特纳综合征课件.ppt

1、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 1v性发育疾病概念及基本分类介绍性发育疾病概念及基本分类介绍v特纳综合征概述特纳综合征概述v症状和体征症状和体征v诊断诊断v核型核型-表型关系表型关系v治疗治疗2v性发育疾病性发育疾病(Disorders of sex development DSD)是性决定和性分化异常的一组异质性遗传病是性决定和性分化异常的一组异质性遗传病,是由是由于染色体畸变或单基因突变导致的性发育遗传和内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。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

2、性反转这些术语用于描述性发育疾病,但有轻蔑含义。v 2019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3v 建议使用建议使用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和性反转等术语,并提出按照染色体核

3、型分析结果给并提出按照染色体核型分析结果给DSD分类。分类。v 按照染色体的分类按照染色体的分类,将其分为性染色体异常的将其分为性染色体异常的DSD;46,XY DSD和和46,XX DSD等三大类。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,XY DSD 46,XY男性性征发育不良女性假两性畸形 46,XX DSD XX女性呈现男性性征真两性畸形卵睾性 DSD XX男性或 XX性反转 46,XX睾丸性 DSD XY性反转 46,XY完全性性腺发育不全4处理原则处理原则: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

4、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。5v 性染色体异常的性染色体异常的DSD v A:47,XXY(Klinefelter综合征及其变体综合征及其变体)v B:45,X(Turner综合征及其变体综合征及其变体)v C:45,X/46,XY(混合性性腺发育不良混合性性腺发育不良)v D:46,XX/46,XY(异源嵌合体异源嵌合体)性发育疾病新的分类和基因诊断性发育疾病新的分类和基因

5、诊断 王卫萍综述王卫萍综述中国优生与遗传杂志2019,18(2):5-86v 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：v 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；v 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

6、或不分离的结果；v 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%）；v 4.有 Y 染色体存在（约 5%）78thorax 胸膛metacarpal 掌骨constriction缢痕aorta 大动脉rudimentary不发育的gonadal streak性索menstruation月经910v Short stature(Usually no taller than 48”)v Obese weight(due to an underactive thyroid)v D

7、rooping eyelidsv Problems with breast developmentv Short fingers and toesv Extra skin on the neck(webbed neck)v Swelling of the hands and feetv Low set ears v Soft nails that turn upward at the ends v Irregular rotation of wrist and elbow jointsv Loss of ovarian functions(infertility)v Heart defects

8、v Kidney problemsv Visual impairmentsv Ear infections and hearing lossv High blood pressurev Weak bones11v 标准型标准型 45，XO 病人有女性表现，但身材矮小、原发病人有女性表现，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，颈）、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”，第二性征发育不良。，第二性征发育不良。v 其发病机制为：女性完

9、整的有功能的两条其发病机制为：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发育及正常卵巢功能所必须的。维持女性性腺发育及正常卵巢功能所必须的。12v Lyon 假说假说认为认为 46，XX 中的一条中的一条 X 染色体失活染色体失活v TS 患者表型不是患者表型不是 X 单体造成的（单体造成的（45，XO 缺失的是失缺失的是失活的活的X），这也是），这也是 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，拟常染色体拟常染色体区（区（PAR pseudo autosomal region）的基因并不）的基因并不

10、失活，这些未失活的基因在性腺发育的调控中可能发挥着失活，这些未失活的基因在性腺发育的调控中可能发挥着作用作用。如果基因的数量有了改变，那么基因的产物（如酶、。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，因而应，因而 X 染色体数目减少、缺失、结构异常都将由于染色体数目减少、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。基因的单倍剂量而导致女性性征的异常。13Diagnosis of TSvPrenatal diagnosisl the finding of fetal edem

11、a on ultrasonography;l abnormal levels of screening of maternal serum (triple screening)l abnormal results of fetal karyotyping performed because of advanced maternal age available data suggest that prenatal cytogenetic diagnosis of TS in the absence of abnormal fetal ultrasound has a high false pos

12、itive rate and seems to be a poor predictor of clinical outcomevPostnatal diagnosisv newborns: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 aortav in midchildhood:short stature;primary or secondary ame

13、norrhea14Mosaicism Iv In 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)v the detection of a normal cell lineage in fewer than 5 percent of cells does not change the prognosis or the

14、 managementv if 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 lineage15v mosaicism

15、 for a cell population with a Y chromosome:at increased risk for gonadoblastoma(risk,7 to 30 percent)in their streak gonadsv in those with masculinization or mosaicism for an unidentified marker:the use of flow cytometry or DNA hybridization to search for Y-chromosome materialMosaicism II16Karyotype

