今日の臨床サポート

自閉症スペクトラム(小児科)

著者: 広瀬宏之 横須賀市療育相談センター

監修: 五十嵐隆 国立成育医療研究センター

著者校正/監修レビュー済:2021/05/26
参考ガイドライン:
  1. アメリカ精神医学会(APA):DSM-5 精神疾患の分類と診断の手引
患者向け説明資料

概要・推奨   

  1. 自閉症スペクトラム(autism spectrum disorder、ASD)を疑った場合は、コミュニケーションの発達と、興味や感覚の偏り有無を確認する(推奨度1
  1. 状況依存性があるため、診察室での様子だけではなく、家庭や集団などさまざまな局面での様子を聴取する(推奨度2
  1. 発達水準を確認するために発達検査や知能検査を行い(推奨度2)、難聴を否定するために聴力検査を行う(推奨度3
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。
※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、実際の保険適用の査定において保険適用及び保険適用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用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:
広瀬宏之 : 特に申告事項無し[2021年]
監修:五十嵐隆 : 特に申告事項無し[2021年]

改訂のポイント
  1. 定期レビューを行い、ケアのポイントを加筆修正した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 自閉症スペクトラム(autism spectrum disorder、ASD)は、発達過程で顕在化する中枢神経系の器質的機能障害による対人コミュニケーション障害を主徴とする発達障害である。
  1. 原因は特定されていないが、80~90%の症例で遺伝性と考えられている。
  1. ASDは広汎性発達障害(pervasive developmental disorders、PDD)とほぼ同じ一群を指す。1994年公表のアメリカ精神医学会の精神疾患診断マニュアルDSM-Ⅳでは、広汎性発達障害の下位カテゴリーとして自閉性障害、レット障害、小児期崩壊性障害、アスペルガー障害、特定不能の広汎性発達障害が含まれている。
  1. 2013年に公表されたDSM-Ⅴでは、これらの下位カテゴリーがなくなり、自閉症スペクトラムに一本化された。(DSM-5におけるASDの診断基準)( >詳細情報 )
  1. 有病率は1.5~2.0%、男女比は3~4:1である。
  1. 医学的に治癒すべき状態ではなく、福祉、教育を含めて、よりよい発達を保証していくことが目標となる。
 
  1. ASDの脳の変化
  1. ASDは発達過程で顕在化する中枢神経系の器質的機能障害を原因とするが、根本原因はまだ明らかでない。これまで報告されてきた障害部位を(表<図表>)に[1]、原因として確定するための必要十分条件を(表<図表>)に示した[2]
  1. 大脳辺縁系仮説は多くの臨床像を説明するが、それでも必要十分とはいえない。すべてのASDで大脳辺縁系の異常同定されているわけではないからである。
  1. 近年のトピックスはニューロンの発達異常、特に「接続不良説」(developmental disconnection)である。高次脳機能を担うシナプス結合に機能的・器質的な接続不良があり、特に、皮質-皮質間などの長い軸策によるシナプス接続の形成や維持の問題がASDの基本障害という説である[3]。これは必要十分性をかなり満たしている。これからの検証を期待したい。
 
自閉症スペクトラムの障害部位仮説

自閉症スペクトラムの障害部位としては、ほぼすべての脳部位について報告があるが、いまだに決定的な定説には到達し得てない。

 
自閉症スペクトラムの原因の必要十分条件

自閉症スペクトラムの原因となる病態が満たすべき必要十分条件は、表の4点である。

 
  1. ASDの遺伝的要因
  1. 同じ遺伝子をもつ一卵性双生児の場合、ASDの一致率は90%であることから、遺伝的要因が強く関連することが示唆されている。また、第1子がASDである場合、次子がASDである確率は約5%、診断には至らないが発達の凸凹がある確率は約20%である。
  1. これまで2番、6番、11番、15番、17番、22番などの染色体で異常が報告されてきたが、これらの異常は全ASD中5~7%でしか検出されない。また、10%程度の患者にCopy Number Variant(CNV)が検出されているが、全例は説明できない[4][5]。つまり、現時点で必要十分条件を満たす遺伝子異常はみつかっていない。
  1. 一方で、ASDが単一遺伝子異常である可能性はほぼ否定され[6]、複数の遺伝子の組合せによる多因子遺伝、もしくは環境との相互作用も加味されて(エピジェネティックス)病因が形成されるという可能性が大きくなっている[7]
 
