Molecular genetic advances in semicircular canalabnormalities and sensorineural hearing loss: A report of 16casesKATHY K. YU, MD, SURESH MUKHERJI, MD, VINCENT CARRASCO, MD, HAROLD C. PILLSBURY, MD, and CAROL G. SHORES, MD,
PHD, Chapel Hill, North Carolina, and Ann Arbor, Michigan
OBJECTIVES: The study goals were (1) to determineif the degree and pattern of semicircular canal dys-morphology and the presence or absence of acochlea in patients with congenital sensorineuralhearing loss predict audiologic outcome, severity,or the frequencies involved and (2) to review therecent advances in molecular genetics of the semi-circular canals and correlate this information withaudiologic and anatomic patterns seen in our se-ries of patientsDESIGN AND SETTING: We conducted a retrospec-tive study at a tertiary care center with a largeotologic and cochlear implant service.PATIENTS AND METHODS: The study populationconsisted of 16 patients with congenital sensori-neural hearing loss in 28 congenitally malformedinner ears consisting of semicircular canal dys-plasia or aplasia, with or without cochlear malfor-mation. History, physical examination, computedtomography scans, and serial audiograms werereviewed. Factors analyzed included other phe-notypic dysmorphology characteristic of syn-dromes, audiometric configuration, severity andtype of hearing loss, and the presence of associ-ated inner ear anomalies other than the vestibularsystem. An extensive review of the literature re-garding molecular genetic factors in semicircularcanal anomalies, with or without cochlear abnor-malities, was performed.RESULTS: Sixteen patients (31 ears) were identifiedwith profound sensorineural hearing loss and semi-
circular canal abnormalities. Only 3 patients hadknown syndromes, although 4 patients had othercongenital anomalies. Most radiographic detect-able abnormalities were bilateral. Audiograms ofthe patients demonstrated pure tone averages be-tween 90 and 100 dB in the affected ears with fewexceptions. No correlation was found betweentype and severity of malformation of either the co-chlea or semicircular canals with the severity ofhearing loss. There was no stepwise progression ofhearing loss increasing malformation severity.Seven of the 16 patients received cochlear im-plants. Of these 7, 3 patients had cochlear hyp-oplasia and 1 patient had a common cavity defor-mity. Audiologic follow-up on all 7 patientsrevealed improvement in both speech assessmentthreshold and pure tone average. Presence or ab-sence of the cochlea was not a factor in outcomeafter cochlear implantation.CONCLUSION: We have assembled the largest se-ries of patients with semicircular canal dysmor-phology, with or without various cochlear abnor-malities. Our study failed to correlate the typeand severity of semicircular canal malformationwith any specific audiologic outcome. The varia-tion in hearing loss severity and pattern even inpatients with similar bony radiographic findingsmust be explained by other non–radiologicallydetectable defects, likely abnormalities in mem-branous labyrinthine development. New molecu-lar genetic discoveries have linked specificgenes to the development of certain inner earstructures in mice studies. The independent de-velopment of the individual semicircular canals inrelation to the cochlea and vestibule and thevariability in hearing loss suggest a more com-plex embryologic process than merely an arrestin development as previously thought. As geneticstudies are extended into humans, we will likelybe able to stratify these patients by moleculardefect and severity of hearing loss. (OtolaryngolHead Neck Surg 2003;129:637-46.)
One in 750 infants has sensorineural hearing loss(SNHL), equaling approximately 2000 to 4000
From the Departments of Otolaryngology–Head and NeckSurgery (Drs Yu, Carrasco, Pillsbury, and Shores) and
Neuroradiology (Dr Mukherji), University of North Carolina–Chapel Hill; Dr Mukherji is now in the Department ofRadiology, University of Michigan.
Reprint requests: Carol G. Shores, MD, PhD, Department ofOtolaryngology, Ground Floor, Neurosciences BuildingCB 7600, University of North Carolina–Chapel Hill,Chapel Hill, NC. 27514; e-mail, [email protected].
hearing impaired infants born per year in theUnited States.1 The etiology of congenital hearinglosses is varied. Genetic factors such as hereditarydisorders and chromosomal abnormalities causecongenital hearing loss mediated by embryologicarrest and other defects in embryogenesis. Otheretiologies include prenatal infection and toxic ex-posures in utero. Congenital hearing loss can be anisolated finding or represent part of a syndrome,with about one third of hearing loss related tosyndromes.
