Common Clinical Features of Children With Enlarged Vestibular Aqueduct and Mondini Dysplasia

Wu, Chen‐Chi; Chen, Yuh‐Shyang; Chen, Pei‐Jer

doi:10.1097/01.mlg.0000150691.85387.3f

Cited by 64 publications

(80 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We show that homozygous mutants have variably penetrant and expressive inner ear morphologies that are characterized most typically by loss of the EDS and common crus, dilatation of the remaining epithelium and poor coiling of the cochlea, phenotypes that are very similar to those of Hoxa1, Mafb and Gbx2 mutants (Pasqualetti et al, 2001;Lin et al, 2005;Choo et al, 2006) as well as to some classes of hearing-impaired patients (Manfre et al, 1997;Kim et al, 2004;Wu et al, 2005). The initial molecular patterning of Fgf3 mutant otocysts was normal, but by E10-10.5 these ears lacked or had reduced domains of dorsal otic genes, suggesting a loss of the cells fated to form the EDS.…”

Section: Introductionmentioning

confidence: 74%

“…The inner ear also has a dorsally projecting non-sensory appendage, the endolymphatic duct and sac (EDS), which plays an important role in maintaining the unique fluid environment essential for normal sensory function of the inner ear. Dysfunction of the inner ear is among the most common congenital disorders, affecting at least 1 in 500 births (Smith et al, 2005;Morton and Nance, 2006) and up to 39% of sensorineural deafness is associated with inner ear malformations (Mafong et al, 2002;Wu et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fgf3is required for dorsal patterning and morphogenesis of the inner ear epithelium

et al. 2007

View full text Add to dashboard Cite

The inner ear, which contains sensory organs specialized for hearing and balance, develops from an ectodermal placode that invaginates lateral to hindbrain rhombomeres (r) 5-6 to form the otic vesicle. Under the influence of signals from intra-and extraotic sources, the vesicle is molecularly patterned and undergoes morphogenesis and cell-type differentiation to acquire its distinct functional compartments. We show in mouse that Fgf3, which is expressed in the hindbrain from otic induction through endolymphatic duct outgrowth, and in the prospective neurosensory domain of the otic epithelium as morphogenesis initiates, is required for both auditory and vestibular function. We provide new morphologic data on otic dysmorphogenesis in Fgf3 mutants, which show a range of malformations similar to those of Mafb (Kreisler), Hoxa1 and Gbx2 mutants, the most common phenotype being failure of endolymphatic duct and common crus formation, accompanied by epithelial dilatation and reduced cochlear coiling. The malformations have close parallels with those seen in hearing-impaired patients. The morphologic data, together with an analysis of changes in the molecular patterning of Fgf3 mutant otic vesicles, and comparisons with other mutations affecting otic morphogenesis, allow placement of Fgf3 between hindbrain-expressed Hoxa1 and Mafb, and otic vesicle-expressed Gbx2, in the genetic cascade initiated by WNT signaling that leads to dorsal otic patterning and endolymphatic duct formation. Finally, we show that Fgf3 prevents ventral expansion of r5-6 neurectodermal Wnt3a, serving to focus inductive WNT signals on the dorsal otic vesicle and highlighting a new example of cross-talk between the two signaling systems.

show abstract

Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Fgf3is required for dorsal patterning and morphogenesis of the inner ear epithelium

et al. 2007

View full text Add to dashboard Cite

show abstract

“…By use of high-resolution computed tomography (HRCT), 20-30% of children with sensorineural hearing loss (SNHL) were found to have inner ear malformations [Antonelli et al, 1999;Mafong et al, 2002;McClay et al, 2002;Wu et al, 2005]. Sometimes also referred to as cochleovestibular malformations in the literature, inner ear malformations consist of morphological abnormalities in the cochlea, vestibule, semicircular canals, vestibular aqueduct, and internal auditory canal (IAC).…”

Section: Introductionmentioning

confidence: 99%

Specificity of <i>SLC26A4</i> Mutations in the Pathogenesis of Inner Ear Malformations

