特纳综合征PPT课件

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 治疗第1页/共30页 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。 2006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 Pard

2、iatric 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、分类标准第2页/共30页 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, XY DSD和46, XX DSD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

3、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第3页/共30页处理原则: (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。第4页/共30页 性染色体异常的DSD A: 47, XXY ( Klinefelter综合征及其变体) B: 45, X (

4、 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2010,18(2):5-8第5页/共30页 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

5、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%）第6页/共30页第7页/共30页thorax 胸膛metacarpal 掌骨constriction缢痕aorta 大动脉rudimentary不发育的gonadal streak性索menstruat

6、ion月经第8页/共30页第9页/共30页Short stature (Usually no taller than 48”)Obese weight (due to an underactive thyroid) Drooping eyelidsProblems with breast development Short fingers and toesExtra skin on the neck (webbed neck)Swelling of the hands and feetLow set ears Soft nails that turn upward at the ends Ir

7、regular rotation of wrist and elbow jointsLoss of ovarian functions (infertility)Heart defectsKidney problemsVisual impairmentsEar infections and hearing lossHigh blood pressureWeak bones第10页/共30页 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：

8、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。第11页/共30页 Lyon 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（PAR pseudo autosomal region）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

9、导致女性性征的异常。第12页/共30页Diagnosis of TS Prenatal diagnosislthe finding of fetal edema on ultrasonography; labnormal levels of screening of maternal serum (triple screening)labnormal results of fetal karyotyping performed because of advanced maternal ageavailable data suggest that prenatal cytogenetic dia

10、gnosis of TS in the absence of abnormal fetal ultrasound has a high false positive rate and seems to be a poor predictor of clinical outcome Postnatal diagnosis newborns :puffy hands and feet or redundant nuchal skin; should be suspected in any newborn girl with edema or hypoplastic left heart or co

11、arctation of the aorta in midchildhood :short stature; primary or secondary amenorrhea第13页/共30页Mosaicism I 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 ) the detection of a n

12、ormal cell lineage in fewer than 5 percent of cells does not change the prognosis or the management 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

13、fibroblasts are indicated to rule out mosaicism or an abnormal cell lineage第14页/共30页 mosaicism for a cell population with a Y chromosome : at increased risk for gonadoblastoma (risk, 7 to 30 percent) in their streak gonads in those with masculinization or mosaicism for an unidentified marker: the us

14、e of flow cytometry or DNA hybridization to search for Y-chromosome materialMosaicism II第15页/共30页Karyotype-phenotype relationship 分子基础lX 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 TSl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（short stature homeobox）基因(位于Xp及Y)lXq13Xq26决定 TS 的体征lXp11、Xq 近端和 Xq 远端片段决定性腺发育和功能l Xq 末端是

15、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。第16页/共30页Karyotype-phenotype relationship loss of the short arm (Xp) results in the full phenotypeVery distal Xp deletions: normal ovarian function with short stature and the typical skeletal changesLoss of a region at Xp22.3 : neurocogn

16、itive problems Loss of interstitial or terminal Xq ：short stature and primary or secondary ovarian failure.第17页/共30页Karyotype-phenotype relationship 45,X karyotype : the most likely to have congenital lymphedema. mosaicism for 45,X/46,XX or 45,X/47,XXX : the most likely to have spontaneous menarche

17、and fertility; mosaicism for 45,X/46,XX are marginally taller than other women with Turners syndrome. isochromosome Xq : an increased risk for hypothyroidism and inflammatory bowel disease. a ring or marker chromosome : an increased risk of mental retardation and atypical phenotypic feature第18页/共30页

18、Management growth developmental and behavioral concerns cardiovascular concerns endocrine concerns ophthalmologic and otologic concerns gastrointestinal manifestations renal manifestations musculoskeletal characteristics Life expectancy第19页/共30页Growth The mean birth length of infants with Turners sy

19、ndrome falls within the low end of the normal range A decrease in growth velocity occurs as early as 18 months of age a significant decrease in linear growth rate by third or fourth grade Some present only when the normal pubertal growth spurt fails to occur -easy to be overlooked Differences in age

20、s at the commencement of treatment and differences in the doses and duration of therapy complicate analysis the cost of recombinant human growth hormone per centimeter of final gain in height is approximately $29,000第20页/共30页Growth Hormone plus Childhood Low-Dose Estrogen in Turners SyndromeJudith L

21、. 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 2011;364:1230-42 Conclusion: growth hormone treatment increases adult height in patients with Turners syndrome. In addition

22、, 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.第21页/共30页developmental and behavioral concerns Most people with Turners syndrome have normal intell

23、igence The risk of mental retardation is highest among patients with a marker chromosome (66 percent) or a ring (X) chromosome (30 percent) deficits in visuospatial organization, social cognition, nonverbal problem-solving, and psychomotor functioning in the patients第22页/共30页cardiovascular concerns

24、The 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. the most common structural alformations: Coarctation of the aorta and bicuspid aortic valve othe

25、r left-sided defects. Hypertension, mitral-valve prolapse, and conduction defects also occur Echocardiography is a mandatory part of the diagnostic workup for Turners syndrome第23页/共30页endocrine concerns Hypothyroidism occurs in 15 to 30 percent of women with Turners syndromel onset is in the third d

26、ecade, though 5 to 10 percent of cases occur before adolescencel Screening of thyroid function, including measurement of thyrotropin levels, should begin at about 10 years of age in asymptomatic patients Gonadal dysgenesis is a cardinal feature of Turners syndrome; 90 percent of patients will requir

27、e hormone-replacement therapy to initiate puberty 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 years第24页/

28、共30页 Spontaneous 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

29、 that are carried to term Pregnancy, by means of gamete intrafallopian transfer with donor eggs, has been attempted in women with Turners syndrome第25页/共30页 The prevalence of insulin resistance and type 2 diabetes may be increased in patients with Turners syndrome The majority of patients with Turner

30、s syndrome and diabetes have adult-onset diabetes, and most are overweight第26页/共30页ophthalmologic and otologic concerns strabismus 18 percent ptosis in 13 percent Cataracts and nystagmus also occur more commonly recurrent otitis media might be a major problem in early childhood but The frequency of ear infections decreases with age and growth of facial structures Progressive sensorineural hearing loss is a major feature of Turners syndrome in adults but the biologic basis