問診・診察のポイント  
  1. 診断は丁寧な臨床観察と発達歴の聴取により行う。

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文献 

著者: Daniel H Geschwind, Pat Levitt
雑誌名: Curr Opin Neurobiol. 2007 Feb;17(1):103-11. doi: 10.1016/j.conb.2007.01.009. Epub 2007 Feb 1.
Abstract/Text Autism is a common and heterogeneous childhood neurodevelopmental disorder. Analogous to broad syndromes such as mental retardation, autism has many etiologies and should be considered not as a single disorder but, rather, as 'the autisms'. However, recent genetic findings, coupled with emerging anatomical and functional imaging studies, suggest a potential unifying model in which higher-order association areas of the brain that normally connect to the frontal lobe are partially disconnected during development. This concept of developmental disconnection can accommodate the specific neurobehavioral features that are observed in autism, their emergence during development, and the heterogeneity of autism etiology, behaviors and cognition.

PMID 17275283  Curr Opin Neurobiol. 2007 Feb;17(1):103-11. doi: 10.101・・・
著者: Francesca Happé, Angelica Ronald, Robert Plomin
雑誌名: Nat Neurosci. 2006 Oct;9(10):1218-20. doi: 10.1038/nn1770.
Abstract/Text We argue that there will be no single (genetic or cognitive) cause for the diverse symptoms defining autism. We present recent evidence of behavioral fractionation of social impairment, communication difficulties and rigid and repetitive behaviors. Twin data suggest largely nonoverlapping genes acting on each of these traits. At the cognitive level, too, attempts at a single explanation for the symptoms of autism have failed. Implications for research and treatment are discussed.

PMID 17001340  Nat Neurosci. 2006 Oct;9(10):1218-20. doi: 10.1038/nn17・・・
著者: Kunio Miyake, Takae Hirasawa, Tsuyoshi Koide, Takeo Kubota
雑誌名: Adv Exp Med Biol. 2012;724:91-8. doi: 10.1007/978-1-4614-0653-2_7.
Abstract/Text Autism was previously thought to be caused by environmental factors. However, genetic factors are now considered to be more contributory to the pathogenesis of autism, based on the recent findings of mutations in the genes which encode synaptic molecules associated with the communication between neurons. Epigenetic is a mechanism that controls gene expression without changing DNA sequence but by changing chromosomal histone modifications and its abnormality is associated with several neurodevelopmental diseases. Since epigenetic modifications are known to be affected by environmental factors such as nutrition, drugs and mental stress, autistic diseases are not only caused by congenital genetic defects, but may also be caused by environmental factors via epigenetic mechanism. In this chapter, we introduce autistic diseases caused by epigenetic failures and discuss epigenetic changes by environmental factors and discuss new treatments for neurodevelopmental diseases based on the recent epigenetic findings.

PMID 22411236  Adv Exp Med Biol. 2012;724:91-8. doi: 10.1007/978-1-461・・・
著者: D L Robins, D Fein, M L Barton, J A Green
雑誌名: J Autism Dev Disord. 2001 Apr;31(2):131-44.
Abstract/Text Autism, a severe disorder of development, is difficult to detect in very young children. However, children who receive early intervention have improved long-term prognoses. The Modified Checklist for Autism in Toddlers (M-CHAT), consisting of 23 yes/no items, was used to screen 1,293 children. Of the 58 children given a diagnostic/developmental evaluation, 39 were diagnosed with a disorder on the autism spectrum. Six items pertaining to social relatedness and communication were found to have the best discriminability between children diagnosed with and without autism/PDD. Cutoff scores were created for the best items and the total checklist. Results indicate that the M-CHAT is a promising instrument for the early detection of autism.

PMID 11450812  J Autism Dev Disord. 2001 Apr;31(2):131-44.
著者: U Frith, F Happé
雑誌名: Cognition. 1994 Apr-Jun;50(1-3):115-32.
Abstract/Text The theory of mind account of autism has been remarkably successful in making specific predictions about the impairments in socialization, imagination and communication shown by people with autism. It cannot, however, explain either the non-triad features of autism, or earlier experimental findings of abnormal assets and deficits on non-social tasks. These unexplained aspects of autism, and the existence of autistic individuals who consistently pass false belief tasks, suggest that it may be necessary to postulate an additional cognitive abnormality. One possible abnormality-weak central coherence--is discussed, and preliminary evidence for this theory is presented.

