今日の臨床サポート

先天性難聴(遺伝子変異による難聴など)

著者: 宇佐美真一 信州大学医学部 人工聴覚器学講座

監修: 森山寛 東京慈恵会医科大学附属病院

著者校正済:2022/08/31
現在監修レビュー中
患者向け説明資料

概要・推奨   

  1. 純音聴力検査を行い、難聴の程度、難聴の型(聴力像)を明らかにする。特に伝音難聴、混合性難聴、感音難聴の鑑別はその後の治療方針決定に必須である。
  1. 非症候群性難聴の場合、少なくとも50%は遺伝子が原因と考えられているため、遺伝学的検査(遺伝子診断)が原因診断として有用である。
  1. 感音難聴に関しては聴力を改善させる根本的な治療法はない。補聴器による効果が十分でない場合、早期に人工内耳装用を行うことが望ましい。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
宇佐美真一 : 未申告[2022年]
監修:森山寛 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 定期レビューを行い用語を一部修正し(顕性遺伝、潜性遺伝)、および残存聴力活用型人工内耳(EAS)など治療に関する情報等を補足した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 先天性難聴とは生下時より難聴を呈する疾患の総称であり、新出生児1,000人に1人に認められる比較的頻度の高い先天性障害の1つである。
  1. 新生児聴覚スクリーニングの普及に伴い難聴の早期発見が可能となってきたため、早期診断および早期療育により音声言語コミュニケーションの発達が可能となってきている。
  1. 先天性難聴あるいは小児期発症の難聴の60~70%は遺伝子の関与によるものと推測されている。遺伝子以外の原因では先天性サイトメガロウイルス感染症によるものが多い(わが国では約10%)。
  1. 遺伝性難聴は、難聴以外の症状を伴う症候群性難聴と、難聴以外の症状を伴わない非症候群性難聴に大別される。
  1. 症候群性難聴は全体の30%程度、非症候群性難聴は全体の70%程度を占める。
  1. 症候群性難聴は400種類を超える疾患群があり、さまざまな随伴症状を伴う症候群が報告されている。
  1. 障害部位が外耳~中耳の場合は伝音難聴、内耳~聴神経の場合は感音難聴となる。また、両方が併さった混合性難聴となる場合もある。
  1. 遺伝子変異の種類により障害部位や程度が異なるため、難聴の程度や予後などの臨床像が異なる。2012年からは保険診療として遺伝子診断を実施することが可能となった。
  1. 原因診断を行うことでサブタイプ分類が可能となり、最適な治療法、介入法を提案する個別化医療が可能となる。
問診・診察のポイント  
問診:
  1. 新生児聴覚スクリーニング検査受検の有無とその結果

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文献 

K Tsukada, S Nishio, S Usami, Deafness Gene Study Consortium
A large cohort study of GJB2 mutations in Japanese hearing loss patients.
Clin Genet. 2010 Nov;78(5):464-70. doi: 10.1111/j.1399-0004.2010.01407.x.
Abstract/Text GJB2 is the gene most frequently associated with hereditary hearing loss, and the GJB2 mutation spectrums vary among different ethnic groups. In this study, the mutation spectrum as well as clinical features of patients with GJB2 mutations as found in more than 1000 Japanese hearing loss families are summarized. The present results show that the frequency of GJB2 mutations in the Japanese population with hearing loss is 14.2% overall and 25.2% in patients with congenital hearing loss. c.235delC was the most frequent allele (49.8%), was associated with a more severe phenotype, and was mainly found in patients who were diagnosed by the age of 3. In contrast, the second most frequent was p.V37I (16.5%), which has a milder phenotype and was mainly found in patients diagnosed at a higher age. Additional clinical features in hearing loss patients with GJB2 mutations in this study were the near absence of tinnitus, vestibular dysfunction and inner ear malformations.

