Genetic Hearing Loss Conditions

Hearing Loss - Overview

- Prelingual: before language development (detected on NBS & have speech delay)

- postlingual: some language dev.

- Severity -> decibels can hear

Hearing Loss - Tests

Auditory brain stem response (ABR or BAER)

- electrode on babies head (NBS)

Evoked otoacoustic emissions

- measure activity of outer hair cells in cochlea

Immitance testing

- tympanometry-> pressure, mobility, function

Hearing Loss - Etiology

Prelingual Hearing Loss (1/500)

- 20% environmental/acquired

- 80% genetic

Genetic Hearing loss

- 20% syndromic

- 80% nonsyndromic

Nonsyndromic Hearing loss

- 80% AR

- 19% AD

-

Waardenburg Syndrome - Genes

- depends on type of WS

Type 1: PAX3

Other genes: EDN3, EDNRB, MITF, SOX10, SNA12, KITLG

WS1 -> AD inheritance

WS2, WS3, WS4 -> AD or AR inheritance

Waardenburg Syndrome - Etiology

- results from mutations in genes impairing migration and differentiation of neural crest cells

Waardenburg Syndrome - Symptoms

- Most common type of AD syndromic hearing loss

- Congenital SNHL, variable severity

Overal features

- hearing loss

- pigmentary changes (white forelock)

- dystopium canthorum

- complete heterochromia, or brilliant blue irides

WS Type 1

- pigmentary changes of iris, hair, & skin

- hearing loss 60% congenital, typically non-progressive, SNHL

WS Type 3 is type 1 + skeletal anom

WS type 4 is type 2 + more severe & Hirchsprung

Waardenburg Syndrome - Diagnosis & Treatment

- Dx typically clinical but can do genetics

- Tx depends on severity

- cochlear implants have been successful

GJB2 Hearing Loss (AR inheritance) - Gene

- biallelic PV in GJB2 (99%)

Compound heterozygosity for 1 GJB2 PV

- deletion is either intragenic del or whole gene del

- noncoding PV or dels up- or downstream of GJB2 (including GJB6)

- mosaic UPD for GJB2

Truncating variants are more severe to profound hearing loss

GJB2 Hearing Loss (AR inheritance) - Symptoms

- Severe-to-profound congenital SNHL

- Can be mild-to-moderate at birth (not detected by NBS & progress)

- NO related systemic findings

GJB2 Hearing Loss (AR inheritance) - Dx & Tx

- genetic testing

- cochlear implants

- hearing aids

Usher Syndrome - Overview

- affects BOTH hearing & vision

- retina & cochlear dysfunction

- onset birth to teenage yrs

- Signs at birth: loss of startling, absence babbling, unresponsive to voices

- Signs in children: speech delay, behavioral changes

- Other signs: blurred vision, sensitivity to light, balance issues, clumsiness

Usher Syndrome - Genes

Both types AR inheritance

Type 1

- MYO7A (53-70%) & USH1C (6-15%)

- CDH23 & PCDH15 -> digenic

Type 2

- USH2A (57-79%)

- can cause nonsyndromic retinitis pigmentosa in homozygous missense variants

Usher Syndrome - Symptoms

Type 1

- most common type

- congenital severe-to-profound SNHL, abnormal vestibular function

- adolescent-onset RP

- delayed walking b/c vestibular dysfunction

Type 2

- congenital mild-to-severe SNHL

- Normal vestibular function

Type 3

- progressive hearing loss

- deterioration of vestibular function

Usher Syndrome - Dx & Tx

- suspected findings & genetic testing

- audiology & ophthalmology

- vestibular compensation therapy

- sensory substitution therapy

- hearing aids & cochlear implants

- gene therapies under investigation

Pendred Syndrome - Gene

- SLC26A4

- AR inheritance

part of SLC26A4 related SNHL phenotypic spectrum

Pendred Syndrome - Symptoms

- inner ear malformations also associated with vestibular dysfunction

- thyroid involvement (goiter occurs gradually typically evident by 2nd decade)

- Onset variable but by age 3 most have bilateral & severe-to-profound hearing loss

- vestibular dysfunction can precede or accompany HL

Pendred Syndrome - Dx & Tx

- suggestive findings & genetic testing

- hearing habilitation -> hearing aids, cochlear implant

- endocrinologist -> thyroid enlargement (more frequent in places without iodized salt)

Branchio-Oto-Renal syndrome - Overview

- second branchial arch anomalies

- malformations of the ear

- congenital anomalies of kidney & urinary tract (CAKUT)

Branchio-Oto-Renal syndrome - Genes

AD inheritance, 100% penetrant

- EYA1

- SIX1

- LOF variants cause phenotype

- around 50% will have identified PV

Branchio-Oto-Renal syndrome - Symptoms

Ear findings

- ear pits or branchial cleft (90%)

- hearing loss -> 70% stable, 30% progressive; mixed HL 52%, conductive & SNHL around 30%

- severe microtia, minor anomalies of pinnae

- malformation of external canal

Renal anomalies

- variable -> minor dysplasia to bilateral renal agenesis

- chronic renal failure (67%)

Branchio-Oto-Renal syndrome - Dx Criteria

Major

- 2nd branchial arch anomalies

- preauricular pits

- auricular malformations

- hearing loss (>90%)

- CAKUT

Minor

- preauricular tags

- external auditory canal anom.

- middle &/or inner ear anom.

- mid face asymmetry

- cleft or high arched palate

- 3 or more major criteria OR 1 major & 1 FDR with BORSD

- 2 major + 2 minor

Testing: sequencing THEN del/dup

Branchio-Oto-Renal syndrome - Treatment

- monitor kidney function

- hearing aids, cochlear implants