PMID 8039356  Cognition. 1994 Apr-Jun;50(1-3):115-32.
著者: G Rizzolatti, L Fadiga, V Gallese, L Fogassi
雑誌名: Brain Res Cogn Brain Res. 1996 Mar;3(2):131-41.
Abstract/Text In area F5 of the monkey premotor cortex there are neurons that discharge both when the monkey performs an action and when he observes a similar action made by another monkey or by the experimenter. We report here some of the properties of these 'mirror' neurons and we propose that their activity 'represents' the observed action. We posit, then, that this motor representation is at the basis of the understanding of motor events. Finally, on the basis of some recent data showing that, in man, the observation of motor actions activate the posterior part of inferior frontal gyrus, we suggest that the development of the lateral verbal communication system in man derives from a more ancient communication system based on recognition of hand and face gestures.

PMID 8713554  Brain Res Cogn Brain Res. 1996 Mar;3(2):131-41.
著者: Lindsay M Oberman, Edward M Hubbard, Joseph P McCleery, Eric L Altschuler, Vilayanur S Ramachandran, Jaime A Pineda
雑誌名: Brain Res Cogn Brain Res. 2005 Jul;24(2):190-8. doi: 10.1016/j.cogbrainres.2005.01.014.
Abstract/Text Autism spectrum disorders (ASD) are largely characterized by deficits in imitation, pragmatic language, theory of mind, and empathy. Previous research has suggested that a dysfunctional mirror neuron system may explain the pathology observed in ASD. Because EEG oscillations in the mu frequency (8-13 Hz) over sensorimotor cortex are thought to reflect mirror neuron activity, one method for testing the integrity of this system is to measure mu responsiveness to actual and observed movement. It has been established that mu power is reduced (mu suppression) in typically developing individuals both when they perform actions and when they observe others performing actions, reflecting an observation/execution system which may play a critical role in the ability to understand and imitate others' behaviors. This study investigated whether individuals with ASD show a dysfunction in this system, given their behavioral impairments in understanding and responding appropriately to others' behaviors. Mu wave suppression was measured in ten high-functioning individuals with ASD and ten age- and gender-matched control subjects while watching videos of (1) a moving hand, (2) a bouncing ball, and (3) visual noise, or (4) moving their own hand. Control subjects showed significant mu suppression to both self and observed hand movement. The ASD group showed significant mu suppression to self-performed hand movements but not to observed hand movements. These results support the hypothesis of a dysfunctional mirror neuron system in high-functioning individuals with ASD.

PMID 15993757  Brain Res Cogn Brain Res. 2005 Jul;24(2):190-8. doi: 10・・・
著者: Lindsay M Oberman, Vilayanur S Ramachandran, Jaime A Pineda
雑誌名: Neuropsychologia. 2008 Apr;46(5):1558-65. doi: 10.1016/j.neuropsychologia.2008.01.010. Epub 2008 Jan 19.
Abstract/Text In an early description of the mu rhythm, Gastaut and Bert [Gastaut, H. J., & Bert, J. (1954). EEG changes during cinematographic presentation. Clinical Neurophysiology, 6, 433-444] noted that it was blocked when an individual identified himself with an active person on the screen, suggesting that it may be modulated by the degree to which the individual can relate to the observed action. Additionally, multiple recent studies suggest that the mirror neurons system (MNS) is impaired in individuals with autism spectrum disorders (ASD), which may affect their ability to relate to others. The current study aimed to investigate MNS sensitivity by examining mu suppression to familiarity, i.e., the degree to which the observer is able to identify with the actor on the screen by using familiar versus unfamiliar actors. The participants viewed four 80s videos that included: (1) stranger: an unfamiliar hand performing a grasping action; (2) familiar: the child's guardian or sibling's hand performing the same action; (3) own: the participant's own hand performing the same action; (4) bouncing balls: two balls moving vertically toward and away from each other. The study revealed that mu suppression was sensitive to degree of familiarity. Both typically developing participants and those with ASD showed greater suppression to familiar hands compared to those of strangers. These findings suggest that the MNS responds to observed actions in individuals with ASD, but only when individuals can identify in some personal way with the stimuli.

PMID 18304590  Neuropsychologia. 2008 Apr;46(5):1558-65. doi: 10.1016/・・・
著者: Atsushi Senju, Victoria Southgate, Sarah White, Uta Frith
雑誌名: Science. 2009 Aug 14;325(5942):883-5. doi: 10.1126/science.1176170. Epub 2009 Jul 16.
Abstract/Text Adults with Asperger syndrome can understand mental states such as desires and beliefs (mentalizing) when explicitly prompted to do so, despite having impairments in social communication. We directly tested the hypothesis that such individuals nevertheless fail to mentalize spontaneously. To this end, we used an eye-tracking task that has revealed the spontaneous ability to mentalize in typically developing infants. We showed that, like infants, neurotypical adults' (n = 17 participants) eye movements anticipated an actor's behavior on the basis of her false belief. This was not the case for individuals with Asperger syndrome (n = 19). Thus, these individuals do not attribute mental states spontaneously, but they may be able to do so in explicit tasks through compensatory learning.

