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 肖文珺 v性发发育疾病概念及基本分类类介绍绍 v特纳综纳综 合征概述 v症状和体征 v诊诊断 v核型-表型关系 v治疗疗 v性发发育疾病(Disorders of sex development DSD) 是性决定和性分化异常的一组组异质质性遗传遗传 病, 是由 于染色体畸变变或单单基因突变导变导 致的性发发育遗传遗传 和 内分泌途径的改变变。 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。 v 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 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 v 建议议使用DSD代替先前延用的雌雄间间体、假两性畸形、真两性畸形 和性反转转等术语术语 ,并提出按照染色体核型分析结结果给给DSD分类类。 v 按照染色体的分类类,将其分为为性染色体异常的DSD; 46, XY DSD和 46, XX DSD等三大类类。 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 处处理原则则: 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。 v 性染色体异常的DSD v A: 47, XXY ( Klinefelter综综合征及其变变体) v B: 45, X ( Turner综综合征及其变变体) v C: 45, X /46, XY (混合性性腺发发育不良) v D: 46, XX /46, XY (异源嵌合体) 性发发育疾病新的分类类和基因诊诊断 王卫卫萍 综综述 中国优生与遗传杂 志2010,18(2):5-8 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： 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%） TURNERS SYNDROME BABYTURNERS SYNDROME BABYTURNERS SYNDROME BABYTURNERS SYNDROME BABY thorax 胸膛 metacarpal 掌骨 constriction 缢痕 aorta 大动脉 rudimentary 不发育的 gonadal streak 性索 menstruation 月经 SYMPTOMS VISUALSYMPTOMS VISUALSYMPTOMS VISUALSYMPTOMS VISUAL PHYSICAL SYMPTOMS PHYSICAL SYMPTOMS PHYSICAL SYMPTOMS PHYSICAL SYMPTOMS v Short stature (Usually no taller than 48”) v Obese weight (due to an underactive thyroid) v Drooping eyelids v Problems with breast development v Short fingers and toes v Extra skin on the neck (webbed neck) v Swelling of the hands and feet v Low set ears v Soft nails that turn upward at the ends v Irregular rotation of wrist and elbow joints v Loss of ovarian functions (infertility) v Heart defects v Kidney problems v Visual impairments v Ear infections and hearing loss v High blood pressure v Weak bones v 标标准型 45，XO 病人有女性表现现，但身材矮小、原发发 闭经闭经 、不孕、智力一般正常或稍差，常合并有颅颅面（ 蹼颈颈）、四肢（肘外翻）及心血管方面的畸形，性腺萎 缩缩，可退化成“索状性腺”，第二性征发发育不良。 v 其发发病机制为为：女性完整的有功能的两条 X 染色体是 维维持女性性腺发发育及正常卵巢功能所必须须的。 v Lyon 假说说认为认为 46，XX 中的一条 X 染色体失活 v TS 患者表型不是 X 单单体造成的（45，XO 缺失的是失 活的X），这这也是 45，XO 能存活的原因。 v 但失活的 X 染色体并非所有的基因都失活，拟拟常染色体 区（PAR pseudo autosomal region）的基因并不 失活，这这些未失活的基因在性腺发发育的调调控中可能发挥发挥 着作用。如果基因的数量有了改变变，那么基因的产产物（如 酶、肽链肽链 等）的量也随之发发生相应应改变变，即产产生基因的 剂剂量效应应，因而 X 染色体数目减少、缺失、结结构异常都 将由于基因的单单倍剂剂量而导导致女性性征的异常。 Diagnosis of TS vPrenatal diagnosis l the finding of fetal edema 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 positive rate and seems to be a poor predictor of clinical outcome vPostnatal diagnosis v 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 aorta v in midchildhood :short stature; primary or secondary amenorrhea Mosaicism I v 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 management v 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 lineage v mosaicism for a cell population with a Y chromosome : at increased risk for gonadoblastoma (risk, 7 to 30 percent) in their streak gonads v in those with masculinization or mosaicism for an unidentified marker: the use of flow cytometry or DNA hybridization to search for Y-chromosome material Mosaicism II Karyotype-phenotype relationship v 分子基础础 l X 染色体不同的位点异常可以导导致不同的体征，即表现现 为为不完全性 TS l 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) l Xq13Xq26决定 TS 的体征 l Xp11、Xq 近端和 Xq 远远端片段决定性腺发发育和功能 l Xq 末端是端粒（telomere）存在的区域:Xq 末端的 缺失与重组组与该类该类 型患者继发继发 性闭经闭经 存在密切关系，可 能是卵巢早衰的特异性基因区段。 Karyotype-phenotype relationship v 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 Loss of a region at Xp22.3 : neurocognitive problems v Loss of interstitial or terminal Xq ：short stature and primary or secondary ovarian failure. Karyotype-phenotype relationship v 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 have 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 phenotypic feature Management vgrowth vdevelopmental and behavioral concerns vcardiovascular concerns vendocrine concerns vophthalmologic and otologic concerns vgastrointestinal manifestations vrenal manifestations vmusculoskeletal characteristics vLife expectancy Growth v The mean birth length of infants with Turners syndrome falls within the low end of the normal range v A decrease in growth velocity occurs as early as 18 months of age v a significant decrease in linear growth rate by third or fourth grade v Some present only when the normal pubertal growth spurt fails to occur -easy to be overlooked v Differences in ages at the commencement of treatment and differences in the doses and duration of therapy complicate analysis v the cost of recombinant human growth hormone per centimeter of final gain in height is approximately $29,000 Growth Hormone plus Childhood Low- Dose Estrogen in Turners Syndrome Judith 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.D N Engl J Med 2011;364:1230-42 v Conclusion: 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. developmental and behavioral concerns vMost people with Turners syndrome have normal intelligence vThe 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 patients cardiovascular concerns v 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. v the most common structural alformations: Coarctation of the aorta and bicuspid aortic valve other left-sided defects. v Hypertension, mitral-valve prolapse, and conduction defects also occur v Echocardiography is a mandatory part of the diagnostic workup for Turners syndrome endocrine concerns v Hypothyroidism occurs in 15 to 30 percent of women with Turners syndrome l onset is in the third decade, though 5 to 10 percent of cases occur before adolescence l Screening of thyroid function, including measurement of thyrotropin levels, should begin at about 10 years of age in asymptomatic patients v Gonadal dysgenesis is a cardinal feature of Turners syndrome; 90 percent of patients will require hormone- replacement therapy to initiate puberty and complete growth l Measurement of follicle-stimulating hormone, luteinizing hormone, and estradiol levels can help determine the need for hormone- replacement therapy l Hormone-replacement therapy should be initiated at about the age of 14 years v 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 that are carried to term v Pregnancy, by means of gamete intrafallopian transfer with donor eggs, has been attempted in women with Turners syndrome vThe prevalence of insulin resistance and type 2 diabetes may be increased in patients with Turners syndrome vThe majority of patients with Turners syndrome and diabetes have adult-onset diabetes, and most are overweight ophthalmologic and otologic concerns v strabismus 18 percent v ptosis in 13 percent v Cataracts and nystagmus also occur more commonly v 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 v Progressive sensorineural hearing loss is a major fe