The adult inner ear is divided into an auditoryapparatus, consisting of the organ of Corti in thecochlea, and a vestibular apparatus, consistingof the saccule, utricle, and semicircular canals(SCCs). These structures are composed of amembranous labyrinth encased in a bony laby-rinth, situated in the petrous portion of the tem-poral bone. The inner ear develops from a thick-ening of ectoderm on the lateral surface of theneural tube termed the otic placode. Duringweek 4 of human gestation, the otic placodeinvaginates into underlying mesenchyme, form-ing the otic vesicle (otocyst). The mesenchymesurrounding the otocyst is the precursor of thecartilaginous capsule of the otocyst termed theotic capsule.
The membranous labyrinth is composed ofthe pars inferior, which gives rise to the mem-branous cochlea and saccule, and the pars supe-rior, the phylogenetically older structure, whichgives rise to the SCC, utricle, and endolym-phatic duct. The vestibular structures begin de-velopment during week 6 of human gestationand attain adult configuration by 8 weeks. SCCembryogenesis first appears as diverticular out-pouchings in the dorsal portion of the otocystduring week 6 of gestation. The lateral wall ofthese outpouchings delaminates from the under-lying mesenchyme and grows toward the medialwall, forming a fusion plate. This fusion plateeventually disappears to form the characteristicclosed tubular form of the SCC.2 The lateralSCC (LSCC), also called the horizontal canal,is the last to mature and is more susceptible toanomalous development. The membranous co-chlea differentiates from the ventral portion ofthe otocyst at week 7 of gestation. The numberof turns of the cochlea increases with progres-
sive development. The adult configuration of 21/2 to 2 turns form by week 8 of gestation. Theendolymphatic sac forms from the dorsal por-tion of the otocyst at week 6 of gestation and isthe only inner ear structure to continue to growafter birth. The hair cells and auditory sensorynetwork are largely complete by week 26 to 28of gestation.
The bony labyrinth encloses the membranouslabyrinth and forms in 3 stages. The initial stageoccurs between weeks 4 and 6 of gestation andconsists of mesenchymal condensation sur-rounding the membranous labyrinth. The secondstage involves the formation of the bony vesti-bule, which encloses the utricle, saccule, andcochlear duct. The perilymph-filled scala tym-pani and scala vestibuli surrounding the en-dolymph-filled cochlear duct form at this time.The third stage involves ossification of the oticcapsule, which begins at week 15 of gestation.Ossification begins in 14 centers and is com-plete by week 23 of gestation, resulting in theformation of the petrous portion of the temporalbone.
Jackler et al2 published a classification systemin 1987 to standardize the description of innerear abnormalities. They noted that the hierarchyof radiographically detectable malformationscorresponded to the embryologic developmentof inner ear structures, indicating that the spec-trum of malformations can be explained by anarrest in the normal development of the innerear at different times. Their classification sys-tem included malformations of both the osseousand membranous labyrinths, based on cochlearinvolvement. The theory behind their classifica-tion system focused on arrest in development atvarious stages of embryogenesis. For example,an arrest in development at the primitive oticplacode would result in complete labyrinthineaplasia—the Michel deformity. Failure of theotocyst to differentiate would result in the com-mon cavity deformity, first described by EdwardCock. Arrested development of the cochlear budwould result in cochlear aplasia with a normalvestibule and SCC. Arrest in progressive co-chlear development would result in varying de-grees of cochlear hypoplasia. The classic Mon-dini deformity is formation of the basal turn of
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the cochlea with a sac instead of the apicalturns. Other variations in malformations mayresult from aberrant rather than arrested devel-opment. This was an attractive hypothesis toexplain the myriad of malformations that wereseen in radiographic studies.2 However, Parnesand Chernoff3 challenged the hypothesis in1990 when they were the first to report 2 casesof bilateral SCC aplasia with concomitant nor-mal or near-normal cochlear development. Thisreport conflicted with the traditional hypothesisthat malformations of the inner ear resultedfrom arrest of development since the SCC de-velops during week 6 of gestation and the co-chlea develops during week 7 of gestation.