PMID 19608858  Science. 2009 Aug 14;325(5942):883-5. doi: 10.1126/scie・・・
著者: L Wing, J Gould
雑誌名: J Autism Dev Disord. 1979 Mar;9(1):11-29.
Abstract/Text The prevalence, in children aged under 15, of severe impairments of social interaction, language abnormalities, and repetitive stereotyped behaviors was investigated in an area of London. A "socially impaired" group (more than half of whom were severely retarded) and a comparison group of "sociable severely mentally retarded" children were identified. Mutism or echolalia, and repetitive stereotyped behaviors were found in almost all the socially impaired children, but to a less marked extent in a minority of the sociable severely retarded. Certain organic conditions were found more often in the socially impaired group. A subgroup with a history of Kanner's early childhood autism could be identified reliably but shared many abnormalities with other socially impaired children. The relationships between mental retardation, typical autism, and other conditions involving social impairment were discussed, and a system of classification based on quality of social interaction was considered.

PMID 155684  J Autism Dev Disord. 1979 Mar;9(1):11-29.
著者: Mats Cederlund, Christopher Gillberg
雑誌名: Dev Med Child Neurol. 2004 Oct;46(10):652-60.
Abstract/Text The objective of this study was to investigate the background and associated factors in a representative group of young males with Asperger syndrome (AS) presenting at a specialized autism clinic. One hundred males aged 5 years 6 months to 24 years 6 months, with a mean age of 11 years 4 months (SD 3y 10mo), who had a clinical diagnosis of AS were included in the study. An in-depth review of their medical records and neuropsychological test data was performed. There was a high rate (51%) of non-verbal learning disability (defined as Verbal IQ more than 15 points higher than Performance IQ), but otherwise there was little or no support for the notion of right-hemisphere brain dysfunction being at the core of the syndrome. There was a very high rate of close relatives with autism spectrum problems, but also high rates of prenatal and perinatal problems, including prematurity and postmaturity. In comparison with general population data, those with AS very often had a combination of genetic and prenatal and perinatal risk factors. Non-verbal learning disability test results applied in about half the group. There was a subgroup of individuals with AS who had macrocephalus. However, there was no support for an association of AS with low body mass index.

PMID 15473168  Dev Med Child Neurol. 2004 Oct;46(10):652-60.
著者: Hitoshi Hara
雑誌名: Brain Dev. 2007 Sep;29(8):486-90. doi: 10.1016/j.braindev.2006.12.012. Epub 2007 Feb 26.
Abstract/Text So-called "idiopathic" autism, which exhibited no major complications before diagnosis is well-known as one of the risk factors for epilepsy. This retrospective follow-up study aimed to clarify the characteristics of epilepsy in the autism; onset of seizure, seizure types, EEG findings and epilepsy outcome and the differences as a group between the autism with epilepsy and those without epilepsy. One hundred thirty individuals with autistic disorder or atypical autism diagnosed in childhood were followed up over 10 years and were evaluated almost every year up to 18-35 years of age. Their medical records related to perinatal conditions, IQ, social maturity scores and several factors of epilepsy were reviewed in October 2005. Thirty-three of the follow-up group (25%) exhibited epileptic seizures. The onset of epilepsy was distributed from 8 to 26 years of age. Two types of seizure were observed; partial seizure with secondarily generalized seizure and generalized seizure. Twenty of the epileptics (61%) showed the partial seizure. Although 18% of the non-epileptic group exhibited epileptic discharges on EEG, 68% of the epileptic group revealed epileptiform EEG findings before the onset of epilepsy. No differences were observed concerning the sex ratio, autistic disorder/atypical autism and past history of febrile seizures between the epileptic and non-epileptic groups. Lower IQ, lower social maturity score and higher frequency of prescribed psychotropics were observed in the epileptic group compared to the non-epileptics. Idiopathic autism was confirmed as the high risk factor for epilepsy. Epileptiform EEG findings predict subsequent onset of epileptic seizures in adolescence. Epilepsy is one of negative factors on cognitive, adaptive and behavioral/emotional outcomes for individuals with autism.

