Pediatr Radiol (2006) 36: 309–324 DOI 10.1007/s00247-005-0042-9
REVIEW
Caroline D. Robson
Congenital hearing impairment
Received: 17 March 2005 / Revised: 10 August 2005 / Accepted: 14 September 2005 / Published online: 8 February 2006 # Springer-Verlag 2006
Abstract Establishing the etiology of congenital hearing impairment can significantly improve treatment for certain causes of hearing loss and facilitates genetic counseling. High-resolution CT and MRI have contributed to the evaluation and management of hearing impairment. In addition, with the identification of innumerable genetic loci and genetic defects involved in hearing loss, genetic testing has emerged as an invaluable tool in the assessment of hearing impairment. Some of the common forms of congenital hearing loss are reviewed and their imaging features illustrated. Keywords Hearing loss . Temporal bone
Introduction Profound congenital hearing impairment is the most frequently occurring birth defect, with an estimated incidence of approximately 0.8–3:1,000 births in the US, with geographic and temporal variation [1, 2]. In the era of immunization, about 50% of cases are estimated to be genetic, with the remainder of cases attributed to environmental causes such as congenital infection, fetal ototoxic drug exposure and trauma. Screening for hearing loss during the newborn period has led to the early detection and diagnosis of deafness as well as to timely intervention. Diagnostic evaluation of infants with positive screening results can include imaging. This review is aimed at describing some of the more common forms of congenital hearing impairment (Table 1) that have associated imaging features. Limited examples of normal temporal bone CT
C. D. Robson (*) Division of Neuroradiology, Department of Radiology, Children’s Hospital and Harvard Medical School, 300 Longwood Ave., Boston, MA 02115, USA e-mail:
[email protected] Tel.: +1-617-3554283
and MR anatomy are shown, focusing primarily on inner ear structures. The Joint Committee on Infant Hearing, of the American Academy of Audiology, American Academy of Pediatrics, American Speech-Language-Hearing Association, and Directors of Speech and Hearing Programs in State Health and Welfare Agencies, originally established in 1969, recommends universal screening for hearing loss in newborns and promotes follow-up, diagnosis and early intervention for infants needing additional care. The goal of this program is to maximize linguistic and communicative competency and the development of literacy in children who are hard of hearing or deaf [3]. Earlier detection of hearing impairment has been facilitated by the development of automated audiologic screening algorithms. Currently in the US, almost 90% of newborns are screened for hearing impairment prior to leaving the hospital [2]. Hearing impairment is defined as permanent, unilateral or bilateral, sensory or conductive loss, averaging 30 dB or more in the frequency region important for speech recognition modes of testing [3]. Hearing loss as defined by these criteria has effects on communication, cognition, behavior, socioemotional development, and academic outcomes as well as subsequent vocational opportunities [4]. Mild hearing loss or hearing loss related to auditory neuropathy or neural conduction disorders might not be detected by initial screening, so any infant who demonstrates delayed auditory and/or communication development should receive subsequent audiologic assessment. Because normal hearing at birth does not preclude delayed onset or acquired hearing loss, indicators have been established that help identify infants at risk who should receive ongoing audiologic and medical monitoring and surveillance [3]. Current physiologic methods used to detect unilateral or bilateral hearing impairment include otoacoustic emissions (OAEs) and/or auditory brainstem response (ABR). OAEs are sensitive to outer hair cell dysfunction and are used to detect sensory hearing (inner ear) loss. However, this technique is affected by outer and middle ear obstruction (vernix, middle ear effusion), which can result in a positive test result in the presence of normal cochlear function [5].
310 Table 1 Causes of profound hearing loss in infancy (adapted from Fig. 1, p 163, in reference 28) Environmental 50%
Genetic 50%
Syndromic 30%
Nonsyndromic 70%
Viral infections; e.g. cytomegalovirus, rubella Bacterial infections; e.g. bacterial meningitis Prematurity Neonatal hyperbilirubinemia Ototoxicity Trauma Alport Norrie Usher Pendred Waardenburg branchio-oto-renal Jervell and Lange-Nielsen CHARGE syndrome X-linked progressive hearing loss with perilymphatic gusher Autosomal dominant (DFNA) Autosomal recessive (DFNB) X-linked (DFN) Mitochondrial
Note that Treacher Collins syndrome, hemifacial microsomia, and Robin sequence are not listed; they are not necessarily associated with “profound” hearing loss
In addition, OAEs will not detect auditory neuropathy or neural conduction disorders without outer hair cell dysfunction. The ABR detects auditory nerve and brainstem dysfunction as well as cochlear etiologies of hearing loss. It is important to recognize that both techniques are susceptible to false-negative results [3]. Infants found to have abnormal screening results should be referred for formal audiologic testing to establish more precisely the type, degree and configuration of the hearing loss. At this point, in conjunction with a detailed history, physical examination, and indicated laboratory tests, radiologic imaging is sometimes requested. When indicated, consultation with a geneticist for chromosomal analysis and evaluation for specific syndromes related to hearing loss should also be obtained. The vast majority of children with bilateral hearing loss benefit from some form of personal amplification or sensory device. Long-term plans can include reconstructive surgery and, in some cases, assessment for cochlear implantation. Cochlear implants are an option for certain children older than 1 year who have profound sensorineural hearing loss (SNHL) and who show only limited benefit from conventional amplification devices [3]. The detection of an external ear anomaly suggests the presence of a conductive hearing impairment. External ear anomalies can manifest as microtia (small pinna) and stenosis or atresia of the external auditory canal, sometimes with associated syndromic features such as micrognathia. External ear anomalies are invariably associated with
abnormalities of the ossicles and middle ear space. Imaging of these patients is often deferred until the time of reconstructive surgery. Establishing the etiology of hearing impairment can improve treatment of some causes of hearing loss, such as cytomegalovirus infection, can assist the family in adjusting to a diagnosis of deafness, and may facilitate genetic counseling. High-resolution CT and MRI have contributed to the evaluation of hearing impairment. In addition, with the identification of myriad genetic loci and genetic defects involved in hearing loss, genetic testing has emerged as an invaluable tool in the assessment of hearing impairment.
