Genetic Hearing Loss

Congenital Hearing Loss
GMWF
‫‪Genetic Hearing Loss‬‬
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‫و قل رب ارحمهمــا كما ربيانى صغيــرا‬ ‫‪GMWF‬‬
Hearing Loss classification:
- It may be classified according to:
1. Causality:
- Genetic vs environmental
- Etiologically based classifications can be broadly divided into genetic versus non-genetic
factors.
- Hereditary deafness does not imply congenital deafness; the latter describes a condition present from
birth regardless of causality, whereas hereditary deafness may be present at birth or may develop at
any time thereafter.
2. Time of onset: congenital or acquired
3. Age of onset: prelingual vs postlingual
4. Clinical presentation: non-syndromic vs syndromic
5. Anatomic defect: CHL, SNHL & mixed HL
6. Severity: mild, moderate, moderately severe, severe & profound
7. Frequency loss: low, mid or high frequency
8. Ear affected: unilateral, bilateral. Symmetrical or asymmetrical
9. Prognosis: stable or progressive.
- Generally, hereditary deafness may be: syndromic or non-syndromic deafness which can be sub-
classified according to inheritance pattern as autosomal dominant, autosomal recessive, X-linked,
mitochondrial, or complex.
- Exposure to the ototoxic aminoglycoside antibiotics. Although at high concentration these
antibiotics do interfere with the normal function of the cochlea, individuals with an A1555G
mutation in their mitochondrial 12S rRNA gene are more susceptible to the ototoxic effect of these
drugs even at normally appropriate dosing levels.
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‫و قل رب ارحمهمــا كما ربيانى صغيــرا‬ GMWF
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Diagnosis of hearing impairment:
- Hearing acuity can be measured quantitatively and objectively by numerous physiologic tests that include:
o auditory brainstem response (ABR) measurements,
o auditory steady-state response evaluation,
o tympanometry
o otoacoustic emission testing.
Epidemiology of HL:
- WHO (World Health Organization) has estimated that worldwide, 360 million people are affected by a
significant hearing loss.
- Or HL affects 4 in every 10,000 infants born.
- Congenital SNHL in developed countries, 2 to 4 children per 1000 born
- Congenital SNHL in developing countries is likely to be much higher,9,10 although more data are required
to conclude this.
Fundamentals of Genetics:
- Genome: is the all genetic information inside the cell.
- DNA made up of sugar, phosphate, and four chemical bases: adenine (A), thymine (T), guanine (G), and
cytosine (C). These molecular building blocks are woven into strands that form the now widely recognized
double helix shape. A always pairs to T, and G always pairs to C.
- Gene: a segment of DNA that code for a functional protein & RNAs (tRNA, rRNA or ribozyme)
- Chromosome: condensation of chromatin, or long stranded DNA containing many genes.(The incidence of
chromosomal abnormalities is approximately 1:150 live births, although they account for a significant
number of
- spontaneous abortions, or miscarriages.
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- The chemical instructions contained within a strand of DNA are determined by the order, or sequence, in
which the bases are arranged. A segment of coding DNA that contains enough information for the
production of a protein or proteins is called a gene, the basic unit of heritability. The DNA contained within
the human genome holds approximately 23,000 genes.
- Each person has 46 chromosomes—22 pairs of autosomes and one pair of sex chromosomes (XY in males
or XX in females). Chromosomal number, structure, and organization is known as karyotype.
- Each chromosome has a short and a long extension, or arm (identified as p and q arms, respectively). The p
and q arms are connected by a centromere. The ends of chromosomes are called telomeres.
- For example, the locus for the gene GJB2 is 13q12.11. This gene is located on chromosome 13, on the long
arm (q) at region 1, band 2, subband 11.
- According to Mendel’s principle of segregation, in sexually reproducing organisms, each partner
contributes only one member of each chromosome pair to an offspring. This fact means that each individual
has inherited one copy of each chromosome from each parent.
- Carried on these chromosomes are genes, estimated to number approximately 30,000.
- Variations in these genes impart uniqueness to each individual. These variations, termed alleles, can
sometimes be deleterious.
- If a mutation changes the normal or wild-type sequence of a gene expressed in the inner ear, and if the
protein translated from this new allele variant does not function as well as the normal protein, deafness
may result.
- However, if the remaining normal protein (recall that each gene is represented in duplicate) is able to
replace or compensate for the defective mutant protein, deafness will manifest only in individuals who
carry two copies of the abnormal gene. This scenario is an example of autosomal-recessive inheritance.
Homozygosity means that a person carries two identical alleles of a gene.
- However, if the abnormal protein interferes with normal protein function, deafness will manifest in an
individual who carries a single abnormal gene. This scenario is an example of autosomal-dominant
inheritance. Heterozygosity represents the state in which a person carries two different variants of a given
gene.
- In men, most genes on the X chromosome do not have a counterpart on the Y chromosome, meaning they
are hemizygous (having only one copy) for those genes.
- For instance, not every person with Waardenburg syndrome type 1 has synophrys, premature graying of
the hair, or heterochromia irides, a phenomenon called variable expressivity  the causative genetic
mutation is said to exhibit incomplete penetrance or to be nonpenetrant. This occurrence can give the
impression that a disease “skips” generations.
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Patterns of Inheritance:
- The basic forms of inheritance can be: mendelian (single-gene inheritance, autosomal or X-linked),
mitochondrial, or complex (chromosomal and multifactorial inheritance).
A. Mendelian Inheritance:
i. Autosomal Dominant:
 In autosomal-dominant diseases, heterozygotes express the disease phenotype. The affected parent can
pass either a disease allele or a normal allele to offspring, with the likelihood of each event being 0.5, or
50%. This means that 50% of offspring inherit the normal allele and 50% inherit the disease allele.
 In the case of dominant diseases, 50% of offspring express the disease.
 Autosomal-dominant transmission characteristics:
o First, no sexual predilection  males and females are equally likely to be affected and to transmit the
disease allele to their offspring.
o Second, unless the disease gene is nonpenetrant, the disease does not skip generations. This type of
transmission is called vertical transmission.
o Third, male-to-male (father-son) transmission is seen. This rules out mitochondrial or X-linked
inheritance.
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ii. Autosomal Recessive:
 2 mutant copies of a gene are necessary for expression of the disease phenotype.
 An affected parent transmits a disease allele to all offspring, but offspring do not show the disease
phenotype unless the other parent carries at least one mutant copy of the same gene.
 Most frequently, however, neither parent is affected, but both carry a single mutant gene, and by chance,
each passes this mutant copy on to the affected offspring. In this scenario, 25% of offspring carry two
mutant copies of the gene and express the disease phenotype; 50% of offspring are carriers of a mutant
copy, similar to the parents; and 25% of offspring have two wild-type copies of the gene.
 Characteristics:
o no sexual predilection; males and females are equally likely to be affected,
o But vertical transmission is rarely seen.
o If the disease is exceptionally rare, the likelihood of parental consanguinity, albeit distant, is high.
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iii. X-Linked Inheritance
 X-linked inheritance may be either recessive or dominant.
 In recessive X-linked inheritance:
o Females are unlikely to be affected, because two mutant copies of the gene are needed for the disease
phenotype to manifest.
o However, heterozygous females do occasionally exhibit subtle aspects of the disease phenotype
because of the randomness of X-chromosome inactivation (the Lyon hypothesis).
o In females, in each cell, only one of the two X chromosomes is active, and when X chromosome
inactivation is entirely random, 50% of cells in a heterozygous female will express the disease-
carrying X chromosome.
o Males have only a single X chromosome and always express the disease phenotype  the trait is seen
more frequently in males; there is no father-son transmission; affected fathers transmit the disease
allele to all female offspring, who may have affected males (“skipped generation”).
o Heterozygous females transmit the disease allele to half of all sons, who manifest the disease, and half
of all daughters, who are heterozygous and phenotypically normal.
 In X-linked– dominant inheritance,
o affected fathers transmit the disease allele to all daughters who exhibit the disease phenotype with
complete penetrance;
o There is no father-son transmission.
o Heterozygous
o Females are affected and transmit the trait to half of all sons and half of all daughters.
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B. Non-Mendelian Inheritance
i. Mitochondrial Inheritance:
 The “powerhouses” of the human cell, mitochondria are the sites of oxidative phosphorylation, the
process that leads to the production of adenosine triphosphate.
 Mitochondria possess their own intrinsic DNA, with several copies of the mitochondrial genome in each
mitochondrion.
 The mitochondrial genome is a 16,569 base pair circular molecule that encodes two ribosomal RNAs, 22
transfer RNAs, and 13 polypeptides.
 The remaining mitochondrial proteins required for oxidative phosphorylation are encoded by the
nuclear genome.
 Mitochondrial DNA (mtDNA) is inherited solely through the maternal lineage, reflecting the presence of
large amounts of mtDNA in the cytoplasm of the egg. Therefore, maternal transmission of the affected
phenotype occurs, but no paternal transmission takes place.
 Homoplasmy  meaning all mtDNA molecules are abnormal  all progeny cells contain abnormal
mitochondria.
 Heteroplasmy  If normal and abnormal mtDNA molecules coexist, a wide range of expression of the
mutant phenotype is seen, which reflects the random distribution of mitochondria to progeny cells.
 Because mitochondria lack a DNA repair mechanism, mtDNA accumulates mutations at a higher rate
than nuclear DNA.
ii. Polygenic inheritance:

 refers to the cumulative effect of many genes on a phenotype, in contrast to effects from a single
gene or pair of genes, known as monogenic inheritance.
 Most traits in humans are inherited in a polygenic fashion, although our understanding of these
complex interactions and ability to identify them are just evolving.
 In which interaction of the independent mutations occurs & is deleterious.
iii. Modifier Genes:

 genetic modifiers can enhance or inhibit the expression of other autonomous genes. Indeed, much of the
phenotypic variability (e.g., expressivity, penetrance, and pleiotropy) observed in single gene
(monogenic) disorders may be explained by variations in genetic background.
 For example, the phenotypic spectrum associated with mutations in the cadherin 23 gene (CDH23)
ranges from age-related hearing loss, to nonsyndromic prelingual hearing loss, to the occurrence of
Usher syndrome
 The most common effect of modifier genes is an increased risk for disease (e.g., hearing loss) by the
interaction of two or more alleles at different loci; in this case, the risk for disease is higher than the risk
associated with either allele individually.
 some modifier genes exert their influence in a protective fashion by decreasing susceptibility for disease
this refine our understanding of heritability and susceptibility, clarify fundamental properties of
auditory function, and guide future therapeutic designs.
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C. Multifactorial Inheritance:
 In multifactorial inheritance individuals have genetic susceptibility for certain diseases or disorders, but do
not express the phenotype until they are exposed to a particular environmental trigger.
 A well-described example of this is a mitochondrial mutation involving an adenine (A) to guanine (G) single
nucleotide transition at position 1555 on the 12S ribosomal RNA gene (A1555G). Individuals with this
mutation have an increased risk for ototoxicity from aminoglycoside exposure.
 Several genes associated with increased susceptibility to noise-induced hearing loss, including but not
limited to Ahl1, which is a gene that is also associated with age-related decline in hearing, and several
candidate genes in humans (GRHL2, KCNQ4, KCNE1, CAT, PCDH15, MYH14, HSP70) have shown promising
evidence for a multifactorial interaction with noise.
Chromosomal abnormalities:
 Euploidy: normal number of 46, XX or 46, XY chromosomes in females and males, respectively,
 Aneuploidy: include either an extra copy of a single chromosome (trisomy) or when one copy is lost
(monosomy).
 The most common viable trisomy syndrome is trisomy 21, which causes Down syndrome (e.g., 47, XY +21 for
a male with Down syndrome) 1:300 live births.
 Polyploidy: cells containing more than two paired sets of chromosomes e.g. three
paired sets of each chromosome (triploidy) would be 69, XXX.
 Similarly, a deletion indicates a region of the chromosome is missing, which often
involves the loss of multiple genes.
 In some cases a portion of a chromosome will break and reverse its order within the same chromosome,
known as an inversion.
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 Other times, a portion of one chromosome will break and attach to another nonhomologous chromosome,
which is known as a translocation.
 Errors in cell division that occur after fertilization has taken place result in an individual with two or more
cell lines that contain different genetic information. This is known as mosaicism.
Genetic HL:
A. Non-Syndromic HL:
B. Syndromic HL:
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Non-Syndromic HL
- Non-syndromic hearing impairment accounts for 70% of hereditary hearing loss.
- In most cases, the inheritance pattern is recessive (75% to 80% of cases), and consequently, the
parents of affected children generally do not exhibit the phenotype.
- Congenital nonsyndromic hearing loss is inherited in an autosomal-dominant (~20%), X-linked (2% to
5%), or mitochondrial (~1%) mode.
- Nomenclature is based on the prefix “DFN” to designate nonsyndromic DeaFNess.
- DFN followed by an A implies dominant inheritance, whereas B implies recessive inheritance and X
implies X-linked inheritance. The integer suffix denotes the order of gene locus discovery. DFNA1 and
DFNB1 were the first autosomal-dominant and recessive nonsyndromic deafness gene loci to be
identified.
1. Autosomal Dominant Non-Syndromic HL:
 inherited as a dominant (DFNA) trait and mapping to one of the 22 autosomal chromosomes
 is genetically heterogeneous with at least 64 loci and more than 25 known genes
 Characteristics:
- sensory/neural HL, with the exception of DFNA23 cause a conductive hearing loss.
- The severity of hearing loss is variable, ranging from mild to profound,
- in general, it is less severe than that of autosomal recessive nonsyndromic hearing loss.
- Configuration:
o most commonly high frequency HL (e.g. DFNA2)
o may occur in low frequencies (e.g., DFNA1 and DFNA6/14/23) or
o mid frequencies with a “cookie-bite” configuration (e.g., DFNA10).
- Onset of the hearing loss:
o is typically postlingual and progressive, beginning in the first or second decade of life;
o however, there are several loci associated with congenital or prelingual onset, stable, or slowly
progressive hearing loss (e.g., DFNA6/14/38).
o A number of loci are associated with progressive hearing loss that begins during the third decade
of life or later (e.g., DFNA9).
o Fluctuating hearing loss has been observed with four loci (e.g., DFNA9).
o SSNHL that respond to treatment with steroids  DFNA16
- Vestibular manifestations, ranging from subjective reports to positive findings on tests of vestibular
function, have been reported for more than 10 autosomal dominant nonsyndromic loci, although this area
of the phenotype in most cases has not been thoroughly explored.
- Due to delayed onset, it is difficult to differentiate a late onset autosomal dominant nonsyndromic hearing
loss from one caused by environmental factors and aging (e.g., DFNA2B).
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a. DFNA2 (Genes: KCNQ4 AND GJB3; Cytogenic locus: Iq34): “High frequency HL”
- There are two genes, KCNQ4 and GJB3, at the DFNA2 locus, which are labeled as DFNA2A and DFNA2B,
respectively.
- Both encode proteins that form channels important for fluid homeostasis.
- Mutations in KCNQ4 are one of the more common causes of autosomal dominant nonsyndromic hearing
loss.
- DFNA2A:
o Hearing loss is progressive
o Post lingual onset
o In the high frequencies during the first or second decade of life, which may progress to the mid and low
frequencies with a sloping configuration.
o Word recognition ability is typically proportionate to the degree of hearing loss.
o Tinnitus.
o Vestibular function is generally normal, vestibular hyperactivity on rotary chair may be reported.
- DFNA2B:
o Later onset HL,
o around the fourth or fifth decade of life,
o Progressive, sloping high-frequency sensory/neural hearing loss.
b. DFNA 6/14/38 (Gene: WFS1; Cytogenic locus 4p16.1):

- DFNA6, DFNA14, and DFNA38 are considered mutations in the same gene, WFS1.
- This gene encodes the protein wolframin, which is expressed in many cells in the body including hair cells
and other inner ear structures  have a role in ion homeostasis within the cochlea.
- Characteristics:
o a low-frequency configuration that progresses slowly. and initially involves 250 and 500 Hz before
10 years of age  gradually progresses to include 1,000 to 2,000 Hz in a low-to-high–frequency
progression with puretone thresholds, on average, exceeding 50 dB HL by age 50 years.
o Preserved word recognition ability and absent distortion product OAEs (DPOAEs)
o Age of onset is in the first and second decades of life.
o Symmetrical HL
o Non-bothersome tinnitus
o Vestibular hyperactivity are reported
- Homozygous mutations in WFS1 can result in “Wolfram syndrome”, an autosomal recessive disease with
clinical manifestations including diabetes insipidus, diabetes mellitus, optic atrophy, hearing loss, and
neurologic symptoms.
- Over half of those with Wolfram syndrome experience:
o Sensory/neural hearing loss that is typically greater in the high frequencies but with a wide range
of severity and configurations.
o Onset of hearing loss is postlingual and in the first decade of life, but cases of congenital and
prelingual hearing loss have been reported.
o Vestibular dysfunction in Wolfram syndrome is possible, but not common.
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c. DFNA8/DFNA12 (DFNA8/12) α-Tectorin Gene :
- Mutations in the α-tectorin gene on chromosome 11q have been found in families with both
autosomal dominant (at the DFNA8 and DFNA12 loci) and autosomal recessive (at the DFNB21
locus) prelingual hearing loss.
- It encodes cochlea-specific protein that interacts with β- tectorin.
- The two proteins constitute approximately 50 % of the total protein content of the tectorial
membrane of the organ of Corti.
- α-tectorin is expressed only in the tectorial membrane of the cochlea and the sensory epithelium
of the vestibule.
- Tectorin mutations probably inhibit the function of the tectorial membrane as a resonator.
d. DFNA9 (GENE: COCH; Cytogenic locus: 14q12)

- COCH, encodes the protein cochlin. COCH is expressed in the cochlea and the vestibular labyrinth
- Contribute to structural integrity of the cochlea and susceptibility to inner ear infection
- Affected individuals have the unique temporal bone histopathological finding of mucopolysaccharide
depositions, which make the dendritec fibers smoother.
- Characteristics:
o auditory and vestibular dysfunction
o Age of hearing loss onset ranges from the second or third decade for some, to as late as the fifth decade
for others, depending on the specific mutation.
o hearing impairment begins as a moderate-to-severe high-frequency (3,000 Hz and above) hearing loss
with progression to a severe-to-profound degree across the entire test frequency range
o Word recognition may be disproportionately reduced relative to puretone thresholds.
o Vestibular symptoms  imbalance, especially in the dark, and episodic vertiginous attacks ranging from
paroxysmal to several hours in duration without aural fullness. Results of velocity step testing indicate
that vestibular dysfunction starts at a younger age and progresses more rapidly than hearing loss; in
some cases vestibular areflexia (absence of vestibular function) may be an early finding. Endolymphatic
hydrops has been observed on histopathology.
o DFNA9-associated auditory dysfunction have been diagnosed with atypical Meniere disease, one with
autoimmune inner ear disease, and another with superior semicircular canal dehiscence.
e. DFNA10 (GENE: EYA4; Cytogenic locus: 6q23)

