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疾?。? 結(jié)締組織病
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什么是非典型結(jié)締組織病？非典型結(jié)締組織?。║ndifferentiatedConnectiveTissueDisease,UCTD）是一組具有結(jié)締組織?。–TD）的某些臨床或?qū)嶒?yàn)室特征，但不符合任何特定結(jié)締組織?。ㄈ缦到y(tǒng)性紅斑狼瘡、類風(fēng)濕關(guān)節(jié)炎、干燥綜合征等）診斷標(biāo)準(zhǔn)的疾病狀態(tài)。它介于健康狀態(tài)與典型自身免疫病之間的“灰色地帶”，可能是某些自身免疫病的早期或不完全表現(xiàn)形式。一、核心特征臨床表現(xiàn)多樣但不典型：常見(jiàn)癥狀：關(guān)節(jié)痛、雷諾現(xiàn)象（手指遇冷變白/紫）、輕度皮疹、疲勞、低熱、口腔潰瘍等；缺乏典型器官損害：如狼瘡的腎臟受累、硬皮病的皮膚硬化等。實(shí)驗(yàn)室指標(biāo)輕度異常：抗核抗體（ANA）陽(yáng)性（通常低滴度，如1:80-1:320），但無(wú)特異性抗體（如抗dsDNA、抗Sm、抗SSA/SSB等）；補(bǔ)體水平正?；蜉p度降低。病程不明確：部分患者長(zhǎng)期穩(wěn)定，部分可能進(jìn)展為典型結(jié)締組織病（如10%-30%最終發(fā)展為系統(tǒng)性紅斑狼瘡、干燥綜合征等）。二、診斷標(biāo)準(zhǔn)目前尚無(wú)國(guó)際統(tǒng)一標(biāo)準(zhǔn)，但通常需滿足以下條件：存在結(jié)締組織病相關(guān)癥狀（至少1項(xiàng)）：關(guān)節(jié)炎、雷諾現(xiàn)象、漿膜炎（胸膜炎/心包炎）、不明原因發(fā)熱等。實(shí)驗(yàn)室異常（至少1項(xiàng)）：ANA陽(yáng)性、抗磷脂抗體陽(yáng)性、補(bǔ)體降低等。不符合任何特定CTD診斷標(biāo)準(zhǔn)：排除系統(tǒng)性紅斑狼瘡（SLEDAI評(píng)分不足）、類風(fēng)濕關(guān)節(jié)炎（無(wú)侵蝕性關(guān)節(jié)炎）、硬皮?。o(wú)皮膚硬化）等。三、與非典型抗磷脂綜合征（Non-criteriaAPS）的區(qū)別UCTD：以結(jié)締組織炎癥為主，可能伴輕度抗體異常。非典型APS：以血栓或產(chǎn)科并發(fā)癥為核心，抗磷脂抗體陽(yáng)性但未達(dá)實(shí)驗(yàn)室診斷標(biāo)準(zhǔn)。四、治療與管理目標(biāo)：控制癥狀、預(yù)防進(jìn)展為典型CTD、減少器官損傷。具體措施：對(duì)癥治療：關(guān)節(jié)痛/發(fā)熱：非甾體抗炎藥（NSAIDs，如布洛芬）；雷諾現(xiàn)象：保暖、鈣通道阻滯劑（如硝苯地平）。免疫調(diào)節(jié)：輕癥：羥氯喹（200-400mg/天），兼具抗炎和免疫調(diào)節(jié)作用；重癥（如漿膜炎）：短期小劑量糖皮質(zhì)激素（如潑尼松10-20mg/天）。監(jiān)測(cè)與隨訪：每6-12個(gè)月復(fù)查抗體譜、補(bǔ)體、血尿常規(guī)等，警惕疾病進(jìn)展。五、預(yù)后穩(wěn)定型：約50%-70%患者長(zhǎng)期保持病情穩(wěn)定，無(wú)需強(qiáng)化治療。進(jìn)展型：約20%-30%在5-10年內(nèi)發(fā)展為典型CTD（如系統(tǒng)性紅斑狼瘡、干燥綜合征）。危險(xiǎn)信號(hào)：出現(xiàn)高滴度特異性抗體（如抗dsDNA）、補(bǔ)體顯著降低、新發(fā)器官損害（如蛋白尿）。六、患者常見(jiàn)疑問(wèn)“會(huì)遺傳嗎？”自身免疫病有遺傳傾向，但非直接遺傳，環(huán)境因素（感染、壓力）更重要?！靶枰K身服藥嗎？”若無(wú)進(jìn)展，可能僅需間歇用藥；若進(jìn)展為典型CTD，需長(zhǎng)期管理?！叭绾晤A(yù)防惡化？”避免日曬（防狼瘡觸發(fā)）、戒煙（防血管痙攣）、定期隨訪?？偨Y(jié)非典型結(jié)締組織病是自身免疫異常的早期或溫和表現(xiàn)，需通過(guò)定期監(jiān)測(cè)和個(gè)體化治療平衡干預(yù)與觀察。關(guān)鍵是與主診醫(yī)生保持溝通，警惕疾病演變信號(hào)！
抗核抗體1：:80、1:100、1:1000，抗核抗體到底是什么呢，陽(yáng)性就是結(jié)締組織病嗎？一、抗核抗體：揭開(kāi)神秘面紗抗核抗體，聽(tīng)起來(lái)挺高大上的，其實(shí)它就是一組針對(duì)細(xì)胞核內(nèi)的DNA、RNA、蛋白質(zhì)或這些物質(zhì)的分子復(fù)合物產(chǎn)生的自身抗體。換句話說(shuō)，它是人體免疫系統(tǒng)誤將自身細(xì)胞核組分當(dāng)作外來(lái)敵人，從而產(chǎn)生的抗體。在風(fēng)濕免疫科，ANA常被用作自身免疫性疾病的一項(xiàng)重要篩查指標(biāo)。二、滴度變化：從低到高的意義當(dāng)我們看到ANA的檢測(cè)結(jié)果時(shí)，最直觀的就是那個(gè)比值，也就是滴度。不同的滴度代表了ANA在血清中的濃度，也反映了人體免疫系統(tǒng)的活躍程度。1:80：這是一個(gè)相對(duì)較低的滴度。在健康人群中，ANA低滴度陽(yáng)性的情況并不少見(jiàn)。有研究顯示，健康人群的ANA陽(yáng)性率約為10%～20%，且隨著年齡的增長(zhǎng)，陽(yáng)性率也會(huì)有所上升。因此，如果ANA的滴度為1:80，且沒(méi)有明顯的臨床癥狀，那么很可能只是生理性的低滴度陽(yáng)性，無(wú)需過(guò)于擔(dān)心。.1:100：這個(gè)滴度仍然處于較低水平。雖然它比1:80的陽(yáng)性率要高一些，但同樣不能單憑此就確診某種疾病。如果患者伴有關(guān)節(jié)疼痛、皮疹、發(fā)熱等臨床癥狀，或者同時(shí)存在其他自身免疫相關(guān)的實(shí)驗(yàn)室指標(biāo)異常，那么ANA1:100就可能具有一定的臨床意義。.1:320：當(dāng)ANA的滴度達(dá)到1:320時(shí)，其臨床意義就相對(duì)增加了。這個(gè)滴度通常被視為陽(yáng)性結(jié)果的閾值之一。雖然它仍然不足以獨(dú)立確診某種自身免疫性疾病，但醫(yī)生通常會(huì)更加關(guān)注患者的臨床表現(xiàn)和其他檢查結(jié)果，以便進(jìn)行進(jìn)一步的評(píng)估。1:1000：這是一個(gè)相對(duì)較高的滴度。當(dāng)ANA的滴度達(dá)到1:1000時(shí)，往往提示患者存在某種自身免疫性疾病的可能性較大。特別是在系統(tǒng)性紅斑狼瘡、類風(fēng)濕關(guān)節(jié)炎、干燥綜合征等結(jié)締組織病中，ANA高滴度陽(yáng)性的情況較為常見(jiàn)。