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1、Tuner Syndrome,北京世纪坛医院检验科细胞分子遗传组 肖文珺,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,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(La
2、wsonWilkins 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,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。,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
3、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。,性染色体异常的DSD A: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2010,18(2):5-8,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
4、%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%）,Turners sy
5、ndrome 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 Visual,Physical Symptoms,Short stature(Usually no taller than 48”)Obese weight(due to an underactive thyroid)Drooping eyelidsProblems with breast development Short fingers and toesExtra s
6、kin on the neck(webbed neck)Swelling of the hands and feetLow set ears Soft nails that turn upward at the ends Irregular rotation of wrist and elbow jointsLoss of ovarian functions(infertility)Heart defectsKidney problemsVisual impairmentsEar infections and hearing lossHigh blood pressureWeak bones,
7、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。,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
8、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。,Diagnosis of TS,Prenatal diagnosisthe finding of fetal edema on ultrasonography;abnormal levels of screening of maternal serum(triple screening)abnormal results of fetal karyotyping performed becaus
9、e of advanced maternal ageavailable 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 outcomePostnatal diagnosisnewborns:puffy hands and feet or redundant nuchal skin;should b
10、e suspected in any newborn girl with edema or hypoplastic left heart or coarctation of the aortain midchildhood:short stature;primary or secondary amenorrhea,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
11、 cell population is about 15 percent)the detection of a normal cell lineage in fewer than 5 percent of cells does not change the prognosis or the managementif the diagnosis of Turners syndrome is suspected clinically but the result of routine testing is normal,increasing the number of cells counted
12、to 100 and performing a skin biopsy for karyotyping of fibroblasts are indicated to rule out mosaicism or an abnormal cell lineage,mosaicism for a cell population with a Y chromosome:at increased risk for gonadoblastoma(risk,7 to 30 percent)in their streak gonadsin those with masculinization or mosa
13、icism for an unidentified marker:the use of flow cytometry or DNA hybridization to search for Y-chromosome material,Mosaicism II,Karyotype-phenotype relationship,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（short stature homeobox）基因(位于Xp及Y)Xq13Xq26决定 TS 的体征Xp11、Xq
14、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。,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 Xp
15、22.3:neurocognitive problemsLoss of interstitial or terminal Xq：short stature and primary or secondary ovarian failure.,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 a
16、nd 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,Management,growt
17、hdevelopmental and behavioral concernscardiovascular concernsendocrine concernsophthalmologic and otologic concernsgastrointestinal manifestationsrenal manifestationsmusculoskeletal characteristicsLife expectancy,Growth,The mean birth length of infants with Turners syndrome falls within the low end
18、of the normal rangeA decrease in growth velocity occurs as early as 18 months of agea significant decrease in linear growth rate by third or fourth gradeSome present only when the normal pubertal growth spurt fails to occur-easy to be overlookedDifferences in ages at the commencement of treatment an
19、d differences in the doses and duration of therapy complicate analysisthe 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 SyndromeJudith L.Ross,M.D.,Charmian A.Quigley,M.B.,B.S.,Dachuan
20、g 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;364:1230-42Conclusion:growth hormone treatment increases adult height in patients with Turners syndrome.In addition,the data suggest that combining childhood ultra-low-dose estrogen
21、with growth hormone may improve growth and provide other potential benefits associated with early initiation of estrogen replacement.,developmental and behavioral concerns,Most people with Turners syndrome have normal intelligenceThe risk of mental retardation is highest among patients with a marker
22、 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,cardiovascular concerns,The prevalence of congenital heart disease among patients with Turners syndrome ranges from 17
23、 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 other left-sided defects.Hypertension,mitral-valve prolapse,and conduction defects also occurEchocardi
24、ography is a mandatory part of the diagnostic workup for Turners syndrome,endocrine concerns,Hypothyroidism occurs in 15 to 30 percent of women with Turners syndromeonset is in the third decade,though 5 to 10 percent of cases occur before adolescenceScreening of thyroid function,including measuremen
25、t of thyrotropin levels,should begin at about 10 years of age in asymptomatic patientsGonadal dysgenesis is a cardinal feature of Turners syndrome;90 percent of patients will require hormone-replacement therapy to initiate puberty and complete growthMeasurement of follicle-stimulating hormone,lutein
26、izing hormone,and estradiol levels can help determine the need for hormone-replacement therapyHormone-replacement therapy should be initiated at about the age of 14 years,Spontaneous fertility is rare among patients with Turners syndrome and is most likely in women with mosaicism for a normal 46,XX
27、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 termPregnancy,by means of gamete intrafallopian transfer with donor eggs,has been attempted in women with Turners syn
28、drome,The prevalence of insulin resistance and type 2 diabetes may be increased in patients with Turners syndromeThe majority of patients with Turners syndrome and diabetes have adult-onset diabetes,and most are overweight,ophthalmologic and otologic concerns,strabismus 18 percentptosis in 13 percen
29、tCataracts and nystagmus also occur more commonlyrecurrent otitis media might be a major problem in early childhood but The frequency of ear infections decreases with age and growth of facial structuresProgressive sensorineural hearing loss is a major feature of Turners syndrome in adults but the bi
30、ologic basis is not known,gastrointestinal manifestationsMore common are instances of inflammatory bowel diseaseMore than half of patients with Turners syndrome and inflammatory bowel disease who have been described in the literature have had an i(Xq)cell lineagerenal manifestationsStructural renal
31、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 dysfunctionScreening renal ultrasonography is necessary for all patients with Turners syndrome,mu
32、sculoskeletal characteristicscharacterized by skeletal dysplasia,with short stature,mild epiphyseal dysplasia,and typical bony alterationsNeoplasiano increase in the relative risk of cancerprophylactic gonadectomy is indicated if a Y chromosome is presentlife expectancyhave a decreased life expectancy,primarily as a result of complications of heart disease and diabetes,
