特納綜合征課件

TunerSyndrome北京世紀(jì)壇醫(yī)院檢驗(yàn)科細(xì)胞分子遺傳組1性發(fā)育疾病概念及基本分類介紹特納綜合征概述癥狀和體征診斷核型-表型關(guān)系治療2性發(fā)育疾病(Disordersofsexdevelopment

DSD)

是性決定和性分化異常的一組異質(zhì)性遺傳病,是由于染色體畸變或單基因突變導(dǎo)致的性發(fā)育遺傳和內(nèi)分泌途徑的改變。曾經(jīng)用雌雄間體、假兩性畸形、真兩性畸形和性反轉(zhuǎn)這些術(shù)語用于描述性發(fā)育疾病,但有輕蔑含義。2019年歐洲兒科內(nèi)分泌協(xié)會(huì)(EuropeanSocietyforPardiatricEndocrinology,ESPE)和LawsonWilkins兒科內(nèi)分泌協(xié)會(huì)(LawsonWilkinsPardiatricEndocrineSociety,LWPES)聯(lián)合召開了由內(nèi)分泌學(xué)家、外科學(xué)家、遺傳學(xué)家、心理學(xué)家和患者支持小組成員參加的會(huì)議,提出了新的術(shù)語、分類標(biāo)準(zhǔn)3建議使用DSD代替先前延用的雌雄間體、假兩性畸形、真兩性畸形和性反轉(zhuǎn)等術(shù)語,并提出按照染色體核型分析結(jié)果給DSD分類。按照染色體的分類,將其分為性染色體異常的DSD;46,XYDSD和46,XXDSD等三大類。先前使用的術(shù)語現(xiàn)提出的術(shù)語雌雄間體性發(fā)育疾病男性假兩性畸形46,XYDSD

46,XY男性性征發(fā)育不良女性假兩性畸形46,XXDSD

XX女性呈現(xiàn)男性性征真兩性畸形卵睪性DSDXX男性或XX性反轉(zhuǎn)46,XX睪丸性DSDXY性反轉(zhuǎn)46,XY完全性性腺發(fā)育不全4處理原則:(1)DSD的個(gè)體都應(yīng)該接受性別確認(rèn),應(yīng)在專家評(píng)估后確定新生兒的性別。(2)長(zhǎng)期的治療和隨訪應(yīng)在有經(jīng)驗(yàn)多學(xué)科的中心進(jìn)行,在治療小組中應(yīng)有兒科內(nèi)分泌專家、外科醫(yī)生、泌尿外科和婦產(chǎn)科專家、遺傳學(xué)家、社會(huì)工作者和醫(yī)學(xué)倫理學(xué)工作者。(3)與患者和家屬進(jìn)行開放式的交流,并且鼓勵(lì)參加性別決定的討論。(4)患者的隱私及家屬關(guān)注的問題應(yīng)該受到尊重。5性染色體異常的DSDA:47,XXY(Klinefelter綜合征及其變體)B:45,X(Turner綜合征及其變體)C:45,X/46,XY(混合性性腺發(fā)育不良)D:46,XX/46,XY(異源嵌合體)

性發(fā)育疾病新的分類和基因診斷王衛(wèi)萍綜述中國優(yōu)生與遺傳雜志2019,18(2):5-86是由于X染色體數(shù)量和結(jié)構(gòu)異常所致的先天性染色體病，是人類出生后唯一能夠生存的染色體單體類型。該病絕大多數(shù)在孕早期流產(chǎn)或胎死于宮內(nèi)，約80%的胎兒在周之內(nèi)死亡，僅1%能存活。在活產(chǎn)女嬰中發(fā)病率為1/5000-1/2500，自發(fā)流產(chǎn)兒中的發(fā)生率為7.5%。

4種核型：1.標(biāo)準(zhǔn)型45,X，約占全部TS病例的30-55%，是由于親代生殖細(xì)胞在減數(shù)分裂過程中X染色體丟失或不分離的結(jié)果，且多為精子形成過程異常所致；2.嵌合型46，XX/45，XO（約10%）是由于早期合子分裂時(shí)X染色體丟失或不分離的結(jié)果；3.結(jié)構(gòu)重排或畸變的X染色體，如X染色體長(zhǎng)臂遠(yuǎn)端或短臂與常染色體平衡易位、X染色體長(zhǎng)臂不同部位的缺失、X染色體短臂缺失、X染色體長(zhǎng)臂或短臂等臂等等（約25%）；4.有Y染色體存在（約5%）7Turner’ssyndromebaby8thorax

