Genetics of hearing loss - PowerPoint Presentation

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Genetics of hearing lossChapter 146/147

Bobby Tajudeen

Slide2

1 child in

every

1000 born will have congenital hearing impairment

At least

50% of congenital hearing impairment has a genetic origin

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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

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Genetics

AD

AS

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X-Linked

Mitochondrial

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Most common type of genetic hearing loss is transmitted in what fashion?

AR

AD

X-linked

Mitochondrial

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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

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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

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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

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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

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Syndromic Hearing loss

Less common than

nonsyndromic

forms

Cosegregate

with other features

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What is the structure?

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A patient with

Pendreds

is most likely to to benefit from:

Synthroid

Thyroidectomy

Amplification

Steroid Burst

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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 2

nd

decade, usually

euthyroid

Perchlorate discharge test

Radiographs always show temporal bone anomaly either

dilated vestibular aqueducts

or

Mondini

dysplasia

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A patient with hearing loss is diagnosed with

Jervell

-Lange Nielsen syndrome. Why did his brother die at a young age?

Neurologic disease

Cardiac disease

Renal disease

Thyroid disease

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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%

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A patient has progressive hearing loss and blurry vision. Ophthalmologic evaluation reveals interstitial keratitis. What syndrome does the patient have?

Usher’s

Cogan’s

Waardenburg

syndrome

Jervell

-Lange Neilson syndrome

Slide20

Two brothers developed congenital deaf-blindness with vestibular dysfunction. Which type of Ushers syndrome do they most likely have?

Type 1

Type 2

Type 3

Type 4

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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 3

rd

-4

th

decade

Type 3 – progressive hearing loss, variable vestibular dysfunction, variable onset of retinitis

pigmentosa

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Which form of

Waardenburg

syndrome is not associated with dystopia

canthorum

?

Type 1

Type 2

Type 3

Type 4

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Which form of

Waardenburg

syndrome is associated with

Hirschsprung

disease?

Type 1

Type 2

Type 3

Type 4

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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

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A patient is diagnosed with

Alport

syndrome. How are they likely to present?

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

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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

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What type of hearing loss does this patient likely to have?

SNHL

Progressive SNHL

Mixed hearing loss

Mild “cookie bite” SNHL

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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