Imaging CT CT images are acquired in the axial plane with images parallel to the hard palate. New-generation multidetector, multislice CT scanners permit the acquisition of submillimeter images with excellent detail provided by coronal and sagittal reconstructed images. For example, technical parameters can include 0.625 mm slice thickness scanned using 100 mAs and 120 kVp. Patient dose is reduced by using a relatively low mAs, which is facilitated in temporal bone imaging by inherent high tissue contrast. The images are optimally displayed using a small field-ofview (e.g. 15 cm), and a wide window width setting, such as 3,000 Hounsfield units (HU) with a level of 350 HU. For a clinical history of SNHL, the inner ear structures should be carefully assessed for malformation. In addition to analysis of the external ear canal, middle ear and ossicles, mastoid air cells and course of the facial nerve canal, the CT report should specifically document cochlear morphology including the number and shape of cochlear turns, and the presence of internal septation, an osseous spiral lamina, and modiolus (Fig. 1). The vestibule and semicircular canals should be assessed for shape and integrity of bony covering. The vestibular aqueduct should be evaluated for enlargement, which is defined as a width greater than 1.5 mm [6]. The internal auditory meatus and aperture for the cochlear nerve should be assessed for shape and crosssectional diameter. Enlargement of the vestibular aqueduct (EVA) is the most commonly observed inner ear abnormality on CT. EVA is associated with the characteristic clinical presentation of fluctuating and sometimes progressive SNHL and symptoms of disequilibrium [7]. EVA has also been associated with the development of sudden SNHL after trauma [8]. The detection of EVA should prompt careful assessment of the cochlea for associated malformation, which may range from subtle asymmetry of the modiolus to deficient septation between the apical and middle turns of the cochlea (Mondini malformation) [9]. The finding of EVA on imaging has implications in terms of potential progression of hearing loss and possible familial and syndromic forms of the disorder (see Pendred syndrome and enlarged vestibular aqueduct syndrome).
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Fig. 1 Normal inner ear anatomy demonstrated on axial CT images of the right temporal bone. a Normal basal turn of the cochlea (bt). The osseous spiral lamina is faintly seen as a linear opacity within the center of the basal turn. b A more cephalad image reveals the entirety of the cochlea. The interscalar septum (iss) between the basal and middle turns is thicker than the septation between the apical and middle turns (arrowhead). The posterior semicircular
canal (pscc) is also seen at this level. c Farther cephalad, the middle and apical turns of the cochlea are shown with the central osseous modiolus (m). The aperture for the cochlear nerve (acn) lies between the base of the modiolus and the internal auditory meatus. This image also reveals the vestibule (v), horizontal semicircular canal (hscc) and vestibular aqueduct (va)
Deficiency of septation between the apical and middle turns of the cochlea (incomplete partition), with a normal basal turn and malformation of the modiolus is termed classic Mondini malformation [6, 10]. Hypoplasia refers to a small cochlea that lacks internal septation and has fewer than the usual number of two and a half turns. This should not be confused with a dilated cochlea that lacks internal septation. Complete absence of the cochlea is termed cochlear aplasia. Common cavity deformity refers to an amorphous, globular structure that contains unsegmented cochlear and vestibule, sometimes with rudimentary semicircular canals. Complete absence of the inner ear structures is termed labyrinthine aplasia. Abnormalities of the vestibule and semicircular canals can be seen in isolation or together with malformation of the cochlea and vestibular aqueduct. Stenosis of the internal auditory canal with thickening of the modiolus and or aperture for the cochlear nerve can indicate hypoplasia or absence of the cochlear nerve. Abnormalities of the external ear focus the radiologist’s attention on the anatomy of the external auditory meati and the middle ear space and contents. The external auditory meatus, middle ear space and ossicles, round and oval windows, course of the facial nerve canal, and mastoid air cells are best assessed using both axial and coronal images. The coronal images are particularly useful for assessment of the tegmen tympani, oval window niche, and tympanic segment of the facial nerve canal, scutum and ossicles. For planned middle ear reconstructive surgery for atresia or stenosis of the external auditory meatus, crucial information provided by CT includes differentiation of atresia from stenosis of the external canal, documentation of the nature of the atresia plate (bony versus membranous),
size of the tympanic cavity, presence and nature of ossicular anomaly (malformation, rotation, fusion of the ossicles to each other and/or the scutum), and anomalous course or dehiscence of the descending facial nerve. Additional features that should be documented include the presence of inner ear malformation (which is unusual in sporadic, nonsyndromic cases), presence of oval window atresia, location of the mandibular condyle, position of the sigmoid sinus and proximity of the dura of the middle cranial fossa to the mastoid and epitympanum. The presence of erosive opacity within a stenotic external auditory meatus can indicate retained keratinaceous debris or cholesteatoma. Congenital cholesteatoma is suggested by the finding of an erosive opacity in the middle ear space. MRI MR imaging is generally used in conjunction with temporal bone CT prior to cochlear implantation in order to document the presence of fluid within the membranous labyrinth and to demonstrate the presence and size of the cochlear division of the vestibulocochlear nerve (Fig. 2). Pulse sequences include a sub-millimeter 3-D fast T2weighted pulse sequence such as the FIESTA sequence (General Electric, Milwaukee, Wis.), and oblique sagittal images perpendicular to the cochlear nerves. We routinely include images of the brain to evaluate for coexistent brain abnormalities. The MR report should document morphology of the brain and inner ear structures and presence of normal fluid signal intensity within the membranous labyrinth. Enlargement of the endolymphatic sac and duct on MR, as with the CT finding of EVA, should prompt a
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Fig. 2 Normal inner ear anatomy on 3-D FIESTA MR image of the right temporal bone. a The basal turn containing fluid signal is shown. The osseous spiral lamina (osl) is more easily appreciated on MR than on CT. b A more cephalad image reveals the osseous modiolus (m), and fluid signal within the membranous labyrinth contained within the vestibule (v) and horizontal semicircular canal (hscc). Within the fluid-filled internal auditory meatus, the hypointense diverging cochlear nerve (cn) and inferior vestibular nerve (ivn) are well seen. c Farther cephalad, the parallel orientation of the
facial nerve ( fn) and superior vestibular nerve (svn) are demonstrated. d Oblique sagittal 3-D FIESTA image reveals the internal auditory meatus in cross-section. Four hypointense dots are visualized. The facial nerve ( fn) lies anterior and superior; the cochlear division of the VIII cranial nerve (cn) lies anterior inferior and is normally of similar size to or larger than the facial nerve. The superior (svn) and inferior (ivn) vestibular divisions of the VIII cranial nerve are shown posteriorly
careful assessment of cochlear morphology for deficient septation and malformation of the modiolus.
Congenital CMV infection
Nongenetic causes of hearing loss The patient history should include specific risk factors for hearing impairment such as intrauterine infections, meningitis, prematurity, hypoxia, persistent pulmonary hypertension and extracorporeal membrane oxygenation, hyperbilirubinemia, and prenatal exposure to alcohol or ototoxic drugs. Congenital infections The strict definition of hearing loss as infectious in etiology requires isolation or detection of the organism from the inner ear, clinical association of hearing loss with the organism and demonstration that the organism can cause similar auditory pathology in experimental animals [11]. Cytomegalovirus (CMV), herpes simplex, rubella, syphilis, toxoplasmosis (TORCH infections), and varicella have all been implicated in the pathogenesis of congenital deafness caused by infection. Congenital infections can result in characteristic or non-specific imaging abnormalities in the brain, and these findings can provide additional clues as to the infectious etiology of the hearing loss. In contrast to brain imaging, however, temporal bone imaging in hearing loss caused by congenital infections is usually unremarkable.
