halfway between the
common crus and its external aperture
is larger than 2 mm. Hearing loss associated with this condition is sensorineural
in nature and present at birth. It often
progresses into the teenage years, but it
can be highly variable in its degree and
progression. Head trauma can result in
marked decreases in hearing when this
condition is present. Estimates are that
approximately 40% of individuals with
this condition will eventually develop
profound hearing loss.
Auditory Nerve and
Internal Auditory Meatus
There are also congenital abnormalities of
the auditory nerve and internal auditory
meatus (IAM). There have been reports of
both narrow and wide internal auditory
canals (Jackler, 1998). These anomalies
were brought to light by cochlear implantation investigations. As Jackler (1998)
relates in his review, a narrow IAM could
indicate an abnormal or absent auditory
nerve. For example, if there is abnormal
facial function and the IAM is less than
3 mm, it is possible that the auditory nerve
is absent. A narrow IAM may accompany anomalies of the inner ear or it can
exist alone. An enlarged IAM may also
be related to inner ear anomalies but, by
itself, is usually an incidental finding in
normal individuals. A large IAM is considered one that is larger than 10 mm in
diameter. Although the presence of a large
IAM usually does not result in any signifi-
cant otologic or audiologic conditions, its
presence could be a factor in stapes surgery in that it could be a potential route
for CSF leak during the surgery.
Central Auditory Nervous
System Malformations
There are multiple types of brain malformations that can affect central auditory
nervous function. These malformations
can be caused by genetic as well as a number of nongenetically based factors, as will
be discussed in the following sections.
number of abnormal brain malforma-
A
tions have been shown to be linked to central auditory dysfunction, and, therefore,
they constitute a relevant consideration
in the evaluation of individuals who have
these disorders.
Mutation in genes that result in malformations of cortical development have
been classified into three distinct groups
(Barkovich, Guerrini, Kuzniecky, Jackson,
& Dobyns, 2012). These groups include
(I) malformations secondary to neuronal
and glial proliferations or apoptosis, (II)
malformations due to abnormal neuronal migration, and (III) malformations
secondary to abnormal postmigrational
development. Each of these groups has
been linked to either peripheral and/or
central auditory involvement.
Microcephaly and
Megalencephaly
Microcephaly and megalencephaly involve
increased or decreased proliferations of
apoptosis (cell death during development), respectively. In cases of microcephaly, this results in a small head size. This is
an uncommon condition that is estimated
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to affect 2 to 12 babies per 10,000 live
births in the United States (National Birth
Defects Prevention Network, 2013). It can
result in a myriad of problems depending
on the severity of the microcephaly. Common problems associated with microcephaly include seizures, developmental and
intellectual delays, problems with movement and balance, feeding issues, hearing
loss, and visual deficits (Centers for Disease Control and Prevention, 2018). While
often associated with specific viruses such
as cytomegalovirus and zika virus, there
have been many genes identified that are
believed to cause primary microcephaly
(the reader is referred to Barkovich et al.,
2012, and/or Pirozzi, Nelson, & Mirzaa,
2018, for information about the genes that
have been linked to this particular brain
malformation). There is also evidence of
neuroauditory deficits in this population.
Specifically, results of auditory brainstem
response testing has shown increased
wave V latency and interpeak latencies
(III–V and I–V) in microcephalic children
as compared to controls (Das, Bandyo-
padhya, Ghuga re, Ghate, & Singh, 2010).
Megalencephaly is a condition in
which the individual has an abnormally
large brain. According to Pavone and
colleagues (2017), this is defined as a
head circumference two standard deviations above the age-related mean. This
typically results in a brain weight that is
greater than that observed in children of
the same gender and age. Megalencephaly
is believed to have genetic contributions
and is often associated with polymicrogyria (see the following discussion). There
are number of genes associated with this
disorder. These are genes that are linked
to human growth disorders and include
such genes as NSD1, EZH2, and DNTM3A
(Tatton-Brown et al., 2017), among many
others (see Pirozzi et al., 2018). Due to
the rarity of this disorder, there is a paucity of literature regarding the effects of
megalencephalic involvement on auditory function. Coupland and Sarnat
(1990) reviewed a number of studies
where evoked potential test results were
reported for patients with a variety of
cerebral malformations including holoprosencephaly, lissencephaly, pachygyria,
and generalized megalencephaly. They
found delayed wave V latencies for 50%
of patients with megalencephaly in their
review. Although there is limited literature regarding auditory function in cases
of megalencephaly, findings such as this
would appear to implicate auditory deficits in this population.