三、陽(yáng)性結(jié)果：并不等同于結(jié)締組織病雖然ANA陽(yáng)性在結(jié)締組織病中較為常見(jiàn)，但陽(yáng)性結(jié)果并不等同于結(jié)締組織病。ANA陽(yáng)性可能由多種原因引起，包括但不限于：自身免疫性疾病：除了結(jié)締組織病外，ANA還可能在其他自身免疫性疾病中呈陽(yáng)性，如系統(tǒng)性硬化癥、多發(fā)性肌炎等。但這些疾病的發(fā)病率相對(duì)較低，且通常伴有其他特定的臨床癥狀和實(shí)驗(yàn)室指標(biāo)異常。感染性疾?。耗承└腥拘约膊?，如寄生蟲(chóng)感染、結(jié)核桿菌感染等，也可能導(dǎo)致ANA陽(yáng)性。但這些疾病通常伴有明顯的感染癥狀，且ANA的滴度往往不會(huì)特別高。腫瘤性疾?。耗承┠[瘤性疾病，如淋巴瘤、白血病等，也可能導(dǎo)致ANA陽(yáng)性。但這些疾病通常伴有其他腫瘤相關(guān)的癥狀和體征。藥物影響：某些藥物，如普魯卡因胺、肼苯噠嗪等，也可能引起ANA的異常。但這些藥物引起的ANA陽(yáng)性通常是在服藥后的一段時(shí)間內(nèi)出現(xiàn)，且停藥后可能會(huì)逐漸恢復(fù)正常。生理性因素：正如前面提到的，健康人群中也可能存在ANA低滴度陽(yáng)性的情況。這可能是由于人體細(xì)胞衰老、凋亡增加等原因?qū)е碌?。這種情況下，ANA陽(yáng)性通常沒(méi)有臨床意義，也不需要特殊治療。四、如何正確看待ANA陽(yáng)性？當(dāng)我們看到ANA陽(yáng)性的檢測(cè)結(jié)果時(shí)，應(yīng)該如何正確看待呢？不要過(guò)于緊張或恐慌。ANA陽(yáng)性并不一定意味著患有結(jié)締組織病或其他自身免疫性疾病。我們需要結(jié)合患者的臨床癥狀、其他實(shí)驗(yàn)室檢查結(jié)果以及影像學(xué)檢查等來(lái)進(jìn)行綜合評(píng)估。如果ANA陽(yáng)性且伴有明顯的臨床癥狀或其他實(shí)驗(yàn)室指標(biāo)異常，那么就需要及時(shí)就醫(yī)并尋求專業(yè)醫(yī)生的幫助。醫(yī)生會(huì)根據(jù)患者的具體情況進(jìn)行進(jìn)一步的檢查和診斷，并制定相應(yīng)的治療方案。即使ANA陽(yáng)性被確診為某種自身免疫性疾病，也不必過(guò)于擔(dān)心。隨著現(xiàn)代醫(yī)學(xué)的不斷進(jìn)步和發(fā)展，許多自身免疫性疾病都可以得到有效的治療和控制。只要我們積極配合醫(yī)生的治療和建議，保持良好的生活習(xí)慣和心態(tài)，就能夠戰(zhàn)勝疾病并恢復(fù)健康。寫在最后抗核抗體作為風(fēng)濕免疫科的一項(xiàng)重要篩查指標(biāo)，其陽(yáng)性結(jié)果并不等同于結(jié)締組織病或其他自身免疫性疾病。我們需要結(jié)合患者的具體情況進(jìn)行綜合評(píng)估，并及時(shí)就醫(yī)并尋求專業(yè)醫(yī)生的幫助。
埃勒斯-當(dāng)洛斯Ehlers-Danlos綜合征的綜述（2020）埃勒斯-當(dāng)洛斯Ehlers-Danlos綜合征的綜述（2020）AreviewofEhlers-Danlossyndrome?MillerE,GroselJM.AreviewofEhlers-Danlossyndrome[J].JAAPA,2020,33(4):23-28.轉(zhuǎn)載文章的原鏈接1：https://pubmed.ncbi.nlm.nih.gov/32175940/轉(zhuǎn)載文章的原鏈接2：https://journals.lww.com/jaapa/fulltext/2020/04000/a_review_of_ehlers_danlos_syndrome.3.aspx?AbstractEhlers-Danlossyndrome(EDS)describesagroupofheritabledisordersofconnectivetissuecomprisingmutationsinthegenesinvolvedinthestructureand/orbiosynthesisofcollagen.ThirteenEDSsubtypesarerecognized,withawidedegreeofsymptomoverlapamongsubtypesandwithotherconnectivetissuedisorders.TheclinicalhallmarksofEDSaretissuefragility,jointhypermobility,andskinhyperextensibility.AppropriatediagnosisofEDSisimportantforcorrectmultidisciplinarymanagementandisassociatedwithbetterclinicaloutcomesforpatients.Ehlers-Danlos綜合征（EDS）描述了一組遺傳性結(jié)締組織疾病，包括參與膠原結(jié)構(gòu)和/或生物合成的基因突變?，F(xiàn)已確認(rèn)的EDS亞型有13種，各亞型之間以及與其他結(jié)締組織疾病的癥狀有很大程度的重疊。EDS的臨床特征是組織脆弱，關(guān)節(jié)過(guò)度活動(dòng)和皮膚過(guò)度伸展。EDS的正確診斷對(duì)于正確的多學(xué)科治療非常重要，并且與患者更好的臨床結(jié)果相關(guān)。?Keywords:Ehlers-Danlossyndrome,connectivetissuedisease,jointhypermobility關(guān)節(jié)過(guò)度活動(dòng),tissuefragility,skinhyperextensibility皮膚伸展過(guò)度,heritabledisease?LearningobjectivesDescribetheclinicalpresentationofEDS.UnderstandthepotentialcomplicationsandappropriatemanagementofEDS.描述EDS的臨床表現(xiàn)。了解EDS的潛在并發(fā)癥和適當(dāng)?shù)奶幚矸椒ā?KeypointsEDSdescribesagroupofheritabledisordersofconnectivetissue.ThirteenEDSsubtypesarerecognized,withawidedegreeofsymptomoverlapamongsubtypesandwithotherconnectivetissuedisorders.TheclinicalhallmarksofEDSaretissuefragility,jointhypermobility,andskinhyperextensibility.PatientswithEDSaremanagedsymptomaticallybecausetheconditionhasnoknowncure.EDS描述了一組遺傳性結(jié)締組織疾病?