特纳综合征课件

Tuner Syndrome北京世纪坛医院检验科细胞分子遗传组北京世纪坛医院检验科细胞分子遗传组 1Tuner Syndrome北京世纪坛医院检验科细胞分子遗传v性性发育疾病概念及基本分育疾病概念及基本分类介介绍v特特纳综合征概述合征概述v症状和体征症状和体征v诊断断v核型核型-表型关系表型关系v治治疗2性发育疾病概念及基本分类介绍2v性性发育疾病育疾病(Disorders of sex development DSD)是性决定和性分化异常的一是性决定和性分化异常的一组异异质性性遗传病病,是由是由于染色体畸于染色体畸变或或单基因突基因突变导致的性致的性发育育遗传和内和内分泌途径的改分泌途径的改变。v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。v2019年欧洲儿科内分泌协会(European Society for Pardiatric Endocrinology,ESPE)和LawsonWilkins儿科内分泌协会(LawsonWilkins Pardiatric Endocrine Society,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性发育疾病(Disorders of sex developv建建议使用使用DSD代替先前延用的雌雄代替先前延用的雌雄间体、假两性畸形、真两性畸形和体、假两性畸形、真两性畸形和性反性反转等等术语,并提出按照染色体核型分析并提出按照染色体核型分析结果果给DSD分分类。v按照染色体的分按照染色体的分类,将其分将其分为性染色体异常的性染色体异常的DSD;46,XY DSD和和46,XX DSD等三大等三大类。4建议使用DSD代替先前延用的雌雄间体、假两性畸形、真两性畸形处理原理原则:v(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。v(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。v(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。v(4)患者的隐私及家属关注的问题应该受到尊重。5处理原则:5v 性染色体异常的性染色体异常的DSD vA:47,XXY(Klinefelter综合征及其合征及其变体体)vB:45,X(Turner综合征及其合征及其变体体)vC:45,X/46,XY(混合性性腺混合性性腺发育不良育不良)vD:46,XX/46,XY(异源嵌合体异源嵌合体)性性发育疾病新的分育疾病新的分类和基因和基因诊断断 王王卫萍萍综述述中国优生与遗传杂志2019,18(2):5-86 性染色体异常的DSD 性发育疾病新的分类和基因诊断 v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。v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%。v 4 种核型：种核型：v1.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；v2.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；v3.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%）；v4.有 Y 染色体存在（约 5%）7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8Turners syndrome baby8thorax 胸膛metacarpal 掌骨constriction缢痕aorta 大动脉rudimentary不发育的gonadal streak性索menstruation月经9thorax constriction910Symptoms Visual10vShort stature(Usually no taller than 48”)vObese weight(due to an underactive thyroid)vDrooping eyelidsvProblems with breast developmentv Short fingers and toesvExtra skin on the neck(webbed neck)vSwelling of the hands and feetvLow set ears vSoft nails that turn upward at the ends vIrregular rotation of wrist and elbow jointsvLoss of ovarian functions(infertility)vHeart defectsvKidney problemsvVisual impairmentsvEar infections and hearing lossvHigh blood pressurevWeak bones11Physical Symptoms Short staturv标准型准型 45，XO 病人有女性表病人有女性表现，但身材矮小、原，但身材矮小、原发闭经、不孕、智力一般正常或稍差，常合并有、不孕、智力一般正常或稍差，常合并有颅面（蹼面（蹼颈）、四肢（肘外翻）及心血管方面的畸形，性腺萎）、四肢（肘外翻）及心血管方面的畸形，性腺萎缩，可退化成可退化成“索状性腺索状性腺”，第二性征，第二性征发育不良。育不良。v其其发病机制病机制为：女性完整的有功能的两条：女性完整的有功能的两条 X 染色体是染色体是维持女性性腺持女性性腺发育及正常卵巢功能所必育及正常卵巢功能所必须的。的。12标准型 45，XO 病人有女性表现，但身材矮小、原发闭经、不vLyon 假假说认为 46，XX 中的一条中的一条 X 染色体失活染色体失活vTS 患者表型不是患者表型不是 X 单体造成的（体造成的（45，XO 缺失的是失缺失的是失活的活的X），），这也是也是 45，XO 能存活的原因。能存活的原因。v但失活的但失活的 X 染色体并非所有的基因都失活，染色体并非所有的基因都失活，拟常染色体区常染色体区（PAR pseudo autosomal region）的基因并不失）的基因并不失活，活，这些未失活的基因在性腺些未失活的基因在性腺发育的育的调控中可能控中可能发挥着作着作用用。如果基因的数量有了改。如果基因的数量有了改变，那么基因的，那么基因的产物（如物（如酶、肽链等）的量也随之等）的量也随之发生相生相应改改变，即，即产生基因的生基因的剂量效量效应，因而，因而 X 染色体数目减少、缺失、染色体数目减少、缺失、结构异常都将由于构异常都将由于基因的基因的单倍倍剂量而量而导致女性性征的异常。致女性性征的异常。13Lyon 假说认为 46，XX 中的一条 X 染色体失活13Diagnosis of TSvPrenatal diagnosisvthe finding of fetal edema on ultrasonography;vabnormal levels of screening of maternal serum (triple screening)vabnormal results of fetal karyotyping performed because of advanced maternal agevavailable data suggest that prenatal cytogenetic diagnosis of TS in the absence of abnormal fetal ultrasound has a high false positive rate and seems to be a poor predictor of clinical outcomevPostnatal diagnosisvnewborns:puffy hands and feet or redundant nuchal skin;should be suspected in any newborn girl with edema or hypoplastic left heart or coarctation of the aortavin midchildhood:short stature;primary or secondary amenorrhea14Diagnosis of TSPrenatal diagnoMosaicism IvIn routine karyotyping,20 cells are counted (to detect