- EYA4 is a transcription regulator expressed in the embryonic cochlea that may be involved in inner ear
development; its continued role in the cochlea later in life is unknown.
- Characteristics:
o Postlingual sensory/neural hearing loss
o starts during the second to fourth decade of life,
o with an initial cookie-bite configuration or with involvement of the middle and high frequencies. There
is progression to moderate-to severe levels across the entire frequency range.
o Word recognition scores and acoustic reflex thresholds are typically commensurate with the degree of
puretone hearing loss.
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o Vestibular symptoms: unilateral vestibular hyporeactivity was documented in three of these cases on
caloric testing, and benign positional vertigo was observed for one case with a positive Dix Hallpike test.
2. Autosomal-Recessive Non-syndromic HL:
- Autosomal recessive nonsyndromic hearing loss (DFNB) is associated with at least 100 known loci and
over 40 known genes.
- The autosomal recessive nonsyndromic hearing losses is:
o Congenital or prelingual, often detected by newborn hearing screenings.
o Severe to profound, stable, and sensory/neural.
o However, several loci are associated with a delayed onset,
o Although the puretone configuration typically involves all frequencies, a sloping, progressive high-
frequency configuration has been reported as well (e.g., DFNB8/10).
o Vestibular dysfunction has been reported for approximately 10 loci (e.g., DFNB8/10) and auditory
neuropathy has been observed for 2 loci (DFNB9 and DFNB14).
o Some autosomal recessive hearing loss loci are also associated with autosomal dominant hearing
loss (e.g., DFNB1 and DFNA6), and some are associated with syndromic forms of hearing loss (e.g.,
DFNB12 and Usher syndrome type 1).
a) DFNB1 A (Gene: GJB2, Cytogenic locus: 13q11-12):

- The first locus described for non-syndromic hearing loss, DFNB1, contains the gene GJB2, which encodes
gap junction beta-2 (also referred to as connexin 26 or CX26), a member of the connexin family of proteins.
- Locus 13q11-12 contains 2 genes: GJB2 encodes connexin 26 & GJB 6 encodes connexin 30.
GJB 2 “Cx 26”:

- A small gene situated on chromosome 13q11;
- it has a length of about 5.5 kilo bases.
- There are two exons  that are transcribed into mRNA  code for amino acids  translated into a
protein with 226 amino acids.
- This protein belongs to the connexin family  Connexins are membrane proteins with four
transmembrane domains.
- Six chains of these proteins form a complex (a hexamer), called connexon  two hexamers in the
membranes of adjacent cells form a cell-to-cell channel, a so called 'gap junction', which allows the
transport of small molecules and ions between cells  hence the communication between adjacent cells
and are involved in a large number of cellular functions including cell growth, differentiation, reaction to
signals, synchronization of activity in excitable tissues, and homeostasis.
- Function:
o Cx 26 protein is essential for maintaining the high potassium concentration in the endolymph of the
inner ear.
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o Cx26 protein is present in gap junctions connecting all cell types in the cochlea, including the spiral
limbus, the supporting cells, the spiral ligament and the basal and intermediate cells of the stria
vascularis.
 Thus, Cx26 is involved in K+ recycling in the cochlea.
o In the vestibular sensory organs: Cx26 expression is in both sensory and non sensory epithelia
- The 35delG mutation accounts for approximately 70 % of GJB2 mutant alleles, with a carrier frequency of
2.3 % to 4%.
- The three other mutations are, 167delT, 235delC or R143W.
- Deletion of a T at 167 of the GJB2 coding sequence was also found in one allele from a chromosome 13-
linked non syndromic autosomal recessive deafness patient. This mutation (designated 167delT) leads to
generation of an out of frame downstream stop codon at amino acid position 81 of the connexin26 gene.
- Mutations in GJB2
o disrupt this recycling process
o prevent normal mechanosensory transduction.
This role is consistent with the expression of GJB2 in the stria vascularis, nonsensory epithelial cells,
spiral ligament, and spiral limbus of the inner ear.
- Characteristics:
o Loss is symmetric between ears and
o does not progress over the long term.
o Temporal bone anomalies are not part of the DFNB1 phenotype, which obviates the need for routine
temporal bone imaging.
- Genetic testing is available to diagnose GJB2-related deafness  facilitates genetic counseling and
prediction of the chance of recurrence. It also provides prognostic information, because several studies
have shown that cochlear implant recipients with GJB2-related deafness do very well.
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GJB 6 “Cx 30”:
- GJB2 and GJB6 are only 35kb apart on chromosome 13. GJB6 is very similar to GJB2, but not interrupted by
introns.
- A role for GJB6 was first suggested in 1999, when a dominant mutation (T5M) was described.
- Mutation in GJB6  causes non-syndromic SNHL when homozygous, or when present on the opposite
allele of a GJB2 mutation.
- Both genes are expressed in the cochlea where they can combine to form multi-unit hemi channels in the
cell membrane, and function as an integral component of the potassium regulation in the inner ear.
- Connexin 30 (Cx30) required mainly for the survival of saccular hair cells. In contrast, it is not required to
maintain the survival of vestibular hair cells in the utricle and ampulla.
- Differences in fluid exchanges between the saccule and the other compartments of the vestibular end
organs may be a factor contributing to heightened sensitivity of saccular hair cell loss. Saccular hair cell
death started with loss of hair bundles and was followed by disappearance of hair cell soma. This pattern of
degeneration is similar to the pattern of vestibular hair cell death after ototoxic insults. It is known that
Cx26 is required for survival of cochlear hair cells, although it is not clear whether the vestibular hair cells
degenerate in the absence of Cx26 protein or not, so both Cx26 and Cx30 are required for normal hearing.
- Prevalence: vary widely depending on ethnicity,
- GJB6 deletion may account roughly for about 10% of all DFNB1 alleles.
- Cx30 significantly contributes not only to the molecular basis of hearing loss, but also it is possible that the
GJB6 deletion modifies the phenotype in individuals who carry two recessive GJB2 mutations.
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b) DFNB 8/10 (Gene: TMPRSS3; Cytogenic Location: 21q22.3)
- TMPRSS3 codes for the protein transmembrane protease serine  contributes to normal development and
maintenance.
- DFNB8/10 characteristics:
o severe-to-profound hearing loss. (precipitously sloping high-frequency)
o DFNB8 hearing loss was postlingual with onset during childhood and
o DFNB10 hearing loss was prelingual.
o Progressive.
c) DFNB9 (Gene: OTOF, Cytogenic location: 2p23.3):
- The OTOF encodes for the protein otoferlin, play an important role in synaptic function.
- DFNB9 reported:
o prelingual,
o severe-to-profound sensory/neural hearing loss and absent ABRs in children in a Lebanese family
o Subsequently, mutations in OTOF were shown to be the major cause of nonsyndromic recessive
auditory neuropathy  puretone hearing loss ranged from mild to profound in degree with intact
OAEs and abnormal ABRs.
o Another non-syndromic recessive locus (DFNB59, PJVK, 2q31.2) is associated with auditory
neuropathy in some kindreds but not in others. The corresponding hearing loss can be prelingual,
stable, and severe to profound, or it can be progressive.
d) DFNB12 (Gene: CDH23; Cytogenic location: 10q22.1)

- The DFNB12 locus is associated with mutations in CDH23, which codes for an adhesion protein involved in
stereociliary bundle cohesion and tip-link formation.
- Missense mutations in CDH23 result in DFNB12-related hearing loss, and more severe nonsense mutations
result in Usher syndrome (type ID)
- Characteristics:
o Congenital or prelingual, but postlingual onset in the first decade has also been reported.
o HL progressive with the final severity ranging from moderate to profound.
o Vestibular function is normal
o Cdh23ahl, is also associated with heritable forms of presbycusis.
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3. X-Linked Non-syndromic Hearing Loss (DFNX):
- Five loci are assigned for X-linked hereditary hearing loss.

- There is no unifying pattern of presentation, with the exception that the auditory phenotype is
more severe in males than in females.
- The most common locus is DFNX2, which encodes POU3F4 (Xq21.1).
- Characteristics: In males:
o Hearing loss is congenital and mixed with a conductive component of 30 to 40 dB in the low
and mid frequencies and narrowing of the air–bone gap in the high frequencies.
o The acoustic reflex is frequently present in early stages of the hearing loss, despite air–
bone gaps.
o Over time, there is progression of the sensory component to severe or profound levels.
o Two anatomic features:
 dilation of the lateral aspect of the internal auditory canal and
 Enlargement of the vestibule, may contribute to the conductive aspect of the hearing loss.
 Attempted stapedectomy has resulted in perilymphatic gushers and subsequent
further loss of hearing and vestibular function.
 This makes it important to consider the possibility of DFNX2 in males with congenital
mixed hearing loss prior to stapedectomy.
o Female heterozygotes have a similar but milder audiologic phenotype.
4. Y-Linked Non-syndromic HL (DFNY):
- A single locus assigned for Y-linked hearing loss, DFNY1, is based on patrilineal inheritance
- Characteristics:
o bilateral, symmetrical SNHL
o from mild to severe HL
o Audiometric configurations include sloping, flat, and U-shaped.
o Age of onset is post-lingual and ranges from 5 to 27 years (≃11.5)
o ABR findings are consistent with a peripheral origin of the hearing loss,
o Caloric irrigations suggest normal vestibular function in at least a subset of affected individuals.
o High-resolution CT scans of the temporal bones  no apparent inner ear abnormalities.
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5. Deafness Modifier Genes (DFM):
- The DFNB26 locus was mapped to chromosome 4q31 in a large,
- Characteristics:
o prelingual,
o severe-to profound SNHL
o sensory/neural hearing loss and the other 47%
- This led to the discovery of the first deafness modifier locus, DFNM1, mapped to a region on chromosome
1q24  which suppressed the associated hearing loss.
6. Auditory neuropathy, Autosomal Dominant (AUNA):

- Currently, there is one known locus for autosomal dominant auditory neuropathy, AUNA1, that maps to
chromosome 13q21–q24; the causative gene is DIAPH3.
- Characteristics:
o Age of onset: 7 to 45 years.
o Hearing loss was symmetrical, worse in the high frequencies, and typically progressed to a profound
degree over a 10- to 20-year period.
o Absent or grossly abnormal ABRs in the presence of intact DPOAEs, typical of auditory neuropathy. As
the puretone hearing loss progressed, there was a loss of DPOAEs, indicating a partial sensory site of
lesion, and a loss of the ABR, if it was present to begin with.
7. Non-Syndromic Mitochondrial HL (MTRNR1):

