Pediatric Hearing Loss: What Causes it and What to Do?

Pediatric Hearing Loss: What Causes it and What to Do? Margaret Kenna, MD, MPH Dept. of Otolaryngology and Communication Enhancement Boston Children’...
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Pediatric Hearing Loss: What Causes it and What to Do?

Margaret Kenna, MD, MPH Dept. of Otolaryngology and Communication Enhancement Boston Children’s Hospital Harvard Medical School

Harvard Medical School Boston Children’s Hospital

Daniel Choo, MD John Greinwald, MD Div. of Otolaryngology-Head and Neck Surgery Cincinnati Children’s Hospital University of Cincinnati

Harvard Medical School Center for Hereditary Deafness

Incidence of SNHL in Children • Hearing loss most common congenital sensory impairment • Congenital 1-3/1000 live births with severe to profound SNHL – Another 1-2/1000 have milder or unilateral hearing loss

• Later onset/Acquired – 19.5% based on NHANES 2005-6 for ages 12-19 years

• Actually acquired since birth: ototoxicity, meningitis, head trauma • May be the hearing loss manifestation of a prenatal occurrence: CMV, anatomic abnormalities, genetics • Better definition of a HL that has always been there

Hearing Loss by Laterality • • • •

Massachusetts 2010 72,698 screened (99.6% births) 2.9% lost to follow-up 907 unilateral refers – 98 (10.8%) with hearing loss • 41/98 (41.8%) with bilateral hearing loss

• 307 bilateral refers – 93 with hearing loss • 83 (89.2%) with bilateral hearing loss

Auditory Dyssynchrony • • • • • • •

Auditory asynchrony Auditory neuropathy Otoacoustic emissions present Absent/very abnormal ABR About 10% get better, many do well with CI Only occasionally helped by HA May be missed in UNHS using OAE’s to screen

Causes of Auditory Dys-synchrony • Likely due to inner hair cell or other neural abnormalities • Hyperbilirubinemia, sometimes less than 20 (especially in extreme preemies) • Extreme prematurity • Sepsis • Often associated with other neurological findings • Abnormal temporal bone anatomy • Genetics – Recessive: Otoferlin (DFNB9), including a temperature sensitive variant and pejvakin (DFNB59) – Dominant: Diaph3 (AUNA) – Syndromic and mitochondrial

Hearing Loss Websites • Harvard Medical School Center for Hereditary Deafness http://hearing.harvard.edu • Hearing and Deafness Center at Cincinnati Children’s Hospital http://chdr.org • Hereditary Hearing Loss Homepage http://webh01.ua.ac.be/hhh/ • Connexin Deafness Homepage http://davinci.crg.es/deafness/

More Websites • To locate genetic testing and genetic clinic sites: – http://www.genetests.org – http://www.geneclinics.org

• Boystown National Research Hospital – http://www.boystownhospital.org – http://www.babyhearing.org (for parents)

• National Center for Hearing Assessment and Management, Utah State University – http://www.infanthearing.org

Genetic Hearing Loss: Genes, Counseling, and why does it matter?

Margaret Kenna, MD, MPH

John Greinwald, MD

Dept. of Otolaryngology and Communication Enhancement Boston Children’s Hospital Harvard Medical School

Div. of Otolaryngology-Head and Neck Surgery Cincinnati Children’s Hospital University of Cincinnati

Harvard Medical School Boston Children’s Hospital

Harvard Medical School Center for Hereditary Deafness

Major Causes of Sensorineural Hearing Loss

Traumas/ Exposures

Anatomical

Infections Drugs

Unknown Syndromic

Genetic Nonsyndromic

Mitochondrial X-Linked

Autosomal Recessive Autosomal Dominant

Cx26

Genetics of Hearing Loss 

Loci (genes) for Non-Syndromic HL   

  



Syndromic hearing loss: hundreds of genes    



71 (41) recessive (DFNB) 54 (25) dominant (DFNA) 5 (3) X-linked (DFNX) 2 modifier (DFNM) 1 Y-linked (DFNY) 1 (1) Auditory neuropathy (AUNA1)

Not always obvious at birth Waardenburg (9 loci/6 genes) (dominant) Branchio-oto-renal (4 loci 3genes)(dominant) Usher (13 loci/10 genes)

