Genetic Hearing Loss

Alice Lee Resident Conference March 8, 2007

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

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

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

Exam
Goldenhar facies Bilateral weak facial motion, lower>upper Bilateral opacified corneas? Lens? PERRL Bilateral EAC atresia with microtia Exam otherwise unremarkable

Audiogram

CT

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 2002;112(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 2005;26(4):610-615.

Algorithm for SNHL eval/mgmt

Recommendations: Unilteral SNHL: Imaging only Sev to profound SNHL: GJB2 Milder SNHL: Imaging All: EKG low yield but easy Labs:ONLY if H&P 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 2005;26(4):610-615.

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

What is your differential diagnosis?

200+ syndromes associated with hearing loss

39 AR, 51 AD, 5 X-linked, 2 mitochondrial loci

1. Morton N: Genetic epidemiology of hearing impairment. Ann N Y Acad Sci 1991; 630:16 2. Brookhouser P. Sensorineural hearing loss in children. Pediatr Clin North Am 1996;43:1195216. 3. Steel KP. Progress in progressive hearing loss. Science 1998;279:187071. 4. McGuirt WT, Smith RJ. Connexin 26 as a cause of herditary hearing loss. A, J Audiol 1999;8:93-100.

Non-syndromic hearing loss

HL in the absence of other phenotypic manifestations 70% of hereditary HL 80% AR, 18%AD, 2% X-linked or mitochondrial DFN = nonsyndromic deafness A=AD, B=AR, _=X-linked
1. Erbe CB, et al. Connexin 26 and connexin 30 mutations in children with nonsyndromic hearing loss. Laryngoscope 2004;114:607-11 2. Cummings

Non-syndromic hearing loss

AD: Usually onset of deafness is postlingual, progressive, milder AR: Usually prelingual and severe to profound across all frequencies DFNB1 gene (Ch 13q11-12)/GJB2/connexin 26 X-linked: Most common locus:DFN3. Mixed HL Congenital stapes fixation (stapedectomy with perilymph gusher CT findings: widening of the lateral internal auditory canal and vestibule dilation Other loci with variable HL

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

Syndromic hearing loss

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

Cummings

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)

OAV syndrome
Name suggested by Gorlin 1990 to encompass spectrum seen in hemifacial microsomia, Goldenhar, first and second brachial arch anomalies Est incidence 1:5,500 live births Etiology: heterogeneous; possible vascular insult to 1st and 2nd BA Actually thought to be sporadic, multifactorial. AD and AR variants reported

OAV syndrome - OMENS

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

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

Neurofibromatosis II
Incidence: 1:40,000 to 1:90,000 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, PLUS a) unilateral vestibular schwannomas at <30 years of age; OR (b) any two of meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract

Neurofibromatosis II
Hearing loss Usually high frequency and SNHL Acoustic neuromas observation vs surgery vs gamma knife Auditory brainstem implants

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 loss 50% mixed, 30%conductive

Branchio-Oto-Renal syndrome
Major and Minor Diagnostic Criteria for Branchiootorenal Syndrome Major Criteria Second branchial arch anomalies Minor Criteria External auditory canal anomalies

Deafness
Preauricular pits Auricular deformity Renal anomalies

Middle ear anomalies

Inner ear anomalies Preauricular tags Other: facial asymmetry, palate abnormalities

Chang EH, Menezes M, Meyer NC, Cucci RA, Vervoort VS, Schwartz CE, Smith RJ. Branchio-otorenal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences. Hum Mutat 2004;23:582-9

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

Branchio-Oto-Renal syndrome
Branchial anomalies: Laterocervical fistulas, sinuses, and cysts Renal anomalies: Found in 25% Ranging from agenesis to dysplasia Less common phenotypic anomalies: Lacrimal duct aplasia, short palate, retrognathia

Waardenburg syndrome
Type Gene Clinical findings 20% SNHL (unilat or bilat), pigmentary abnormalities (white forelock, heterochromia irides, patchy skin depigmentation), dystopia canthorum Synophrys, broad nasal root, hypoplasia of the alae nasi, patent metopic suture, and a square jaw Congenital hearing loss in 36% to 66.7% No dystopia canthorum (displacement of inner canthi and lacrimal punctum) Congenital hearing loss in 57% to 85%

WS type I

AD

PAX3

WS type II

AD

MITF

WS type II

SLUG

WS type III WS type IV

AD AR

PAX3 EDNRB

WS type I features + hypoplasia or contracture of the upper limbs + Hirschsprung disease

WS type IV

EDN3

+ Hirschsprung disease

WS type IV

SOX10

+ Hirschsprung disease

Stickler syndrome
Prevalence 1:10,000 Mutations in either COL2A1, COL11A2, or CO11A1, genes that encode for the constituent proteins of type II and type XI collagen Craniofacial anomalies: midfacial flattening, mandibular hypoplasia, short upturned nose, long philtrum. Pierre Robin sequence in 28-65% Submucous clefting is most common

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.