- Non-syndromic sensory/neural hearing loss caused by mutations in mitochondrial genes shows a pattern
of matrilineal inheritance.
- The most common non-syndromic HL results from A1555G mutation in the ribosomal RNA (MTRNR1).
- This mutation cause:
o Non-syndromic,
o congenital,
o severe-to-profound SNHL
o hearing loss occurs only after aminoglycoside exposure
8. Otosclerosis (OTSC)
- Otosclerosis is a common cause of progressive hearing loss
- With a prevalence of 0.2% to 1%.
- C/P: mixed hearing loss with air–bone gaps that narrow in the mid frequencies, normal tympanograms, and
absent acoustic reflexes.
- Age of clinical onset ranges from the second to the sixth decade of life.
- Currently eight loci for clinical otosclerosis (OTSC) have been identified.
- Each of the known OTSC loci segregates as an autosomal dominant trait.
- Because of the variable penetrance and large range in the age of clinical onset, it is likely that there are
modifier genes or environmental factors that impact the expression of hearing loss.
21
‫‪22‬‬
SYNDROMIC HEARING LOSS
- Syndromic hearing loss is categorized by its association with other affected systems of the body
including the external ear, integumentary system (skin, hair, nails), eye, nervous system, skeletal
system, renal system, and other abnormalities.
- Here, we present several syndromes  examples of Mendelian inheritance are provided, as well
mitochondrial inheritance and chromosomal abnormality.
Autosomal-Dominant Syndromic HL
A. Branchio-Oto-Renal Syndrome, BOR,(Branchio-oto syndrome) or (Melnick-Fraser
syndrome):
- one of the more common syndromic conditions associated with hearing loss
- Inheritance pattern: autosomal dominant transmission pattern.
- Prevalence: in 1:40,000 live births
- mutation in EYA1 (8q13.3), but may result from mutations in SIX1 (14q23.1) and SIX5 (19q13.32)
as well  these genes play important roles in embryologic development and regulate the activity
of other genes.
- Named for the triad of:
a) Branchial arch remnants:
 Disrupted development of 2nd branchial arch, which contributes to the formation of
tissues in the front and sides of the neck leads to branchial cleft cysts and fistulas
associated with BOR
b) Renal dysfunction: include abnormalities of both structure and function and, in severe
cases, end-stage renal disease may develop, requiring dialysis or kidney transplant. A
variation of BOR without renal dysfunction has also been described, known as branchio-
otic syndrome, and can be observed in the same family as someone with BOR
c) Ear and hearing abnormalities:

 Ear-related anomalies: preauricular pits, pinna deformities (e.g., cupped auricle), and
stenosis of the external auditory canal. A less frequent (<20%) manifestation is
preauricular tags.
23
 Structural anomalies of the outer ear, middle and inner ear anatomy may be
compromised (e.g., ossicular fixation, cochlear hypoplasia).
 Hearing loss:
- Occur in more than 70% - 93% of affected individuals.
- Range from mild to profound
- May be conductive, sensory/neural, or, most often, mixed. HL
- Onset: from birth to young adulthood
- may be stable or progressive
 Vestibular involvement has neither been confirmed nor ruled out as an associated
phenotype.
d) Lacrimal duct anomalies may be seen: aplasia or stenosis
- Signs and symptoms may differ significantly within the same individual between the right and left
sides across affected systems.
- Management:
 A comprehensive audiologic & otological evaluation in all patients suspected of BOR is
necessary
 Renal assessment: U/S, RFT.
 Genetic study
 Re/habilitation strategies will vary depending on the type and degree of hearing loss, but
some form of amplification and educational accommodation(s) is necessary for many
children with BOR.
Differential diagnosis:
 Branchio-oculo-facial syndrome is a rare disorder inherited through an autosomal dominant trait. Major symptoms
may include abnormal sinuses, growth retardation, premature aging and an unusual facial appearance. Other features
of this disorder may be: low birth weight; premature aging and graying of the hair; a highly arched palate;
abnormalities of the teeth; and/or cysts under the skin of the scalp.
 Goldenhar syndrome is a rare congenital disorder that may involve the cheekbones, jaw, mouth, ears, eyes, and
bones of the spinal column. Often, one side of the body is affected more than the other.
 Treacher-Collins syndrome is a rare disorder characterized by distinctive abnormalities of the head and facial area
due to underdevelopment of certain portions of the skull.
 Towns-Brocks syndrome is a rare genetic disorder the characteristics of which may include hearing loss or deafness
and the absence of an anal opening, in association with hand, foot, or ear abnormalities.
24
‫‪25‬‬
B. Neurofibromatosis Type 2
- Disease of connective tissue
- Characterized by the development of bilateral vestibular schwannomas and other intracranial and
spinal tumors that include:
o schwannomas,
o meningiomas,
o gliomas,
o ependymomas.
- In addition, patients may have posterior subcapsular lenticular opacities.
- The causative gene is a 17-exon gene that codes for a 595–amino acid protein named merlin on
chromosome 22q12.2 Merlin is a tumor suppressor that regulates the actin cytoskeleton. There
are numerous other genes that become deregulated during tumorigenesis.
- Incidence: 1 per 40,000 to 90,000 population
- Diagnostic criteria include
1) bilateral vestibular schwannomas that usually develop by the second decade of life,
2) family history of NF2 in a first-degree relative, plus one of the following: unilateral vestibular
schwannomas before age 30 or any two of meningioma, glioma, schwannoma, or juvenile
posterior subcapsular lenticular opacities/juvenile cortical cataract (loss of transparency of
the lenses of the eyes).
- C/P: Depending on the exact location and size of the schwannomas,
 HL is usually high frequency and SNHL, gradually progressive
 vertigo,
 tinnitus
 facial nerve paralysis
 headache
 eye issues including: Juvenile Cataracts, Double Vision, Light sensitivity, Poor-Vision,
Temporary or Permanent Blindness
 family history
 physical examination,
 Imaging studies (MRI with gadolinium).
- Treatment:
 surgery,
 Gamma Knife is considered in selected cases.
 Auditory brainstem implants although their use is limited if the patient has a history of
Gamma Knife treatment.
- It is a second, distinct form of NF known as neurofibromatosis type I (NF1). More common than
NF2.
26
- NF1:
 is primarily characterized by the development of multiple noncancerous (benign) tumors of
nerves and skin (neurofibromas).
 C/P:
o Skin:
- Cafe-au-lait spots Brown spots on the skin that are light brown in color, flat, and
approximately fifteen millimeters in adults and five millimeters in size in patients under
puberty age.
- more than six there is a strong possibility of NF1.
- present at birth or show up during the first year of life. After they appear, they stabilize.
- not serious but may be a cosmetic concern.
- Freckling in your groin or armpit area that appears by the age four or five.
o Eye:
- Lisch nodules on iris of the eye  not cause vision problems.
- Optic glioma which is a tumor on your optic nerve
o Bone deformities such as bow leg or a curved spine called scoliosis. Large Head size &
below average in height
o Learning disabilities such as thinking skills that are impaired
 Hearing loss
 In contrast, in individuals with NF2, benign fibrous tumors of the skin (cutaneous
neurofibromas) and areas of abnormal pigmentation are considered relatively rare.
 As with NF2, NF1 may be inherited as an autosomal dominant trait or appear to occur
randomly due to new (sporadic) genetic changes.
27
C. Stickler syndrome:
- Inheritance pattern: autosomal dominant connective tissue disorder that affects the eye, ear,
development of facial structures, and musculoskeletal system.
- Incidence: in 1:7,500 to 9,000 births and is a clinically and genetically heterogeneous condition.
- Gene:
o Mutations in one of five causative collagen genes have been identified to date. A mutation in
COL2A1 is found in 80% to 90% of cases & COL11A1 mutations occur in 10% to 20% 
contribute to the normal production of different types of collagen throughout the body
o Found in the inner ear.
- C/P:
o Craniofacial & bone findings:
- Flattened facial profile, which is more pronounced during
childhood, because of midface hypoplasia involving the maxilla
and nasal bridge.
- Under developed jaw and cleft palate. .
- Early onset osteoarthritis, hypermobile joints, and short
stature.
o Ocular anomalies:
- early-onset progressive myopia,
- retinal abnormalities,
- Cataract, and risk for retinal detachment.
o Hearing loss:
- When the causative mutation is COL2A1  HL mild, confined to
the higher frequencies, and progression of SNHL appears to be no
greater than that associated with typical age-related decline.
- Mutations in COL11A2 and COL11A1 are associated with a more
severe degree of hearing loss, affecting a broader frequency range,
and the loss may be progressive.
- Conductive HL with chronic/recurrent otitis media occurs
frequently.
- Hypermobile middle ear systems, which may be related to sequela
of chronic/recurrent otitis media or because of reduced amounts
of type II collagen in the tympanic membrane.
- Vestibular dysfunction has not been reported.
- Management:
o Serial audiologic monitoring with fitting of amplification for
functionally significant hearing loss, as necessary.
o Educational accommodations for these children, who are at risk for
cosensory loss of vision and hearing, should be emphasized.
28
D. Treacher Collins syndrome
- Inheritance pattern: autosomal dominant disorder  underdeveloped bony structures and
tissues of the face and surrounding areas.
- Incidence: in approximately 1:50,000 live births
- Mutant gene:
o a single mutation in TCOF1 (5q32) encoding the protein treacle, which appears to be vital for
normal embryologic development of the face.
o Causative mutations in POLR1 C (6q21.1) and POLR1D (13q12.2) have also been identified.
- C/P:
 Craniofacial anomalies:
- midface hypoplasia because of
underdeveloped zygomatic bones,
- a small chin and jaw (micrognathia),
- with or without cleft lip
- Dental anomalies such as tooth agenesis,
uneven placement of teeth and defects of
the tooth enamel.
- On rare occasions, malocclusion may form
which may pose difficulties in closing one’s
mouth or in feeding oneself.
- This can also result in speech problems as
well as difficulties in communication
- constricted or restrictive airway passage, which may result in breathing difficulties and even
death
- The skull may have an irregular or abnormal shape, including narrowing of the bitemporal
region
- Eyes: down-slanting eyes, coloboma of the lower eyelid.
 Ear:
- External ear: microtia or severe malformation of the pinnae and atresia of the external
auditory canal.
- Middle ear cavity and ossicular structures may be underdeveloped or missing, and cleft
palate
- Inner ear anatomy is typically unaffected.
 Bilateral congenital conductive hearing loss. It is usually
 severe in degree
 Sensory/neural hearing loss is not often reported, but because of the severity and
complexity of the external and middle ear anomalies
29
- Management:
o combination of surgeries that are medically necessary (e.g., cleft palate repair) and cosmetic
(e.g., construction of an artificial pinna, known as an aural episthesis).
o Surgical reconstruction cannot be carried out safely during the first few years of life and
outcomes rarely restore hearing to within normal limits.
o Amplification. Traditional hearing aids may not be appropriate, depending on the degree to
which the ear anatomy is compromised. Bone conduction hearing aids, either removable or
implantable, are essential for many of these children to develop normal speech and language
o There are no cognitive delays associated with Treacher Collins syndrome.
30
E. Waardenburg syndrome:
- Incidence:
o 1:40,000 to 100,000
o account for 2-5 % of congenital hereditary hearing loss
- C/P:
o Pigmentary anomalies in the skin, hair, and eyes
o primary features often include
 diminished coloration (pigmentation) of the hair, white lock of hair growing above the
forehead (white forelock),
 premature graying or whitening of the hair
 Iris: differences in the coloration of the two irides or in different regions of the same iris
(heterochromia irides);
 Patchy abnormally light (depigmented) regions of skin (leukoderma).
 Presence of a cleft lip (happens rarely), Constipation, Abdominal pain or swelling
o SNHL.
o There are four subtypes of Waardenburg syndrome, distinguished by their clinical presentation
and mode of inheritance (see table)
o There is marked inter- and intrafamilial variable expression:
 HL
 Cochlear dysfunction: normal to profound in degree
 Usually stable, but may be progressive,
 Can be unilateral or bilateral.
 more common in type II than type I, although it is possible some individuals with type II and
less severe phenotypes may be diagnostically unrecognized because of the absence of
dystopia canthorum.
 Configuration can reveal a greater loss in the low frequencies, or an inverted U, with sparing
of mid-frequency hearing.
 Dysplasia of SCC and saccular degeneration  patients may present with vestibular
complaints and dysfunction with or without accompanying hearing loss.
 pigmentary anomalies:
 partial or complete iris heterochromia (differently colored areas of the same eye, or each eye
being a different color)
 or strikingly blue irises.
 Distinctive patterns in hair color, congenital or premature white forelock, are common.
 Facial features
 a wide, high nasal root, broad confluent eyebrow, and a square jaw.
- Management: Depending on the severity of the auditory phenotype, patients with Waardenburg
syndrome may benefit from hearing aids or cochlear implantation.
31
Type Type Type Type
I III II IV
Types
Klein–Waardenburg Waardenburg–
syndrome Shah syndrome
Autosomal dominant
Inheritance pattern Autosomal recessive
MITF, 3p14.1-p12.3) and genes involved with
the development of melanocytes (e.g., SOX10,
22q13)  Melanocytes produce melanin that
helps promote:
Mutant Gene PAX3 (2q35)
 Skin and eye color,
 Normal development and function of inner
ear  in the stria vascularis and vestibular
dark cells.
commonest Less Commonest Less
Dystopia Canthorum
( lateral displacement
of the inner canthus of +ve +ve -ve -ve
the eyes gives
appearance of a wide
nasal bridge)
+ve
hypoplasia of limb
Upper Limb
-ve muscles; -ve -ve
abnormalities
contracture
of elbows or fingers
Hirschsprung disease:
Intestinal Absence of groups of