Congenital cytomegalovirus (CMV) infection is the most common intrauterine infection, with an estimated incidence of 0.4% to 2.3% of live births in the US [12]. CMV infection is a major cause of SNHL and neurologic impairment in children. Approximately 10–15% of infected infants display clinical evidence of congenital infection at birth, and these infants are more likely to experience sequelae such as SNHL and neurologic symptoms [13]. Evidence of disseminated disease at birth is predictive of hearing loss, and this can be more important in the development of hearing loss than isolated neurologic involvement [14]. About half of symptomatic infants with congenital CMV infection develop SNHL, and the majority of these infants experience continued postnatal deterioration in hearing [13, 14]. Approximately 7% of patients with subclinical infection also have hearing loss [12]. It has been estimated that congenital CMV infection can be the cause of 20% to 30% of all cases of deafness [15]. A histopathologic examination of the temporal bones in a premature infant who died of hyaline membrane disease and was found to have CMV infection at autopsy showed CMV infection of the endolabyrinth. This led to the proposal that late gestational or perinatal CMV infection could result in an endolymphatic labyrinthitis [16]. Persistence of CMV within endolymph and perilymph has been detected at necropsy in an infant who had probable congenital CMV infection, normal auditory brain stem-evoked responses and normal temporal bone examination by light and electron microscopy, leading the
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authors to propose that CMV can persist within the inner ear for prolonged periods after congenital infection [17]. CMV has also been identified, using polymerase chain reaction, from perilymphatic fluid obtained at the time of cochleotomy for cochlear implantation in patients with symptomatic congenital CMV infection [18]. CMV testing should be performed for any child suspected of having non-genetic hearing loss. A negative test result for CMV antibodies in early infancy can exclude CMV as a cause of the hearing loss; however, a positive test does not necessarily provide conclusive proof of CMV-related hearing loss. Ganciclovir therapy commencing during the neonatal period for infants showing symptoms of CMV infection involving the central nervous system has been shown to prevent hearing deterioration at 6 months [19]. However, almost two-thirds of treated infants have significant neutropenia during therapy. CMV infection is generally not associated with inner or middle ear malformation. However, characteristic findings in brain parenchyma should alert the radiologist to the diagnosis of congenital CMV infection (Fig. 3). Findings on fetal sonography performed during the third trimester in CMV-infected gestations include abnormal periventricular echogenicity, echogenic intraparenchymal foci with ventriculomegaly, intraventricular adhesions, periventricular pseudocysts, sulcal and gyral malformations, hypoplasia of the corpus callosum, cerebellar and cisterna magna abnormalities, and signs of striatal artery vasculopathy [20]. Frequent findings on CT in symptomatic patients are intracranial calcifications, ventriculomegaly, white matter abnormalities, neuronal migration abnormalities, and ex-
tensive parenchymal destruction [21] (Fig. 3). Imaging abnormalities can also be observed in asymptomatic patients. After birth, MR demonstrates a range of findings such as dilated ventricles, enlarged subarachnoid spaces, cortical malformations, delayed myelination, and white matter lesions. More specifically, the combination of cerebellar hypoplasia, delayed myelination, and diffuse cortical malformation (lissencephaly or polymicrogyria) should suggest the diagnosis of congenital CMV infection [22] (Fig. 3). A distinct pattern of MR imaging abnormalities has also been reported in a group of patients with neonatally asymptomatic but proven congenital CMV infection. In the absence of gyral abnormalities, the white matter abnormalities consist of multifocal lesions, predominantly involving the deep white matter, largest in the parietal area, with relative sparing of the immediate periventricular and subcortical white matter. In patients with gyral abnormalities, both diffuse and multifocal white matter abnormalities can occur. In addition, characteristic abnormalities of the anterior parts of the temporal lobes, including abnormal white matter, cysts, and focal enlargement of the most anterior aspects of the temporal horns of the lateral ventricles, are particularly suggestive of congenital CMV infection [23] (Fig. 3). The white matter changes of CMV infection do not usually progress and occasionally show improvement on follow-up. Recognition of these white matter changes as characteristic of CMV can help prevent attribution of the lesions to a progressive metabolic brain disorder [23].
Fig. 3 Congenital CMV infection. a CT of the brain in a 6-year-old boy demonstrates scattered punctate foci of parenchymal calcification. There is hypodensity of the periventricular white matter and ventriculomegaly. The Sylvian fissures appear prominent and the peri-Sylvian gyri appear thickened, consistent with cortical malformation. b Sagittal T1-weighted MR image in a toddler demonstrates
extensive frontal polymicrogyria (long arrow) and prominent cysticappearing hypointensity involving the anterior temporal lobe (arrowheads). c Axial FSE T2-weighted image in a different patient reveals extensive polymicrogyria (arrow), abnormal T2 prolongation (hyperintensity) within the white matter, and mild ventriculomegaly
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Ototoxic medications and substances The ingestion of ototoxic drugs by pregnant women can result in congenital hearing loss in affected babies, particularly if maternal drug exposure occurs during the first trimester [24]. Congenital hearing loss has been described in association with exposure to alcohol (fetal alcohol syndrome), trimethadione, and methylmercury. Macroscopic abnormalities of the inner ear that have been attributed to in-utero exposure to ototoxic drugs include aplasia of the inner ear, middle ear anomalies including ossicular malformations, and absence of the seventh and eighth cranial nerves [25]. One example of an ototoxic teratogenic drug is isoretinoin, an analogue of vitamin A that is used for the treatment of severe, refractory cystic acne. Exposure to isoretinoin during pregnancy has been associated with the subsequent development of craniofacial (micrognathia, cleft palate), ear (microtia/anotia), cardiac, thymic, and central nervous system abnormalities in affected fetuses [26] (Fig. 4). Histopathologic examination of the temporal bone in two affected human fetuses exposed to isoretinoin in early gestation revealed anomalies of the ossicles, underdevelopment of the tympanic cavity and dehiscence of the facial nerve canal. Examination of the cochlea revealed a reduction in the number of cochlear turns, and dilatation of the saccule [27].
Genetic causes of hearing loss Deafness that is caused by a genetic defect can be part of a syndrome or be non-syndromic. Approximately 70% of cases of hereditary deafness are classified as non-syndromic, where the inner ear is the only organ system affected [28]. Syndromic deafness Syndromic hearing loss can be conductive, sensorineural or mixed, unilateral or bilateral and symmetric or asymmetric. Nearly 400 forms of syndromic deafness have been identified where the presence of additional clinical findings permits the diagnosis of a specific syndrome. A detailed family history helps identify key genetic and/or phenotypic characteristics of suspected genetic forms of hearing loss. Additional important clinical clues are: eye anomalies (e.g. heterochromia irides), facial and or cervical dysmorphisms (e.g. micrognathia, preauricular pits, aural atresia), endocrine abnormalities (e.g. thyromegaly, diabetes), cardiac signs/symptoms (e.g. prolonged QT interval, arrhythmias), renal abnormalities and changes involving the skin/hair (e.g. white forelock) [28]. Gene-specific mutation analysis can be obtained for many syndromic genetic disorders. Genetic testing can lead to improvement in health care, such as avoidance of aminoglycoside therapy in children with the mitochondrial mutation associated with aminoglycoside sensitivity [28].