mosaicism at a level of about 5 percent)(Mosaicism for a second,normal 46,XX cell population is about 15 percent)vthe detection of a normal cell lineage in fewer than 5 percent of cells does not change the prognosis or the managementvif the diagnosis of Turners syndrome is suspected clinically but the result of routine testing is normal,increasing the number of cells counted to 100 and performing a skin biopsy for karyotyping of fibroblasts are indicated to rule out mosaicism or an abnormal cell lineage15Mosaicism IIn routine karyotypvmosaicism for a cell population with a Y chromosome:at increased risk for gonadoblastoma(risk,7 to 30 percent)in their streak gonadsvin those with masculinization or mosaicism for an unidentified marker:the use of flow cytometry or DNA hybridization to search for Y-chromosome materialMosaicism II16mosaicism for a cell populatioKaryotype-phenotype relationshipv分子基分子基础vX 染色体不同的位点异常可以染色体不同的位点异常可以导致不同的体征，即表致不同的体征，即表现为不完全性不完全性 TSv控制身高的基因位于控制身高的基因位于 X 染色体短臂上，具体定位于染色体短臂上，具体定位于 p21 的矮小身材同源框（的矮小身材同源框（SHOX（short stature homeobox）基因）基因(位于位于Xp及及Y)vXq13Xq26决定决定 TS 的体征的体征vXp11、Xq 近端和近端和 Xq 远端片段决定性腺端片段决定性腺发育和功能育和功能v Xq 末端是端粒（末端是端粒（telomere）存在的区域）存在的区域:Xq 末端的末端的缺失与重缺失与重组与与该类型患者型患者继发性性闭经存在密切关系，可能存在密切关系，可能是卵巢早衰的特异性基因区段。是卵巢早衰的特异性基因区段。17Karyotype-phenotype relationshKaryotype-phenotype relationshipvloss of the short arm(Xp)results in the full phenotypevVery distal Xp deletions:normal ovarian function with short stature and the typical skeletal changesvLoss of a region at Xp22.3:neurocognitive problemsvLoss of interstitial or terminal Xq：short stature and primary or secondary ovarian failure.18Karyotype-phenotype relationshKaryotype-phenotype relationshipv45,X karyotype:the most likely to have congenital lymphedema.vmosaicism for 45,X/46,XX or 45,X/47,XXX :the most likely to have spontaneous menarche and fertility;mosaicism for 45,X/46,XX are marginally taller than other women with Turners syndrome.visochromosome Xq:an increased risk for hypothyroidism and inflammatory bowel disease.va ring or marker chromosome:an increased risk of mental retardation and atypical phenotypic feature19Karyotype-phenotype relationshManagementvgrowthvdevelopmental and behavioral concernsvcardiovascular concernsvendocrine concernsvophthalmologic and otologic concernsvgastrointestinal manifestationsvrenal manifestationsvmusculoskeletal characteristicsvLife expectancy20Managementgrowth20GrowthvThe mean birth length of infants with Turners syndrome falls within the low end of the normal rangevA decrease in growth velocity occurs as early as 18 months of ageva significant decrease in linear growth rate by third or fourth gradevSome present only when the normal pubertal growth spurt fails to occur -easy to be overlookedvDifferences in ages at the commencement of treatment and differences in the doses and duration of therapy complicate analysisvthe cost of recombinant human growth hormone per centimeter of final gain in height is approximately$29,00021GrowthThe mean birth length Growth Hormone plus Childhood Low-Dose Estrogen in Turners SyndromeJudith L.Ross,M.D.,Charmian A.Quigley,M.B.,B.S.,Dachuang Cao,Ph.D.,Penelope Feuillan,M.D.,*Karen Kowal,P.A.,John J.Chipman,M.D.,and Gordon B.Cutler,Jr.,M.DN Engl J Med 2019;364:1230-42vConclusion:growth hormone treatment increases adult height in patients with Turners syndrome.In addition,the data suggest that combining childhood ultra-low-dose estrogen with growth hormone may improve growth and provide other potential benefits associated with early initiation of estrogen replacement.22Growth Hormone plus Childhood developmental and behavioral concernsvMost people with Turners syndrome have normal intelligencevThe risk of mental retardation is highest among patients