胸膛metacarpal掌骨constriction縊痕aorta大動(dòng)脈rudimentary不發(fā)育的gonadalstreak性索menstruation月經(jīng)9SymptomsVisual10PhysicalSymptomsShortstature(Usuallynotallerthan4’8”)Obeseweight(duetoanunderactivethyroid)DroopingeyelidsProblemswithbreastdevelopmentShortfingersandtoesExtraskinontheneck(webbedneck)SwellingofthehandsandfeetLowsetearsSoftnailsthatturnupwardattheendsIrregularrotationofwristandelbowjointsLossofovarianfunctions(infertility)HeartdefectsKidneyproblemsVisualimpairmentsEarinfectionsandhearinglossHighbloodpressureWeakbones11標(biāo)準(zhǔn)型45，XO病人有女性表現(xiàn)，但身材矮小、原發(fā)閉經(jīng)、不孕、智力一般正常或稍差，常合并有顱面（蹼頸）、四肢（肘外翻）及心血管方面的畸形，性腺萎縮，可退化成“索狀性腺”，第二性征發(fā)育不良。其發(fā)病機(jī)制為：女性完整的有功能的兩條X染色體是維持女性性腺發(fā)育及正常卵巢功能所必須的。12Lyon假說認(rèn)為46，XX中的一條X染色體失活TS患者表型不是X單體造成的（45，XO缺失的是失活的X），這也是45，XO能存活的原因。但失活的X染色體并非所有的基因都失活，擬常染色體區(qū)（PARpseudoautosomalregion）的基因并不失活，這些未失活的基因在性腺發(fā)育的調(diào)控中可能發(fā)揮著作用。如果基因的數(shù)量有了改變，那么基因的產(chǎn)物（如酶、肽鏈等）的量也隨之發(fā)生相應(yīng)改變，即產(chǎn)生基因的劑量效應(yīng)，因而X染色體數(shù)目減少、缺失、結(jié)構(gòu)異常都將由于基因的單倍劑量而導(dǎo)致女性性征的異常。13DiagnosisofTSPrenataldiagnosisthefindingoffetaledemaonultrasonography;abnormallevelsofscreeningofmaternalserum(triplescreening)abnormalresultsoffetalkaryotypingperformedbecauseofadvancedmaternalageavailabledatasuggestthatprenatalcytogeneticdiagnosisofTSintheabsenceofabnormalfetalultrasoundhasahighfalsepositiverateandseemstobeapoorpredictorofclinicaloutcomePostnataldiagnosisnewborns:puffyhandsandfeetorredundantnuchalskin;shouldbesuspectedinanynewborngirlwithedemaorhypoplasticleftheartorcoarctationoftheaortainmidchildhood:shortstature;primaryorsecondaryamenorrhea14MosaicismIInroutinekaryotyping,20cellsarecounted(todetectmosaicismatalevelofabout5percent)(Mosaicismforasecond,normal46,XXcellpopulationisabout15percent)thedetectionofanormalcelllineageinfewerthan5percentofcellsdoesnotchangetheprognosisorthemanagementifthediagnosisofTurner’ssyndromeissuspectedclinicallybuttheresultofroutinetestingisnormal,increasingthenumberofcellscountedto100

andperformingaskinbiopsyforkaryotypingoffibroblastsareindicatedtoruleoutmosaicismoranabnormalcelllineage15mosaicismforacellpopulationwithaYchromosome:atincreasedriskforgonadoblastoma(risk,7to30percent)intheirstreakgonadsinthosewithmasculinizationormosaicismforanunidentifiedmarker:theuseofflowcytometryorDNAhybridizationtosearchforY-chromosomematerialMosaicismII16Karyotype-phenotyperelationship分子基礎(chǔ)X染色體不同的位點(diǎn)異?？梢詫?dǎo)致不同的體征，即表現(xiàn)為不完全性TS控制身高的基因位于X染色體短臂上，具體定位于p21的矮小身材同源框（SHOX（shortstaturehomeobox）基因(位于Xp及Y)Xq13～Xq26決定TS的體征Xp11、Xq近端和Xq遠(yuǎn)端片段決定性腺發(fā)育和功能Xq末端是端粒（telomere）存在的區(qū)域:Xq末端的缺失與重組與該類型患者繼發(fā)性閉經(jīng)存在密切關(guān)系，可能是卵巢早衰的特異性基因區(qū)段。17Karyotype-phenotyperelationshiplossoftheshortarm(Xp)resultsinthefullphenotypeVerydistalXpdeletions:normalovarianfunctionwithshortstatureandthetypicalskeletalchangesLossofaregionatXp22.3:neurocognitiveproblemsLossofinterstitialorterminalXq：shortstatureandprimaryorsecondaryovarianfailure.18Karyotype-phenotyperelationship45,Xkaryotype:themostlikelytohavecongenitallymphedema.mosaicismfor45,X/46,XXor45,X/47,XXX:themostlikelytohavespontaneousmenarcheandfertility;mosaicismfor45,X/46,XXaremarginallytallerthanotherwomenwithTurner’ssyndrome.isochromosomeXq:anincreasedriskforhypothyroidismandinflammatoryboweldisease.aringormarkerchromosome:anincreasedriskofmentalretardationandatypicalphenotypicfeature19ManagementgrowthdevelopmentalandbehavioralconcernscardiovascularconcernsendocrineconcernsophthalmologicandotologicconcernsgastrointestinalmanifestationsrenalmanifestationsmusculoskeletalcharacteristicsLifeexpectancy20