This is a retrospective study of 16 patientswith 28 congenitally malformed labyrinths. Inlight of recent molecular genetic discoverieslinking specific genes to development of certaininner ear structures in mice, we also present adiscussion of these studies. The discovery ofhomologous genes that, when mutated, causecochlear and vestibular aberrancies in mice mayhave many applications in humans. As geneticstudies are extended into humans, we will likelybe able to stratify patients by molecular defect.
PATIENTS AND METHODSPatients from 16 different families were com-
piled through the Department of Otolaryngologyat a tertiary care university hospital with a largeotologic and cochlear implant (CI) practice. Allpatients were identified by temporal bone com-puted tomography (CT), which were obtainedfor the evaluation of SNHL and possible co-chlear implantation. The criterion for inclusionin this study was unilateral or bilateral SCCdysplasia or aplasia identified by CT, regardlessof the status of cochlear development. We didnot exclude or specifically target patients withknown syndromes or other phenotypic abnor-malities. The audiograms of each patient werethen reviewed to determine if (1) the severity ofdysmorphology correlated with the severity ofhearing loss, (2) the unilateral deformities cor-related with normal hearing on the contralateralside, and (3) certain frequencies or audiologicpatterns were more commonly affected with cer-tain anatomic patterns. Audiograms from initial
presentation were analyzed and compared withpost-CI audiogram, if applicable, to determinewhether the severity of radiologic abnormalityimplied poorer outcome after cochlear implan-tation.
CT findings were divided into ossicles, vesti-bule, cochlea, vestibular aqueduct, SCC (lateral,posterior, superior), external auditory canal(EAC), and oval window. Radiologic interpreta-tions were based on the following definitions:small cochlea (�7 mm in diameter measured ver-tically [normal, 8 to 10 mm]), enlarged vestibule(�5 mm in vertical dimension), and enlarged ves-tibular aqueduct (�2 mm in diameter in its in-traosseous portion). Mondini malformation wasdefined as formation of the basal turn of the co-chlea with a sac instead of the apical turns.
RESULTSSixteen patients (28 ears) were identified (Ta-
ble 1). A majority of the cases were nonsyn-dromic. Three patients had defined syndromes:2 children with CHARGE (Coloboma, Heartdefects, Atresia choanae, Retardation of growthand development, Genitourinary problems, andEar abnormalities) association and 1 with Gold-enhar syndrome. Three patients had other nono-tologic congenital anomalies: specifically tetra-ology of Fallot, esophageal atresia, and cleftlip/palate. Only 2 patients had abnormalities ofthe middle ear, consisting of a lateralized incusand fusion of the malleus and incus. This wasnot surprising considering the distinctly sepa-rate embryologic origins of the middle and innerear.
Twelve patients had bilateral deformities, withanatomic patterns on each side usually identical.Those with unilateral deformities (patients 10, 12,15, and 16) demonstrated normal hearing on theunaffected side and profound SNHL on the radio-graphically abnormal side.
Six of 16 patients had complete aplasia of theSCC (12 ears). Of the 12 ears, 7 had normalcochleas and vestibules, 1 had bilateral cochlearhypoplasia, 1 had an ipsilateral Mondini mal-formation, and 1 had bilateral Mondini malfor-mations. Two patients had common cavities (3ears) with associated malformation of the SCC.Five patients had classic Mondini malforma-
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tions (9 ears). Of these 5 patients, 1 had SCCaplasia, 3 had SCC dysplasia, and 1 had pre-served SCC with only a dilated crus of thesuperior canal noted. Three of the 16 had iso-lated lateral SCC dysplasia (patients 6, 15, and16). One of the 16 had isolated superior SCCdysplasia (patient 11). Three of the 16 had com-plete aplasia of the posterior SCC (patients 1, 2,and 10), with some development of the lateraland superior SCC. Of these 3, patient 10 hadGoldenhar syndrome with normal lateral andsuperior SCC bilaterally and a normal posteriorSCC on the contralateral side. Patients 1 and 2had dysplastic but present lateral and superiorSCC. The vestibular aquaduct was normal bilat-erally in all cases.