，F(xiàn)已確認(rèn)的EDS亞型有13種，各亞型之間以及與其他結(jié)締組織疾病的癥狀有很大程度的重疊。EDS的臨床特征是組織脆弱，關(guān)節(jié)過(guò)度活動(dòng)和皮膚過(guò)度伸展。EDS患者需要對(duì)癥治療，因?yàn)檫@種疾病沒(méi)有已知的治愈方法。?CASEFigure?A12-year-oldgirlpresentedtoherprimarycareprovidertodiscussseveralcomplaints,includingworseningjointpainthathadstartedwhenshewasage5years.Sheparticipatedinnumerousathleticactivitiesthroughoutherchildhood,buthadbeguntolimitherphysicalactivityasherjointpainmadeitincreasinglydifficult.?HistoryAtbirth,thepatientwasfoundtohaveacongenitaldislocationofherrighthip,whichwastreatedconservatively,andaright-sidedpneumothoraxthatimprovedwithoutintervention.Whenthepatientwasage11months,hermothernotedanunusualheadpostureandtookhertoapediatrician.Radiographsofherspinerevealeda24-degreerightthoracolumbarcurvature,ordextroscoliosis.Duetotheseradiographicfindings,thepatientwasreferredtoapediatricorthopedicclinic,whereMRIrevealedaC4hemivertebraandradiographsshowedasignificantsubluxationofC3onC4withflexion.Toprotectthespinalcord,thepatientunderwentananteriorandposteriorfusionofC3throughC5atage18monthsandwasplacedinahaloandcastvestfor6weeks.Atage5years,thepatientbeganhavingbilateralchronickneejointpain.Physicalexaminationatthattimerevealedexcessivepatellarmovementatbothkneejoints,andthepatientwasdiagnosedwithpatellartrackingsyndrome髕骨軌跡綜合征.Whenshewasage7years,flexionandextensionradiographsofthepatient'scervicalspineshowedanterolisthesisofC2onC3withneckflexion(Figure1).Shealsowasfoundtohavearight-sidedinguinalherniaandunderwentsurgicalrepair.??FIGURE1.:Flexion(A)andextension(B)radiographsofthecasepatientdemonstratinganterolisthesisoftheC2vertebraeonC3onflexionview,whichresolvesonextensionview.Alsonotepostoperativechangesofthepatient'sC3-C5vertebraefromherspinalfusionsurgery.??Thepatient'skneejointpaincontinuedtoprogressuntilshewasage9years,alsospreadingtothehipandshoulderjoints.Whenshebeganseeinganorthodontistatage11years,herorthodontistnotedanabnormallyhighpalate.Atapediatricianvisitshortlyafterthepatientturnedage12years,areviewofsystemswaspositiveforchronicfatigue,easybruising,anddelayedwoundhealing.Physicalexaminationrevealedjointhypermobilityandacardiacmurmur.Herpediatricianalsonotedthehyperextensibilityandvelvetytextureofherskin.Atthisappointment,thepatientdemonstratedher“partytrick,”inwhichshewasabletoexternallyrotateherarm360degreeswhilekeepinghershoulderinaneutralposition(seevideoonwww.jaapa.com).Anechocardiogramrevealedaorticvalveinsufficiencyandmildaorticrootdilation.Overtheyears,thepatientandhermotherhadbeentoldbyseveralhealthcareprovidersthathermultiplemedicalproblemswereunrelated.However,withthenewdiagnosticfindingsandathoroughreviewofthepatient'sfullmedicalhistory,clinicianshadahighdegreeofsuspicionforEhlers-Danlossyndrome(EDS);therefore,shewasreferredtoapediatricgeneticist.ShewaslaterdiagnosedwithEDStypeII,nowknownasclassicalEDS(cEDS).GenotypingshowedaheterozygousmutationoftheCOL52Agene,confirmingthediagnosis.Intheyearsfollowingherdiagnosis,thepatientcontinuedtoreceivemedicalmonitoringanddevelopedmanymedicalconditionsknowntoberelatedtoEDS,includingmigraines,posturalorthostatictachycardiasyndrome,agradeVpatentforamenovale,anddeltagranulestoragepooldeficiency.Inaddition,shehadtostopplayingsportsduetodebilitatingjointpainshortlyafterher15thbirthday.?OutcomeAtages16and17years,thepatientunderwentsurgeryonherleftandrightfeet,respectively,forrepairofhammertoesofallfivedigitsbilaterally.ContinuedimagingofhercervicalspinerevealedfurtherinstabilityofherC2onC3vertebrae(Figure2).Totreatandmonitorhervarioussymptoms,thepatientregularlyseesseveralspecialists,includingcardiology,orthopedics,internalmedicine,neurology,andEDSspecialists.Shealsoroutinelyreceivesphysicaltherapy.?FIGURE2.:Radiographsofthecasepatient'srightfootbefore(A)andafter(B)surgeryonallfivedigitsforcorrectionofhammertoes.??UNDERSTANDINGEDSEDSisabroadtermthatdescribesagroupofheritableconnectivetissuedisordersthatareclassifiedtogetherduetosharedphenotypicandgenotypicfeatures.1,2Thephenotypichallmarksaretissuefragility,jointhypermobility,andskinhyperextensibility.1-3Thesesharedfeaturesvaryindegreeinallsubtypes,whichhelpstodifferentiateEDSfromotherjointhypermobilitydisorders.2,4Genetically,EDSresultsfromdefectsingenesinvolvedincollagenbiosynthesisorstructure膠原蛋白的生物合成或結(jié)構(gòu).2Thesyndromeisestimatedtoaffectabout1in5,000peopleworldwide.4,6-8SincethediscoveryofEDS,fivedifferentclassificationsystemshavebeenusedbyclinicians.1,2,4TheVillefrancheNosology,whichwasthemostrecentnosologyuseduntil2017,recognizedsixEDSsubtypesaccordingtomajorandminorclinicalcriteria.1,2SincetheintroductionoftheVillefrancheNosology,researchonEDShasexpandedandnewsubtypeswerediscovered.Therefore,anupdatedclassificationsystemforEDSwasproposed.1TheInternationalConsortiumonEDS,formedin2012,devisedthe2017InternationalClassificationoftheEhlers-DanlosSyndromes,whichdelineated13clinicalsubtypesofEDSaccordingtotheirclinicalmanifestations.1,2Majorclinicalcriteriawereproposedforeachsubtype,whichprovidehighspecificityfordiagnosis.Minorcriteriaweredevelopedwithlessspecificity;theycanbeusedtosupportaclinicaldiagnosisofsuspectedEDS.2Eachsubtypewasgivenanamethatdescribesitscharacteristicphenotypicmanifestations.2EDSoncewasconsideredtobearelativelyrarecondition,butasscientificknowledgeofEDSincreases,cliniciansaroundtheworldhaveagreedthatitisunderdiagnosed.5,6Theabnormalcollagencanaffectvirtuallyeverybodysystem.5ThepresentationandseverityofEDSrangefromundetectableorverymildsymptomstosevereorevenlife-threateningdisease.6ThisheterogeneityinpresentationcanmakediagnosingEDSaclinicalchallenge.7?CLINICALSUBTYPESThe13clinicalsubtypesofEDSaccordingtothe2017InternationalClassificationoftheEhlers-DanlosSyndromesare:根據(jù)2017年《國(guó)際埃勒-丹洛斯綜合征分類》，EDS的13種臨床亞型是:ClassicalEDS(cEDS)VascularEDS(vEDS)KyphoscolioticEDS(kEDS)ArthrochalasiaEDS(aEDS)DermatosparaxisEDS(dEDS)Brittlecorneasyndrome(BCS)Classical-likeEDS(clEDS)SpondylodysplasticEDS(spEDS)MusculocontracturalEDS(mcEDS)MyopathicEDS(mEDS)PeriodontalEDS(pEDS)Cardiac-valvularEDS(cvEDS)HypermobileEDS(hEDS).2EachsubtypehasasetofmajorandminorcriteriatoguidecliniciansevaluatingpatientswithsuspectedEDS.2IfapatientmeetsthecriteriaforasubtypeofEDS,furtherworkupisneeded.Thesuspectedclinicaldiagnosisshouldbeconfirmedwiththeappropriatemoleculartesting分子檢測(cè).?GENETICANDPATHOGENETICMECHANISMSInadditiontotheupdatedclinicalclassificationsystem,the2017InternationalClassificationoftheEhlers-DanlosSyndromesalsoproposedageneticclassificationsystem遺傳學(xué)分類系統(tǒng).Thissystemorganizestheclinicalsubtypesintosixgroups,AthroughF,accordingtotheirunderlyingpathogeneticmechanisms.GroupingthesubtypesinthismannerisbeneficialforboththedevelopmentoftreatmentoptionsandforguidingfutureEDSresearch.2GroupA(cEDS,vEDS,aEDS,dEDS,cvEDS):DisordersofcollagenprocessinganddisordersoftheprimarystructureofcollagenGroupB(kEDS):AdisorderofcollagenfoldingorcrosslinkingGroupC(clEDSandmEDS):DisordersofthestructureandfunctionofthemyomatrixGroupD(spEDS[B3GALT6andB4GALT7subtypes]andmcEDS):DisordersofglycosaminoglycanbiosynthesisGroupE(pEDS):AdisorderofthecomplementpathwayGroupF(spEDS[SLC39A13subtype]andBCS):Thesearebelievedtobedisordersofintracellularprocesses;however,thepathogeneticmechanismsofthesesubtypesarenotwellunderstood.BecausethegeneticmechanismofhEDSisunknown,itisnotincludedinthesegroups.2由于hEDS的遺傳機(jī)制尚不清楚，因此未被列入這些類群。?INHERITANCEPATTERNSAllsubtypesofEDSexcepthEDShaveaknowngeneticbasis.EDScanbeinheritedinanautosomaldominantorrecessivemanner,orcanoccurasanovelgeneticmutation.2除hEDS外，所有EDS亞型都有已知的遺傳基礎(chǔ)。EDS可以常染色體顯性遺傳或隱性遺傳，也可以作為一種新的基因突變發(fā)生Forexample,mEDScanbeinheritedbyeitherdominantorrecessivepattern;cEDS,vEDS,hEDS,aEDS,andpEDSallareautosomaldominant.Theremainingsubtypesareinheritedinanautosomalrecessivepattern.2Therefore,familyhistoryandgeneticcounselingareimportantwhenevaluatingapatientwithsuspectedEDS.6Geneticcounselingwillbefurtherdiscussedinthediagnosissection.?PHYSICALEXAMINATIONOFHALLMARKSYMPTOMSTheextensivenumberofwaysinwhichEDSmanifestscancausemanyabnormalphysicalexaminationfindings;therefore,recognizingtheunderlyingpathologycanprovedifficult.5TherecognitionandevaluationofthehallmarksymptomsofEDS(tissuefragility,jointhypermobility,andskinhyperextensibility)areimportantfirststepsinthediagnosisandworkupofthesepatients.2,5?TissuefragilitySymptomsoftissuefragilityarecommonamongpatientswithEDSandcanmanifestinmanyways.Minormanifestationsoftissuefragilitymayincludepoorwoundhealing,dystrophicscars,andeasybruising.3Moresevereandevenlife-threateningmanifestationsoftissuefragilitycancausegastrointestinalbleeding,cerebrovascularorintracranialbleeding,andaneurysmformationandrupture.8組織脆弱的癥狀在EDS患者中很常見(jiàn)，并且可以通過(guò)多種方式表現(xiàn)出來(lái)。組織脆弱的輕微表現(xiàn)可能包括傷口愈合不良、疤痕營(yíng)養(yǎng)不良和容易擦傷更嚴(yán)重甚至危及生命的組織脆弱表現(xiàn)可引起胃腸道出血、腦血管或顱內(nèi)出血、動(dòng)脈瘤形成和破裂。?JointhypermobilityThisdescriptivetermisusedtodescribeajointthathasanincreasedrangeofmotioncomparedwithanormaljoint.Generalizedjointhypermobilitymayindicatealargerunderlyingpathology.Inpatientswithgeneralizedjointhypermobility,affectedjointsaretypicallypresentinthefourlimbsandaxialskeleton.WhenconsideringadiagnosisofEDS,cliniciansmustdifferentiatebetweenasinglehypermobilejointandgeneralizedjointhypermobility.2,9Severalmethodscanbeusedtoassessgeneralizedjointhypermobility;themostcommonmethodinvolvescalculatingtheBeightonscore(Table1).9-12這個(gè)描述性術(shù)語(yǔ)用于描述與正常關(guān)節(jié)相比活動(dòng)范圍增加的關(guān)節(jié)。全身性關(guān)節(jié)過(guò)度活動(dòng)可能表明更大的潛在病理。在全身性關(guān)節(jié)活動(dòng)過(guò)度的患者中，受影響的關(guān)節(jié)通常存在于四肢和軸骨。