Fig. 4 Fetal exposure to isoretinoin. Axial CT of the right temporal bone reveals atresia of the external auditory canal. The vestibule and horizontal semicircular canal appears globular (arrow). There is asymmetric thickening of the cochlear modiolus (arrowhead ). The combination of external/middle ear and inner ear malformation is suggestive of either a genetic defect or teratogenic insult, as in this case
The most common syndromic forms of hearing loss are Alport, Pendred, Norrie, Usher, Waardenburg, branchio-oto-renal and Jervell and Lange-Nielsen syndromes. Because ear malformations are associated with an increased frequency of clinically significant structural renal anomalies compared with the general population, a renal US should be performed in patients with isolated preauricular pits, cup ears, or any other ear anomaly accompanied by one or more of the following: other malformations or dysmorphic features, a family history of deafness, auricular and/or renal malformations, or a maternal history of gestational diabetes [29]. Branchio-oto-renal (BOR) syndrome BOR syndrome is characterized by SNHL or mixed hearing loss (MHL) associated with branchial cleft fistulas and
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cysts, preauricular pits, malformations of the pinna, malformations of the inner ears and renal anomalies [30] (Fig. 5). BOR syndrome is caused by mutations of the EYA1 gene, a human homologue of the Drosophila eyes absent gene [31]. Transmission is autosomal dominant, and approximately 80% of gene carriers have some degree of
hearing impairment. Characteristic findings on CT of the temporal bone in patients with BOR syndrome include a distinctive malformation of the cochlea with a tapered basal turn and hypoplasia of the middle and apical turns (Fig. 5). This appearance is dissimilar to and should be distinguished from the classic Mondini malformation. Additional find-
Fig. 5 Branchio-oto-renal syndrome. A 10-day-old boy with renal failure and microtia. a Axial CT of the right temporal bone demonstrates atresia of the external auditory meatus; malformation, rotation and fusion of the ossicles (arrowhead ); and tapering of the basal turn of the cochlea (arrow). b The dysmorphic ossicles are again seen (arrowhead), with surrounding middle ear opacification. The cochlea has small middle and apical turns that are offset anteriorly and appear separated (arrow) from the basal turn. This
appearance is quite characteristic of branchio-oto-renal syndrome, which was diagnosed on the basis of the CT. c The vestibule and semicircular canals appear globular (arrow). The internal auditory canal (iac) is orientated closer to the sagittal plane than normal. d Axial T1-weighted MR image of the neck demonstrates a second branchial cleft cyst on the right (arrowhead ). e Renal US reveals a solitary kidney on the left. The kidney appears echogenic and contains multiple cysts
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ings that have been described include hypoplasia of the middle ear cavity, malformations of the ossicular chain, EVA on CT and/or an enlargement of the endolymphatic sac on MR, and bilateral hypoplasia of the cochlear branch of the eighth cranial nerve on MR [32]. Absent or hypoplastic semicircular canals have also been observed [33]. Waardenburg syndrome Waardenburg syndrome (WS) is an autosomal-dominant disorder with an incidence of approximately 1 in 40,000, characterized by SNHL and pigmentation defects of the hair, skin and iris [34]. An estimated 1–2% of patients with profound hearing loss have Waardenburg syndrome [1]. Clinical features include strikingly blue eyes, heterochromia, and patches of cutaneous hyper- or hypopigmentation [35]. WS is classified into four types, depending on the presence or absence of additional symptoms. Type 1 WS is associated with dystopia canthorum or lateral displacement of the inner canthus of each eye, and type 2 WS lacks dystopia canthorum. The presence of limb abnormalities (bilateral upper limb defects, flexion contractures, fusion of the carpal bones, and syndactyly) distinguishes type 3 WS (Klein-Waardenburg syndrome) from type 1 [36]. Type 4 WS, also known as Shah-Waardenburg syndrome or Waardenburg-Hirschsprung disease, is characterized by the presence of an aganglionic megacolon [37]. WS is characterized by defects of structures derived from neural crest cells and a deficiency of melanocytes [38]. The genes involved in WS have roles in neural crest development and affect both the auditory process and melanocyte migration and differentiation [39]. Melanocyte deficiency is responsible for both the pigmentary defects and the high incidence of deafness caused by loss of migratory melanocytes from the stria vascularis of the cochlea [40]. Types 1 and 3 WS and WS are caused by mutations in the PAX3 gene [41, 42]. Some WS2 patients show mutations in the microphthalmia-associated transcription factor (MITF) gene [43]. Type 4 WS phenotype can result from mutations in the endothelin-B receptor gene (EDNRB), the gene for its ligand, endothelin-3 (EDN3) or mutations in SOX10, a cotranscription factor that functions during neural crest development [44–46]. CT of the temporal bones in patients with type 2 WS has been reported to show characteristic aplasia of the posterior semicircular canal associated with underdevelopment of the vestibule [47]. Other reported abnormalities include EVA and enlargement of the upper vestibule, narrowing of the internal auditory canal porus, and hypoplasia of the modiolus [48]. Pendred syndrome and the enlarged vestibular aqueduct syndrome (EVAS) Pendred syndrome, first described by Vaughan Pendred in 1896, is an autosomal recessive disorder characterized by severe congenital SNHL and an iodine organification
defect that leads to the development of thyroid goiter [49]. Pendred syndrome has been estimated to account for as much as 10% of hereditary deafness [50]. The disorder is caused by mutations on a putative sulfate transporter gene, PDS (SLC26A4), that produces a defect in a protein known as pendrin [50]. Pendrin is thought to have a role in thyroid hormonogenesis and the maintenance of endolymph homeostasis [51]. Classically, the goiter occurs in mid-childhood or during adolescence and is rarely congenital [49]. Interestingly, mutation in the SLC26A4 gene has also been reported in isolated enlargement of the endolymphatic duct and sac without the other classic features of Pendred syndrome [52, 53]. Conversely, SLC26A4 gene mutations are not the only cause of enlarged endolymphatic duct and sac/Mondini malformation, and the mechanisms producing this malformation are unclear. It is estimated that SLC26A4 gene mutations are present in approximately 78% of patients with isolated SNHL and EVA. On CT and/or MR of the temporal bones, deficiency of the interscalar septum between the apical and middle turns of the cochlea (Mondini deformity) is a common but not invariable feature of Pendred syndrome and EVAS [54, 55] (Fig. 6). The inner ear malformation in Pendred syndrome is more in accordance with Mondini’s original description than in other syndromes in which a Mondini-like cochlea has been described [55]. Enlargement of the endolymphatic sac and duct is also usually present in association with a large vestibular aqueduct [56] (Fig. 6). CHARGE syndrome The association of hearing loss/ear anomalies with choanal atresia, ocular colobomas and a variety of other malformations was independently recognized by Hittner et al. [57] and Hall [58] in the late 1970s. Subsequently, the mnemonic CHARGE was proposed to describe the nonrandom association of coloboma, heart disease, atresia choanae, retarded growth and retarded development and/or CNS anomalies, genital hypoplasia and ear anomalies and/ or deafness [59]. The prevalence of this disorder is approximately 1 in 8,500–12,000 births [60, 61]. Until recently, the term “association” was applied to CHARGE, indicating a nonrandom cluster of developmental anomalies. More recently, it has been recognized that CHARGE is indeed more appropriately termed a syndrome and is characterized by very specific developmental anomalies thought to represent a complex neurocristopathy. Accordingly, coloboma, atresia choanae and hypoplastic semicircular canals have been proposed as major signs (three Cs) of CHARGE syndrome (Fig. 7). Minor signs include rhombencephalic dysfunction (brainstem dysfunction, cranial nerve VII to XII palsies, SNHL), hypothalmic-hypophyseal dysfunction, abnormal middle or external ears, malformation of the heart and/or esophagus and mental retardation. A diagnosis of typical CHARGE is made if there are three major signs or two major and two minor signs. Borderline phenotypes are then described as partial (incomplete) or atypical CHARGE [62].