© 2010 John Wiley & Sons A/S.
PMID 20497192
Kunihiro Fukushima, Kennichi Sugata, Norio Kasai, Shouichirou Fukuda, Rie Nagayasu, Naomi Toida, Nobuhiko Kimura, Teruaki Takishita, Mehmet Gunduz, Kazunori Nishizaki
Better speech performance in cochlear implant patients with GJB2-related deafness.
Int J Pediatr Otorhinolaryngol. 2002 Feb 1;62(2):151-7.
Abstract/Text OBJECTIVE: We applied mutation screening in seven cochlear implant users to identify those persons with GJB2-related deafness to determine whether etiology of deafness was predictive of speech performance after implantation.
METHODS: Direct sequence of GJB2 was conducted over seven cochlear implant users with prelingual hearing impairment and their speech, language and cognitive performance was examined.
RESULTS: The three persons with GJB2-related deafness had a mean vocabulary of 1243 words compared to a mean vocabulary of 195 words in the four children with GJB2-unrelated deafness, although the number of patients examined here was limited. The developmental quotient (DQ) of cognitive ability also was higher in those children with GJB2-related deafness.
CONCLUSIONS: These preliminary results suggest that better speech performance after cochlear implantation may be observed in persons with GJB2-related deafness. In the future, detailed phenotypic studies and mutation screening for non-syndromic hearing loss may play an important role in the preoperative assessment of prelingually-deafened children.

PMID 11788148
Hiroaki Suzuki, Aki Oshima, Koji Tsukamoto, Satoko Abe, Kozo Kumakawa, Kyoko Nagai, Hitoshi Satoh, Yukihiko Kanda, Satoshi Iwasaki, Shin-ichi Usami
Clinical characteristics and genotype-phenotype correlation of hearing loss patients with SLC26A4 mutations.
Acta Otolaryngol. 2007 Dec;127(12):1292-7. doi: 10.1080/00016480701258739.
Abstract/Text CONCLUSIONS: The present study confirmed the clinical characteristics of patients with SLC26A4 mutations: congenital, fluctuating, and progressive hearing loss usually associated with vertigo and/or goiter during long-term follow-up. This clarification should help to facilitate appropriate genetic counseling and proper medical management for patients with these mutations, but there was no particular genotype-phenotype correlation among them, suggesting that other factors may contribute to such variability.
OBJECTIVES: Due to the wide range of phenotypes caused by SLC26A4 mutations, there is controversy with regard to genotype-phenotype correlation. The present study was performed: (1) to determine phenotypic range in patients with biallelic SLC26A4 mutations, and (2) to evaluate whether possible genotype-phenotype correlation exists.
SUBJECTS AND METHODS: Phenotypes in 39 hearing loss patients with SLC26A4 mutations were summarized and genotype-phenotype correlation was analyzed.
RESULTS: Hearing level varied in the individuals from mild to profound severity. Most of the patients had fluctuating and progressive hearing loss that may have been of prelingual onset. Twenty-four (70.6%) patients had episodes of vertigo, and 10 (27.8%) patients had goiter, which had appeared at age 12 or older. In contrast to such phenotypic variabilities, no apparent correlation was found between these phenotypes and their genotypes.

PMID 17851929
S Y Lu, S Nishio, K Tsukada, T Oguchi, K Kobayashi, S Abe, S Usami
Factors that affect hearing level in individuals with the mitochondrial 1555A.G mutation.
Clin Genet. 2009 May;75(5):480-4.
Abstract/Text The mitochondrial 1555A>G mutation is one of the most common mutations responsible for hearing loss in Asians. Although the association with aminoglycoside exposure is well known, there is great variation in the severity of hearing loss. We analyzed hearing levels in 221 Japanese individuals with this mutation and attempted to identify relevant covariants including (i) age, (ii) aminoglycoside exposure, (iii) heteroplasmy ratio, and (iv) other gene mutations. At every age, average hearing levels were worse than those in normal subjects, suggesting that mitochondrial function itself may affect the severity of hearing loss. Although the hearing loss in individuals with the 1555A>G mutation progressed with age, the rate did not differ from that of the normal subjects. Those who had reported aminoglycoside exposure had moderate-to-severe hearing impairment regardless of age, confirming that such exposure is the most important environmental variable. We also confirmed the presence of heteroplasmy, which is known to modify the expression of other mitochondrial diseases, but found no evidence for a significant correlation with hearing impairment. A high prevalence of GJB2 heterozygous mutations was noted, indicating that these mutations may exhibit epistatic interaction with the 1555A>G mutation.