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

Syndromic hearing loss: AR

Usher Pendred Jervell and Lange-Nielsen

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

Usher

Subtype

Gene

Protein

Location

Hearing Loss

Retinitis Pigmentosa Childhood

Vestibular Dysfxn Yes

+USH2A= 80% of all USs

Usher I

USH1A

N/A

N/A

14q32

Profound

*USH1B

MYO7A

Myosin VIIA

11q13.5

Profound

Childhood

USH1C

USH1C

Harmonin

11p15.1

Profound

Childhood

USH1D

CDH23

Cadherin23

10q

Profound

Childhood

USH1E

N/A

N/A

21q21

Profound

Childhood

USH1F

PCDH15

Protocadherin15

10

Profound

Childhood
Most Common form in US

Usher II

*USH2A

USH2A

Usherin

1q41

Progression? Sloping
Sloping

20s-30s

No

USH2B

N/A

N/A

3p23-24.2

20s-30s

USH2C

N/A

N/A

5q14.3-21.3

Sloping

20s-30s Variable onset; Adult

Usher III

USH3

USH3A

Clarin-1

3q24

Progressive

Variable

Variable

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

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/condition=pendredsyndrome

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

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

Syndromic hearing loss: X-linked

ALPORTs 80% X-linked (COL4A5), AR and AD patterns Prevalence ~1:5,000 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%

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

Mitochondrial syndromic HL
Syndrome MELAS Mutation
Mitochondrial Encephalopathy, Lactic Acidosis, Strokelike episodes

Hearing Loss
Hearing loss in 30% cases

HL: high freq, SN, bilateral, progressive Temp bone histo: Severe atrophy of the stria vascularis

Point mutation

MERRF

Myoclonic epilepsy and red ragged fibers

Hearing loss, ataxia, dementia, optic nerve atrophy, and short stature Progressive external ophthalmoplegia, atypical retinal pigmentation, and heart block typically commencing before the age of 20 Temp bone histo: Cochleosaccular degeneration

Point mutation

Kearns-Sayre

Hearing loss in 50% of cases

Large deletions and duplications in mtDNA 0.5% to 2.8% of diabetic patients Affected: 1st Basal turn OHCs, then apical OHCs and IHCs

NIDDM Susceptibility to AG toxicity

Hearing loss: late, progressive, bilateral, high frequency A1555G found in 17% to 33% of persons with aminoglycosideinduced hearing loss, which makes the 12S ribosomal RNA gene more similar to bacterial rRNA.

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

Prenatal hearing loss

Maternal infections TORCHES Teratogenic drugs Retin A, thalidomide Ototoxic drugs

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. 2000;106:798817.

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 SNHL Associated with Pendreds, Stapes Gusher syndrome, lateral SCC dysplasia, Mondini deformity Are at risk for progressive HL after minor heard trauma 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, 1998:201210. 2. Shirazi A, Fenton JE, Fagan PA. Large vestibular aqueduct syndrome and stapes fixation. J Laryngol Otol 1994;108: 989990. 3. Okumura T, Takahashi H, Honjo I, Takagi A, Mitamura K. Sensorineural hearing loss in patients with large vestibular aqueduct. Laryngoscope 1995;105:289293.

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 2000;110(10):1715-1719.

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? 20%
1. Jackler RK, Luxford WM, House WF: Congenital malformations of the inner ear: a classification based on embryogenesis. Laryngoscope 1987; 97(suppl 40):2.

Superdeafy Doll

www.Deafnation.com

References
Cummings Morton N: Genetic epidemiology of hearing impairment. Ann N Y Acad Sci 1991;630:16. Brookhouser P. Sensorineural hearing loss in children. Pediatr Clin North Am 1996;43:1195216. Steel KP. Progress in progressive hearing loss. Science 1998;279:187071. McGuirt WT, Smith RJ. Connexin 26 as a cause of herditary hearing loss. A, J Audiol 1999;8:93-100. Erbe CB, et al. Connexin 26 and connexin 30 mutations in children with nonsyndromic hearing loss. Laryngoscope 2004;114:607-11. 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 2005;26(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 2002;112(1):1-7. NIH Nonsyndromic Hearing Loss website: http://ghr.nlm.nih.gov/condition=nonsyndromicdeafness;jsessionid=56ECF4F9E59A9D2D737D6909F66A4F90 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, 1998:201210. Jackler RK, Luxford WM, House WF: Congenital malformations of the inner ear: a classification based on embryogenesis. Laryngoscope 1987; 97(suppl 40):2. Park AH, Kou B, Hotaling A, Azar-Kia B, Leonetti J, Papsin B. Clinical Course of Pediatric Congenital Inner Ear Malformations. Laryngoscope 2000;110(10):1715-1719. Shirazi A, Fenton JE, Fagan PA. Large vestibular aqueduct syndrome and stapes fixation. J Laryngol Otol 1994;108:989 990. Okumura T, Takahashi H, Honjo I, Takagi A, Mitamura K. Sensorineural hearing loss in patients with large vestibular aqueduct. Laryngoscope 1995;105:289293. Anonymous: Joint Committee on Infant Hearing.Year 2000 position statement: principles and guidelines for early hearing detection and intervention. Pediatrics. 2000;106:798817. 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 23:582-9. Baileys