Genetic Hearing Loss

1
Genetic Hearing Loss

• Alice Lee
• Resident Conference
• March 8, 2007

2
History

• 20 yo M with a particular diagnosis, comes to
  your clinic with complaints of pain and
  dissatisfaction with his bone conduction hearing
  aid
• Bilateral hearing loss since birth

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PMH

• Goldenhar syndrome
• Vesicoureteral reflux
• Left solitary kidney with hydronephrosis and mild
  CRI
• Bilateral retinitis pigmentosa legally blind
• Hypercholesterolemia
• Pulmonary valve regurgitation, mild tricuspid
  valve regurgitation
• Scoliosis
• Torticollis

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PMH

• GU surgery for VUR
• Titanium rod placement for scoliosis
• Bilateral auricular reconstructions for microtia
• Meds None
• ALL sulfa, erythromycin
• Fam hx Unknown, pt is adopted
• Soc hx Lives with adopted sister, no tob, no
  IVDA, occ EtOH

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Exam

• Goldenhar facies
• Bilateral weak facial motion, lowergtupper
• Bilateral opacified corneas? Lens? PERRL
• Bilateral EAC atresia with microtia
• Exam otherwise unremarkable

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Audiogram
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CT
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Diagnostics

• Audiogram
• CBC R/O leukemia (rare assoc with HL)
• Platelet Fechner syndrome-rare, AD,
  macrothrombocytopenia, leukocyte inclusions
• ANA/ESR/RF R/O lupus, JRA
• TFTs/Perchlorate discharge test Pendred
• BUN/Cr/UA Alports
• Random blood glucose Alstrom syndrome, DM
• FTA-ABS (more specific than VDRL) syphilis
• EKG Jervell and Lange-Nielsen syndrome
• CT For symmetric HL
• MRI Asymmetric HL to r/o retrocochlear
  pathology
• Cholesterol/TG levels /- related to HL in
  literature
• GJB2 genetic testing

1. Mafong DD, Shin EJ, Lalwani AK. Use of
Laboratory Evaluation and Radiologic Imaging in
the Diagnostic Evaluation of Children With
Sensorineural Hearing Loss. Laryngoscope
2002112(1)1-7. 2. Preciado DA, Greinwald JH, et
al. Improved Diagnostic Effectiveness with a
Sequential Diagnostic Paradigm in Idiopathic
Pediatric Sensorineural Hearing Loss. Otology
Neurotology 200526(4)610-615.
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Algorithm for SNHL eval/mgmt
Recommendations Unilteral SNHL Imaging
onlySev to profound SNHL GJB2 Milder SNHL
Imaging All EKG low yield but easy LabsONLY
if HP warrants it
We would recommend that after a positive GJB2
screen, given the low probability of finding any
anomalies, and considering the cost of temporal
bone imaging, subsequent routine imaging is not
warranted. Along the same argument, GJB2 screens
do not appear to be warranted in children who
have had initial positive imaging results (if the
imaging study has been obtained as a first
diagnostic step).
Preciado DA, Greinwald JH, et al. Improved
Diagnostic Effectiveness with a Sequential
Diagnostic Paradigm in Idiopathic Pediatric
Sensorineural Hearing Loss. Otology Neurotology
200526(4)610-615.
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Classifications

• Genetic vs. non-genetic
• Congenital vs. hereditary
• Hereditary syndromic vs. non-syndromic
• Syndromic/non-syndromic AR, AD, X-linked,
  mitochondrial, complex

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What is your differential diagnosis?
200 syndromes associated with hearing loss
39 AR, 51 AD, 5 X-linked, 2 mitochondrial loci²
1. Morton N  Genetic epidemiology of hearing
impairment.   Ann N Y Acad Sci  1991 63016 2.
Brookhouser P. Sensorineural hearing loss in
children. Pediatr Clin North Am
1996431195216. 3. Steel KP. Progress in
progressive hearing loss. Science
1998279187071. 4. McGuirt WT, Smith RJ.
Connexin 26 as a cause of herditary hearing loss.
A, J Audiol 1999893-100.
13
Non-syndromic hearing loss

• HL in the absence of other phenotypic
  manifestations
• 70 of hereditary HL
• 80 AR, 18AD, 2 X-linked or mitochondrial
• DFN nonsyndromic deafness
• AAD, BAR, _X-linked