當(dāng)考慮EDS的診斷時(shí)，臨床醫(yī)生必須區(qū)分單一關(guān)節(jié)過(guò)度活動(dòng)和廣泛性關(guān)節(jié)過(guò)度活動(dòng)2,9。有幾種方法可用于評(píng)估廣泛性關(guān)節(jié)過(guò)度活動(dòng);最常用的方法是計(jì)算貝頓分?jǐn)?shù)(表1)??TABLE1.:TheBeightonscoringsystemforevaluationofgeneralizedjointhypermobility.Foreachsymptompresentthepatientgetsonepoint.Ascoreof5orgreaterisindicativeofgeneralizedjointhypermobility.ReproducedfromSmits-EngelsmanB,KlerksM,KirbyA.Beightonscore:avalidmeasureforgeneralizedhypermobilityinchildren.JPediatr.2011;158(1):119-123,withpermissionofElsevier.??UndertheBeightonscoringsystem,patientsaregivenanumericscoreonascaleof0to9;ascoreof5orgreaterindicatesgeneralizedjointhypermobility.TheupdatedEDSclassificationsystemproposesthatcliniciansusingtheBeightonscoretoassesspatientswithsuspectedhEDSmusttakepatientageintoaccountbecausejointrangeofmotiondecreaseswithage.Therefore,whenevaluatingprepubertalpatientswithsuspectedhEDS,ascoreof6orgreaterisconsideredpositive.Forpatientsofpubertalageuptoage50years,ascoreof5orgreaterisconsideredpositive,andforpatientsolderthanage50years,ascoreof4orgreaterisconsideredpositive.2?SkinhyperextensibilityEvaluateskinextensibilitybypullingthecutaneousandsubcutaneousskinlayersuntilresistanceisfelt.Theskinshouldstretcheasily,anduponreleaseshouldsnapbackintoplace.Testingshouldbeperformedinareasthatarelesslikelytoundergomechanicaltraumaorscarring.2,3通過(guò)拉皮膚和皮下皮膚層來(lái)評(píng)估皮膚的延展性，直到感覺(jué)到阻力。皮膚應(yīng)該很容易伸展，釋放后應(yīng)該彈回原位。測(cè)試應(yīng)在不太可能遭受機(jī)械創(chuàng)傷或疤痕的區(qū)域進(jìn)行。Skinshouldbeconsideredhyperextensibleifitcanbestretchedexcessivelyinatleastthreeoftheselocations:distalforearms,dorsumofthehands,neck,elbows,orknees.2Iftheskinofthedistalforearmsanddorsumofthehandscanbestretchedatleast1.5cm,orskinoftheneck,elbow,andkneesstretchedatleast3cm,itisconsideredhyperextensible(Figure3).2如果皮膚在前臂遠(yuǎn)端、手背、頸部、肘部或膝蓋至少三個(gè)部位可以過(guò)度拉伸，則應(yīng)考慮皮膚過(guò)度拉伸。如果前臂遠(yuǎn)端和手背的皮膚可拉伸至少1.5cm，或頸部、肘部和膝蓋的皮膚可拉伸至少3cm，則認(rèn)為是超可伸性(圖3)。??FIGURE3.:Thecasepatientdemonstratinghyperextensibilityofherskinatherelbow(A)andknee(B).??DIAGNOSISDiagnosingEDSisconsideredcomplexforseveralreasons.5,13,14Medicalprofessionals'trainingoftendoesnotincludeacomprehensiveeducationonthediagnosisandmanagementofEDS.15Furthermore,manysignsandsymptomsmaybesubtle,andthusmaynotreadilyalertclinicianstothepossibilityofanunderlyingpathology.13FeaturesofEDSoftenoverlapwithsymptomsofotherconnectivetissuedisorders,suchasjointhypermobilitysyndrome關(guān)節(jié)過(guò)度活動(dòng)綜合征,Marfansyndrome馬凡綜合征,orosteogenesisimperfecta脆骨病.7,11,14ClinicaldifferentiationamongtheEDSsubtypesalsocanbedifficultbecauseofoverlappingclinicalfindings.2OncetheclinicianhasaclinicalsuspicionofEDSinapatient,referraltoageneticistforgenetictestingisneededtoconfirmthediagnosis.2However,hEDSistheonlysubtypethatdoesnothaveaconfirmatorygenetictest.Therefore,thediagnosisofthisconditionmustremainclinical.2PromptrecognitionofEDSoftenisnotachieved,anddiagnosistypicallyoccurslate.16Somepatientsmaybediagnosedduringtheirchildhood;othersmaynotbediagnoseduntiladulthood.17ConclusiveresearchabouttheaveragelengthoftimeuntilEDSisdiagnosedislacking;however,astudypublishedbyHamonetandcolleaguesin2018reportedanaverageof22yearsfromsymptomonsettodiagnosis.7PatientsmaybeseenbymanyhealthcareprovidersbeforereceivingadiagnosisofEDS.EarlyrecognitionanddiagnosisofEDSareassociatedwithbetterclinicaloutcomesandcanreduceunnecessaryuseofmedicalresourcesandtesting.16Anearlydiagnosisalsocanhelpreducesymptomseverity,preventcomplications,andimprovepatientqualityoflife.11,16?GENETICCOUNSELINGConsidergeneticcounselingandtestingforimmediatefamilymembersofpatientswithEDS.6ReferringtheparentsofapatientwithEDSforevaluationisappropriateeveniftheyareasymptomatic.Ifaparentisfoundtobeaffected,oriftheparent'sstatuscannotbedetermined,refersiblingsforgeneticevaluationaswell.PatientswithEDSwhowishtoconceiveshouldreceivegeneticcounselingtodiscusstheriskoftheirchildreninheritingthedisorder.18Geneticcounselingprovidespatientsandtheirfamilieswithimportantinformationabouttheinheritancepatternandimplicationsofthedisorder.This,alongwithgenetictesting,letspatientsandtheirfamiliesmakemoreinformedmedicalandpersonaldecisions.13,18?MANAGEMENTPatientswithEDSaremanagedsymptomaticallybecausetheconditionhasnoknowncure.17However,noguidelineshavebeenestablishedformanagingpatientswithEDSandtreatmentvariessignificantlyamongpatients.1Documentthepatient'ssymptomsthroughacomprehensivehistoryandphysicalexamination,thenmakereferralstotheappropriatespecialists.BecauseEDStypicallyinvolvesseveralorgansystems,managementoftenentailscollaborativeeffortsamonghealthcareprovidersfromseveralspecialties.5,16,17EDS患者的治療是對(duì)癥的，因?yàn)檫@種病沒(méi)有已知的治愈方法。然而，目前還沒(méi)有針對(duì)EDS患者的管理指南，而且不同患者的治療方法也有很大差異，通過(guò)全面的病史和體格檢查記錄病人的癥狀，然后轉(zhuǎn)診給適當(dāng)?shù)膶？漆t(yī)生。由于EDS通常涉及多個(gè)器官系統(tǒng)，因此管理通常需要來(lái)自多個(gè)專業(yè)的醫(yī)療保健提供者之間的協(xié)作努力。Patienteducationisanimportantcomponentofdiseasemanagement,andmayinvolvewaystopreventunwantedjointevents,suchasdislocation.17Ahealthfullifestylecanhelppatientsstrengthenjoints,preventjointinjury,andcanhelppreventincreasedjointpainlaterinlife.Inaddition,physicaltherapyandoccupationaltherapymaybebeneficial.19患者教育是疾病管理的一個(gè)重要組成部分，可能包括預(yù)防不希望發(fā)生的聯(lián)合事件，如脫位的方法健康的生活方式可以幫助患者加強(qiáng)關(guān)節(jié)，防止關(guān)節(jié)損傷，并有助于防止晚年關(guān)節(jié)疼痛加劇。此外，物理治療和職業(yè)治療可能是有益的。SeveralstudieshaveshownanassociationamongEDS,psychologicaldistress,andreducedqualityoflife.5,20Manypatientsaresusceptibletoanxiety,depression,disability,andsocialisolation.15,17PatientsdiagnosedwithEDSmayneedpsychologicalsupport,andearlyinterventionmayleadtobetterclinicaloutcomes.16一些研究表明EDS、心理困擾和生活質(zhì)量下降之間存在關(guān)聯(lián)5,20。許多患者易患焦慮、抑郁、殘疾和社會(huì)孤立15,17。診斷為EDS的患者可能需要心理支持，早期干預(yù)可能導(dǎo)致更好的臨床結(jié)果。?SurgeryandotherproceduresPatientswithEDSmayhavecomplicationsduringroutinemedicalprocedures,surgery,andtheperioperativeperiod.Forexample,onestudyshowedthatpatientswithvEDSarehighlysusceptibletosurgicalcomplicationssuchasseverebleedingandcomplicationsofanesthesia.PatientswithEDSshouldobtainpreoperativeclearancebeforeundergoingsurgery.Cliniciansmayconsidersendingthesepatientstoaspecializedpreoperativeevaluationcenterforclearance.6EDS患者可能在常規(guī)醫(yī)療程序、手術(shù)和圍手術(shù)期出現(xiàn)并發(fā)癥。例如，一項(xiàng)研究表明，vEDS患者極易出現(xiàn)手術(shù)并發(fā)癥，如大出血和麻醉并發(fā)癥。