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Genetics of hearing loss
Chapter 146/147
Bobby Tajudeen
• 1 child in every 1000 born will have congenital
hearing impairment
• At least 50% of congenital hearing impairment
has a genetic origin
Classification
• Causality
– Genetic (hereditary)
– Environmental
(nonhereditary)
– Multifactorial
• Time of onset
– Congenital (at birth)
– Acquired (late-onset)
• Age of onset
– Prelingual (before speech
development)
– Postlingual (after speech
development)
• Clinical Presentation
– Nonsyndromic (hearing loss
only symptom)
– Syndromic (hearing loss and
other symptoms)
• Anatomic Defect –
CHL/SNHL/Mixed
• Severity
• Frequency loss
• Ears affected
• Prognosis – stable vs.
progressive
Genetics
AD
AS
X-Linked
Mitochondrial
• Most common type of genetic hearing loss is
transmitted in what fashion?
a.
b.
c.
d.
AR
AD
X-linked
Mitochondrial
Autosomal Recessive Nonsyndromic
Hearing Loss
• Usually prelingual and severe to profound
across all frequencies
• Connexin 26 mutation most common
– GJB2 gene – integral for gap junction formation
and mechanosensry transduction
Autosomal Dominant Nonsyndromic
Hearing Loss
• Onset generally postlingual, progressive, and
milder with characteristic audioprofiles
• DFNA2 – high frequency hearing loss
• DFNA8/12/13 – midfrequency hearing loss
• DFNA6/14/38 – low frequency hearing loss
X-linked Nonsyndromic Hearing loss
• Accounts for less than 2% of nonsyndromic
hearing loss
• DFN3 most common – mutation in POU3F4
– Congenital stapes fixation
– Widening of lateral IAC
– Dilation of vestibule
– Mixed HL
– Stapedectomy  gusher
Mitochondrial Nonsyndromic Hearing
Loss
• 1555 A-to-G mtDNA mutation best
characterized
• Associated with aminoglycoside ototoxicity
• Mild high frequency loss that progresses
• Presbycusis may have mitochondrial basis due
to mtDNA mutation accumulation
Syndromic Hearing loss
• Less common than nonsyndromic forms
• Cosegregate with other features
What is the structure?
• A patient with Pendreds is most likely to to
benefit from:
a.
b.
c.
d.
Synthroid
Thyroidectomy
Amplification
Steroid Burst
Pendred Syndrome
•
•
•
•
•
•
Most common form of hereditary syndromic SNHL
Autosomal recessive
Affected individuals also have goiter
Congenital severe-profound HL, bilateral
Mutation in SLC26A4 gene
Pendrin anion transporter involved in chloride and iodine
transport
• Goiter in 2nd decade, usually euthyroid
• Perchlorate discharge test
• Radiographs always show temporal bone anomaly either
dilated vestibular aqueducts or Mondini dysplasia
• A patient with hearing loss is diagnosed with
Jervell-Lange Nielsen syndrome. Why did his
brother die at a young age?
a.
b.
c.
d.
Neurologic disease
Cardiac disease
Renal disease
Thyroid disease
Jervell and Lange-Nielsen Syndrome
• Autosomal recessive
• Characterized by congenital deafness, prolonged
Q-T, syncopal attacks
• KVLQT1 and KCNE1 genes important for
potassium channels expressed in heart and inner
ear
• Congenital, bilateral, severe to profound SNHL
• Prolonged QT can leads to ventricuar
arrhythmias, syncopal attacks, and death
• Beta blockers reduce mortality from 71% to 6%
• A patient has progressive hearing loss and
blurry vision. Ophthalmologic evaluation
reveals interstitial keratitis. What syndrome
does the patient have?
a.
b.
c.
d.
Usher’s
Cogan’s
Waardenburg syndrome
Jervell-Lange Neilson syndrome
• Two brothers developed congenital deafblindness with vestibular dysfunction. Which
type of Ushers syndrome do they most likely
have?
a.
b.
c.
d.
Type 1
Type 2
Type 3
Type 4
Usher syndromes
• Autosomal recessive
• SNHL, retinitis pigmentosa, and often vestibular
dysfunction
• Cause of 50% of deaf-blindness
• Three variants:
– Type 1 – severe to profound congenital HL, vestibular
dysfunction, retinitis pigmentosa develops in childhood
– Type 2 – mod to severe HL, no vestibular dysfunction,
retinal degeneration in 3rd-4th decade
– Type 3 – progressive hearing loss, variable vestibular
dysfunction, variable onset of retinitis pigmentosa
• Which form of Waardenburg syndrome is not
associated with dystopia canthorum?
a.
b.
c.
d.
Type 1
Type 2
Type 3
Type 4
• Which form of Waardenburg syndrome is
associated with Hirschsprung disease?
a.
b.
c.
d.
Type 1
Type 2
Type 3
Type 4
Waardenburg syndrome
• Autosomal dominant (except type
4)
• SNHL, pigmentary abnormalities
(heterochromic iridis, white
forelock, patchy skin
depigmentation), craniofacial
abnormalities (dystopia canthorum,
synophrys, broad nasal root)
• Four types
– Type 1 – presence of dystopia
canthorum
– Type 2 – no dystopia canthorum
– Type 3 – skeletal abnormalities
– Type 4 – associated with
Hirschsprung disease
• A patient is diagnosed with Alport syndrome.
How are they likely to present?
a.
b.
c.
d.
Congenital hearing loss that is progressive
Congenital hearing loss that is stable
Adolescent onset hearing loss that is progressive
Adolescent onset hearing loss that is stable
Alport Syndrome
• X-linked syndrome of Type IV collagen
• Hematuric nephritis, hearing impairment, ocular changes
• Diagnostic criteria: three of following
–
–
–
–
Positive family history of hematuria
Progressive high-tone SNHL
Typical eye lesion (anterior lenticonus or macular flecks)
Histologic changes of glomerular basement membrane of the
kidney
• Hearing loss is symmetric, high-frequency that can be
detected in late childhood and progresses to involve all
frequencies
• Ultimately progress to end-stage renal disease
• What type of hearing
loss does this patient
likely to have?
a.
b.
c.
d.
SNHL
Progressive SNHL
Mixed hearing loss
Mild “cookie bite”
SNHL
Treacher Collins
• Autosomal dominant
• Abnormalities of
craniofacial development
– Maldevelopment of the
mandible and maxilla
– Abnormal canthi placement
– Downsloping palpebral
fissures
– Ocular colobomas
– Choanal atresia
• Typically normal intelligence
• Otologic symptoms findings
–
–
–
–
–
–
Auricular deformities
Atresia/stenosis of EAC
Malformed ossicles (CHL)
Preauricular fistulas
Malformed ossicles
Bony plate replacement of
TM
– Widened aqueduct
– Abberrant facial nerve
– Mondini malformation