Audiograms of the patients demonstratedpure tone averages (PTAs) between 90 and 120dB in the affected ears with a few exceptions
(Table 2). There was no PTA better than 55 dBat the time of initial presentation. The data dem-onstrate no specific patterns of audiologic find-ings that would correlate with the severity ofcochlear radiographic findings. Patients with de-formities that preserved the cochlear architec-ture did not consistently have better hearingthan patients with cochlear malformations. Forexample, patient 12 with a common cavity hadthe best PTA in this series of patients.
Seven of the 16 patients received a CI (Table 2).Age at implantation ranged from 1.8 to 6 years.Implanted cochleas ranged from normal (3 pa-tients) to hypoplastic (3 patients) to a commoncavity (1 patient). There were no intraoperative orpostoperative complications.
Audiologic follow-up was available for 0 to12 months after implantation. Improvements inspeech assessment thresholds (SAT) and PTAs
Table 1. Computed tomography findings of patients with congenital sensorineural hearing loss andsemicircular canal abnormalities
Patient/Age/other dx Ossicles Vestibule Cochlea
LateralSCC
PosteriorSCC
SuperiorSCC EAC
OvalWindow
1/6 y Nl (B) CC (B) CC (B) Dys (B) Apl (B) Dilatedbases (B)
Age, Age when computed tomography scan performs; SCC, semicircular canal; EAC, external auditory canal; B, bilateral; R, right; L, left; Nl,normal; CC, common cavity; Enl, enlarged; Abn, abnormal; Apl, aplastic; Hypo, hypoplastic; Dys, dysplastic; Mnd, Mondini malformation;CHARGE association: Coloboma, Heart defects, Atresia choanae, Retardation of growth and development, Genitourinary problems, and Earabnormalities; TOF, tetralogy of Fallot; TEF, tracheoesophageal fistula.
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were independent of cochlear maldevelopment(Table 2). The common cavity patient had agood result with an SAT of 30 dB and a PTA of35 dB. The patients with cochlear hypoplasia/Mondini malformation had postoperative SATsof 10 to 50, whereas the patients with normalcochleas had SATs ranging from 5 to 25 dB.Patient 3 has CHARGE association and at1-year follow-up, his auditory brainstem re-sponse (ABR) indicated responses but his per-formance remains poor with PTAs of 60 to 80dB. Although with only 7 patients with CI it isnot possible to prove statistical significance, allof the implanted patients achieved improvementin both SAT and PTA.
DISCUSSIONOf the patients with congenital SNHL, 30%
demonstrate abnormalities on radiographic stud-
ies, emphasizing the significance of both themembranous and osseous components of theinner ear with regard to functional hearing.4 Asa general rule, it was believed that the moresevere the radiographic abnormality, the poorerwas the hearing. However, this was not the casein our study. There was variation in hearing lossfrequencies even among patients with very sim-ilar osseous anomalies. Our analysis failed tofind any correlation between severity of hearingloss and frequencies involved with radiographicabnormality. The hearing loss associated withSCC dysplasias is most likely due to anomalousmembranous labyrinth development, which isnot radiologically detectable.
