特纳综合征课件

TunerSyndrome北京世纪坛医院检验科细胞分子遗传组1性发育疾病概念及基本分类介绍特纳综合征概述症状和体征诊断核型-表型关系治疗2性发育疾病(Disordersofsexdevelopment

DSD)

是性决定和性分化异常的一组异质性遗传病,是由于染色体畸变或单基因突变导致的性发育遗传和内分泌途径的改变。曾经用雌雄间体、假两性畸形、真两性畸形和性反转这些术语用于描述性发育疾病,但有轻蔑含义。2019年欧洲儿科内分泌协会(EuropeanSocietyforPardiatricEndocrinology,ESPE)和LawsonWilkins儿科内分泌协会(LawsonWilkinsPardiatricEndocrineSociety,LWPES)联合召开了由内分泌学家、外科学家、遗传学家、心理学家和患者支持小组成员参加的会议,提出了新的术语、分类标准3建议使用DSD代替先前延用的雌雄间体、假两性畸形、真两性畸形和性反转等术语,并提出按照染色体核型分析结果给DSD分类。按照染色体的分类,将其分为性染色体异常的DSD;46,XYDSD和46,XXDSD等三大类。先前使用的术语现提出的术语雌雄间体性发育疾病男性假两性畸形46,XYDSD

46,XY男性性征发育不良女性假两性畸形46,XXDSD

XX女性呈现男性性征真两性畸形卵睾性DSDXX男性或XX性反转46,XX睾丸性DSDXY性反转46,XY完全性性腺发育不全4处理原则:(1)DSD的个体都应该接受性别确认,应在专家评估后确定新生儿的性别。(2)长期的治疗和随访应在有经验多学科的中心进行,在治疗小组中应有儿科内分泌专家、外科医生、泌尿外科和妇产科专家、遗传学家、社会工作者和医学伦理学工作者。(3)与患者和家属进行开放式的交流,并且鼓励参加性别决定的讨论。(4)患者的隐私及家属关注的问题应该受到尊重。5性染色体异常的DSDA:47,XXY(Klinefelter综合征及其变体)B:45,X(Turner综合征及其变体)C:45,X/46,XY(混合性性腺发育不良)D:46,XX/46,XY(异源嵌合体)

性发育疾病新的分类和基因诊断王卫萍综述中国优生与遗传杂志2019,18(2):5-86是由于X染色体数量和结构异常所致的先天性染色体病，是人类出生后唯一能够生存的染色体单体类型。该病绝大多数在孕早期流产或胎死于宫内，约80%的胎儿在周之内死亡，仅1%能存活。在活产女婴中发病率为1/5000-1/2500，自发流产儿中的发生率为7.5%。

4种核型：1.标准型45,X，约占全部TS病例的30-55%，是由于亲代生殖细胞在减数分裂过程中X染色体丢失或不分离的结果，且多为精子形成过程异常所致；2.嵌合型46，XX/45，XO（约10%）是由于早期合子分裂时X染色体丢失或不分离的结果；3.结构重排或畸变的X染色体，如X染色体长臂远端或短臂与常染色体平衡易位、X染色体长臂不同部位的缺失、X染色体短臂缺失、X染色体长臂或短臂等臂等等（约25%）；4.有Y染色体存在（约5%）7Turner’ssyndromebaby8thorax

胸膛metacarpal掌骨constriction缢痕aorta大动脉rudimentary不发育的gonadalstreak性索menstruation月经9SymptomsVisual10PhysicalSymptomsShortstature(Usuallynotallerthan4’8”)Obeseweight(duetoanunderactivethyroid)DroopingeyelidsProblemswithbreastdevelopmentShortfingersandtoesExtraskinontheneck(webbedneck)SwellingofthehandsandfeetLowsetearsSoftnailsthatturnupwardattheendsIrregularrotationofwristandelbowjointsLossofovarianfunctions(infertility)HeartdefectsKidneyproblemsVisualimpairmentsEarinfectionsandhearinglossHighbloodpressureWeakbones11标准型45，XO病人有女性表现，但身材矮小、原发闭经、不孕、智力一般正常或稍差，常合并有颅面（蹼颈）、四肢（肘外翻）及心血管方面的畸形，性腺萎缩，可退化成“索状性腺”，第二性征发育不良。其发病机制为：女性完整的有功能的两条X染色体是维持女性性腺发育及正常卵巢功能所必须的。12Lyon假说认为46，XX中的一条X染色体失活TS患者表型不是X单体造成的（45，XO缺失的是失活的X），这也是45，XO能存活的原因。但失活的X染色体并非所有的基因都失活，拟常染色体区（PARpseudoautosomalregion）的基因并不失活，这些未失活的基因在性腺发育的调控中可能发挥着作用。如果基因的数量有了改变，那么基因的产物（如酶、肽链等）的量也随之发生相应改变，即产生基因的剂量效应，因而X染色体数目减少、缺失、结构异常都将由于基因的单倍剂量而导致女性性征的异常。13DiagnosisofTSPrenataldiagnosisthefindingoffetaledemaonultrasonography;abnormallevelsofscreeningofmaternalserum(triplescreening)abnormalresultsoffetalkaryotypingperformedbecauseofadvancedmaternalageavailabledatasuggestthatprenatalcytogeneticdiagnosisofTSintheabsenceofabnormalfetalultrasoundhasahighfalsepositiverateandseemstobeapoorpredictorofclinicaloutcomePostnataldiagnosisnewborns:puffyhandsandfeetorredundantnuchalskin;shouldbesuspectedinanynewborngirlwithedemaorhypoplasticleftheartorcoarctationoftheaortainmidchildhood:shortstature;primaryorsecondaryamenorrhea14MosaicismIInroutinekaryotyping,20cellsarecounted(todetectmosaicismatalevelofabout5percent)(Mosaicismforasecond,normal46,XXcellpopulationisabout15percent)thedetectionofanormalcelllineageinfewerthan5percentofcellsdoesnotchangetheprognosisorthemanagementifthediagnosisofTurner’ssyndromeissuspectedclinicallybuttheresultofroutinetestingisnormal,increasingthenumberofcellscountedto100

andperformingaskinbiopsyforkaryotypingoffibroblastsareindicatedtoruleoutmosaicismoranabnormalcelllineage15mosaicismforacellpopulationwithaYchromosome:atincreasedriskforgonadoblastoma(risk,7to30percent)intheirstreakgonadsinthosewithmasculinizationormosaicismforanunidentifiedmarker:theuseofflowcytometryorDNAhybridizationtosearchforY-chromosomematerialMosaicismII16Karyotype-phenotyperelationship分子基础X染色体不同的位点异常可以导致不同的体征，即表现为不完全性TS控制身高的基因位于X染色体短臂上，具体定位于p21的矮小身材同源框（SHOX（shortstaturehomeobox）基因(位于Xp及Y)Xq13～Xq26决定TS的体征Xp11、Xq近端和Xq远端片段决定性腺发育和功能Xq末端是端粒（telomere）存在的区域:Xq末端的缺失与重组与该类型患者继发性闭经存在密切关系，可能是卵巢早衰的特异性基因区段。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