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Fig. 6 Pendred syndrome and EVAS. An 11-year-old boy with severe bilateral SNHL. Axial CT of the temporal bone. a There is absent septation between the apical and middle turns of the right cochlea, which appears slightly globular and resembles a baseball cap (arrow). b The modiolus appears deformed and offset anteromedially (arrowhead),
resulting in asymmetric scalar chambers. There is marked dilatation of the vestibular aqueduct (arrow). This patient subsequently developed hypothyroidism. c 3-D FSE T2-weighted MR image in a child with EVAS. Enlarged endolymphatic sacs/ducts are seen bilaterally (arrows). Mondini malformation of the left cochlea is also shown on this image
Fig. 7 CHARGE syndrome. a Axial CT of the nose in a newborn baby demonstrates bilateral bony and membranous choanal atresia. The vomer is thickened posteriorly (long arrow). There is medial deviation and thickening of the bone of the lateral nasal cavity at the level of the choanae (short arrow). These represent the osseous components of the atresia. The atresia is completed by a membrane (arrowhead). There are small fluid levels within the posterior nasal cavities. b Axial CT of a different patient demonstrates bilateral colobomas. On the right there is microphthalmos and a large colobomatous cyst (left arrow). There is a small coloboma on the left (right arrow). Axial CTs of the temporal bone in three patients with CHARGE syndrome demonstrate a spectrum of anomalies. c Image reveals severe hypoplasia of the right cochlea, which has less than a full turn (long arrow). The aperture for the cochlear nerve is absent,
and the internal auditory meatus is narrow (arrowhead). The vestibule is hypoplastic (short arrow), and the semicircular canals are absent. An enlarged occipitomastoid emissary foramen (ef) is present. d There is asymmetry and increased ossification of the modiolus on the right (long arrow), and the aperture for the cochlear nerve is absent. e There is stenosis of the aperture for the left cochlear nerve (left arrow), compared with a more normal appearing aperture for the right cochlear nerve (right arrow). Bilaterally, the vestibules are small and the semicircular canals are absent. Note the high-riding right jugular bulb, which should not be confused with an enlarged vestibular aqueduct. f Coronal CT of the right temporal bone demonstrates that the facial nerve canal (arrowhead) is inferomedially located as a result of the absence of the horizontal semicircular canal. The hypoplastic vestibule is also shown (long arrow)
318 Fig. 7 (continued)
Recently, mutations of the gene CHD7, a member of the chromodomain gene family located on chromosome 8q12, were identified in 10 of 17 individuals meeting the criteria for CHARGE syndrome [61]. A de novo interstitial deletion involving bands 8q11.2 to 8q13 was also detected in a neonate with characteristics of CHARGE syndrome [63]. The most specific finding in patients with CHARGE syndrome on CT of the temporal bones is absence of the semicircular canals (Fig. 7). Additional features include hypoplasia of the semicircular canals and vestibules,
sometimes hypoplasia of the upper turn of the cochlea, and abnormalities of the incus and stapes, along with ossicular chain fixation, absence of the stapedius muscle and oval window, and absence of the pyramidal eminence and sinus tympani [64]. Aberrant facial nerve canal has also been described on histologic examination [65]. We have also noted absence or stenosis of the aperture for the cochlear nerve on CT (Fig. 7). Other features on imaging include bilateral choanal atresia, and ocular colobomas (Fig. 7).
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X-linked progressive hearing loss with perilymphatic gusher X-linked mixed hearing loss, also known as DFN3, is a condition that was originally described in males and characterized by profound mixed hearing loss, vestibular abnormalities and congenital fixation of the stapes with perilymphatic otorrhea on attempted stapedectomy [66]. More recently, it has been suggested that that DFN3 should be characterized not by mixed conductive and sensorineural deafness associated with perilymphatic gusher at stapes surgery but by profound SNHL, with or without a conductive element, associated with a unique developmental abnormality of the ear [67]. The locus for the mutation associated with this disorder has been mapped to the X chromosome, and affected males have been found to have a mutation in a DNA-binding regulatory gene known as POU3F4 [68]. Interestingly, some female carriers seem to have a milder form of the same anomaly associated with slight hearing loss. Genetic studies on some of the deaf males with apparently normal inner ear anatomy suggest a different locus on the X chromosome and hence a different pathogenesis for their deafness [69]. There are both non-syndromic (DFN3) and syndromic forms of X-linked mixed hearing loss. For example, in many families the genetic abnormality manifests as a deletion that can be quite large, resulting in a contiguous gene syndrome involving genes in close proximity that cause mental retardation, choroidemia and deafness, with affected family members having some or all of these manifestations [1]. The findings on CT of the temporal bone that appear most characteristic of this disorder are marked bulbous dilatation of the lateral end of the internal auditory meatus with a deficient or absent modiolus and a lack of internal cochlear septation (Fig. 8). It is thought that this results in a communication between the subarachnoid space in the internal auditory meatus and the perilymph in the cochlea, leading to perilymphatic hydrops and a “gusher” if the stapes is disturbed. Given the risk of CSF/perilymph gusher attending stapes surgery in these patients, and the potential to cause severe aggravation of hearing loss, boys presenting with congenital mixed hearing loss should be studied with temporal bone CT prior to middle ear exploration [70].