1. Erbe CB, et al. Connexin 26 and connexin 30
mutations in children with nonsyndromic hearing
loss. Laryngoscope 2004114607-11 2. Cummings
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Non-syndromic hearing loss

• ADUsually onset of deafness is postlingual,
  progressive, milder
• ARUsually prelingual and severe to profound
  across all frequenciesDFNB1 gene (Ch
  13q11-12)/GJB2/connexin 26
• X-linkedMost common locusDFN3. Mixed
  HLCongenital stapes fixation (stapedectomy with
  perilymph gusherCT findings widening of the
  lateral internal auditory canal and vestibule
  dilation Other loci with variable HL

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Non-syndromic HL mitochondrial

• Maternal transmission
• Phenotype is similar to aminoglycoside
  ototoxicity. Assoc with AG ototoxicity
• Mild, high-frequency loss with progression
• Usually of later onset in individuals who have
  not been exposed to aminoglycosides
• Presbycusis may have a mitochondrial basis.
  Increase in the mtDNA mutation load has been
  demonstrated in aged cochlea

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Syndromic hearing loss

• Over 200 syndromes associated with SNHL,
  although it is a minority of all cases of
  hereditary HL (30)

Cummings
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Syndromic hearing loss AD

• Oculo-auriculo-vertebral/ Hemifacial microsomia/
  Goldenhar
• Treacher Collins
• Branchio-oto-renal
• Waardenburg
• NF II
• Stickler
• Crouzon (Craniofacial Dysostosis)
• Apert Syndrome (Acrocephalosyndactyly)

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OAV syndrome

• Name suggested by Gorlin 1990 to encompass
  spectrum seen in hemifacial microsomia,
  Goldenhar, first and second brachial arch
  anomalies
• Est incidence 15,500 live births
• Etiology heterogeneous possible vascular insult
  to 1st and 2nd BA
• Actually thought to be sporadic, multifactorial.
  AD and AR variants reported

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OAV syndrome - OMENS

• Epibulbar dermoids, Upper eyelid colobomas
• Mandibular hypoplasia
• Microtia, preauricular appendages, ME XX( HL)
• FN involvement?facial muscle hypoplasiaHemifacial
  microsomia 90 unilateral
• Lateral facial clefts/Macrosomia
• Cardiac, renal, pulmonary, CNS, skeletal
  alterations described
• OMENS ocular, mandibular, ear, FN, soft tissue

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Treacher Collins syndrome

• Gene TCOF, Protein treacle nucleolar protein
• Incidence 1/50,000 live births
• Maldevelopment of the maxilla and mandible,
  downward slanting palpebral fissures, lower lid
  colobomas, choanal atresia, cleft palate
• Conductive hearing loss secondary to ossicular
  fixation

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Neurofibromatosis II

• Incidence 140,000 to 190,000
• Merlin protein, Ch22q12, tumor suppressor gene
  that regulates actin cytoskeleton
• Diagnostic criteria(1) bilateral vestibular
  schwannomas that usually develop by the second
  decade of life OR (2) a family history of NFII
  in a first-degree relative, PLUSa) unilateral
  vestibular schwannomas at lt30 years of age OR
  (b) any two of meningioma, glioma, schwannoma,
  or juvenile posterior subcapsular lenticular
  opacities/juvenile cortical cataract

25
Neurofibromatosis II

• Hearing lossUsually high frequency and SNHL
• Acoustic neuromas - observation vs surgery vs
  gamma knife
• Auditory brainstem implants

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Branchio-Oto-Renal syndrome

• Coined by Melnick in 1975
• AD, nearly 100 penetrance, prevalence 1 in
  40,000 live births,affects 2 of profoundly deaf
  children
• Gene EYA1, encodes for 559 amino acids, mutation
  found in 25
• Most common finding in BOR hearing loss50
  mixed, 30conductive

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Branchio-Oto-Renal syndrome
Major and Minor Diagnostic Criteria for
Branchiootorenal Syndrome
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 Mutat 200423582-9
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Branchio-Oto-Renal syndrome

