Epidemiological and Genetic Study in Patients with Inner Ear Malformations
Date Issued
2004
Date
2004
Author(s)
DOI
zh-TW
Abstract
PART I. Epidemiological Study in patients with Inner Ear Malformation
Background
With the improvements in imaging technology, congenital bony inner ear malformation, traditionally considered as a rare disease entity, has proven to be a common cause of pediatric deafness. However, a number of unanswered questions remain concerning the pathogenesis of the hearing loss associated with inner ear malformations. Only a careful review of temporal bone images in affected patients with well documented hearing data will clarify these questions.
Objective
As a pilot study for genetic research of inner ear malformation, the first purpose of the study is to establish the epidemiological data in the Taiwanese hearing-impaired population. Also to be investigated are the etiologies and the audiologic data of different types of malformations, which we think might be helpful in elucidating the interrelation between malformations and shedding light on the pathogenesis.
Study design
Retrospective study from 1998 to 2002 at a tertiary-care university hospital.
Methods
One hundred and sixty consecutive children with a total of 302 affected ears undergoing high-resolution CT of the temporal bone for sensorineural hearing loss were enrolled. The image results were correlated with etiologies, hearing loss patterns, hearing levels and audiogram configurations
Results
As many as 37% hearing-impaired children who visited our clinic turned out to demonstrate inner ear malformations on high-resolution CT, and inner ear malformation was present in a total of 114 (38%) ears. The most common malformations were enlarged vestibular aqueduct, incomplete partition of cochlea (Mondini dysplasia), large vestibule, and semicircular canal dysplasia, presenting either as isolated finding or in combination. Eighty-four (74%) ears have abnormalities confined to these four malformations, and only 30 (26%) ears showed other malformations. Patients with complex of enlarged vestibular aqueduct, Mondini dysplasia, large vestibule and semicircular canal dysplasia (EMVS complex) demonstrated a significantly higher incidence of fluctuating hearing loss (93%) and a better hearing level compared to those with other malformations. Homogeneity in audiologic features among these four malformations was also disclosed.
Conclusions
Inner ear malformation proves to be a common finding in the hearing-impaired Taiwanese. By comparing the audiologic data of children with various inner ear malformations, we also identify a distinct clinical entity, the EMVS complex, which is characterized by fluctuating hearing loss and a better hearing level. Based on the homogeneity of audiologic features and previous knowledge about embryogenesis, we propose that malformations belonging to this complex result from a common pathogenetic mechanism.
PART II. Genetic Study in Patients with Inner Ear Malformation
Background
The traditional hypothesis concerning the pathogenesis of inner ear malformations holds that various types of malformations represent different stages of developmental arrest during embryogenesis. Among the various types of inner ear malformations, enlarged vestibular aqueduct (EVA) and Mondini’s dysplasia are by far the most common findings on HRCT, and have been recently linked to mutations in the SLC26A4 (PDS) gene. However, a clear and complete correlation between the SLC26A4 genotypes and the phenotypes still cannot be deciphered. Whether SLC26A4 gene mutations are present in patients with malformations other than EVA and Mondini’s dysplasia is also a question of great interest, because it would undoubtedly yield insight into the pathogenesis of the various types of inner ear malformations.
Objective
This first purpose of the study is to determine the mutation spectrum of the SLC26A6 gene among Taiwanese hearing-impaired patients associated with inner ear malformations. Secondly, the correlation between the genotypes and the phenotypes is investigated, with a special emphasis placed on comparison of the severity of inner ear malformations and the hearing levels, which was scarcely documented in the literature. In order to testify the hypothesis of developmental arrest, we also survey SLC26A4 gene mutations in patients with various types of inner ear malformations, including those with EVA and/or Mondini’s dysplasia, as well as those with other malformations.
Study design
Prospective study from 2002 to 2004 at a tertiary-care university hospital.
Methods
Thirty-five families in which at least one family member demonstrated both hearing impairment and inner ear malformation on HRCT were recruited in the study. Mutations of the SLC26A4 gene were screened in the probands of these families, as well as in 30 hearing-impaired patients without inner ear malformations and 50 unaffected subjects with normal hearing for comparison. The radiological and audiological results of the probands were then compared according to the genotypes.
Results
In 25 families, the probands showed EVA and/or Mondini’s dysplasia as the main temporal bone abnormalities, whereas the probands in the remaining 10 families revealed other types of malformations. A total of 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 the mutated alleles segregated the malformation of EVA and Mondini’s dysplasia, whereas no mutated allele was found in the 10 probands with other types of malformations, confirming the specificity of the SLC26A4 mutations in the pathogenesis of EVA and Mondini’s dysplasia.
Among the 7 mutations, the splice site mutation IVS7-2A>G, surprisingly comprised 30 (79%) of the 38 mutated alleles, demonstrating a unique SLC26A4 mutation spectrum in Taiwanese and suggesting a founder effect. Meanwhile, analyses of the radiological findings and audiological results showed no obvious correlation between the genotypes and phenotypes.
Conclusion
Although the radiological findings of the various types of inner ear malformations to some extent resemble each other, and together appear to follow a continuum of morphological changes, their pathogenetic mechanisms are essentially different. The mutation spectrum of the SLC26A4 gene in Taiwanese is different from those in the Caucasoid and the Japanese series, and may be representative of those in Southeastern Asian populations. The lack of genotype-phenotype correlation and the evidence that only one mutated allele was detected in certain affected patients suggest interplay of other genetic or environmental factors with the PDS gene in the pathogenesis.
Subjects
Pendred氏症候群
Mondini氏發育不全
內耳畸形
聽力學檢查結果
大前庭導水管
發育停止
PDS基因
聽障病因
SLC26A4基因
耳蝸未完全分隔
Audiologic findings
Inner ear malformation
IVS7-2A>
G
EMVS complex
Pendred syndrome
Developmental arrest
Incomplete partition of cochlea
Etiology
SLC26A4 gene
Taiwanese
PDS gene
Enlarged vestibular aqueduct
High-resolution computed tomography
Type
text
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