Fig. 8 X-linked mixed hearing loss in a young boy with developmental delay and profound SNHL. The fundus of the internal auditory meatus appears prominent, and the aperture for the cochlear nerve is widened (long arrow). The cochlea lacks internal septations, and the modiolus is completely absent. This patient has also developed ossification of the horizontal semicircular canal (short arrow)
bone abnormalities include atresia or stenosis of the external auditory canal with associated severe hypoplasia or atresia of the middle ear cavity and contents. Inner ear abnormalities such as flattening of the cochlear turns and malformation of the vestibule and semicircular canals are sometimes also seen (Fig. 9).
Mandibulofacial dysostosis (Treacher Collins syndrome)
Hemifacial microsomia
Treacher Collins syndrome is a hereditary disorder characterized by bilateral symmetric maxillary and mandibular hypoplasia, cleft lip and cleft palate and colobomas (Fig. 9). Treacher Collins syndrome is caused by a mutation in the treacle gene (TCOF1), which is involved in ribosomal DNA gene transcription and plays a fundamental role in development of the craniofacial region during early embryonic development [71, 72]. Temporal
The hemifacial microsomia spectrum (HFM) is a group of disorders that have unilateral or bilateral and often asymmetric abnormalities of first and second pharyngeal arch derivatives, with associated facial asymmetry and maxillary and/or mandibular hypoplasia (Fig. 10). Most cases in this spectrum are sporadic, but rare familial cases occur. HFM includes entities described as the first and second branchial arch syndrome, oculoauriculovertebral spectrum,
320
Fig. 9 Treacher-Collins syndrome. a Lateral scout projection CT image reveals severe micrognathia and underdevelopment of the maxilla. The airway is poorly visualized. b Axial CT image through the orbits demonstrates bilateral colobomas (arrows). c Axial CT image of the temporal bones shows complete bilateral atresia of the external auditory meati (arrowhead), with atresia or severe hypo-
plasia of the middle space bilaterally and absence of the ossicles. There is a globular malformation of the horizontal semicircular canal (hscc) and vestibule. The mandibular condyles and zygomatic arches are absent. The maxilla (m) is hypoplastic and posteriorly slanted on each side
Fig. 10 Hemifacial microsomia spectrum with spinal anomalies. a 3-D CT of the spine reveals vertebral segmentation anomalies within the cervical and upper thoracic spine. There are also sternal anomalies. b Coronal T2-weighted MR image reveals scoliosis with malformation of C2, butterfly-type anomalies of the mid-cervical vertebrae, and an upper thoracic hemivertebra on the right. c Frontal 3-D CT image of the mandible reveals asymmetric left mandibular and maxillary hypoplasia. d Lateral 3-D CT image demonstrates
severe hypoplasia of the left mandibular ramus (arrow) with absence of the mandibular condyle. There is also complete absence of the left external auditory meatus (compare with Fig. 11). e Coronal CT image reveals atresia of the left external auditory meatus with a thin bony and membranous atresia plate (arrow). The middle ear space is opacified. Ossicular malformation is not shown on this image. f Axial CT image of the left temporal bone reveals a globular malformation of the horizontal semicircular canal (hscc)
321 Fig. 10 (continued)
facioauriculovertebral syndrome, and Goldenhar syndrome. These syndromes are associated with microtia, stenosis or atresia of the external auditory canal and sometimes ocular abnormalities. HFM that is characterized by bilateral facial microsomia, vertebral anomalies, epibulbar dermoid and sometimes abnormalities of other organ systems is sometimes referred to as Goldenhar syndrome. CT of the temporal bones in HFM reveals unilateral or bilateral stenosis or atresia of the external auditory meatus, hypoplasia or atresia of the middle ear space, ossicular malformation, and atresia or hypoplasia of the oval window [73] (Fig. 10). The additional presence of micrognathia provides a useful clue as to the presence of a syndromic etiology. Inner ear anomalies have been observed in just over a third of patients described as having “Goldenhar syndrome” [74] (Fig. 10).
Robin sequence The Robin sequence is characterized by cleft palate, glossoptosis secondary to micrognathia, and feeding problems (Fig. 11). The Robin sequence can be sporadic or syndromic in nature. The Robin sequence refers to a clinical triad that can be observed in a variety of different syndromes, most commonly Stickler syndrome and velocardiofacial syndrome. Hearing loss is variable and usually conductive in nature. Ear malformations include deformed and low-set auricles, abnormal stapes, small or dehiscent facial nerve, anomalies of the cochlea and semicircular canals, and small internal auditory canals. Conductive hearing loss is most often caused by eustachian tube dysfunction and middle ear effusion—a common sequela of cleft palate.
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Fig. 11 Robin sequence. a Fetal MR SSFSE T2-weighted sagittal image reveals severe micrognathia. The tongue is elevated and displaced posteriorly (t). The secondary palate cannot be identified. After birth, the infant was noted to have glossoptosis with a U-
shaped cleft palate, as well as feeding difficulties. b 3-D CT reveals severe symmetric micrognathia. c 3-D CT lateral view reveals severe micrognathia. Note the presence of the external auditory meatus (arrow)
Nonsyndromic deafness
BOR syndrome, and the inner ear, nasal and ocular findings in the CHARGE syndrome. For many years, it has been recognized that one of the most frequently encountered temporal bone imaging abnormalities in children with SNHL is dilatation of the vestibular aqueduct (>1.5 mm in diameter) on CT with enlargement of the endolymphatic duct and sac on MR [6, 76]. This finding is almost invariably associated with abnormalities of the cochlea ranging from deficiency of the modiolus to absent septation between the apical and middle turns of the cochlea (Mondini malformation) [9, 10]. More recently, the association between EVA and the SLC26A4 gene mutation as part of EVAS or Pendred syndrome has been recognized, so that patients with these characteristic findings on imaging should undergo thyroid endocrinologic evaluation and testing for the SLC26A4 gene mutation. Abnormalities on imaging that are associated with deficiency of the cochlear modiolus as is seen in the Mondini malformation and X-linked mixed hearing loss are at risk of CSF leak during cochleotomy for cochlear implantation [77]. Stenosis of the aperture for the cochlear nerve, as can be seen with the CHARGE syndrome, usually indicates hypoplasia or complete absence of the cochlear nerve resulting in failure of cochlear implantation. Finally, the importance of imaging children with congenital deafness lies not only in recognizing temporal bone malformations but in assessing the brain for abnormalities that could indicate congenital infection such as CMV.
Congenital non-syndromic hearing impairment is most likely to be sensorineural. Although deafness is typically the only detectable symptom, in some cases vestibular symptoms are present [39]. The non-syndromic DeaFNess gene loci are designated as DFNB (77% of cases, autosomal recessive), DFNA (22% of cases, autosomal dominant), and DFN (1% of cases, X-linked). Mitochondrial inheritance is also responsible for a small proportion of cases of non-syndromic hearing impairment and has considerable variability in incidence, depending on the population group studied [28]. Although abnormalities in many different genes or gene pairs cause deafness, more than half of genetic cases of profound deafness in the US are linked to DFNA3 with a defect in a single gene, GJB2. The GJB2 gene encodes a gap junction protein named connexin 26 that is involved in cell-to-cell diffusion and the recycling of small molecules [28]. GJB2 mutation screening can be obtained. However, a negative mutation screening analysis does not exclude a genetic etiology of the hearing loss. Abnormalities of the cochlea and dilatation of the vestibular aqueducts have been reported in a small number of patients with connexin 26 mutations; however, these findings are in the process of being more fully characterized and analyzed [75].