• Otologic findings
• External - preauricular pits (82), preauricular
  tags, auricular malformations (32), microtia,
  and external auditory canal narrowing
• Middle - ossicular malformation (fusion,
  displacement, underdevelopment), facial nerve
  dehiscence, absence of the oval window, and
  reduction in size of the middle ear cleft
• Inner - cochlear hypoplasia and dysplasia,
  /-enlargement of the cochlear or vestibular
  aqueducts, hypoplasia of the lateral semicircular
  canal

30
Branchio-Oto-Renal syndrome

• Branchial anomaliesLaterocervical fistulas,
  sinuses, and cysts
• Renal anomaliesFound in 25Ranging from
  agenesis to dysplasia
• Less common phenotypic anomalies Lacrimal duct
  aplasia, short palate, retrognathia

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Waardenburg syndrome
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Stickler syndrome

• Prevalence 110,000
• Mutations in either COL2A1, COL11A2, or CO11A1,
  genes that encode for the constituent proteins of
  type II and type XI collagen
• Craniofacial anomaliesmidfacial flattening,
  mandibular hypoplasia, short upturned nose, long
  philtrum.
• Pierre Robin sequence in 28-65Submucous
  clefting is most common

35
Stickler syndrome

• Snead and Yates diagnosis criteria(1)
  congenital vitreous anomaly AND (2) any three
  of (a) myopia with onset before age 6 years,
  (b) rhegmatogenous retinal detachment or
  paravascular pigmented lattice degeneration,
  (c) joint hypermobility with abnormal Beighton
  score, (d) sensorineural hearing loss
  (audiometric confirmation), OR (e) midline
  clefting.

36
Stickler syndrome

• Type I COL2A1, membranous vitreous, normal or
  mild HL
• Type II COL112A, NO ocular findings because not
  expressed in vitreous, HL intermediate
• Type III COL11A1, mod to sev HL
• HL can be SN, C, or mixed
• CHL with ETD secondary to palatal abnormalities
• SNHL Mech unknown, may be due to abnl in inner
  ear pigmented epithelium or collagen

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Syndromic hearing loss AR

• Usher
• Pendred
• Jervell and Lange-Nielsen

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Usher syndrome

• SNHL, retinitis pigmentosa, /- vestibular
  dysfunction
• Prevalence 4.4 per 100,000 in the United States,
  3 to 6 of congenitally deaf persons carrying
  this diagnosis
• The cause of 50 of deaf-blindness in the United
  States
• Dx electroretinography

39

Adapted from Van Camp G, Smith RJH Hereditary
Hearing Loss Homepage, http//dnalab-www.uia.ac.be
/dnalab/hhh/
40
Pendred syndrome

• Hereditary deafness with euthyroid goiter
• AR 7.5 to 10 per 100,000 persons estimated to
  account for 10 of hereditary deafness
• SLC26A4 gene codes for protein pendred
• Pendred protein Chloride/iodide transporter in
  thyroid, inner ear, kidney.

http//ghr.nlm.nih.gov/conditionpendredsyndrome
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Pendred syndrome

• Severe to profound SNHL, often congenital but can
  occur later in infancy or early childhood
  associated with dilated VA or Mondini dysplasia
• Euthyroid goiter develops in second decade of
  life
• Dx positive perchlorate test (not currently
  available) genetic testing now preferred
• Rx T4 to suppress goiter growth (no affect on
  hearing), amplification
• DFNB4 mutation in same gene causes this
  non-syndromic phenotype

42
Jervell and Lange Nielson

• Congenital deafness, prolonged QT interval,
  syncopal attacks
• Estimated incidence 1.6 6 per million
• Prevalence 0.21 of all with congenital deafness
• Heterogeneous with mutations in KVLQT1(Ch11) and
  KCNE1(Ch21) encodes for subunits of the delayed
  rectifier K channel expressed in the inner ear
  and heart. Causes delays in myocellular
  repolarization
• AD long QT syndrome named Romano-Ward syndrome,
  more common, no deafness
• Rx Beta-blockers reduces mortality from 71 to
  6, amplification

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Syndromic hearing loss X-linked

• ALPORTs
• 80 X-linked (COL4A5), AR and AD
  patternsPrevalence 15,000 in U.S.
• Disease of type IV collagen
• Diagnostic criteria-at least 3 of 4 (1)
  positive family history of hematuria with or
  without chronic renal failure (2) histologic
  changes of the glomerular basement membrane of
  the kidney (3) progressive high-freq SN
  deafness (usu by late childhood) and (4)
  typical eye lesion (anterior lenticonus, and/or
  macular flecks) -33