Heterotopias
Heterotopias are migrational problems of
neurons in the brain that yield what could
be considered morphologic abnormalities
in the cortex. The neuron migration problem, in essence, is one that is incomplete.
The lack of complete development (i.e.,
the lack of complete migration) in the 6th
to 24th week of pregnancy results in nests
of nerve cells that develop in the wrong
location. This genetic disorder often
results from mutations of the FLNA gene
(Fox & Walsh, 1999, also see U.S. National
Library of Medicine, 2019f). In most
cases, there are multiple heterotopias that
can lead to connectivity problems in the
brain. Although heterotopias have been
linked to seizures and severe cognitive
involvement (and other developmental problems), they have received much
attention as a result of their documented
link with dyslexia (Galaburda, Sherman,
Rosen, Aboitiz, & Geschwind, 1985). In
the cases of dyslexia, the heterotopias
tend to be located in the perisylvian and/
or periventricular regions of the left hemi-
9. Hereditary and Congenital Hearing Loss 441
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sphere, but not to the exclusion of other
regions of the cortex. As heterotopias are
known to occur throughout the brain, and
central auditory processing deficits have
been frequently associated with dyslexia
(see Musiek & Chermak, 2014), it is likely
that the auditory areas of the brain may
be involved.
Polymicrogyria
Polymicrogyria is a malformation of
cortical development that results in the
overfolding of brain tissue and the overproduction of small gyri in the brain’s
surface. This gives the appearance macroscopically of multiple small gyri that
are abnormally clustered together (Barkovich, Kuzniecky, Jackson, Guerrini,
& Dobyns, 2005; Squier & Jansen, 2014;
Stutterd & Leventer, 2014). Polymicrogyria is phenotypically heterogeneous but
can be broadly categorized by its extent
and severity, which determines its clinical manifestations. This particular brain
abnormality can affect either one or both
sides of the brain (Stutterd & Leventer,
2014). Additionally, polymicrogyria can
be focal, constrained to a small localized
area, or widespread and diffused throughout the brain. Unilateral focal polymicrogyria, which affects a small localized
region on one side of the brain, is considered a mild form. Neurologically, this can
manifest as mild seizures that are readily
controlled with pharmacologic management (U.S. National Library of Medicine,
2019g). Dyslexia has also been linked to
(mild) polymicrogyria (Boscariol et al.,
2009). Conversely, polymicrogyria that is
bilaterally diffuse is considered the most
severe type of this brain abnormality, and
it has been associated with recurrent and
intractable seizures, severe intellectual
disabilities, and movement disorders (U.S.
National Library of Medicine, 2019g).
In an imaging study examining clinical
correlates of polymicrogyria, these brain
abnormalities manifested 61% of the time
in the perisylvian regions. The most common clinical sequelae of polymicrogyria
included epilepsy (78%), global developmental delay (70%), and spasticity (51%)
(Leventer et al., 2010). Auditory processing disorders have been identified in
patients with perisylvian polymicrogyria.
Boscariol and colleagues (2010) demonstrated poor performance with respect to
auditory processing function in the presence of such cortical malformations. These
authors found abnormal performance for
children with perisylvian polymicrogyria
on dichotic listening and gap detection
tasks. In addition, they were able to correlate the extent of cortical involvement
with the severity of auditory dysfunction.
The exact etiology of polymicrogyria
is unclear. There is evidence to support
both genetic and environmental causes of
polymicrogyria. With regard to the former,
mutations in the gene ADGRG1, which
is normally responsible for producing a
G-coupled protein that regulates cortical
patterning via neuronal growth and neuronal migration signaling, has been identified in individuals with bilateral frontoparietal polymicrogyria (U.S. National
Library of Medicine, 2019g). Additionally,
mutations in the TUBB2B gene, which is
responsible for encoding the protein tubulin, have also been implicated in abnormal neuronal migration processes. This
particular mutation has also been associated with polymicrogyria (Parrini, Conti,
Dobyns, & Guerrini, 2016). Environmental factors that have been associated with
polymicrogyria include cytomegalovirus,
hypoxia, in-utero ischemic insults, and
some metabolic diseases (see Leventer
et al., 2010; Squier & Jansen, 2014).
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