PMID 19475720
Maiko Miyagawa, Shin-ya Nishio, Shin-ichi Usami
Prevalence and clinical features of hearing loss patients with CDH23 mutations: a large cohort study.
PLoS One. 2012;7(8):e40366. doi: 10.1371/journal.pone.0040366. Epub 2012 Aug 10.
Abstract/Text Screening for gene mutations in CDH23, which has many exons, has lagged even though it is likely to be an important cause for hearing loss patients. To assess the importance of CDH23 mutations in non-syndromic hearing loss, two-step screening was applied and clinical characteristics of the patients with CDH23 mutations were examined in this study. As a first screening, we performed Sanger sequencing using 304 probands compatible with recessive inheritance to find the pathologic mutations. Twenty-six possible mutations were detected to be pathologic in the first screening. For the second screening, using the probes for these 26 mutations, a large cohort of probands (n = 1396) was screened using Taqman amplification-based mutation analysis followed by Sanger sequencing. The hearing loss in a total of 52 families (10 homozygous, 13 compound heterogygous, and 29 heterozygous) was found to be caused by the CDH23 mutations. The majority of the patients showed congenital, high frequency involved, progressive hearing loss. Interestingly, some particular mutations cause late onset moderate hearing loss. The present study is the first to demonstrate the prevalence of CDH23 mutations among non-syndromic hearing loss patients and indicated that mutations of the CDH23 gene are an important cause of non-syndromic hearing loss.

PMID 22899989
Shin-ichi Usami, Maiko Miyagawa, Shin-ya Nishio, Hideaki Moteki, Yutaka Takumi, Mika Suzuki, Yoko Kitano, Satoshi Iwasaki
Patients with CDH23 mutations and the 1555A>G mitochondrial mutation are good candidates for electric acoustic stimulation (EAS).
Acta Otolaryngol. 2012 Apr;132(4):377-84. doi: 10.3109/00016489.2011.649493.
Abstract/Text CONCLUSIONS: CDH23 mutations and the 1555A>G mitochondrial mutation were identified among our series of electric acoustic stimulation (EAS) patients, confirming that these genes were important in hearing loss with involvement of high frequency. Successful hearing preservation as well as good outcomes from EAS indicated that patients with this combination of mutations are good candidates for EAS.
OBJECTIVES: Screening for gene mutations that possibly cause hearing loss involving high frequency was performed to identify the responsible genes in patients with EAS. In addition to a review of the genetic background of the patients with residual hearing loss, the benefit of EAS for patients with particular gene mutations was evaluated.
METHODS: Eighteen patients (15 late-onset, 3 early-onset) with residual hearing who had received EAS were included in this study. Genetic analysis was performed to identify GJB2, CDH23, SLC26A4, and the 1555 mitochondrial mutations.
RESULTS: Three early-onset patients had CDH23 mutations. One late-onset patient had the 1555 A>G mitochondrial mutation.

PMID 22443853
Sakiko Furutate, Satoshi Iwasaki, Shin-ya Nishio, Hideaki Moteki, Shin-ichi Usami
Clinical profile of hearing loss in children with congenital cytomegalovirus (CMV) infection: CMV DNA diagnosis using preserved umbilical cord.
Acta Otolaryngol. 2011 Sep;131(9):976-82. doi: 10.3109/00016489.2011.583268. Epub 2011 May 26.
Abstract/Text CONCLUSIONS: Congenital cytomegalovirus (CMV) infection is a major cause of bilateral and unilateral sensorineural hearing loss (SNHL) in children, accounting for 9.0% of SNHL cases. The diagnostic rate using combined genetic deafness test and CMV DNA detection test was determined to be 46.4% in bilateral profound SNHL.
OBJECTIVES: The present study investigated the prevalence of congenital CMV infection diagnosed retrospectively by detection of CMV DNA in dried umbilical cord specimens from children with unilateral or bilateral SNHL up to the age of 12 years.
METHODS: Preserved dried umbilical cords were collected from 134 children with bilateral (46 children) or unilateral (88 children) SNHL. DNA was extracted from the dried umbilical cords and CMV DNA was detected by quantitative PCR. Genetic deafness tests based on the invader assay were performed in children with bilateral SNHL.
RESULTS: CMV DNA from the dried umbilical cords was detected in 8.7% of the bilateral SNHL and 9.1% of unilateral SNHL. Deafness gene mutations were identified in 21.7% (10/46) of children with bilateral SNHL.

PMID 21612560

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