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Objective: to report the first case series of Brazilian children diagnosed with Kleefstra syndrome, present a possible phenotype expansion to the syndrome and to raise physicians' awareness for this rare disease., Results: seven patients with confirmed KS were evaluated, including 5 males and 2 females. Abnormal prenatal findings were observed in 4 patients. Most patients were born at term, with normal birth measurements. All patients had neurodevelopmental delay and 6 evolved with intellectual disability. Hearing loss was present in 57.1% of patients and 28.7% had congenital heart disease. In males, cryptorchidism was present in 75%. Despite the facial dysmorphisms, only 2 out of 7 patients had a pre-test clinical suspicion of KS. One specific patient presented bilateral agenesis of the semicircular canals, a very rare ear manifestation in Kleefstra syndrome, representing a possible phenotype expansion of the syndrome., Conclusion: this report aims to promote awareness among physicians evaluating patients in a context of neurodevelopmental delay or congenital malformations, especially congenital heart defects. We also highlight a possible phenotype expansion of the syndrome, with a case of semicircular anomaly, not reported in this syndrome so far., Competing Interests: Declaration of competing interest nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Congenital deformities of the labyrinth of the inner ear may be associated with an increased risk of infection and varying degrees of otologic and vestibular dysfunction. Lateral semicircular canal abnormalities specifically can be associated with either normal hearing or hearing loss (conductive or sensorineural). In our patient, the acute symptoms of vertigo and tinnitus coincided with the diagnosis of COVID-19. It is unlikely that the symptomatology was related to the acute infection, even in the face of the underlying congenital abnormality. It has been shown that there is no correlation between the severity of the radiological abnormality and vestibular symptomatology in patients with isolated abnormalities of the semicircular canals. The abnormality can be asymptomatic.

Objectives: This paper attempts to create a new classification type of cochlear hypoplasia (CH)-type malformation taking into consideration of vestibular section and internal auditory canal (IAC)., Materials and Methods: Preoperative computed-tomography (CT) scans of cochlear implant (CI) candidates (N=31) from various clinics across the world with CH type malformation were taken for analysis. CT dataset were loaded into 3D-slicer freeware for three-dimensional (3D) segmentation of the inner-ear by capturing complete inner-ear structures from the entire dataset. Cochlear size in terms of diameter of available cochlear basal turn and length of cochlear lumen was measured from the dataset. In addition, structural connection between IAC and cochlear portions was scrutinized, which is highly relevant to the proposed CH classification in this study., Results: CH group-I has the normal presence of IAC leading to cochlear and vestibular portions, whereas CH group-II is like CH group-I but with some degree of disruption in vestibular portion. In CH group-III, a disconnection between IAC and the cochlear portion irrespective of other features. Within all these three CH groups, the basal turn diameter varied between 3.1 mm and 9.6 mm, and the corresponding cochlear lumen length varied between 3 mm and 21 mm for the CI electrode array placement., Conclusion: A new classification of CH mainly based on the IAC connecting the cochlear and vestibular portions is presented in this study. CI electrode array length could be selected based on the length of the cochlear lumen, which can be observed from the 3D image.

Our aim was to investigate the relationship between facial canal dehiscence (FCD) and surgical findings and procedures in patients with cholesteatoma. A total of 186 patients (118 males, 39.2 ± 15 years) who underwent surgery for advanced cholesteatoma between 2013 and 2018 were included in the study. The relationship between FCD and surgical findings was investigated via the surgical registries. The prevalence of FCD was 36.6% (68/186). The prevalence of FCD was 44%, and 13.2% for the patients who underwent canal wall down mastoidectomy (62/141) and canal wall up mastoidectomy (6/45), respectively ( P < .001). Facial canal dehiscence was detected in 73.9% of the 23 patients who had a lateral semicircular canal (LSCC) defect ( P < .001), in 61.9% of 21 patients who had a tegmen tympani defect, and in 58.1% of the 31 patients who had erosion on the posterior wall of the external auditory canal (EAC; P < .05). The prevalence of FCD was 3.1% in patients with isolated incus erosion, 59.1% in patients with erosion of malleus and incus, 60.7% in patients with erosion of stapes suprastructure and incus, and 43.2% in patients with whole ossicular chain deformation ( P < .001). The defects on LSCC, EAC, tegmen tympani, and malleus and incus might be cautionary findings for the presence of FCD during cholesteatoma surgery.