-ve -ve -ve specialized nerve cell bodies
disorder
within a region of the smooth
(involuntary) muscle wall of
the large intestine.
32
F. Osteogenesis Imperfecta:
- Incidence: 6 to 7 per 100,000 people
- Inheritance pattern: autosomal dominant pattern but Less commonly, osteogenesis imperfecta has
an autosomal recessive pattern of inheritance.
- Mutant Gene: COL1A, COL1A2, CRTAP, and P3H1
- These genes provide instructions for making proteins that are used to assemble type I collagen.
This type of collagen is the most abundant protein in bone, skin, and other connective tissues that
provide structure and strength to the body. Mutations  causes bones to be brittle and to fracture
easily.
- Osteogenesis imperfecta (OI) is a group of genetic disorders that mainly affect the bones.
- The term "osteogenesis imperfecta" means imperfect bone formation.
- C/P:
o People with this condition have bones that break easily, often from mild trauma or with no
apparent cause. Multiple fractures are common, and in severe cases, can occur even before
birth. Milder cases may involve only a few fractures over a person's lifetime.
o There are at least eight recognized forms of osteogenesis imperfecta, designated type I through
type VIII. The types can be distinguished by their signs and symptoms, although their
characteristic features overlap. Type I is the mildest form of osteogenesis imperfecta and type
II is the most severe; other types of this condition have signs and symptoms that fall
somewhere between these two extremes.
o Type I, characterized by bone fractures during childhood and adolescence that often result
from minor trauma. Fractures occur less frequently in adulthood. People with mild forms of
the condition typically have a blue or grey tint to the part of the eye that is usually white (the
sclera), and may develop hearing loss in adulthood. Affected individuals are usually of normal
or near normal height.
o Other types of osteogenesis imperfecta are more severe, causing frequent bone fractures that
may begin before birth and result from little or no trauma. Additional features of these
conditions can include blue sclerae, short stature, hearing loss, respiratory problems, and a
disorder of tooth development called dentinogenesis imperfecta. The most severe forms of
osteogenesis imperfecta, particularly type II, can include an abnormally small, fragile rib cage
and underdeveloped lungs. Infants with these abnormalities have life-threatening problems
with breathing and often die shortly after birth.
o So, The classic symptoms include: Blue tint to the whites of their eyes (blue sclera), Multiple
bone fractures, Early hearing loss (deafness)
o Because type I collagen is also found in ligaments, persons with OI often have loose joints
(hypermobility) and flat feet. Some types of OI also lead to the development of poor teeth.
33
o Symptoms of more severe forms of OI may include: Bowed legs and arms, Kyphosis, Scoliosis
(S-curve spine)
 HL: may be CHL (ossicular chain anomalies), SNHL or mixed

 Vestibular symptoms: rare (20% of cases)
 Skull involvement “Soldier’s Helmet” appearance.
34
AUTOSOMAL-RECESSIVE SYNDROMIC HEARING IMPAIRMENT
A. Pendred Syndrome (DFNB4):

- Incidence: one of the more common syndromic forms of HL, accounting between 5 -10% of all early-
onset hereditary hearing loss. Or may be non-syndromic presented only by isolated EVA.
- Inheritance pattern:
o Autosomal recessive disorder from biallelic mutations in SLC26A4 (7q31). SLC26A4 codes for
protein pendrin, which transports ions across cell membranes in the inner ear,
thyroid, and kidneys, as well as other organs in the body.
Pendrin is present in endolymphatic duct, sac non-sensory parts of utricle,
saccule & cochlea  involved in regulation and resorption of the endolymph 
inner-ear fluid homeostasis.
o An autosomal recessive locus for non-syndromic deafness designated DFNB4
also maps to 7q31, the same region as SLC26A4 gene.
o Mutations of the SLC26A4 gene are causative for both Pendred syndrome and
DFNB4.
- C/P:
o Goiter:
- Of a later onset in childhood or early adulthood
- goiter is incompletely penetrant and, thus, not a good diagnostic requirement.
- usually euthyroid, can be hypothyroid defective organic binding of iodine
- positive potassium perchlorate discharge test
35
o Commonest finding  enlargement of the vestibular aqueduct (EVA),
o Additional structural anomalies of the bony labyrinth can also occur (e.g., incomplete partition
of the cochlea, also known as a “Mondini” cochlea)
o Hearing Loss:
- can develop during the prelingual and perilingual periods.
- It is typically bilateral but may not be symmetrical
- associated with fluctuating or progressive changes in hearing, or both.
- When hearing loss occurs, progression may be stepwise
- head trauma is often reported as a precipitating event. avoid contact sports or barotrauma
(e.g., scuba diving)
- The configuration of the hearing loss is gradually sloping or flat, but it may also present
initially as a high-frequency loss or with sparing of the mid-frequency test region (inverted
U).
- hearing loss may be SNHL; however, CHL or MHL may be observed, because EVA is  a third
mobile window in the labyrinth, air–bone gaps in the presence of normal tympanometry are
often observed. In such cases, placement of pressure-equalization tubes is not beneficial.
o Vestibular dysfunction of varying severity is reported in Pendred syndrome.
o In kidney: SLC24A4 it is involved in bicarbonate secretion. SLC26A4 is acting as a Cl‾ / HCOз‾
exchanger.
- Diagnosis of Pendred syndrome:
o asymmetries in hearing and even unilateral presentations, milder degrees of loss, air–bone gaps
with normal tympanometry, and the risk for sudden or stepwise progressive changes in hearing,
all of which can impact intervention and re/habilitation strategies.
o Some children with Pendred syndrome will pass newborn hearing screenings, and most will be
good candidates for hearing aids or cochlear implantation.
Role of SLC26A4 in EVA:

