Genetics of Hearing Loss Dr Nayyar

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    By:- Dr. Supreet Singh Nayyar, AFMC

    For more presentations, visitwww.nayyarENT.com

    7/22/2012www.nayyarENT.com

    1

    Genetics of hearing loss

    http://www.nayyarent.com/http://www.nayyarent.com/http://www.nayyarent.com/http://www.nayyarent.com/
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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

    http://www.nayyarent.com/http://www.nayyarent.com/
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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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    7/22/2012www.nayyarENT.com4

    HEARING LOSS

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    Syndromic Deafness

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    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

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    Waardenburg Syndrome

    Branchio-oto-renal Syndrome

    Stickler Syndrome

    Neurofibromatosis II

    Treacher Collins Syndrome

    Goldenhar Syndrome

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    Waardenburg 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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    Waardenburg Syndrome

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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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    Waardenburg Syndrome

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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

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    Melnick - 1975

    Penetrance is nearly 100%

    Prevalence 1 in 40, 000

    2% of profoundly deaf children

    EYA1 , 1q31

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    Branchio-oto-renal Syndrome

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    Otologic findings

    External ear

    Middle ear

    Inner ear

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    Branchio-oto-renal Syndrome

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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

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    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

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    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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    Neurofibromatosis II

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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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    Neurofibromatosis II

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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

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    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

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    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

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    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

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    Usher Syndrome

    Pendred Syndrome

    Jervell and Lange-Nielsen Syndrome

    Biotinidase Deficiency

    Refsum Disease

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    Usher Syndrome

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    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

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    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

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    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

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    Mondini dysplasia

    Enlargement of Vestibular aqueducts

    Endolymphatic sac

    NormalDilated

    endolymphatic sac

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    Pendred Syndrome

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    Thyroid goiter

    Second decade

    Euthyroid

    Perchlorate discharge test >10% radioactivity +ve test

    Sensitivity low

    Genetic