Genetics of Hearing Loss Dr Nayyar

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By:- Dr. Supreet Singh Nayyar, AFMC
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7/22/2012www.nayyarENT.com
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Genetics of hearing loss
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Overview
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Introduction
Types of genetic hearing impairment
Common types of syndromic deafness
Common types of non-syndromic deafness Genetic evaluation
Genetic counseling
Recent advances in genetic treatment
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Introduction
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Gregor Mendel - father of modern genetics
Human genome project
Otolaryngologist role in genetic hearing loss
Hearing impairment possibilities

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HEARING LOSS

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Syndromic Deafness
Over 400 syndromes
Two syndromes by different mutations of same
gene
Mutations of more than one gene can cause thesame clinical phenotype
Mode of inheritance

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Autosomal Dominant Syndromic
Hearing Impairment
Waardenburg Syndrome
Branchio-oto-renal Syndrome
Stickler Syndrome
Neurofibromatosis II
Treacher Collins Syndrome
Goldenhar Syndrome

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Petrus J. Waardenburg - 1951
Aggregate prevalence 1:10,000 to 20,000
Usually autosomal dominant
Sensorineural hearing loss Pigmentary abnormalities
Hair
Iris Skin
4 clinical subtypes

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Type 1: With dystopia canthorum
Penetrance 36% to 58%
PAX3
Type 2:
Like type 1 but without dystopia canthorum Hearing loss penetrance as high as 87%
MITF

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Type 3 (Klein-Waardenburg syndrome): Type 1 clinical features + hypoplastic muscles
and contractures of the upper limbs
PAX3
Type 4 ( Shah-Waardenburg syndrome): Type 2 clinical features + Hirschsprungs
disease EDN3 , EDNRB , SOX10
Autosomal recessive

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Branchio-oto-renal syndrome
Melnick - 1975
Penetrance is nearly 100%
Prevalence 1 in 40, 000
2% of profoundly deaf children
EYA1 , 1q31

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Otologic findings
External ear
Middle ear
Inner ear

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PTA
Branchial anomalies
Renal anomalies
Less common phenotypic anomalies

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Major and Minor Diagnostic Criteria for Branchiootorenal Syndrome
Major Criteria Minor Criteria
Second branchial arch anomalies External auditory canal anomalies
Deafness Middle ear anomaliesPreauricular pits Inner ear anomalies
Auricular deformity Preauricular tags
Renal anomaliesOther: facial asymmetry, palate
abnormalities
Chang EH, Menezes M, Meyer NC, Cucci RA, Vervoort VS, Schwartz CE, Smith RJ. Branchio-oto-renal
syndrome: the mutation spectrum in EYA1 and its phenotypic consequences. Hum Mutat2004;23:582-9
Branchio-oto-renal syndrome

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Stickler Syndrome
Dr. Gunner Stickler - 1965
Prevalence 1:10,000
Mutations - type II and type XI collagen
Snead and Yates criteria (1) Congenital vitreous anomaly (2) Any three of
Sensorineural hearing loss Myopia with onset before age 6 years Midline clefting Joint hypermobility with abnormal beighton score Rhegmatogenous retinal detachment

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Stickler Syndrome
SS type I COL2A1
Classical ocular findings with a "membranous" vitreous
Normal hearing or only a mild impairment
SS type II
COL11A2
Minimal ocular abnormalities
Mild to moderate hearing loss
SS type III
COL11A1
Vitreous - irregularly thickened fiber
Moderate-to-severe hearing loss
Hearing loss Conductive- eustachian tube dysfunction that commonly occurs
with palatal clefts
Sensorineural Alterations in the pigmented epithelium of the inner ear
Abnormalities of inner ear collagen
Mixed

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Hallmark hearing loss secondary to bilateralvestibular schwannomas
Incidence 1:40,000 to 1:90,000
Hearing loss usually begins in the third decade
Generally unilateral and gradual
Risk of other tumors including meningiomas,astrocytomas, ependymomas, and
meningioangiomatosis

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Diagnostic criteria
Bilateral CN VIII schwannomas on MRI or CT scan (no biopsynecessary) (age

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Treacher Collins Syndrome
Incidence - 1/50,000 live births
Gene TCOF
Clinical features
Maldevelopment of the maxilla and mandible Downward slanting palpebral fissures
(anti mongoloid fissure)
Lower lid colobomas
Choanal atresia
Cleft palate
Conductive hearing loss Ossicular fixation

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Goldenhar syndrome
Maurice Goldenhar 1952 OAV - Gorlin 1990
Incidence 1/3500 to 1/26000
Etiology
Possible vascular insult to 1st and 2nd branchial arches Mostly sporadic & multifactorial
AD and AR variants reported
Incomplete development Ear Nose Soft palate,lip, and mandible
Usually one side of the body

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Goldenhar syndrome
Clinical features Epibulbar dermoids
Upper eyelid colobomas
Mandibular hypoplasia
Microtia, preauricular appendages FN involvementfacial muscle hypoplasia
Hemifacial microsomia 90% unilateral
Lateral facial clefts/Macrosomia
Hemi vertebrae anomalies
Cardiac, renal, pulmonary, CNS, skeletal
OMENS ocular, mandibular, ear, FN, soft tissue

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Autosomal Recessive Syndromic
Hearing Impairment
Usher Syndrome
Pendred Syndrome
Jervell and Lange-Nielsen Syndrome
Biotinidase Deficiency
Refsum Disease

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Usher Syndrome
Prevalence 4.4 per 100,000
3% to 6% of congenitally deaf persons
Cause of 50% of deaf-blindness
Characterized by Sensorineural hearing loss
Retinitis pigmentosa
Vestibular dysfunction
11 loci and 6 genes have been identified

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Usher Syndrome
Type 1 Type 2 Type 3Hearing loss Profound since
birth
Moderate-to-
severe ,
sloping curve
Progressive
Vestibularresponse
Absent Normal Variable
Onset ofretinitispigmentosa
First decade of
life
First or second
decade of life
Variable onset
Timing of cochlear implantation in Usher Syndrome

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Pendred Syndrome
Vaughan Pendred - 1896
Prevalence 7.5 to 10 per 100,000
SLC26A4, encodes pendrin
Functions as a chloride/iodide transporter
Expressed in inner ear, thyroid, and kidney
Hearing loss
SNHL
Prelingual
Bilateral
Profound

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Pendred Syndrome
Mondini dysplasia
Enlargement of Vestibular aqueducts
Endolymphatic sac
NormalDilated
endolymphatic sac

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Pendred Syndrome
Thyroid goiter
Second decade
Euthyroid
Perchlorate discharge test >10% radioactivity +ve test
Sensitivity low
Genetic

Genetics of Hearing Loss Dr Nayyar

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