EDS患者應(yīng)在手術(shù)前獲得術(shù)前清除。臨床醫(yī)生可能會(huì)考慮將這些患者送到專門的術(shù)前評(píng)估中心進(jìn)行檢查。?ObstetricconsiderationsConsiderreferraltoanobstetricianwhohandleshigh-riskpregnanciesforallpregnantpatientswithEDS,becausecomplicationssuchasprematureruptureofmembranes,uterinehemorrhage,oruterinerupturecanoccurduringpregnancyanddelivery.13,18考慮轉(zhuǎn)診到產(chǎn)科醫(yī)生處理高危妊娠的所有妊娠EDS患者，因?yàn)椴l(fā)癥，如膜早破，子宮出血，或子宮破裂可能發(fā)生在懷孕和分娩期間。?CardiovascularproblemsEDSisassociatedwithanincreasedincidenceofcardiovascularabnormalities,suchasmitralvalveprolapseandaorticdissection.13AlthoughstandardizedguidelinesarelackingforevaluatingcardiovascularabnormalitiesinpatientswithEDS,baselineechocardiogramsoftenareobtainedatthetimeofdiagnosis.13Aorticdiametermeasurementalsoisrecommended,andmayrequireadditionalevaluationwithCTorMRIangiographyifvisibilityonechocardiogramislimited.7,13ReferraltoacardiologistofteniswarrantedforpatientswithEDS.16,19EDS與心血管異常的發(fā)生率增加有關(guān)，如二尖瓣脫垂和主動(dòng)脈夾層雖然缺乏標(biāo)準(zhǔn)化的指南來(lái)評(píng)估EDS患者的心血管異常，但在診斷時(shí)通?？梢垣@得基線超聲心動(dòng)圖主動(dòng)脈直徑測(cè)量也是推薦的，如果超聲心動(dòng)圖上的可見(jiàn)性有限，可能需要額外的CT或MRI血管造影評(píng)估7,13。對(duì)于EDS患者，轉(zhuǎn)診給心臟病專家通常是有保證的。?ChronicpainThisisoneofthemostcommoncomplaintsinpatientswithEDS,andcanimpairpatients'schoolandworklives,personalrelationships,andpsychologicalwell-being.TreatingpaininpatientswithEDScanbechallengingandmayrequirereferraltoapainspecialist.21-23Managementtypicallyinvolvesamultimodalapproach,usingsuchmethodsasphysical,occupationalandcognitivebehavioraltherapies,pharmacologicagents,splintingofunstablejoints,compressiongarments,shoeinserts,andspecializedexerciseprograms.22,23這是EDS患者最常見(jiàn)的主訴之一，并且會(huì)損害患者的學(xué)習(xí)和工作生活、人際關(guān)系和心理健康。治療EDS患者的疼痛是具有挑戰(zhàn)性的，可能需要轉(zhuǎn)介到疼痛專家21-23。典型的治療包括多模式的方法，使用諸如物理、職業(yè)和認(rèn)知行為療法、藥物、不穩(wěn)定關(guān)節(jié)夾板、壓縮服裝、鞋墊和專門的鍛煉計(jì)劃等方法。Opioidsmaybeusefulinthesepatients,butshouldbeusedwithcaution.Onestudyfoundthat,comparedwithage-matchedcontrols,patientswithEDSareprescribedopioidsmorefrequentlyandathigherdosesthanpatientswhodonothaveEDS.Chronicopioidusecanleadtotoleranceandanincreasedriskfordependence.21阿片類藥物可能對(duì)這些患者有用，但應(yīng)謹(jǐn)慎使用。一項(xiàng)研究發(fā)現(xiàn)，與年齡匹配的對(duì)照組相比，EDS患者比沒(méi)有EDS的患者更頻繁地服用阿片類藥物，劑量也更高。長(zhǎng)期使用阿片類藥物可導(dǎo)致耐受性和依賴性風(fēng)險(xiǎn)增加。?CONCLUSIONEDSisacomplexdiseasecausedbymutationsingenesinvolvedinthestructureandbiosynthesisofcollagen.ThenewestEDSclassificationsystemcanserveasadiagnosticframeworkforclinicalevaluationofpatientswithsuspectedEDS.Thediagnosisshouldbeconfirmedwiththeappropriategenetictesting.Promptrecognition,diagnosis,andinitiationoftreatmentinpatientswithEDSareassociatedwithbetterclinicaloutcomesandqualityoflife.AlthoughanupdatedsystemfordiagnosingthesubtypesofEDShasbeenestablished,nostandardcriteriaexistformanagingthesyndrome;referraltomultiplemedicalspecialiststypicallyisrequired.EDS是一種復(fù)雜的疾病，由參與膠原結(jié)構(gòu)和生物合成的基因突變引起。最新的EDS分類系統(tǒng)可作為臨床評(píng)估疑似EDS患者的診斷框架。診斷應(yīng)通過(guò)適當(dāng)?shù)幕驒z測(cè)來(lái)證實(shí)。EDS患者的及時(shí)識(shí)別、診斷和開(kāi)始治療與更好的臨床結(jié)果和生活質(zhì)量相關(guān)。雖然已經(jīng)建立了診斷EDS亞型的最新系統(tǒng)，但沒(méi)有管理該綜合征的標(biāo)準(zhǔn)準(zhǔn)則;通常需要轉(zhuǎn)介給多名醫(yī)學(xué)專家。