The hierarchy of development or maldevelop-ment of the SCC is most likely not simply anarrest in embryogenesis, as has been previouslysuggested. The high degree of variability in
Table 2. Radiographic findings with associated audiologic data in patients with sensorineural hearing lossand semicircular canal abnormalities
Patient
Audio at diagnosis(poorer hearing
ear))PTA at diagnosis
(poorer hearing ear)Post CI audio-
(implanted ear)
Post CI PTA(implanted
ear)
1 SAT NR aided 120, 130, 120 SAT 30 dB 35, 35, 302 SRT (R) 80dB 100, 90, 100 SAT 10dB 25, 30, 30
SRT (L) 90dB3 SAT (B) 80 dB 110, 110, 110 SRT 50 dB 60, 65, 804 SAT (R) NR 125, 125, 120 SAT 10 dB 25, 30, 30
SAT (L) 80 dB5 SET (R( 115dB 90, 80, 90 SAT 5dB 25, 25, 30
SRT (L) 110dB6 SAT (R) 50dB 70,70,70 SAT 25dB 40, 40, 457 SAT NR at 90dB 120, 130, 120 SAT 25 dB 30, 30, 308 SRT (R) 75dB 120, 120, 120
SRT (L) 15dB13 Not available Not available14 Not available Not available15 SAT (R) 80dB 105, 110, 110
SAT (L) 45dB16 SAT (R) NR 90, 110, 110
SAT (L) 10
SAT, Speech assessment threshold; SRT, speech reception threshold; dB, decibels; NR, nonreactive; PTA, pure tone average.
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radiologic findings or associated cochlear mal-formations argues against a single classificationsystem based on embryogenic arrest. With theadvent of new molecular genetic information, amuch more complex story evolves regarding theetiology and pathogenesis of SCC anomalies.
Molecular genetic research is progressing atan astonishing rate, fueled by innovative tech-nologies such as knockout mice, which allowresearchers to examine the effect of a singlegene inactivation. Disruption of specific genescan result in gross structural abnormalities, as
seen in patients reviewed here, or in disruptionof cellular functions within a normal bony lab-yrinth and cochlea.5 This discussion concen-trates on the former type of mutations.
Genes with mutations leading to gross ana-tomic alteration of the inner ear of mice gener-ally encode transcription factors (Table 3). Mu-tation in these genes results in a variety of innerear defects with variable penetrance (Fig 2).Transcription factors are proteins that modulatethe expression of other genes. During embry-onic development, transcription factors serve
Fig 1. Axial and coronal CT scans of these 3 patients with SNHL demonstrate complete aplasia of the SCCs with normaldevelopment of the cochlea and vestibule.
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critical roles as switches in the elaboration ofgeneral body plan, organ commitment, and dif-ferentiation of specific cell types. Most of thegenes discussed display variable penetrance ofabnormalities, even in knockout mice. Tran-scription factors ultimately act in an all-or-nonefashion: either the regulated gene is turned on ornot, and many transcription factor genes areredundant, with more than one (particularly inthe same family) functioning to activate thesame genes. For example, Hoxa1 knockoutshave variable inner ear dysmorphogenesis,while Hoxa1/Hoxb1 double mutants have uni-form hypomorphic development of the innerear.6 Mutations in the homoebox genes Prx1 andPrx2 also act synergistically in the developmentof inner ear abnormalities. If activation dependson the local concentration of related transcrip-tion factors and one gene is mutated, than by asimple twist of fate some cells will turn on thedownstream genes, and some will not. This re-sults in variable deficiencies from one individ-ual to another, even when the same mutation isexpressed in identical genetic backgrounds.
Mutations in Hoxa2, Hoxa1/Hoxb1, Kreisler,and Fgf3 result in aplasia/dysplasia of the entireinner ear5,7 (Fig 2). Patients 1, 7, 12, and 14 haveabnormalities that span all areas of the inner earand may harbor mutations in the human homo-logues of these genes. Interestingly, patients 1 and7 underwent successful implantation, proving thatsome cochlear nerve fibers had formed in the innerear and could support auditory signaling.
Two transcription factors, Nkx5-1 and Pax2,are expressed in a complementary pattern in theotic placode and vesicle in mice.2 Homozygousmutation in Nkx5-1, also called Hmx3, results inaplasia of most of the vestibular system withapparently normal hearing, whereas homozy-gous mutations of Pax2 result in cochlear apla-sia.9 Nkx5-1 mutant mice show no defects inhearing ability nor display any morphologic orhistologic abnormalities of the cochlea.10 Thissuggests that the cochlea and vestibule developvia independent mechanisms and do not inter-change critical information during their devel-opmental course. Another gene mutation thatcan affect all 3 SCCs is netrin-1.10,11 netrin-1 isexpressed at high levels in otic epithelium, par-ticularly around cells of the SCC fusion plate.When mutated, no posterior or lateral SCCsform and the superior SCC is diminished. It isbelieve that netrin-1 is involved in stimulatingmesenchyme to push together the medial andlateral walls of the fusion plate. netrin-1 is notexpressed in hair cells, and all sensory areas,including the cochlear ganglions, develop nor-mally in netrin-1 mutant mice.