Superior semicircular canal dehiscence is caused by a bone defect on the roof of the superior semicircular canal. The estimated prevalence when unilateral varies between 0.4% and 0.7% and is still unknown when bilateral. Patients may present with audiologic and vestibular symptoms that may vary from asymptomatic to disabling. We report a case of a 72-year-old Caucasian woman presented to otolaryngology department reporting imbalance, bilateral pulsatile tinnitus, hypoacusis while being very sensitive to certain sounds. Physical examination was unremarkable, except for the Rinne test that was negative in both sides. The patient underwent an audiometry revealing a mild bilateral conductive hearing loss. A temporal bone CT scan was performed which evidenced bilateral superior semicircular canal dehiscence. Cervical vestibular evoked myogenic potentials and electrocochleography confirmed diagnosis. Although rare, superior semicircular canal dehiscence shall be considered in conductive hearing loss with vestibular symptoms., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Little is known about the role of TBX1 in post-otocyst stages of inner ear development. Here, we report on mice with a missense mutation of Tbx1 that are viable with fully developed but abnormally formed inner ears. Mutant mice are deaf due to an undeveloped stria vascularis and show vestibular dysfunction associated with abnormal semicircular canal formation. We show that TBX1 is expressed in endolymph-producing strial marginal cells and vestibular dark cells of the inner ear and is an upstream regulator of Esrrb, which previously was shown to control the developmental fate of these cells. We also show that TBX1 is expressed in sensory cells of the crista ampullaris, which may relate to the semicircular canal abnormalities observed in mutant mice. Inner ears of mutant embryos have a non-resorbed fusion plate in the posterior semicircular canal and a single ampulla connecting anterior and lateral canals. We hypothesize that the TBX1 missense mutation prevents binding with specific co-regulatory proteins. These findings reveal previously unknown functions of TBX1 during later stages of inner ear development., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: This study aimed to evaluate the efficacy of magnetic resonance imaging (MRI) for diagnosing superior semicircular canal dehiscence (SSCD)., Materials and Methods: The radiological records of patients who were admitted to our clinic with complaints of otologic and neuro-otologic symptoms between October 2014 and December 2015 were retrospectively reviewed. Among these patients, those who underwent both computed tomography and MRI and were reported to have SSCD in the temporal bone on at least one side were included in the study group. MRI records of patients with a confirmed diagnosis were then assessed for the presence of SSCD., Results: The left and right semicircular canals of 52 patients were evaluated in this study. The sensitivity and specificity of MRI in the diagnosis of SSCD was 89.06% and 90%, respectively. The positive and negative predictive values were 93.44% and 83.72%, respectively., Conclusion: The use of multiplanar reformats and angulation techniques during MRI assessment of patients with neuro-otologic symptoms can improve the diagnostic process for patients with SSCD. This may allow early diagnosis of the disease by using just one imaging method, which would also reduce the costs per patient during the diagnosis period.