Chen²,

Hsu³

2005

Audiol Neurotol

Self Cite

View full text Add to dashboard Cite

The traditional hypothesis concerning the pathogenesis of inner ear malformations holds that various types of malformations represent different stages of developmental arrest during embryogenesis. In order to verify this hypothesis, we surveyed mutations in the SLC26A4(PDS) gene, which were documented to cause enlarged vestibular aqueduct (EVA) and Mondini’s dysplasia (incomplete partition of the cochlea), in 35 families with various types of inner ear malformations. In 25 families, the probands showed EVA or Mondini’s dysplasia as the main temporal bone abnormalities, whereas the probands in the remaining 10 families revealed other types of malformations. In total, 7 mutated SLC26A4 alleles, including 6 missense mutations (A372V, A387V, T410M, S448L, T721M, and H723R) and 1 splice site mutation (IVS7-2A→G), were detected. All mutated alleles segregated the malformations of EVA and Mondini’s dysplasia, whereas no mutated alleles were found in the 10 probands with other types of malformations. SLC26A4 mutations were found in 22 of the 25 probands with EVA or Mondini’s dysplasia, indicating that these might be specific to the development of Mondini’s dysplasia and EVA. It is inferred that the pathogenetic mechanisms of the various malformations essentially differ, although their radiological findings appear to follow a continuum of morphological changes.

show abstract

“…Dysfunction of the inner ear is among the most common congenital disorders, affecting at least 1 in 500 births (1) and ∼40% of sensorineural deafness is associated with inner ear malformations (2). However, the study of hearing and balance impairment in humans is limited by the inability to follow inner ear development.…”

mentioning

confidence: 99%

Sp8 regulates inner ear development

Chung

Medina-Ruiz

Harland

2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

A forward genetic screen of N-ethyl-N-nitrosourea mutagenized Xenopus tropicalis has identified an inner ear mutant named eclipse (ecl). Mutants developed enlarged otic vesicles and various defects of otoconia development; they also showed abnormal circular and inverted swimming patterns. Positional cloning identified specificity protein 8 (sp8), which was previously found to regulate limb and brain development. Two different loss-of-function approaches using transcription activator-like effector nucleases and morpholino oligonucleotides confirmed that the ecl mutant phenotype is caused by down-regulation of sp8. Depletion of sp8 resulted in otic dysmorphogenesis, such as uncompartmentalized and enlarged otic vesicles, epithelial dilation with abnormal sensory end organs. When overexpressed, sp8 was sufficient to induce ectopic otic vesicles possessing sensory hair cells, neurofilament innervation in a thickened sensory epithelium, and otoconia, all of which are found in the endogenous otic vesicle. We propose that sp8 is an important factor for initiation and elaboration of inner ear development.T he vertebrate inner ear is a sensory organ responsible for balance and sound detection. Dysfunction of the inner ear is among the most common congenital disorders, affecting at least 1 in 500 births (1) and ∼40% of sensorineural deafness is associated with inner ear malformations (2). However, the study of hearing and balance impairment in humans is limited by the inability to follow inner ear development. Vertebrates share similarities in the sequence of developmental events that form the inner ear: the formation of an otic placode from an ectodermal thickening, morphogenesis to form the otocyst, and regional patterning of the otic vesicle (OV), resulting in the 3D membranous labyrinth (3, 4). Multipotent sensory progenitor cells are induced in the ectoderm surrounding the anterior neural plate, a domain termed the preplacodal region (PPR), and six1 has been characterized as marking this panplacodal domain. Signals from hindbrain and the regional expression of different transcription factors differentiate the PPR into the otic placode. The OV is partitioned by asymmetrical expression of various developmental regulators to pattern subdomains of the developing inner ear.The abilities of Xenopus to elucidate the cellular and molecular aspects of developmental processes position it as a valuable model organism (5-7). Earlier studies of lineage analysis and spatiotemporal expression of transcription factors during inner ear development led to construction of an inner ear fate map in Xenopus and this fate map allows us to interpret gene expression patterns within the context of the anatomy (8, 9). In recent years, genetic and genomic approaches have been developed in Xenopus tropicalis (10-13). To advance our understanding of inner ear development, we have screened N-ethyl-N-nitrosourea (ENU) mutagenized X. tropicalis colonies and recovered an inner ear mutant named eclipse (ecl). The ecl mutant perturbs specificity protei...

show abstract

Common Clinical Features of Children With Enlarged Vestibular Aqueduct and Mondini Dysplasia

Abstract: The authors identified a distinct clinical entity, the EMVS complex, which is characterized by fluctuating hearing loss and a better hearing level. The authors proposed that malformations belonging to this complex result from a common pathogenetic mechanism.

Cited by 64 publications

References 15 publications

Fgf3is required for dorsal patterning and morphogenesis of the inner ear epithelium

Fgf3is required for dorsal patterning and morphogenesis of the inner ear epithelium

Specificity of <i>SLC26A4</i> Mutations in the Pathogenesis of Inner Ear Malformations

Sp8 regulates inner ear development

Contact Info

Product

Resources

About