44
Syndromic hearing loss X-linked

• Wildervanck Syndrome
• Seen in females almost exclusively. Prob X-linked
  dominant or polygenic inheritance.
• Comprises the Klippel-Feil malformation
• Congenital fusion of 2-7 cervical vertebrae, SNHL
  or mixed HL related to bony malformation of inner
  ear , 6th nerve palsy, cleft, scoliosis,
  multisytem abnormalities

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Mitochondrial syndromic HL
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Acquired hearing loss

• Most common cause of prenatal hearing loss is
• Intrauterine infection
• Common causes of perinatal HL
• hyperbilirubinemia
• infection
• medication toxicity
• Most common cause of postnatal HL
• meningitis

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Prenatal hearing loss

• Maternal infectionsTORCHES
• Teratogenic drugs Retin A, thalidomide
• Ototoxic drugs

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High-Risk Indicators for Hearing Loss Checklist
of high-risk indicators for hearing loss in
children

• Birth to 28 d
• Family history of sensorineural hearing loss,
  presumably congenital
• In utero infection associated with SNHL (eg,
  toxoplasmosis, rubella, cytomegalovirus, herpes,
  syphilis)
• Ear and other craniofacial anomalies
• Hyperbilirubinemia at levels requiring exchange
  transfusion
• Birth weight less than 1500 g
• Bacterial meningitis
• Low Apgar 03 at 5 min 06 at 10 min
• Respiratory distress (eg, meconium aspiration)
• Prolonged mechanical ventilation for more than 10
  d
• Ototoxic medication (eg, gentamicin) administered
  for more than 5 d or used in combination with
  loop diuretics
• Physical features or other stigmata associated
  with a syndrome known to include SNHL (eg, Down
  syndrome)

• 29 d to 24 mo
• Parental or caregiver concern about hearing,
  speech or language, and/or developmental delay
• Any of the newborn risk factors listed above
• Recurrent or persistent OME for at least 3 mo
• Head trauma with fracture of temporal bone
• Childhood infectious diseases associated with
  SNHL (eg, meningitis, mumps, measles)
• Neurodegenerative disorders (eg, Hunter syndrome)
  or demyelinating diseases (eg, Friedreich ataxia,
  Charcot-Marie-Tooth syndrome)

Joint Committee on Infant Hearing.Year 2000
position statement principles and guidelines for
early hearing detection and intervention.
Pediatrics. 2000106798817.
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Enlarged vestibular aqueduct

• Most common inner ear abnormality detected in
  children with SNHL
• Familial AD inheritance reported, AR cases also
  reported
• At least 40 of those with DVA will develop
  profound SNHL¹
• Associated with Pendreds, Stapes Gusher
  syndrome, lateral SCC dysplasia, Mondini
  deformity²
• Are at risk for progressive HL after minor heard
  trauma³
• CT temporal bone reasonable given frequency of
  finding and for counseling purposes

1.Reilly GP, Lalwani AK, Jackler RK. Congenital
anomalies of the inner ear. In Lalwani A,
Grundfast K, eds. PediatricOtology and
Neurotology. Philadelphia Lippincott-Raven,
1998201210. 2. Shirazi A, Fenton JE, Fagan PA.
Large vestibular aqueduct syndrome and stapes
fixation. J Laryngol Otol 1994108 989990. 3.
Okumura T, Takahashi H, Honjo I, Takagi A,
Mitamura K. Sensorineural hearing loss in
patients with large vestibular aqueduct.
Laryngoscope 1995105289293.
51
Inner ear deformities

• Scheibe dysplasia Cochleosaccular dysgenesis,
  most common inner ear dysplasias, membranous
  defect of pars inferior. AR NS trait
• Michel deformity Complete aplasia of
  labyrinthine capsule common cavity profound HL.
  AD in mice, prob AR forms also
• Mondini deformity Arrest of bony and membranous
  labyrinth in 7th wk of gestation. Small cochlea,
  incomplete partition, widened vestibule and VA.
  Assoc with Pendred, Waardenburg, BOR, TC,
  Wildervanck. AD, AR, syndromic, non-syndromic
• Alexander dysplasia Abnormal cochlear duct.
  Affects the organ of Corti and ganglion cells at
  basal coil. Most common high freq SNHL