Purpose: The goal of this retrospective study was to investigate the differential diagnosis of endolymphatic hydrops in patients with Meniere's disease (MD) symptoms by using magnetic resonance imaging (MRI) with intravenous injection of gadolinium chelate and delayed acquisition., Material and Method: Two hundred patients (133 women, 67 men; mean age=67.2±11 ([SD] years) with unilateral MD underwent MRI at 3-T, between 4.5 and 5.5hours after intravenous administration of gadoterate meglumine at a dose of 0.1mmol/kg. MR images were analyzed for the presence of saccular hydrops, perilymphatic fistulae, inner ear malformations, semicircular canal (SCC) abnormal enhancement and brain lesions. We also tested the potential relationship between past history of gentamicin intratympanic administration and perilymphatic fistula presence and SCC aspect., Results: Saccular hydrops were found in 96/200 patients with MD (48%). Three patients (1.5%) had perilymphatic fistulas associated with saccular hydrops, as confirmed by surgery. There was a correlation between the presence of perilymphatic fistula and past history of intratympanic gentamicin administration (P=0.02). We detected inner ear malformations in 5 patients (2.5%), SCC local enhancement in 15 patients (7.5%) always on the same side than the clinical symptoms of MD. There was a correlation between the presence of SCC abnormal enhancement and past intratympanic gentamicin administration (P=0.001). Five patients (2.5%) had brain lesions along central cochleovestibular pathways., Conclusion: MRI may reveal brain lesions, SCC abnormalities and perilymphatic fistulae in patients with clinical MD., (Copyright © 2017 Editions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Lateral semicircular canal aplasia is a malformation of the inner ear, usually associated with vestibular and cochlear malformations in the context of congenital malformation syndromes. We report a rare case of a young patient with isolated lateral semicircular canal aplasia and no associated vestibular symptoms., Clinical Case Summary: A 20-year-old man with no personal or family history presented with persistent unilateral tinnitus for three years with no associated vestibular symptoms. Moderate unilateral right sensorineural hearing loss was detected. Magnetic resonance imaging demonstrated isolated aplasia of the right lateral semicircular canal. Videonystagmography revealed right hyporeflexia. Vestibular evoked myogenic potentials were absent after stimulation on the right side and normal on the left side., Discussion: Although the morphological abnormalities appeared to be isolated on imaging, the patient presented functional signs of global cochlear, semicircular canal and otolithic lesions, probably related to a developmental disorder of the membranous labyrinth. Functional investigations must be performed in the presence of isolated semicircular canal aplasia, even when it is an incidental finding, to exclude more extensive labyrinthine lesions., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Head direction (HD) cells fire when an animal faces a particular direction in its environment, and they are thought to represent the neural correlate of the animal's perceived spatial orientation. Previous studies have shown that vestibular information is critical for generating the HD signal but have not delineated whether information from all three semicircular canals or just the horizontal canals, which are primarily sensitive to angular head rotation in the horizontal (yaw) plane, are critical for the signal. Here, we monitored cell activity in the anterodorsal thalamus (ADN), an area known to contain HD cells, in epstatic circler (Ecl) mice, which have a bilateral malformation of the horizontal (lateral) semicircular canals. Ecl mice and their littermates that did not express the mutation (controls) were implanted with recording electrodes in the ADN. Results confirm the important role the horizontal canals play in forming the HD signal. Although normal HD cell activity (Raleigh's r > 0.4) was recorded in control mice, no such activity was found in Ecl mice, although some cells had activity that was mildly modulated by HD (0.4 > r > 0.2). Importantly, we also observed activity in Ecl mice that was best characterized as bursty--a pattern of activity similar to an HD signal but without any preferred firing direction. These results suggest that the neural structure for the HD network remains intact in Ecl mice, but the absence of normal horizontal canals results in an inability to control the network properly and brings about an unstable HD signal. Significance statement: Cells in the anterior dorsal thalamic nucleus normally fire in relation to the animal's directional heading with respect to the environment--so-called head direction cells. To understand how these head direction cells generate their activity, we recorded single-unit activity from the anterior dorsal thalamus in transgenic mice that lack functional horizontal semicircular canals. We show that the neural network for the head direction signal remains intact in these mice, but that the absence of normal horizontal canals results in an inability to control the network properly and brings about an unstable head direction signal., (Copyright © 2016 the authors 0270-6474/16/360741-14$15.00/0.)