16、-phenotype relationshipv 分子基础分子基础l X 染色体不同的位点异常可以导致不同的体征，即表现为染色体不同的位点异常可以导致不同的体征，即表现为不完全性不完全性 TSl 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)l Xq13Xq26决定决定 TS 的体征的体征l Xp11、Xq 近端和近端和 Xq 远端片段决定性腺发育和功能远端片段决定性腺发育和功能l Xq 末端是端粒（末端是端粒（tel

17、omere）存在的区域）存在的区域:Xq 末端的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。是卵巢早衰的特异性基因区段。17Karyotype-phenotype relationshipv loss of the short arm(Xp)results in the full phenotype Very distal Xp deletions:normal ovarian function with short stature and the typical skeletal changes Los

18、s of a region at Xp22.3:neurocognitive problemsv Loss of interstitial or terminal Xq：short stature and primary or secondary ovarian failure.18Karyotype-phenotype relationshipv 45,X karyotype:the most likely to have congenital lymphedema.v mosaicism for 45,X/46,XX or 45,X/47,XXX :the most likely to h

19、ave spontaneous menarche and fertility;mosaicism for 45,X/46,XX are marginally taller than other women with Turners syndrome.v isochromosome Xq:an increased risk for hypothyroidism and inflammatory bowel disease.v a ring or marker chromosome:an increased risk of mental retardation and atypical pheno

20、typic feature19Managementvgrowthvdevelopmental and behavioral concernsvcardiovascular concernsvendocrine concernsvophthalmologic and otologic concernsvgastrointestinal manifestationsvrenal manifestationsvmusculoskeletal characteristicsvLife expectancy20Growthv The mean birth length of infants with T

21、urners syndrome falls within the low end of the normal rangev A decrease in growth velocity occurs as early as 18 months of agev a significant decrease in linear growth rate by third or fourth gradev Some present only when the normal pubertal growth spurt fails to occur -easy to be overlookedv Diffe

22、rences in ages at the commencement of treatment and differences in the doses and duration of therapy complicate analysisv the cost of recombinant human growth hormone per centimeter of final gain in height is approximately$29,00021Growth Hormone plus Childhood Low-Dose Estrogen in Turners SyndromeJu

23、dith 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;364:1230-42v Conclusion:growth hormone treatment increases adult height in patients with Turners syndrome.In addition,the data su

24、ggest 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.22developmental and behavioral concernsvMost people with Turners syndrome have normal intelligencevThe risk of m

25、ental 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 patients23cardiovascular concernsv The prevalence of congenital heart

26、 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.v the most common structural alformations:Coarctation of the aorta and bicuspid aortic valve other left-sided defects.v Hypertension,

27、mitral-valve prolapse,and conduction defects also occurv Echocardiography is a mandatory part of the diagnostic workup for Turners syndrome24endocrine concernsv Hypothyroidism occurs in 15 to 30 percent of women with Turners syndromel onset is in the third decade,though 5 to 10 percent of cases occu

28、r before adolescencel Screening of thyroid function,including measurement of thyrotropin levels,should begin at about 10 years of age in asymptomatic patientsv Gonadal dysgenesis is a cardinal feature of Turners syndrome;90 percent of patients will require hormone-replacement therapy to initiate pub

29、erty and complete growthl Measurement of follicle-stimulating hormone,luteinizing hormone,and estradiol levels can help determine the need for hormone-replacement therapyl Hormone-replacement therapy should be initiated at about the age of 14 years25v Spontaneous fertility is rare among patients wit

30、h 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 termv Pregnancy,by means of gamete i

31、ntrafallopian transfer with donor eggs,has been attempted in women with Turners syndrome26vThe 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 ov

32、erweight27ophthalmologic and otologic concernsv strabismus 18 percentv ptosis in 13 percentv Cataracts and nystagmus also occur more commonlyv recurrent otitis media might be a major problem in early childhood but The frequency of ear infections decreases with age and growth of facial structuresv Pr

33、ogressive sensorineural hearing loss is a major feature of Turners syndrome in adults but the biologic basis is not known28v gastrointestinal manifestationsl More common are instances of inflammatory bowel diseasel More than half of patients with Turners syndrome and inflammatory bowel disease who h

34、ave been described in the literature have had an i(Xq)cell lineagev renal manifestationsl Structural 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 ca

35、use renal dysfunctionl Screening renal ultrasonography is necessary for all patients with Turners syndrome29v musculoskeletal characteristicsv characterized by skeletal dysplasia,with short stature,mild epiphyseal dysplasia,and typical bony alterationsv Neoplasial no increase in the relative risk of cancerl prophylactic gonadectomy is indicated if a Y chromosome is presentv life expectancyv have a decreased life expectancy,primarily as a result of complications of heart disease and diabetes30