Malformation of all 3 SCCs was the mostcommon pattern seen in our patients. Patients 2,5, 9, and 13 had abnormalities of all 3 SCCswith normal cochleas, whereas patients 3, 4, and14 also had similar SCC abnormalities alongwith Mondini malformations of the cochlea. The2 patients in our series with CHARGE associa-tion both had aplasia of the semicircular canals.In a series of 15 patients with semicircular canal
Table 3. Genes with mutations leading to gross structural abnormalities of the inner ear
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Fig 2. Mutations that alter the morphology of the inner ear. Phenotypes can vary between individual mice within the samestrain, between strains of mice, and for different mutation. Shaded areas indicate malformations that result from mutationsin these genes. (Reproduced with permission from Fedete 1999.6) (Asc, ascending semicircular canal; cc, common crus;ed, endolyphatic duct; es, endolymphatic sac; hsc, horizontal semicircular canal; psc, posterior semicircular canal; s,saccule; u � utricle.) The most severe phenotypes are shown.
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aplasia, Satar et al12 found 9 patients withCHARGE association. Patient 8 had 3 abnormalSCCs, with 1 normal cochlea and 1 Mondinimalformation. The human homologues ofNkx5-1 or netrin-1 may be mutated in this pa-tient population. All of our patients were origi-nally selected because of hearing loss, so that ifthe human homologue of Nkx5-1 were involvedin these changes, mutations would have a dif-ferent phenotype in mice and humans. It may bepossible to define a human population with anaplastic vestibular system but normal hearing,by obtaining temporal bone CT scans oforchil-dren with a developmental delay in walking(�18 months). This vestibular phenotype isseen in children with Usher’s syndrome type 1,who lack a functional vestibular system, buthave normal temporal bone CT scans.13,14
In our series, the most common isolated SCCmalformation is seen in the lateral SCC (patients6, 15, and 16). In mice, genetic pertubations alsomost often affect this canal.5 Mutations in otx1lead to isolated malformations of the lateralSCC and lateral ampulla.15 Changes in the prx1/prx2 gene pair lead to aplasia of the lateral SCCand diminished superior and posterior SCCs,16
and Nkx5-1 mutations preferentially affect thelateral SCC.2,10 The maxim “embryology reca-pitulates phylogeny” is a recurring theme indevelopmental biology. This maxim emphasizesthe relationship between a structure’s phyloge-netic age and its resistance to developmentalabnormalities.16 The lateral SCC is phylogeneti-cally the most recent, as demonstrated by jaw-less vertebrates that exhibit a 2-canal inner earcomposed of the anterior (superior) and poste-rior SCC.6 This suggests that Nkx5-1, otx1, andprx1/prx2 are responsible for lateral SCC devel-opment and their human homologues may bemutated in patients exhibiting this abnormality.
Our series of patients exhibit a wide range ofinner ear structural abnormalities. Parallel phe-notypes are seen in mice and humans, and asmurine phenotypes are translated into humangenetics, it will be possible to direct genetictesting of patients with inner ear abnormalities.This will lead to effective genetic counseling forthese families. So far, we have had reasonableresults with cochlear implantation in these pa-
tients, but it is likely that some mutations thatresult in cochlear nerve abnormalities will notsupport cochlear implants. For example, muta-tions in the mouse transcription factor neuroge-nin-1 results in the failure of development of allinner ear neural elements, including the spiraland vestibular ganglia.17 Humans with a similarphenotype would undoubtedly fail to respond tocochlear implantation. Specific genetic testingwill allow the eventual identification of patientswho will and will not benefit from cochlearimplantation.
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