Background: Superior semicircular canal dehiscence (SSCD) is gradually recognized by otologists in recent years. The patients with SSCD have a syndrome comprising a series of vestibular symptoms and hearing function disorders which can be cured by the operation. In this study, we evaluated the characteristics of patients with SSCD and determined the effectiveness of treating this syndrome by resurfacing the canal via the transmastoid approach using a dumpling structure., Methods: Patients with SSCD, confirmed by high-resolution computed tomography and hospitalized at Beijing Tongren Hospital between November 2009 and October 2012, were included in the study. All of the patients underwent the unilateral transmastoid approach for resurfacing the canal, and received regular follow-up after surgery. Data from preoperative medical records and postoperative follow-up were comparatively analyzed to evaluate the effect of surgery., Results: In total, 10 patients and 13 ears (three left ears, four right ears, three bilateral ears) were evaluated in the study, which included 7 men and 3 women. Different symptoms and distinctive manifestations of vestibular evoked myogenic potential were found in these patients. After surgery, 4 patients had complete resolution, 5 had partial resolution, and 1 patient, with bilateral SSCD, had aggravation. None of the patients suffered from serious complications such as sensorineural hearing loss, facial paralysis, cerebrospinal fluid leakage, or intracranial hypertension., Conclusions: In patients with unilateral SSCD, resurfacing the canal via the transmastoid approach using a dumpling structure is an effective and safe technique. However, more consideration is needed for patients with bilateral SSCD.

Morphogenesis of the semicircular canal ducts in the vertebrate inner ear is a dramatic example of epithelial remodelling in the embryo, and failure of normal canal development results in vestibular dysfunction. In zebrafish and Xenopus, semicircular canal ducts develop when projections of epithelium, driven by extracellular matrix production, push into the otic vesicle and fuse to form pillars. We show that in the zebrafish, extracellular matrix gene expression is high during projection outgrowth and then rapidly downregulated after fusion. Enzymatic disruption of hyaluronan in the projections leads to their collapse and a failure to form pillars: as a result, the ears swell. We have cloned a zebrafish mutant, lauscher (lau), identified by its swollen ear phenotype. The primary defect in the ear is abnormal projection outgrowth and a failure of fusion to form the semicircular canal pillars. Otic expression of extracellular matrix components is highly disrupted: several genes fail to become downregulated and remain expressed at abnormally high levels into late larval stages. The lau mutations disrupt gpr126, an adhesion class G protein-coupled receptor gene. Expression of gpr126 is similar to that of sox10, an ear and neural crest marker, and is partially dependent on sox10 activity. Fusion of canal projections and downregulation of otic versican expression in a hypomorphic lau allele can be restored by cAMP agonists. We propose that Gpr126 acts through a cAMP-mediated pathway to control the outgrowth and adhesion of canal projections in the zebrafish ear via the regulation of extracellular matrix gene expression.

Introduction: Bilateral semicircular canal aplasia is extremely rare; discovery, when the cochlear-vestibular system is normal and there is no hearing loss, is serendipitous., Case Report: Bilateral semicircular canal aplasia was serendipitously discovered in a 24-year-old male during assessment of unilateral mixed hearing loss with subnormal contralateral hearing. The deformity was isolated, with no associated syndrome., Discussion/conclusion: Incidence of this isolated entity is unknown, but doubtless greatly underestimated due to the absence of associated symptomatology. To the best of our knowledge, this is only the second report of bilateral aplasia of the entire semicircular canal system involving unilateral hearing loss. A review of the literature focuses on the embryological and molecular aspects., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background and Purpose: Waardenburg syndrome, characterized by deafness and pigmentation abnormalities, is clinically and genetically heterogeneous, consisting of 4 distinct subtypes and involving several genes. SOX10 mutations have been found both in types 2 and 4 Waardenburg syndrome and neurologic variants. The purpose of this study was to evaluate both the full spectrum and relative frequencies of inner ear malformations in these patients., Materials and Methods: Fifteen patients with Waardenburg syndrome and different SOX10 mutations were studied retrospectively. Imaging was performed between February 2000 and March 2010 for cochlear implant work-up, diagnosis of hearing loss, and/or evaluation of neurologic impairment. Eleven patients had both CT and MR imaging examinations, 3 had MR imaging only, and 1 had CT only., Results: Temporal bone abnormalities were bilateral. The most frequent pattern associated agenesis or hypoplasia of ≥1 semicircular canal, an enlarged vestibule, and a cochlea with a reduced size and occasionally an abnormal shape, but with normal partition in the 13/15 cases that could be analyzed. Three patients lacked a cochlear nerve, bilaterally in 2 patients. In addition, associated abnormalities were found when adequate MR imaging sequences were available: agenesis of the olfactory bulbs (7/8), hypoplastic or absent lacrimal glands (11/14), hypoplastic parotid glands (12/14), and white matter signal anomalies (7/13)., Conclusions: In the appropriate clinical context, bilateral agenesis or hypoplasia of the semicircular canals or both, associated with an enlarged vestibule and a cochlear deformity, strongly suggests a diagnosis of Waardenburg syndrome linked to a SOX10 mutation.