Mitochondrial  

Numerous syndromic and non-syndromic Many non-syndromic predispose to ototoxicity Van Camp G, Smith RJH. http://hereditaryhearingloss.org 9.20.2013

Case #1  



Full term newborn passes AABR screen Since mom was CMV positive, baby tested for CMV but is negative. Develops recurrent acute otitis media, tympanostomy tubes placed at 12 months 



Tympanostomy tubes extrude 



Post-op audiogram in sound field normal Audio 6 months later suggests mild SNHL

Child referred for evaluation of the SNHL

Case #1 

What do we know? CMV negative  Passed NBHS at 35 dB AU  Normal term birth, no NICU  Both parents and older sib with normal hearing, but grandparents with childhood onset SNHL  Family on both sides of Asian descent 

Pedigree Case # 1 HL

HL

HL

Is this genetic?    



Most consistent with recessive inheritance Hearing loss seems progressive Most likely genetic cause is GJB2 (Connexin 26) Although many GJB2 mutations have been reported to be associated with progressive SNHL, the V37I mutation is one of the more common mutations associated with this Children with GJB2 SNHL may have normal hearing at birth and progress over time

FREQUENCY IN HERTZ (Hz) 125

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-10

HEARING LEVEL (HL) IN DECIBELS (dB)

0 10

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35delG / 35delG

AC (AIR)

Age 15 months

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MASKED

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BC (BONE)

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SPEECH AUDIOMETRY R L

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SDT

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Tympanograms: normal

SPEECH DISCRIM. (WORD RECOG.)

25 30

FREQUENCY IN HERTZ (Hz) HEARING LEVEL (HL) IN DECIBELS (dB)

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35delG / 35delG Age 10 years Sibling has similar audiogram

R=O L=x

FREQUENCY IN HERTZ (Hz) 125

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HEARING LEVEL (HL) IN DECIBELS (dB)

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M34T / M34T Age 3 years Tympanograms: normal

SPEECH AUDIOMETRY R L SDT SRT

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SPEECH DISCRIM. (WORD RECOG.)

GJB2 – aka Connexin 26  

13q12 @ DFNB1 locus Phenotype Usually congenital  Recessive (rarely dominant)  ~50% with severe to profound hearing loss (>75dB HL) 

35delG (>50%, varies with population)  167delT (Ashkenazi)  235delC (Asian)  R143W (African) 



Generally no other physical or radiographic findings (except for isolated families with PPK)

Severity of Cx26 Hearing Loss 45 40

Number of Ears

35 30 25 20 15 10 5 0

M34T/V37I M34T/M34T V37I/V37I Normal

M34T/Other Truncated/NT V37I/Other Mild

Moderate

Severe

Truncated/ Truncated Profound

Data from Boston Children’s Hospital (Kenna and Rehm, 2005)

Other Findings in GJB2 Hearing Loss 

Most studies show normal inner ear structures  





Progression rates vary 



99-100%

Lower cost-~$2500 Can add genes easily

Future of genetic testing 

NextgenSensitivity and Specificity > 99-100%  Can detect indels and CNV’s 

 

 

Whole exome Whole genome Microarray Detect nearly 95% of all genetic HL

Uses of Genetic testing  

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Diagnostic and carrier status Surveillance (look for other organ system involvement) Family planning Risk reduction (BRCA1) Non-inherited disorders Pharmacogenetics Genetic therapy

Concerns about genetic testing



Technical: not all tests give the same results   

  







Single gene; targeted mutations or sequencing Cytogenomics: trisomies, indels, CNV’s Cytogenetics: array CGH, Microarrays Gene chips: multiple genes at once Exome and genome Patients may misinterpret negative testing as “negative” forever

Genetic counseling: not always provided and not provided at same level Information about genetic testing uneven and hard to understand and locate Find things you did not anticipate: non-paternity, nonmaternity, diseases you were not looking for

Incidental findings  

 

Should they be reported Who should they be reported to Education of the person getting the findings ACMG March 22, 2013 with regard to exome and genome sequencing Patient autonomy  Incidental findings in children  Clinical laboratory considerations  Result communication  Predicting disease likelihood 