with a marker chromosome(66 percent)or a ring(X)chromosome(30 percent)vdeficits in visuospatial organization,social cognition,nonverbal problem-solving,and psychomotor functioning in the patients23developmental and behavioral ccardiovascular concernsvThe prevalence of congenital heart disease among patients with Turners syndrome ranges from 17 to 45 percent,with no clear phenotypegenotype correlations.Death from cardiac causes is a serious concern.vthe most common structural alformations:Coarctation of the aorta and bicuspid aortic valve other left-sided defects.vHypertension,mitral-valve prolapse,and conduction defects also occurvEchocardiography is a mandatory part of the diagnostic workup for Turners syndrome24cardiovascular concernsThe preendocrine concernsvHypothyroidism occurs in 15 to 30 percent of women with Turners syndromevonset is in the third decade,though 5 to 10 percent of cases occur before adolescencevScreening of thyroid function,including measurement of thyrotropin levels,should begin at about 10 years of age in asymptomatic patientsvGonadal dysgenesis is a cardinal feature of Turners syndrome;90 percent of patients will require hormone-replacement therapy to initiate puberty and complete growthvMeasurement of follicle-stimulating hormone,luteinizing hormone,and estradiol levels can help determine the need for hormone-replacement therapyvHormone-replacement therapy should be initiated at about the age of 14 years25endocrine concernsHypothyroidivSpontaneous fertility is rare among patients with Turners syndrome and is most likely in women with mosaicism for a normal 46,XX cell lineage or a 47,XXX cell lineage,or very distal Xp deletions.These women have an increased risk of spontaneous pregnancy loss,twins,and aneuploidy in fetuses that are carried to termvPregnancy,by means of gamete intrafallopian transfer with donor eggs,has been attempted in women with Turners syndrome26Spontaneous fertility is rare vThe prevalence of insulin resistance and type 2 diabetes may be increased in patients with Turners syndromevThe majority of patients with Turners syndrome and diabetes have adult-onset diabetes,and most are overweight27The prevalence of insulin resiophthalmologic and otologic concernsvstrabismus 18 percentvptosis in 13 percentvCataracts and nystagmus also occur more commonlyvrecurrent otitis media might be a major problem in early childhood but The frequency of ear infections decreases with age and growth of facial structuresvProgressive sensorineural hearing loss is a major feature of Turners syndrome in adults but the biologic basis is not known28ophthalmologic and otologic covgastrointestinal manifestationsvMore common are instances of inflammatory bowel diseasevMore than half of patients with Turners syndrome and inflammatory bowel disease who have been described in the literature have had an i(Xq)cell lineagevrenal manifestationsvStructural renal malformations,including horseshoe kidney and duplication of the collecting system,are found in up to 40 percent of patients with Turners syndrome Whereas most structural malformations do not cause renal dysfunctionvScreening renal ultrasonography is necessary for all patients with Turners syndrome29gastrointestinal manifestationvmusculoskeletal characteristicsvcharacterized by skeletal dysplasia,with short stature,mild epiphyseal dysplasia,and typical bony alterationsvNeoplasiavno increase in the relative risk of cancervprophylactic gonadectomy is indicated if a Y chromosome is presentvlife expectancyvhave a decreased life expectancy,primarily as a result of complications of heart disease and diabetes30musculoskeletal characteristic供娄浪颓蓝辣袄驹靴锯澜互慌仲写绎衰斡染圾明将呆则孰盆瘸砒腥悉漠堑脊髓灰质炎(讲课2019)脊髓灰质炎(讲课2019)谢谢！供娄浪颓蓝辣袄驹靴锯澜互慌仲写绎衰斡染圾明将呆则孰盆瘸