Proper morphogenesis of inner ear semicircular canals requires precise regulation of cellular proliferation, epithelial-to-mesenchymal transition, and fusion of epithelial plates. Epigenetic regulation of these processes is not well understood, but is likely to involve chromatin remodeling enzymes. CHD7 is a chromodomain-containing, ATP dependent helicase protein that is highly expressed in the developing ear and is required for semicircular canal development in both humans and mice. Here we report that mice with heterozygous loss of Chd7 function exhibit delayed semicircular canal genesis, delayed Netrin1 expression and disrupted expression of genes that are critical for semicircular canal formation (Bmp2, Bmp4, Msx1 and Fgf10). Complete loss of Chd7 results in aplasia of the semicircular canals and sensory vestibular organs, with reduced or absent expression of Otx1, Hmx3, Jagged1, Lmo4, Msx1 and Sox2. Our results suggest that Chd7 may have critical selector gene functions during inner ear morphogenesis. Detailed analysis of the epigenetic modifications underlying these gene expression changes should provide insights into semicircular canal development and help in the design of therapies for individuals with inner ear malformations., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: The vestibular apparatus of the vertebrate inner ear uses three fluid-filled semicircular canals to sense angular acceleration of the head. Malformation of these canals disrupts the sense of balance and frequently causes circling behavior in mice. The Epistatic circler (Ecl) is a complex mutant derived from wildtype SWR/J and C57L/J mice. Ecl circling has been shown to result from the epistatic interaction of an SWR-derived locus on chromosome 14 and a C57L-derived locus on chromosome 4, but the causative genes have not been previously identified., Methodology/principal Findings: We developed a mouse chromosome substitution strain (CSS-14) that carries an SWR/J chromosome 14 on a C57BL/10J genetic background and, like Ecl, exhibits circling behavior due to lateral semicircular canal malformation. We utilized CSS-14 to identify the chromosome 14 Ecl gene by positional cloning. Our candidate interval is located upstream of bone morphogenetic protein 4 (Bmp4) and contains an inner ear-specific, long non-coding RNA that we have designated Rubie (RNA upstream of Bmp4 expressed in inner ear). Rubie is spliced and polyadenylated, and is expressed in developing semicircular canals. However, we discovered that the SWR/J allele of Rubie is disrupted by an intronic endogenous retrovirus that causes aberrant splicing and premature polyadenylation of the transcript. Rubie lies in the conserved gene desert upstream of Bmp4, within a region previously shown to be important for inner ear expression of Bmp4. We found that the expression patterns of Bmp4 and Rubie are nearly identical in developing inner ears., Conclusions/significance: Based on these results and previous studies showing that Bmp4 is essential for proper vestibular development, we propose that Rubie is the gene mutated in Ecl mice, that it is involved in regulating inner ear expression of Bmp4, and that aberrant Bmp4 expression contributes to the Ecl phenotype.

Objective: To explore the clinical characteristics and possible pathological mechanisms of vertigo due to enlarged vestibule with lateral semicircular canal dysplasia., Methods: A retrospective review was conducted for 5 cases of peripheral vertigo due to enlarged vestibule with lateral semicircular canal dysplasia. Their characteristics of medical history, precipitating factors, course of vertigo, auditory tests, vestibular tests and imaging examine results were analyzed., Results: The clinical characteristics were as follows. (1) Specifics of medical history: 4 cases suffered delays in gross motor development and potential equilibrium dysfunctions. One case failed to recount an earlier medical history, but could maintain normal hearing and vestibular functions for a long time in adulthood. (2) Most cases could identify the precipitating factors of initial attacks, such as head-bumping, nose-blowing and constipation, etc. resulting in sudden rises of intracranial or abdominal pressures. (3) Paroxysmal vertigo and progressive hearing loss were mimicking Meniere disease or large vestibular aqueduct syndrome. But its course of vertigo was different from those of Meniere disease and large vestibular aqueduct syndrome with regards to hearing levels and audiograms. (4) Some cases had positional vertigo. But the results of Dix-Hallpike and Roll tests were different from benign paroxysmal positioning vertigo (BPPV). (5) The inner ear imaging showed enlarged vestibule with lateral semicircular canal dysplasia., Conclusion: The enlarged vestibule with lateral semicircular canal dysplasia is a rare etiology of peripheral vertigo. The history of delays in gross motor development and potential equilibrium dysfunctions in childhood may offer important diagnostic clues. And audiological and vestibular tests, high-resolution computed tomography and magnetic resonance may help to ascertain the diagnosis.