(http://www.acmg.net/docs/ACMG_Releases_Recommendations_on_I ncidental_Findings_in_Clinical_Exome_and_Genome_Sequencing.pdf)

Congenital CMV and Hearing Loss • Take Home Points: – This is one of the potential treatable forms of pediatric sensorineural hearing loss – There is a time-sensitive diagnostic window – There is probably a time-sensitive treatment window – There may be otolaryngologist-specific treatment modality (intratympanic delivery)

Congenital CMV & Hearing Loss • Cytomegalovirus (CMV) is the most common non - genetic cause of hearing loss in children, with about 10 – 15% of CMV - positive children eventually developing hearing deficits.

Congenital CMV and Antiviral Therapy •

Link Between Newborn Infection and Childhood Hearing Loss? NIDCD-funded Researchers to Lead a Multicenter Study



100,000 infants will be screened for congenital CMV infection via blood, urine, saliva testing



$15M contract awarded - led by UAB (S. Bhoppana)



7 center study (UAB, Carolinas Med Ctr, UTSW Dallas, U of Pittsburgh, St. Petersburg Med Ctr, U of MS and U of Cincinnati)



Follow those children who are CMV(+) for 4 years clinically and audiologically to determine the natural history of hearing loss in CMV-related hearing loss

The CMV & Hearing Multicenter Screening Study

CMV testing • The consortium reported developing a PCR method using dried blood spot samples and comparing it with rapid culture, with disappointing results (JAMA 2010;303:1375-82). ―Unfortunately, we found that blood spot-based PCR detects less than 40 percent of babies with congenital CMV infection…..

CMV testing – using saliva/PCR • The liquid-saliva assay had sensitivity and specificity of 100% and 99.9%, respectively, with positive and negative predictive values of 91.4% and 100%, respectively. • The sensitivity and specificity of the dried-saliva PCR assay were slightly lower, at 97.4% and 99.9%, respectively, yielding lower positive and negative predictive values of 90.2% and 99.9%, respectively

CMV testing • CMV Microculture of salivary swab is also widely available and highly sensitive and specific – Slightly more time consuming – Slightly higher personnel costs (depending upon your laboratory)

Congenital CMV infection • Leading cause of neurological disease and hearing loss in children • 1% of all live births • 95% of children asymptomatic at birth • 5% of children are symptomatic • Commonest neurological defect is SNHL (30-65% prevalence)

Congenital CMV and SNHL • Could this have been due to congenital CMV infection? – Can you test for CMV at this point? Not really – Should you empirically treat for CMV infection? No – Bottom line: its too late to diagnose or really do anything about a potential CMV-related hearing loss

Congenital CMV infection • Leading cause of neurological disease and hearing loss in children • 1% of all live births • 95% of children asymptomatic at birth • 5% of children are symptomatic • Commonest neurological defect is SNHL (30-65% prevalence)

Clinical features • • • • • • •

Mental retardation (IQ98% – One-tailed distribution curve

Size of VA

MR vs CT • Distinct benefit of MR imaging over CT • No radiation exposure • Higher sensitivity at identifying CNS lesions, demyelinating processes

CT vs MR Imaging for SNHL

CT vs MR Imaging for SNHL

Enlarged Vestibular Aqueduct Probability of Progressive SNHL

VA Size and Progressive SNHL 0.6

0.5

0.4

Linear (Midpoint) 0.3 Linear (Operculum)

Linear (Prevalence of Progressive SNHL)

0.2

0.1

0

VA Width in mm

Xray exposure from CT scanning Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study Dr Mark S Pearce PhD a Corresponding AuthorEmail Address, Jane A Salotti PhD a, Mark P Little PhD c, Kieran McHugh FRCR d, Choonsik Lee PhD c, Kwang Pyo Kim PhD e, Nicola L Howe MSc a, Cecile M Ronckers PhD c f, Preetha Rajaraman PhD c, Alan W Craft MD b, Louise Parker PhD g, Amy Berrington de González DPhil c

Background Although CT scans are very useful clinically, potential cancer risks exist from associated ionising radiation, in particular for children who are more radiosensitive than adults. We aimed to assess the excess risk of leukaemia and brain tumours after CT scans in a cohort of children and young adults.

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