Conclusion There have been major advances in the characterization of the genetic and molecular mechanisms of congenital deafness. This provides the opportunity to correlate imaging findings in patients with established etiologic diagnoses. In some cases, typical imaging findings can provide clues to a diagnosis that had not been suspected, such as the characteristic cochlear anomalies seen in the
References 1. Nance WE (2003) The genetics of deafness. Ment Retard Dev Disabil Res Rev 9:109–119 2. White KR (2004) Early hearing detection and intervention programs: opportunities for genetic services. Am J Med Genet A 130:29–36
323 3. Joint Committee on Infant Hearing; American Academy of Audiology; American Academy of Pediatrics; American Speech-Language-Hearing Association; Directors of Speech and Hearing Programs in State Health and Welfare Agencies (2000) Year 2000 position statement: principles and guidelines for early hearing detection and intervention programs. Pediatrics 106:798–817 4. Karchmer MA, Allen TE (1999) The functional assessment of deaf and hard of hearing students. Am Ann Deaf 144:68–77 5. Doyle KJ, Burggraaff B, Fujikawa S, et al (1997) Neonatal hearing screening with otoscopy, auditory brain stem response, and otoacoustic emissions. Otolaryngol Head Neck Surg 116:597–603 6. Valvassori GE, Clemis JD (1978) The large vestibular aqueduct syndrome. Laryngoscope 88:723–728 7. Abe S, Usami S, Hoover DM, et al (1999) Fluctuating sensorineural hearing loss associated with enlarged vestibular aqueduct maps to 7q31, the region containing the Pendred gene. Am J Med Genet 82:322–328 8. Kou B, Macdonald R (1998) Toronto’s Hospital for Sick Children study of traumatic sudden sensorineural hearing loss. J Otolaryngol 27:64–68 9. Lemmerling MM, Mancuso AA, Antonelli PJ, et al (1997) Normal modiolus: CT appearance in patients with a large vestibular aqueduct. Radiology 204:213–219 10. Mondini C (1997) Minor works of Carlo Mondini: the anatomical section of a boy born deaf. Am J Otol 18:288–293 11. Davis LE, Johnson RT (1976) Experimental viral infections of the inner ear. I. Acute infections of the newborn hamster labyrinth. Lab Invest 34:349–356 12. Stagno S (1995) Cytomegalovirus. In: Remington JS, Klein JO (eds) Infectious diseases of the fetus and newborn infant. WB Saunders, Philadelphia, pp 312–353 13. Demmler GJ (1991) Infectious Diseases Society of America and Centers for Disease Control. Summary of a workshop on surveillance for congenital cytomegalovirus disease. Rev Infect Dis 13:315–329 14. Rivera LB, Boppana SB, Fowler KB, et al (2002) Predictors of hearing loss in children with symptomatic congenital cytomegalovirus infection. Pediatrics 110:762–767 15. Barbi M, Binda S, Caroppo S, et al (2003) A wider role for congenital cytomegalovirus infection in sensorineural hearing loss. Pediatr Infect Dis J 22:39–42 16. Davis GL, Spector GJ, Strauss M, et al (1977) Cytomegalovirus endolabyrinthitis. Arch Pathol Lab Med 101:118–121 17. Davis LE, Rarey KE, Stewart JA, et al (1987) Recovery and probable persistence of cytomegalovirus in human inner ear fluid without cochlear damage. Ann Otol Rhinol Laryngol 96:380–383 18. Sugiura S, Yoshikawa T, Nishiyama Y, et al (2004) Detection of human cytomegalovirus DNA in perilymph of patients with sensorineural hearing loss using real-time PCR. J Med Virol 69:72–75 19. Kimberlin DW, Lin CY, Sanchez PJ, et al (2003) Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr 143:16–25 20. Malinger G, Lev D, Zahalka N, et al (2003) Fetal cytomegalovirus infection of the brain: the spectrum of sonographic findings. AJNR 24:28–32 21. Boppana SB, Fowler KB, Vaid Y, et al (1997) Neuroradiographic findings in the newborn period and long-term outcome in children with symptomatic congenital cytomegalovirus infection. Pediatrics 99:409–414 22. Barkovich AJ, Lindan CE (1994) Congenital cytomegalovirus infection of the brain: imaging analysis and embryologic considerations. AJNR 15:703–715 23. van der Knaap MS, Vermeulen G, Barkhof F, et al (2004) Pattern of white matter abnormalities at MR imaging: use of polymerase chain reaction testing of Guthrie cards to link pattern with congenital cytomegalovirus infection. Radiology 230:529–536
24. Roizen NJ (2003) Nongenetic causes of hearing loss. Ment Retard Dev Disabil Res Rev 9:120–127 25. Roizen NJ (1999) Etiology of hearing loss in children. Nongenetic causes. Pediatr Clin North Am 46:49–64 26. Lammer EJ, Chen DT, Hoar RM, et al (1985) Retinoic acid embryopathy. N Engl J Med 313:837–841 27. Moerike S, Pantzar JT, De Sa D (2002) Temporal bone pathology in fetuses exposed to isotretinoin. Pediatr Dev Pathol 5:405–409 28. ACMG (2002) Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic Evaluation of Congenital Hearing Loss Expert Panel. ACMG statement. Genet Med 4:162–171 29. Wang RY, Earl DL, Ruder RO, et al (2001) Syndromic ear anomalies and renal ultrasounds. Pediatrics 108:E32 30. Melnick M, Bixler D, Nance WE, et al (1976) Familial branchio-oto-renal dysplasia: a new addition to the branchial arch syndromes. Clin Genet 9:25–34 31. Abdelhak S, Kalatzis V, Heilig R, et al (1997) A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family. Nat Genet 15:157–164 32. Ceruti S, Stinckens C, Cremers CW, et al (2002) Temporal bone anomalies in the branchio-oto-renal syndrome: detailed computed tomographic and magnetic resonance imaging findings. Otol Neurotol 23:200–207 33. Ostri B, Johnsen T, Bergmann I (1991) Temporal bone findings in a family with branchio-oto-renal syndrome (BOR). Clin Otolaryngol 16:163–167 34. Read AP, Newton VE (1997) Waardenburg syndrome. J Med Genet 34:656–665 35. Waardenburg PJ (1951) A new syndrome combining developmental anomalies of the eyelids, eyebrows, and nose root with pigmentary defects of the iris and head hair with congenital deafness. Am J Hum Genet 3:195–253 36. Klein D (1983) Historical background and evidence for dominant inheritance of the Klein-Waardenburg syndrome (type III). Am J Med Genet 14:231–239 37. Shah KN, Dalal SJ, Desai MP, et al (1981) White forelock, pigmentary disorder of irides, and long