Aplasia of the common crus is an uncommon congenital anomaly. We present the case of a patient with common crus aplasia and discuss the relevant embryology and the role of 3D CT in evaluation of this rare congenital anomaly.

Background and Purpose: This paper describes the CT findings that characterize the middle and inner ear anomalies in coloboma, heart defects, choanal atresia, mental retardation, genitourinary, and ear anomalies (CHARGE) syndrome. With this information, neuroradiologists will be better prepared to provide clinically relevant information to their referring physicians regarding this rare syndrome., Materials and Methods: CT studies from 13 patients were reviewed by 2 neuroradiologists with Certificate of Additional Qualification. Each ear was counted separately for a total of 26 ears. Middle and inner ear anomalies associated with CHARGE syndrome were categorized. Investigational review board approval was obtained., Results: Twenty of 26 (77%) ears demonstrated cochlear aperture atresia. Four of these ears were evaluated with MR imaging and were found to lack a cochlear nerve. Twenty-one of 26 (81%) cochlea had some form of dysplasia. Six of 26 (23%) round windows were aplastic. Three of 26 (12%) round windows were hypoplastic. Twenty-one of 26 (81%) oval windows were atretic or aplastic. Fifteen of 26 (58%) vestibules were hypoplastic or dysplastic. There were 5 of 26 (19%) enlarged vestibular aqueducts. Twelve of 26 (46%) vestibular aqueducts had an anomalous course. All cases demonstrated absent semicircular canals. Twenty-three of 26 (88%) facial nerve canals had an anomalous course. Four of 26 (15%) tympanic segments were prolapsed. Three of 26 (12%) temporal bones had an anomalous emissary vein referred to as a petrosquamosal sinus. Twenty-one of 26 (81%) middle ear cavities were small. Twenty-three of 26 (93%) ossicles were dysplastic with ankylosis. Three of 26 (12%) internal auditory canals were small., Conclusion: The CT findings that correlate to the anomalies of CHARGE syndrome affect conductive as well as sensorineural hearing. Stenosis of the aperture for the cochlear nerve aperture on CT is suggestive of hypoplasia or absence of the cochlear nerve, which has been demonstrated in some cases by MR. Absence of the cochlear nerve would be a contraindication to cochlear implantation.

The Superior Canal Dehiscence Syndrome (SCDS) was first reported by Minor at. Al. (1998), and has been characterized by vertigo and vertical-torsional eye movements related to loud sounds or stimuli that change middle ear or intracranial pressure. Hearing loss, for the most part with conductive patterns on audiometry, may be present in this syndrome. We performed a literature survey in order to to present symptoms, signs, diagnostic and therapeutic approaches to the SCDS, also aiming at stressing the great importance of including this syndrome among the tractable cause of vertigo. We should emphasize that this is a recent issue, still unknown by some specialists. The Correct SCDS diagnosis, besides enabling patient treatment, precludes misdiagnosis and inadequate therapeutic approaches.