PMID 17321709  Brain Dev. 2007 Sep;29(8):486-90. doi: 10.1016/j.braind・・・
著者: Danielle C Llaneza, Susan V DeLuke, Myra Batista, Jacqueline N Crawley, Kristin V Christodulu, Cheryl A Frye
雑誌名: Physiol Behav. 2010 Jun 1;100(3):268-76. doi: 10.1016/j.physbeh.2010.01.003. Epub 2010 Jan 21.
Abstract/Text Autism spectrum disorders (ASD) affect approximately 1 in 150 children across the U.S., and are characterized by abnormal social actions, language difficulties, repetitive or restrictive behaviors, and special interests. ASD include autism (autistic disorder), Asperger Syndrome, and Pervasive Developmental Disorder not otherwise specified (PDD-NOS or atypical autism). High-functioning individuals may communicate with moderate-to-high language skills, although difficulties in social skills may result in communication deficits. Low-functioning individuals may have severe deficiencies in language, resulting in poor communication between the individual and others. Behavioral intervention programs have been developed for ASD, and are frequently adjusted to accommodate specific individual needs. Many of these programs are school-based and aim to support the child in the development of their skills, for use outside the classroom with family and friends. Strides are being made in understanding the factors contributing to the development of ASD, particularly the genetic contributions that may underlie these disorders. Mutant mouse models provide powerful research tools to investigate the genetic factors associated with ASD and its co-morbid disorders. In support, the BTBR T+tf/J mouse strain incorporates ASD-like social and communication deficits and high levels of repetitive behaviors. This commentary briefly reviews the reciprocal relationship between observations made during evidence-based behavioral interventions of high- versus low-functioning children with ASD and the accumulating body of research in autism, including animal studies and basic research models. This reciprocity is one of the hallmarks of the scientific method, such that research may inform behavioral treatments, and observations made during treatment may inform subsequent research.

Copyright 2010 Elsevier Inc. All rights reserved.
PMID 20093134  Physiol Behav. 2010 Jun 1;100(3):268-76. doi: 10.1016/j・・・
著者: S L Smalley
雑誌名: Am J Hum Genet. 1997 Jun;60(6):1276-82. doi: 10.1086/515485.
Abstract/Text
PMID 9199546  Am J Hum Genet. 1997 Jun;60(6):1276-82. doi: 10.1086/51・・・
著者: Scott M Myers, Chris Plauché Johnson, American Academy of Pediatrics Council on Children With Disabilities
雑誌名: Pediatrics. 2007 Nov;120(5):1162-82. doi: 10.1542/peds.2007-2362. Epub 2007 Oct 29.
Abstract/Text Pediatricians have an important role not only in early recognition and evaluation of autism spectrum disorders but also in chronic management of these disorders. The primary goals of treatment are to maximize the child's ultimate functional independence and quality of life by minimizing the core autism spectrum disorder features, facilitating development and learning, promoting socialization, reducing maladaptive behaviors, and educating and supporting families. To assist pediatricians in educating families and guiding them toward empirically supported interventions for their children, this report reviews the educational strategies and associated therapies that are the primary treatments for children with autism spectrum disorders. Optimization of health care is likely to have a positive effect on habilitative progress, functional outcome, and quality of life; therefore, important issues, such as management of associated medical problems, pharmacologic and nonpharmacologic intervention for challenging behaviors or coexisting mental health conditions, and use of complementary and alternative medical treatments, are also addressed.

PMID 17967921  Pediatrics. 2007 Nov;120(5):1162-82. doi: 10.1542/peds.・・・
著者: O I Lovaas
雑誌名: J Consult Clin Psychol. 1987 Feb;55(1):3-9.
Abstract/Text
PMID 3571656  J Consult Clin Psychol. 1987 Feb;55(1):3-9.
著者: Serena Wieder, Stanley I Greenspan
雑誌名: Autism. 2003 Dec;7(4):425-35. doi: 10.1177/1362361303007004008.
Abstract/Text The developmental, individual-difference, relationship-based model (DIR), a theoretical and applied framework for comprehensive intervention, examines the functional developmental capacities of children in the context of their unique biologically based processing profile and their family relationships and interactive patterns. As a functional approach, it uses the complex interactions between biology and experience to understand behavior and articulates the developmental capacities that provide the foundation for higher order symbolic thinking and relating. During spontaneous 'floor time' play sessions, adults follow the child's lead utilizing affectively toned interactions through gestures and words to move the child up the symbolic ladder by first establishing a foundation of shared attention, engagement, simple and complex gestures, and problem solving to usher the child into the world of ideas and abstract thinking. This process is illustrated by a case example of a young boy on the autism spectrum interacting with his father during 'floor time' over a 3 year period.

PMID 14678681  Autism. 2003 Dec;7(4):425-35. doi: 10.1177/136236130300・・・

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契約期間が通常12ヵ月のところ、14ヵ月ご利用いただけます。

優待コード: (利用期限:まで)

ご契約はこちらから