segment Hirschsprung disease: possible variant of Waardenburg syndrome. J Pediatr 99:432–435 38. Bondurand N, Pingault V, Goerich DE, et al (2000) Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Hum Mol Genet 9:1907–1917 39. Robertson NG, Morton CC (1999) Beginning of a molecular era in hearing and deafness. Clin Genet 55:149–159 40. Steel KP, Barkway C (1989) Another role for melanocytes: their importance for normal stria vascularis development in the mammalian inner ear. Development 107:453–463 41. Tassabehji M, Read AP, Newton VE, et al (1992) Waardenburg’s syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. Nature 355:635–636 42. Hoth CF, Milunsky A, Lipsky N, et al (1993) Mutations in the paired domain of the human PAX3 gene cause KleinWaardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I). Am J Hum Genet 52:455–462 43. Tassabehji M, Newton VE, Read AP (1994) Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nat Genet 8:251–255 44. Puffenberger EG, Hosoda K, Washington SS, et al (1994) A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung’s disease. Cell 79:1257–1266 45. Edery P, Attie T, Amiel J, et al (1996) Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nat Genet 12:442–444 46. Pingault V, Bondurand N, Kuhlbrodt K, et al (1998) SOX10 mutations in patients with Waardenburg-Hirschsprung disease. Nat Genet 18:171–173 47. Higashi K, Matsuki C, Sarashina N (1992) Aplasia of posterior semicircular canal in Waardenburg syndrome type II. J Otolaryngol 21:262–264
324 48. Madden C, Halsted MJ, Hopkin RJ, et al (2003) Temporal bone abnormalities associated with hearing loss in Waardenburg syndrome. Laryngoscope 113:2035–2041 49. Reardon W, Trembath RC (1996) Pendred syndrome. J Med Genet 33:1037–1040 50. Everett LA, Glaser B, Beck JC, et al (1997) Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 17:411–422 51. Fugazzola L, Mannavola D, Cerutti N, et al (2000) Molecular analysis of the Pendred’s syndrome gene and magnetic resonance imaging studies of the inner ear are essential for the diagnosis of true Pendred’s syndrome. J Clin Endocrinol Metab 85:2469–2475 52. Usami S, Abe S, Weston MD, et al (1999) Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations. Hum Genet 104:188–192 53. Naganawa S, Koshikawa T, Fukatsu H, et al (2004) Enlarged endolymphatic duct and sac syndrome: relationship between MR findings and genotype of mutation in Pendred syndrome gene. Magn Reson Imaging 22:25–30 54. Illum P, Kiaer HW, Hvidberg-Hansen J, et al (1972) Fifteen cases of Pendred’s syndrome. Congenital deafness and sporadic goiter. Arch Otolaryngol 96:297–304 55. Johnsen T, Jorgensen MB, Johnsen S (1986) Mondini cochlea in Pendred’s syndrome. A histological study. Acta Otolaryngol 102:239–247 56. Phelps PD, Coffey RA, Trembath RC, et al (1998) Radiological malformations of the ear in Pendred syndrome. Clin Radiol 53:268–273 57. Hittner HM, Hirsch NJ, Kreh GM, et al (1979) Colobomatous microphthalmia, heart disease, hearing loss, and mental retardation—a syndrome. J Pediatr Ophthalmol Strabismus 16:122– 128 58. Hall BD (1979) Choanal atresia and associated multiple anomalies. J Pediatr 95:395–398 59. Pagon RA, Graham JM Jr, Zonana J, et al (1981) Coloboma, congenital heart disease, and choanal atresia with multiple anomalies: CHARGE association. J Pediatr 99:223–227 60. Carey JC (2005) CHARGE syndrome: 2005. Am J Med Genet A 133:227 61. Vissers LE, van Ravenswaaij CM, Admiraal R, et al (2004) Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 36:955–957 62. Verloes A (2005) Updated diagnostic criteria for CHARGE syndrome: a proposal. Am J Med Genet A 133:306–308 63. Arrington CB, Cowley BC, Nightingale DR, et al (2005) Interstitial deletion 8q11.2–q13 with congenital anomalies of CHARGE association. Am J Med Genet 133:326–330
64. Lemmerling M, Dhooge I, Mollet P, et al (1998) CT of the temporal bone in the CHARGE association. Neuroradiology 40:462–465 65. Wright CG, Brown OE, Meyerhoff WL, et al (1986) Auditory and temporal bone abnormalities in CHARGE association. Ann Otol Rhinol Laryngol 95:480–486 66. Nance WE, Setleff R, McLeod A, et al (1971) X-linked mixed deafness with congenital fixation of the stapedial footplate and perilymphatic gusher. Birth Defects Orig Artic Ser 07:64–69 67. Bitner-Glindzicz M, Turnpenny P, Hoglund P, et al (1995) Further mutations in Brain 4 (POU3F4) clarify the phenotype in the X-linked deafness, DFN3. Hum Mol Genet 4:1467–1469 68. de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, et al (1995) Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4. Science 267:685– 688 69. Phelps PD, Reardon W, Pembrey M, et al (1991) X-linked deafness, stapes gushers and a distinctive defect of the inner ear. Neuroradiology 33:326–330 70. Talbot JM, Wilson DF (1994) Computed tomographic diagnosis of X-linked congenital mixed deafness, fixation of the stapedial footplate, and perilymphatic gusher. Am J Otol 15:177–182 71. Valdez BC, Henning D, So RB, et al (2004) The Treacher Collins syndrome (TCOF1) gene product is involved in ribosomal DNA gene transcription by interacting with upstream binding factor. Proc Natl Acad Sci U S A 101:10709–10714 72. Treacher Collins Syndrome Collaborative Group (1996) Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. Nat Genet 12:130–136 73. Rahbar R, Robson CD, Mulliken JB, et al (2001) Craniofacial, temporal bone, and audiologic abnormalities in the spectrum of hemifacial microsomia. Arch Otolaryngol Head Neck Surg 127:265–271 74. Bisdas S, Lenarz M, Lenarz T, et al (2005) Inner ear abnormalities in patients with Goldenhar syndrome. Otol Neurotol 26:398–404 75. Kenna MA, Wu BL, Cotanche DA, et al (2001) Connexin 26 studies in patients with sensorineural hearing loss. Arch Otolaryngol Head Neck Surg 127:1037–1042 76. Davidson HC, Harnsberger HR, Lemmerling MM, et al (1999) MR evaluation of vestibulocochlear anomalies associated with large endolymphatic duct and sac. AJNR 20:1435–1441 77. Luntz M, Balkany T, Hodges AV, et al (1997) Cochlear implants in children with congenital inner ear malformations. Arch Otolaryngol Head Neck Surg 123:974–977