Nor-1 belongs to the nur subfamily of nuclear receptor transcription factors. The precise role of Nor-1 in mammalian development has not been established. However, recent studies indicate a function for this transcription factor in oncogenesis and apoptosis. To examine the spatiotemporal expression pattern of Nor-1 and the developmental and physiological consequences of Nor-1 ablation, Nor-1-null mice were generated by insertion of the lacZ gene into the Nor-1 genomic locus. Disruption of the Nor-1 gene results in inner ear defects and partial bidirectional circling behavior. During early otic development, Nor-1 is expressed exclusively in the semicircular canal forming fusion plates. After formation of the membranous labyrinth, Nor-1 expression in the vestibule is limited to nonsensory epithelial cells localized at the inner edge of the semicircular canals and to the ampullary and utricular walls. In the absence of Nor-1, the vestibular walls fuse together as normal; however, the endolymphatic fluid space in the semicircular canals is diminished and the roof of the ampulla appears flattened due to defective continual proliferative growth of the semicircular canals.

A patient with Goldenhar's syndrome (oculoauriculovertebral dysplasia) and unilateral aplasia of all semicircular canals is presented. This is the first report of such a finding and may support the hypothesis that Goldenhar's syndrome and the CHARGE association have a common pathogenetic mechanism.

Mice lacking the EphB2 receptor tyrosine kinase display a cell-autonomous, strain-specific circling behavior that is associated with vestibular phenotypes. In mutant embryos, the contralateral inner ear efferent growth cones exhibit inappropriate pathway selection at the midline, while in mutant adults, the endolymph-filled lumen of the semicircular canals is severely reduced. EphB2 is expressed in the endolymph-producing dark cells in the inner ear epithelium, and these cells show ultrastructural defects in the mutants. A molecular link to fluid regulation is provided by demonstrating that PDZ domain-containing proteins that bind the C termini of EphB2 and B-ephrins can also recognize the cytoplasmic tails of anion exchangers and aquaporins. This suggests EphB2 may regulate ionic homeostasis and endolymph fluid production through macromolecular associations with membrane channels that transport chloride, bicarbonate, and water.

Targeted mutagenesis in mice demonstrates that the POU-domain gene Brn4/Pou3f4 plays a crucial role in the patterning of the mesenchymal compartment of the inner ear. Brn4 is expressed extensively throughout the condensing mesenchyme of the developing inner ear. Mutant animals displayed behavioral anomalies that resulted from functional deficits in both the auditory and vestibular systems, including vertical head bobbing, changes in gait, and hearing loss. Anatomical analyses of the temporal bone, which is derived in part from the otic mesenchyme, demonstrated several dysplastic features in the mutant animals, including enlargement of the internal auditory meatus. Many phenotypic features of the mutant animals resulted from the reduction or thinning of the bony compartment of the inner ear. Histological analyses demonstrated a hypoplasia of those regions of the cochlea derived from otic mesenchyme, including the spiral limbus, the scala tympani, and strial fibrocytes. Interestingly, we observed a reduction in the coiling of the cochlea, which suggests that Brn-4 plays a role in the epithelial-mesenchymal communication necessary for the cochlear anlage to develop correctly. Finally, the stapes demonstrated several malformations, including changes in the size and morphology of its footplate. Because the stapes anlage does not express the Brn4 gene, stapes malformations suggest that the Brn4 gene also plays a role in mesenchymal-mesenchymal signaling. On the basis of these data, we suggest that Brn-4 enhances the survival of mesodermal cells during the mesenchymal remodeling that forms the mature bony labyrinth and regulates inductive signaling mechanisms in the otic mesenchyme.

The inner ear develops from the otic vesicle, a one-cell-thick epithelium, which eventually transforms into highly complex structures including the sensory organs for balance (vestibulum) and hearing (cochlea). Several mouse inner ear mutations with hearing and balance defects have been described but for most the underlying genes have not been identified, for example, the genes controlling the development of the vestibular organs. Here, we report the inactivation of the homeobox gene, Nkx5-1, by homologous recombination in mice. This gene is expressed in vestibular structures throughout inner ear development. Mice carrying the Nkx5-1 null mutation exhibit behavioural abnormalities that resemble the typical hyperactivity and circling movements of the shaker/waltzer type mutants. The balance defect correlates with severe malformations of the vestibular organ in Nkx5-1(-/-) mutants, which fail to develop the semicircular canals. Nkx5-1 is the first ear-specific molecule identified to play a crucial role in the formation of the mammalian vestibular system.