Growth

ThemeanbirthlengthofinfantswithTurner’ssyndromefallswithinthelowendofthenormalrangeAdecreaseingrowthvelocityoccursasearlyas18monthsofageasignificantdecreaseinlineargrowthratebythirdorfourthgradeSomepresentonlywhenthenormalpubertalgrowthspurtfailstooccur----easytobeoverlookedDifferencesinagesatthecommencementoftreatmentanddifferencesinthedosesanddurationoftherapycomplicateanalysisthecostofrecombinanthumangrowthhormonepercentimeteroffinalgaininheightisapproximately$29,00021GrowthHormoneplusChildhoodLow-DoseEstrogeninTurner’sSyndromeJudithL.Ross,M.D.,CharmianA.Quigley,M.B.,B.S.,DachuangCao,Ph.D.,PenelopeFeuillan,M.D.,*KarenKowal,P.A.,JohnJ.Chipman,M.D.,andGordonB.Cutler,Jr.,M.DNEnglJMed2019;364:1230-42Conclusion:growthhormonetreatmentincreasesadultheightinpatientswithTurner’ssyndrome.Inaddition,thedatasuggestthatcombiningchildhoodultra-low-doseestrogenwithgrowthhormonemayimprovegrowthandprovideotherpotentialbenefitsassociatedwithearlyinitiationofestrogenreplacement.22developmentalandbehavioralconcernsMostpeoplewithTurner’ssyndromehavenormalintelligenceTheriskofmentalretardationishighestamongpatientswithamarkerchromosome(66percent)oraring(X)chromosome(30percent)deficitsinvisuospatialorganization,socialcognition,nonverbalproblem-solving,andpsychomotorfunctioninginthepatients23cardiovascularconcernsTheprevalenceofcongenitalheartdiseaseamongpatientswithTurner’ssyndromerangesfrom17to45percent,withnoclearphenotype–genotypecorrelations.Deathfromcardiaccausesisaseriousconcern.themostcommonstructuralalformations:Coarctationoftheaortaandbicuspidaorticvalveotherleft-sideddefects.Hypertension,mitral-valveprolapse,andconductiondefectsalsooccurEchocardiographyisamandatorypartofthediagnosticworkupforTurner’ssyndrome24endocrineconcernsHypothyroidismoccursin15to30percentofwomenwithTurner’ssyndromeonsetisinthethirddecade,though5to10percentofcasesoccurbeforeadolescenceScreeningofthyroidfunction,includingmeasurementofthyrotropinlevels,shouldbeginatabout10yearsofageinasymptomaticpatientsGonadaldysgenesisisacardinalfeatureofTurner’ssyndrome;90percentofpatientswillrequirehormone-replacementtherapytoinitiatepubertyandcompletegrowthMeasurementoffollicle-stimulatinghormone,luteinizinghormone,andestradiollevelscanhelpdeterminetheneedforhormone-replacementtherapyHormone-replacementtherapyshouldbeinitiatedatabouttheageof14years25SpontaneousfertilityisrareamongpatientswithTurner’ssyndromeandismostlikelyinwomenwithmosaicismforanormal46,XXcelllineage

or

a47,XXXcelllineage,orverydistalXpdeletions.

Thesewomenhaveanincreasedriskofspontaneouspregnancyloss,twins,andaneuploidyinfetusesthatarecarriedtotermPregnancy,bymeansofgameteintrafallopiantransferwithdonoreggs,hasbeenattemptedinwomenwithTurner’ssyndrome26Theprevalenceofinsulinresistanceandtype2diabetesmaybeincreasedinpatientswithTurner’ssyndromeThemajorityofpatientswithTurner’ssyndromeanddiabeteshaveadult-onsetdiabetes,andmostareoverweight27ophthalmologicandotologicconcernsstrabismus18percentptosisin13percentCataractsandnystagmusalsooccurmorecommonlyrecurrentotitismediamightbeamajorprobleminearlychildhood

butThefrequencyofearinfectionsdecreaseswithageandgrowthoffacialstructuresProgressivesensorineuralhearinglossisamajorfeatureofTurner’ssyndromeinadultsbutthebiologicbasisisnotkn