Park AH, Kou B, Hotaling A, Azar-Kia B, Leonetti
J, Papsin B. Clinical Course of Pediatric
Congenital Inner Ear Malformations. Laryngoscope
2000110(10)1715-1719.
52
Quiz

• 1 cause of hereditary, nonsyndromic SNHL
• Connexin 26 or gap junction beta 2 gene mutation
• 1 cause of syndromic SNHL
• Usher syndrome
• 1 cause of acquired congenital deafness
• In utero CMV infection
• Approx what with congenital SNHL will have
  abnormal inner ear findings on imaging?
• 20¹

1. Jackler RK, Luxford WM, House WF  Congenital
malformations of the inner ear a classification
based on embryogenesis.   Laryngoscope  1987 97(s
uppl 40)2.
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Superdeafy Doll
www.Deafnation.com
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References

• Cummings
• Morton N Genetic epidemiology of hearing
  impairment. Ann N Y Acad Sci 199163016.
• Brookhouser P. Sensorineural hearing loss in
  children. Pediatr Clin North Am 1996431195216.
• Steel KP. Progress in progressive hearing loss.
  Science 1998279187071.
• McGuirt WT, Smith RJ. Connexin 26 as a cause of
  herditary hearing loss. A, J Audiol
  1999893-100.
• Erbe CB, et al. Connexin 26 and connexin 30
  mutations in children with nonsyndromic hearing
  loss. Laryngoscope 2004114607-11.
• Colvin IB, Beale T, Harrop-Griffiths K. Long-Term
  Follow-up of Hearing Loss in Children and Young
  Adults With Enlarged Vestibular Aqueducts
  Relationship to Radiologic Findings and Pendred
  Syndrome Diagnosis. Laryngoscope.
  116(11)2027-2036, November 2006.
• Madden C, Halsted M, Benton C, Greinwald J Choo,
  D. Enlarged Vestibular Aqueduct Syndrome in the
  Pediatric Population. Otology Neurotology 2003
  24(4)625-632.
• Preciado DA, Greinwald JH, et al. Improved
  Diagnostic Effectiveness with a Sequential
  Diagnostic Paradigm in Idiopathic Pediatric
  Sensorineural Hearing Loss. Otology Neurotology
  200526(4)610-615.Mafong DD, Shin EJ, Lalwani
  AK. Use of Laboratory Evaluation and Radiologic
  Imaging in the Diagnostic Evaluation of Children
  With Sensorineural Hearing Loss. Laryngoscope
  2002112(1)1-7.
• NIH Nonsyndromic Hearing Loss website
  http//ghr.nlm.nih.gov/conditionnonsyndromicdeafn
  essjsessionid56ECF4F9E59A9D2D737D6909F66A4F90
• Reilly GP, Lalwani AK, Jackler RK. Congenital
  anomalies of the inner ear. In Lalwani A,
  Grundfast K, eds. Pediatric Otology and
  Neurotology. Philadelphia Lippincott-Raven,
  1998201210.
• Jackler RK, Luxford WM, House WF  Congenital
  malformations of the inner ear a classification
  based on embryogenesis.   Laryngoscope  1987 97(s
  uppl 40)2.
• Park AH, Kou B, Hotaling A, Azar-Kia B, Leonetti
  J, Papsin B. Clinical Course of Pediatric
  Congenital Inner Ear Malformations. Laryngoscope
  2000110(10)1715-1719.
• Shirazi A, Fenton JE, Fagan PA. Large vestibular
  aqueduct syndrome and stapes fixation. J Laryngol
  Otol 1994108989990.
• Okumura T, Takahashi H, Honjo I, Takagi A,
  Mitamura K. Sensorineural hearing loss in
  patients with large vestibular aqueduct.
  Laryngoscope 1995105289293.
• Anonymous Joint Committee on Infant Hearing.Year
  2000 position statement principles and
  guidelines for early hearing detection and
  intervention. Pediatrics. 2000106798817.
• Chang EH, Menezes M, Meyer NC, Cucci RA, Vervoort
  VS, Schwartz CE, Smith RJ (2004)
  Branchio-oto-renal syndrome the mutation
  spectrum in EYA1 and its phenotypic consequences.
  Hum Mutat 2004 23582-9.
• Baileys