We describe an unusual labyrinthine malformation in a case of Goldenhar syndrome studied with CT and steady-state MR imaging. A single posterosuperior semicircular canal was found with no common crus formation. The malformation could not be attributed to any embryologic development. Nosologic considerations are discussed.

Mutations giving rise to anatomical defects in the inner ear have been isolated in a large scale screen for mutations causing visible abnormalities in the zebrafish embryo (Haffter, P., Granato, M., Brand, M. et al. (1996) Development 123, 1-36). 58 mutants have been classified as having a primary ear phenotype; these fall into several phenotypic classes, affecting presence or size of the otoliths, size and shape of the otic vesicle and formation of the semicircular canals, and define at least 20 complementation groups. Mutations in seven genes cause loss of one or both otoliths, but do not appear to affect development of other structures within the ear. Mutations in seven genes affect morphology and patterning of the inner ear epithelium, including formation of the semicircular canals and, in some, development of sensory patches (maculae and cristae). Within this class, dog-eared mutants show abnormal development of semicircular canals and lack cristae within the ear, while in van gogh, semicircular canals fail to form altogether, resulting in a tiny otic vesicle containing a single sensory patch. Both these mutants show defects in the expression of homeobox genes within the otic vesicle. In a further class of mutants, ear size is affected while patterning appears to be relatively normal; mutations in three genes cause expansion of the otic vesicle, while in little ears and microtic, the ear is abnormally small, but still contains all five sensory patches, as in the wild type. Many of the ear and otolith mutants show an expected behavioural phenotype: embryos fail to balance correctly, and may swim on their sides, upside down, or in circles. Several mutants with similar balance defects have also been isolated that have no obvious structural ear defect, but that may include mutants with vestibular dysfunction of the inner ear (Granato, M., van Eeden, F. J. M., Schach, U. et al. (1996) Development, 123, 399-413,). Mutations in 19 genes causing primary defects in other structures also show an ear defect. In particular, ear phenotypes are often found in conjunction with defects of neural crest derivatives (pigment cells and/or cartilaginous elements of the jaw). At least one mutant, dog-eared, shows defects in both the ear and another placodally derived sensory system, the lateral line, while hypersensitive mutants have additional trunk lateral line organs.

Purpose: To describe the steady-state free-precession MR sequence and its application to the study of the inner ear., Method: The inner ear was imaged with CT and a 0.5-T MR unit in three dimension, to evaluate the various signals from the lumen of the labyrinth., Results: Normally, the signal from the perilymphatic and endolymphatic spaces is homogeneous. However, among our cases of neurosensory deafness, differences of signal and morphology were seen in patients with otosclerosis, ossifying labyrinthitis, and inner ear malformations., Conclusion: Three-dimensional MR, used together with routine two-dimensional fast spin-echo, is another diagnostic too]l that can provide new data in the evaluation of the normal and unhealthy inner ear.

We identified a semidominant, chemically induced, mouse mutation with a complex array of abnormal behaviors including bidirectional circling and hyperactivity, abnormal circadian rhythmicity and abnormal responses to light. In this report, we genetically and phenotypically characterized the circling/waltzing component of the abnormal behavior. We mapped the locus controlling this trait by heterozygosity mapping of partially congenic lines carrying the mutagenized chromosome outcrossed to different inbred strains for three generations. Analysis of 68 PCR-based markers in 13 affected individuals indicated that the mutant locus, named Wheels (Whl), resides in the subcentromeric portion of mouse chromosome 4. The statistical evaluation of data obtained by heterozygosity mapping validates this efficient mapping approach. Further characterization of the Whl mutation demonstrated that Whl/Whl homozygotes die during embryonic life and that the penetrance of circling behavior depends on genetic background. Morphological analysis of the inner ears of Whl/+ mice revealed a variable number of abnormalities in the sensory and nonsensory portions of their semicircular canals. Abnormalities ranged from slight atrophy of one or more cristae to complete absence of the lateral crista and canal. The molecular characterization of the gene disrupted in the Whl mutation will provide insight into developmental mechanisms involved in inner ear formation.