- The pH of the endolymph varies greatly between different regions in the inner ear.
- In the cochlea and utricle, the endolymphatic pH is slightly alkaline (pH7.5).
- In the endolymphatic sac, on the other hand, the pH is more acidic (pH 6.6 - 7.1).
- These differences underscores that fluid homeostasis in different compartments of the inner ear is
controlled by local ion transport in adjacent epithelia rather than via a fluid flow between different
compartments of the inner ear.
- The homeostasis of endolymphatic pH depends on the secretion of H+ and HCOз‾. Epithelial cells that
express H+-ATPase in their apical membrane include interdental cells of the spiral limbus and strial
marginal cells as well as endolymphatic duct and sac epithelial cells.
- Furthermore, epithelial cells that express in their apical membrane the HCOЗ‾-permeable anion
exchanger SLC26A4 (pendrin) include spiral prominence and outer sulcus epithelial cells and spindle
36
cells of the stria vascularis as well as endolymphatic duct and sac epithelial cells. The main buffers, at
least in the cochlear endolymph, appear to be CO2 and HCOз‾.
- Glycosaminglycans, which are found in high concentrations in the endolymph of the endolymphatic
sac, may contribute to pH buffering.
- Proteins, however, that contribute to the buffering capacity of blood plasma appear to play a lesser
role in the buffering of the cochlear endolymph due to their low concentration. Marginal cells of the
stria vascularis are a significant local source of CO2 due to their high metabolic rate.
- Carbonic anhydrases in the stria vascularis, spiral ligament, and spiral limbus capture metabolically
derived CO2 and convert it to HCO3‾. HCO3‾ generated within the fibrocyte gap junction network may
be secreted into the endolymph via the HCO3‾ permeable anion exchanger pendrin (SLC26A4).
- Consistent with HCO3‾ secretion into the endolymph is the observation that mice lacking pendrin have
an acidic endolymphatic pH. Furthermore, increased metabolic rates during acoustic stimulation cause
an alkalization of the endolymph, which is consistent with an increased rate of HCO3‾ secretion.
- Endolymphatic pH homeostasis is necessary for hearing and the prevention of hearing loss, although
effects of pH may be indirect. For example, acidification of the endolymph inhibits Ca²+ reabsorption
via pH-sensitive TRPV5 and TRPV6 Ca²+ channels and elevates the endolymphatic Ca²+ concentration,
which impairs cochlear function.
- Furthermore, acidification enhances free radical stress and promotes hearing loss. Whether mutations
of the B1 subunit (ATP6V1B1) or A4 subunit (ATPV0A4) of H+-ATPase cause an alkalinization of
endolymph pH is currently unknown.
- Nevertheless, mutations of either subunit may cause, in humans, a progressive sensorineural hearing
loss in addition to renal tubular acidosis.
- EVA was documented in a patient with Waardenburg syndrome and in positive GJB2 mutation screen,
a homozygous 35delG mutation. This shows that existing mutations/disorders can coexist within the
same patient and cause confusion regarding the likely cause of a SNHL.
Mechanism of hearing loss in EVAS :

- Precipitating factors: minor head trauma, common cold, exercises such as weightlifting and diving,
and also long-term exposure to sunshine.
- SNHL theories:
1) Reflux of hyperosmotic endolymphatic sac contents infused through a wide patent
endolymphatic duct into cochlear duct under rapid changes of intracranial pressure, leading to
damage of the neuroepithelium at the basal end of the cochlear duct, producing high-frequency
SNHL.
2) The second speculation is that the membranous labyrinth ruptures causing the mixture of
endo-perilymph, most probably by a defect or tear in an area of congenital weakness in the
basilar membrane or Reissner's membrane which might result in hearing loss.
37
3) The third speculation is that rapid fluctuations of CSF pressure might create transient force
imbalances that damages the membranous labyrinth when the VA is enlarged and cochlear
aqueduct is normal as there is a dilated communication between the cerebrospinal fluid and the
vestibule that forms a fistula.
4) high incidence of round window abnormalities that may predispose the LVA patient to
perilymph fistulas, which could be the cause of sensorineural hearing loss as the perilymphatic
fistula is known to be relatively frequent in congenitally malformed ears
5) endolymphatic hydrops played a role in LVAS endolymphatic hydrops causes damage to the
apical region of the cochlea resulting in alow-frequency SNHL as opposed to a high-frequency
SNHL seen in LVAS
Management of EVA:
1) Conservative management and amplification:
- avoid precipitating factors: head trauma or barotraumas, common cold, exercises such as
weightlifting, diving and also long-term exposure to sunshine
- suitable hearing aids according to HL degree.
2) Surgical interventions:
- include the endolymphatic subarachnoid mastoid shunt and packing of the endolymphatic sac.
The endolymphatic subarachnoid mastoid shunt was strongly discouraged due to reported decline
in puretone average of 25 dB and 37% speech discrimination after shunt placement.
- There are two other surgical procedures attempting to stabilize hearing in patients with EVAS.
 Intraluminal occlusion of the endolymphatic sac.
 extraluminal extradural occlusion of the endolymphatic duct
- endolymphatic sac decompression, arachnoid bypass, or endolymphatic sac occlusion may worse
the hearing loss.
3) Corticosteroid therapy: sudden hearing deterioration in children with EVAS who underwent
corticosteroid therapy.
4) Hyperbaric oxygen (HBO) therapy: some cases with SNHL due to EVA showed improvement in
hearing threshold after HBO therapy.
5) Chemical labyrinthectomy: recommended in patients with incapacitating vertigo due to unilateral
vestibular aqueduct enlargement.
6) The cochlear implantation: recommendation criteria:
 if the hearing deteriorates to a BKB (the Bamford-2DKowal-2DBench Sentence Test) score of
< 40% despite the optimal hearing aids.
 If the periods of inadequate hearing begin to adversely affect school performance, or
 if there are more than 3 episodes of significantly decreased hearing within 1 year, the child
becomes a possible candidate.
38
‫‪39‬‬
B. Jervell and Lange-Nielsen syndrome
- Incidence: rare (1.6 – 6 : 1,000,000)
- Inheritance pattern: autosomal recessive disorder resulting from mutations in either the KCNE1
(21q22.12) or KCNQ1 (11p15.5) genes  regulate the formation and function of potassium
channels that control the flow of potassium ions across cell membranes, which is a critical
component to normal function in both the heart and inner ear
-
- C/P:
 congenital bilateral profound SNHL
 in ECG: a heart arrhythmia characterized by a long QT interval, which increases the risk
for fainting episodes and, in some cases, sudden death. This aspect of the phenotype is
treatable with medication, which underscores the importance of early diagnosis.
 HL:
- profound bilateral SNHL and are audiologic candidates for cochlear implantation.
- Because of the advent of newborn hearing screening, most children with JLNS will be
identified during the neonatal period, prior to recognition of cardiovascular symptoms.
- Cardiac work-up is recommended in any child with profound congenital
sensory/neural hearing loss, especially in cases of unconfirmed etiology, and prior to
surgical intervention.
- Vestibular phenotype is currently poorly described.
 Heterozygous carriers of mutations in either gene have normal hearing but may have the
long QT phenotype (called Romano–Ward syndrome).
- Management:
 Cochlear implantation is not contraindicated in these patients, necessarily, but special
precautions during surgery and activation may be necessary
 Cardiac signs by B-blockers.
40
C. Usher Syndrome:
- Synonyms : deafness-retinitis pigmentosa syndrome, Graefe-Usher syndrome, Hallgren syndrome
retinitis pigmentosa-deafness syndrome.
- Associated with both vision and hearing loss,
- incidence: 4 - 5:100,000 births
- Ethnic prevalence: higher among certain ethnic groups (e.g., Ashkenazi Jewish ancestry, Acadian
populations in Louisiana).
- Mutant Gene: 15 known loci, associated with autosomal recessive forms of non-syndromic hearing
loss and at least one mutant allele has a non-syndromic dominant transmission (DFNA11).
- Inheritance Pattern: autosomal recessive condition that is clinically and genetically heterogeneous.
- C/P: three distinct subtypes based on:
o A progressive loss of vision (retinitis pigmentosa (RP):
- initially as difficulty seeing in the dark,
- followed by a progressive degeneration in the peripheral field of vision
- and, in end-stage disease, a loss of visual acuity
o Varying degrees of vestibular dysfunction.
o HL,
Type I Type II Type III IV
90% of Usher patients 10 % of all cases <1%
MYO7A (11q13.5) and X-
Mutant Gene USH2A (1q41) CLRN1
CDH23 (10q22.1) linked
severe to profound mild to severe HL *normal hearing at birth.
hearing loss since since birth (sloping) *Hearing loss typically begins
birth mainly affects the postlingual, late in childhood or
(left corner ability to hear high- adolescence, becomes more
HL audiogram) frequency sounds severe over time.
(Atrophied organ of *in middle age  profound
Corti) hearing loss
Similar to type II
UNH Screen Fail Pass
Progressive vision Retinitis pigmentosa also
Progressive retinitis
loss begins in develops in late childhood or
Vision pigmentosa appears in
adolescence or adolescence.
childhood (age of 10)
adulthood.
Balance problems
Delayed sitting
independently and
walking, difficult in No vestibular Normal or may develop vestibular
Balance
riding a bicycle and abnormalities abnormalities
playing certain sports.
- Absent vestibular
response
HL Ttt CI HA HA
41
- Those mentioned genes are coding for proteins involved in:
 Normal hearing,  proteins are involved in the development and function of specialized cells
called hair cells, which help to transmit sound and signals from the inner ear to the brain.
 Balance, proteins in sensory hair cells.
 Vision  proteins contribute to the maintenance of light-sensing cells called rod photoreceptors
(which provide vision in low light) and cone photoreceptors (which provide color vision and
vision in bright light)
- Most of the gene mutations responsible for Usher syndrome lead to a loss of hair cells in the inner
ear and a gradual loss of rods and cones in the retina  cause the hearing loss, balance problems,
and vision loss that occur with Usher syndrome.
- Any child with congenital severe-to profound hearing loss for whom the etiology of their loss has not
been identified should be evaluated for possible Usher syndrome, especially if the child is a late
walker or has delays in motor milestones.
- Comprehensive vestibular assessments are warranted for any patient diagnosed with Usher
syndrome. Computerized dynamic platform posturography can serve as an especially useful tool, as
the complex interaction of somatosensory, visual, and vestibular systems in the maintenance of
balance is of concern in these patients for whom one or two of these systems are compromised.
Diagnosis of Usher syndrome

The major problems arise in hearing, vision and balancing. The diagnostic tests are related to these three
indications.
Eye related diagnostic tests are
1. A visual field test to examine the peripheral vision
2. An electroretinogram (ERG) to evaluate the electrical reaction of the light-sensitive cells of the
eyes
3. A retinal examination to examine the retina and other internal structures in the rare portion of the
eye
Ear related diagnostic tests are
1. A hearing (audiologic) assessment
2. An electronystagmogram (ENG) evaluation to assess the involuntary eye movements, which
indicates a balancing problem.
3. Early diagnosis can help to affected child for adapting the difficult circumstances arise due to
hearing and vision loss by providing special educational training programs.
42
‫‪43‬‬
D. Biotinidase Deficiency
- Body is unable to recycle the vitamin biotin
- Incidence: 1 in 60,000 newborns
- Mutant gene:
 BTD gene  forming enzyme called biotinidase.
 This enzyme recycles biotin, a B vitamin found in foods such as liver, egg yolks, and milk.
 Biotinidase removes biotin that is bound to proteins in food, leaving the vitamin in its free
(unbound) state.
 Free biotin is needed by enzymes called biotin-dependent carboxylases to break down fats,
proteins, and carbohydrates. Because several of these enzymes are impaired in biotinidase
deficiency, the condition is considered a form of multiple carboxylase deficiency.
 Profound biotinidase deficiency results when the activity of biotinidase is reduced to less than
10 percent of normal.
 Partial biotinidase deficiency occurs when biotinidase activity is reduced to between 10
percent and 30 percent of normal.
 Without enough of this enzyme, biotin cannot be recycled.
 The resulting shortage of free biotin impairs the activity of biotin-dependent carboxylases,
leading to a buildup of potentially toxic compounds in the body.
- If biotinidase deficiency is not recognized and corrected by daily addition of biotin to the diet,
affected individuals develop:
o neurologic features such as seizures, hypertonia,
o Breathing problems
o Hair loss
o developmental delay
o Balance problems: ataxia
o Visual problems: optic atrophy in severe cases.
o SNHL: In at least 75% of children who become symptomatic, SNHL develops and can be
profound and persistent even after treatment is initiated.
o Cutaneous features include a skin rash, alopecia, and conjunctivitis. .
o metabolic coma
o Child with episodic or progressive ataxia and progressive SNHL, with or without neurologic
or cutaneous symptoms  biotinidase deficiency should be considered
- Trearment:
o Biotin replacement  the neurologic and cutaneous manifestations resolve; however, the
hearing loss and optic atrophy are usually irreversible.
o If a child is brought to medical attention
44
E. Refsum Disease:
- Mutant Gene: Two genes, PHYH and PEX7
- Inheritance pattern: an autosomal recessive pattern.
- Although Refsum disease is extremely rare, it is important that it be considered in the evaluation
of a deaf person.
- Mutant Gene: PHYH gene and less commonly PEX7 gene.
- Phytanic acid  is obtained from the diet, particularly from beef and dairy products. It is normally
broken down through a process called alpha-oxidation  gene mutation causes defective phytanic
acid metabolism  its accumulation is toxic to cells.
- C/P:
 Post-lingual, severe, progressive SNHL
 retinitis pigmentosa,
 anosmia: loss of smell sensation.
 peripheral neuropathy,
 cerebellar ataxia, and
 Elevated protein levels in the cerebrospinal fluid without an increase in the number of cells.
- Diagnosis is established by determining the serum concentration of phytanic acid.
- Treatment: dietary modification and plasmapheresis
45
F. CHARGE Syndrome:
- a multisystem congenital disorder
- Incidence: in 1:8,500 to 10,000 births
- Inheritance pattern: an autosomal dominant fashion.
- Mutant Gene: Dominant mutations in CHD7 (8q12.2) result in CHARGE syndrome, but SEMA3E
(7q21.11) is also associated. The CDH7 gene is believed to play an important role in the
organization and packaging of DNA into chromosomes  Shortage of this protein is thought to
disrupt chromatin remodeling and the regulation of gene expression during embryonic
development likely cause the signs and symptoms of CHARGE syndrome.
- C/P: presence of major and minor diagnostic features:
 Coloboma,
 Heart defects,
 Atresia of choanae,
 Retarded growth and development with or without CNS involvement,
 Genital hypoplasia,
 Ear anomalies with or without hearing loss.
Major clinical features Minor diagnostic findings

- Underdeveloped genitals, small penis
- Coloboma, (micropenis) and undescended testes
- Atretic or stenotic choanae, (cryptorchidism)
- Cranial nerve involvement (I, VII, VIII, IX/X), - Developmental delay,
- Structural anomalies of the auditory system. - Cleft palate or lip,
- cranial nerve abnormalities - Tracheoesophageal fistulas,
- Growth deficiency,
- CVS structural abnormalities
46
- Many of these features present as life-threatening conditions during the neonatal period.
- Ear anomalies:
o pinnae deformity, in all cases which is often asymmetrical,
o with or without hearing loss.
o Auricles can be short and wide, possibly protruding, with triangular concha and a missing
helical fold that gives a “snipped off” appearance.
o Lobes may be absent or small.
o The external auditory canal is usually unaffected,
o middle ear ossicles may be malformed.
o Temporal bone abnormalities occur in most patients  a major diagnostic finding.
o Mondini dysplasia and underdeveloped or absent semicircular canals are common, and
vestibular areflexia has been reported
o At least 80% of individuals with CHARGE syndrome have hearing loss. Mixed hearing loss
is most common, and the sensory/neural component is believed to be congenital. The
conductive contribution is likely because of either malformation of the ossicles or high
rates of chronic/recurrent middle ear disease secondary to craniofacial anomalies, or
both.
o The hearing loss may range from mild to profound,  affect speech and language
development, and it may be progressive.
- Children with CHARGE syndrome can benefit from air- or bone-conducted hearing aids, assistive
listening devices, or cochlear implants, depending on the type and severity of the hearing loss and
their medical candidacy.
47
‫‪48‬‬
G. Turner syndrome (Ullrich Turner Syndrome):
- Monosomy 45, X, known as Turner syndrome, . Alternatively, mosaicism is common
(approximately one-third of cases),
- a chromosomal disorder resulting from the missing or structurally altered an X or Y chromosome.
- Incidence: (1:2,500 girl live births), more in miscarriages and stillbirths.
- Most cases of Turner syndrome are not inherited, occurs as a random event during the formation of
reproductive cells .
- C/P:
o short stature and
o premature ovarian failure leading to infertility.
o The majority of fetuses with Turner syndrome spontaneously abort in the first or second
trimester because of developmental abnormalities in the cardiovascular and lymphatic
systems.
o Fetuses that survive are phenotypically female and have:
- heart disease such as a narrowing of the large artery  coarctation of the aorta or
abnormalities of the valve
- lymphedema
- urinary system dysfunction,
- vision loss,
- autoimmune conditions,
- skeletal abnormalities,
- extra folds of skin on the neck (webbed neck), a low hair line at the back of the neck,
puffiness or swelling (lymphedema) of the hands and feet, skeletal abnormalities, or kidney
problems.
o Hearing loss:
- in approximately 50% of females with Turner syndrome,
- Pinna deformities such as low set, posteriorly rotated, cupped, and protruding ears and
narrow external auditory canals are common.
- characterized by transient, recurrent middle ear pathology
- Heightened monitoring for and aggressive treatment of otitis media is recommended, and
whether because of active otitis media or sequelae from recurrent disease, middle ear
dysfunction remains an issue for many women with Turner syndrome throughout their
lifetime.
- progressive SNHL in approximately one-third of those with Turner syndrome and can be
greater in degree in the mid frequencies, especially for those with complete monosomy 45,
X karyotypes
- Women with Turner syndrome are at risk for progressive changes in sensory hearing,
particularly in the high frequencies, at an accelerated rate beyond typical age-related
decline.
49
- frequency and severity of SNHL and auricular anomalies is greater in women with a larger
percentage of monosomy 45, X cells.
- Patients with deletions involving the short arm of the X chromosome have a greater degree
of conductive hearing loss than patients with deletions affecting only the long arm (45,
XdelXq).
- Many girls with Turner syndrome are not diagnosed until absence of menstruation in the
early teenage years.
- Diagnosis:
o Routine audiologic monitoring is warranted throughout the lifetime regardless of prior
documentation of normal hearing.
o Many can benefit from hearing aids.
o Genetic study:
50
‫‪51‬‬
X-LINKED SYNDROMES
A. Alport syndrome:
- Incidence: 1:50,000 live births
- Inheritance pattern: X-linked or autosomal recessive
- Mutant Gene:
o 85% of cases are inherited in an X-linked transmission pattern, because of mutations in
the COL4A5 gene (Xq22).
o The remaining cases  autosomal recessive inheritance pattern resulting from biallelic
mutations in either COL4A3 (2q36–q37) or COL4A4 (2q35–q37).
o All three of these genes contribute to the production of a protein known as type IV
collagen  a critical component in the network of proteins that make up basement
membrane structures, Type IV collagen appears to be especially critical for the basement
membrane structures that are found in the cochlea (the basilar membrane, parts of the
spiral ligament, and stria vascularis), as well as the kidney and eye.
- C/P:
o Progressive renal disease  by blood and high levels of protein in the urine (hematuria and
proteinuria, respectively), and progressive renal failure that can result in end-stage renal
disease.
o Ocular anomalies: include a bulging lens, typically in the anterior direction (anterior
lenticonus) that is so rarely observed outside of Alport syndrome, it is considered, practically,
a pathognomonic finding. Additional ocular manifestations, including cataract and retinal
flecks, can also occur.
o HL.
- Late onset,
- occurring in older children or adolescents, but congenital
hearing loss has also been reported.
- It is bilateral SNHL in origin and may be more severe in the
higher frequencies.
- hearing loss can vary in degree and may be progressive in
the first or second decade of onset.
- Management: usually benefit from hearing aids.
52
B. Mohr-Tranebjaerg Syndrome
- Mohr-Tranebjaerg syndrome was first described in a large Norwegian family
- The gene for this syndrome, TIMM8A, is involved in the translocation of proteins from the cytosol
across the inner mitochondrial membrane system and into the mitochondrial matrix
- C/P:
o Males with deafness-dystonia-optic neuronopathy (DDON) syndrome have:
 prelingual or postlingual SNHL in early childhood,
 slowly progressive dystonia or ataxia in the teens,
 slowly progressive decreased visual acuity from optic atrophy beginning approximately
age 20 years,
 dementia beginning at approximately age 40 years.
 Psychiatric symptoms such as personality change and paranoia may appear in childhood
and progress.
 The hearing impairment appears to be consistent in age of onset and progression,
whereas the neurologic, visual, and neuropsychiatric signs vary in degree of severity and
rate of progression.
 Females may have mild hearing impairment and focal dystonia.
 fractures,
 mental retardation—
53
MITOCHONDRIAL SYNDROMES
Mitochondrial encephalomyopathy with ragged red fibers (MERRF) (Myoclonic

Epilepy)
- results from mutations in mtDNA
- a rare condition,
- The majority of cases are associated with mutations in MT-TK, which encodes for the production of
transfer RNAs that help to build functional proteins, produce energy within cells, and process
oxygen.
- The most common mutation is A8334G.
- C/P:
o The initial presenting symptom is an involuntary twitching in a muscle or group of muscles,
called myoclonus.
o Epilepsy, ataxia, and muscle weakness follow and may include additional central nervous
system symptoms such as dysarthria, neuropathy, and dementia.
o The onset of symptoms may range from childhood to adulthood and, as such, young children
with MERRF almost always reach early developmental milestones.
o As the phenotype progresses, clumps of mutated mitochondria collect in muscle tissue
throughout the body, which can be stained and viewed through a microscope where they
appear as red, ragged fibers.
o Hearing loss associated with mitochondrial encephalopathy disorders may be:
- Cochlear or retrocochlear in origin, or both.
- Absent OAEs
- Additional retrocochlear findings (prolonged interpeak latencies) on ABR measures have
been reported in patients with MERRF.
- Differentiating MERRF from other progressive mitochondrial encephalopathy disorders
can be challenging, and MERRF should be considered as a possible etiology in any patient
with myoclonic epilepsy and SNHL.
Kearns Sayre Syndrome (KSS) Ophthalmoplegia Plus:

 Mitochondrial defect
 C/P: ophthalmoplegia, retinitis pigmentosa, complete heart block, HL, short stature
 Diagnosis: mitochondrial deletion detection by polymerase.
54
GENETIC EVALUATION AND DIAGNOSIS:
It is appropriate for any person with hearing loss of unknown etiology, regardless of their age, to
consider a genetic evaluation.
Benefits & Limitations of Genetic Testing:

- Aim:
 carrier screening to assist in reproductive decisions,
 prenatal screening to detect the presence of a genetic condition in an embryo or fetus, newborn
 screening for current disorders (e.g., biotinidase deficiency which, if left untreated, may lead to
hearing loss),
 pre-symtomatic predictive testing for hearing loss and other conditions that occur later in life,
 predispositional testing for genetic mutations that increase the risk of developing a condition (e.g.,
the well-known mutations in BRCA1 or BRCA2 associated with increased risk for breast or ovarian
cancer),
 diagnostic testing to determine the etiology of a disease (Arnos, 2003).
 In some cases, a genetic diagnosis may result in avoidance of expensive and more invasive tests.
- Advantages:
o Knowing the inheritance pattern contributes to understanding recurrence risks.
o In some cases, hearing loss may be the first manifestation of a syndrome for which critical
medical intervention is necessary (e.g., JLNS).
o A genetic diagnosis may facilitate timely referrals to appropriate specialists and management of
associated conditions.
o Predictive information about hearing loss progression is useful in planning management and
making amplification and educational choices.
o In persons with an increased risk for age-related, noise-induced, or drug-induced hearing loss, a
genetic diagnosis may lead to avoidance of environmental causes of hearing loss.
- Limitations:
 Some families may find the process and information emotionally upsetting.
 Genetic testing will not lead to a diagnosis in all cases;
 the etiology of congenital hearing loss may remain unknown in as many as 30% to 40%
 Negative findings on genetic testing do not mean that the hearing loss is not hereditary, but may
occur when the causative gene or the specific mutation has not been previously identified.
55
Diagnostic Evaluation of Hereditary Hearing Loss:
- A multidisciplinary team comprising audiologists, otolaryngologists, medical geneticists, geneticists,
and genetic counselors is necessary for the diagnosis and management of hereditary hearing loss and
family support.
- Guidelines for genetic evaluation to determine the etiology of congenital hearing loss:
(1) The patient’s family history of hearing loss and other medical conditions,
 identification of other medical problems, physical characteristics, or known genetic
conditions in the family provides insight regarding the possibility of a syndromic form
of hearing loss.
 Careful inspection and interpretation of family member audiograms and hearing loss
history, including age of onset, comorbid conditions, and environmental exposures,
assists in assuring that the auditory phenotype is correctly identified
(2) the patient’s medical history and risk factors for hearing loss:
 Reviews risk factors for hearing loss. These include:
o in utero exposures such as maternal infections (cytomegalovirus, herpes,
syphilis, and toxoplasmosis) and maternal drug or alcohol use.
o Neonatal risk factors comprise extracorporeal membrane oxygenation (ECMO),
assisted ventilation, exposure to ototoxic medications, hyperbilirubinemia
requiring exchange transfusion, neonatal intensive care stay lasting more than 5
days, or culture-positive postnatal infections such as meningitis which is
associated with SNHL.
 For older children, a review of speech and language development, including vocal play,
gives insight as to the time of hearing loss onset.
 Vestibular function in young children and toddlers can be indirectly assessed by factors
such as age at independent walking, nystagmus, clumsiness, and torticollis.
(3) examination of the patient for physical features of a syndrome and other concomitant
conditions:
 patient should be examined for ear pits, tags or cysts, defects of the pinna, patency of
the ear canals, and status of the tympanic membrane,
 other craniofacial structural abnormalities.
 ophthalmologic evaluation on every child with a confirmed SNHL to evaluate visual
acuity and rule out other ocular disorders.
 Referrals to other medical specialists, including cardiologists, neurologists, and
nephrologists, may be required based on clinical findings.
 Imaging studies (CT or MRI) of the temporal bone may be indicated for diagnostic
purposes (e.g., enlarged vestibular aqueduct) and for assessment of surgical
rehabilitative candidacy (e.g., cochlear patency).
56
 It is also suggested that siblings of children identified with hearing loss be evaluated for
hearing loss themselves.
57
Genetic Professionals:
- Geneticists participate in evaluation, diagnosis, and management of hereditary disorders.
- Genetic counselors are trained to
(1) interpret family and medical histories and assess occurrence and recurrence risk;
(2) educate patients and families regarding basic concepts of inheritance, available testing, and
resources;
(3) provide counseling to enable families to make informed decisions
Genetic Testing:
- Testing for specific genes if a hearing loss syndrome was suspected.
- In the case of possible non-syndromic hearing loss, testing for cytomegalovirus and genetic testing
for a GJB2 mutation served as the starting point for what amounted to a one-gene-at-a-time
methodology.
- Recent technologies are more efficient, less expensive, and more accurate, allowing for the screening
of thousands of genetic loci at one time.
FUTURE DIRECTIONS
- Gene therapy for hearing loss:
o It is a method that uses genetic material to halt, reverse, or prevent disease by replacing or
stopping the function of a mutated gene or inserting a gene.
o Gene therapy is considered an experimental treatment and is used currently in very limited
situations for humans with diseases that have no other cures.
o The application of gene therapy to treatment of SNHL is in the early stages of discovery in
animal models, but holds promise for eventual use in humans.
o The potential use of gene therapy in cases of hereditary hearing loss includes
(1) delivery of functional copies of the gene to the cochlea to overcome the genetic defect,
(2) delivery of genes that will initiate hair cell regeneration,
(3) delivery of genes capable of providing a protective effect on the cells of the organ of
Corti and spiral ganglion to minimize the loss of these cells.
58

Genetic Hearing Loss

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Genetic Hearing Loss

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Congenital Hearing Loss

ii. Polygenic inheritance:

iii. Modifier Genes:

1. Autosomal Dominant Non-Syndromic HL:

b. DFNA 6/14/38 (Gene: WFS1; Cytogenic locus 4p16.1):

d. DFNA9 (GENE: COCH; Cytogenic locus: 14q12)

e. DFNA10 (GENE: EYA4; Cytogenic locus: 6q23)

2. Autosomal-Recessive Non-syndromic HL:

a) DFNB1 A (Gene: GJB2, Cytogenic locus: 13q11-12):

GJB 2 “Cx 26”:

d) DFNB12 (Gene: CDH23; Cytogenic location: 10q22.1)

- Five loci are assigned for X-linked hereditary hearing loss.

4. Y-Linked Non-syndromic HL (DFNY):

6. Auditory neuropathy, Autosomal Dominant (AUNA):

7. Non-Syndromic Mitochondrial HL (MTRNR1):

c) Ear and hearing abnormalities:

Intestinal Absence of groups of

 HL: may be CHL (ossicular chain anomalies), SNHL or mixed

A. Pendred Syndrome (DFNB4):

Role of SLC26A4 in EVA:

Mechanism of hearing loss in EVAS :

Diagnosis of Usher syndrome

Major clinical features Minor diagnostic findings

- Management: usually benefit from hearing aids.

Mitochondrial encephalomyopathy with ragged red fibers (MERRF) (Myoclonic

Kearns Sayre Syndrome (KSS) Ophthalmoplegia Plus:

Benefits & Limitations of Genetic Testing:

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