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1、Trisomy 21 Downs syndromenMost common Most common trisomy 1:800 trisomy 1:800 in new bornin new bornnMost common Most common sever mental sever mental retardationretardationnEyes with brushfield Eyes with brushfield spot spot nFlat nosal bridgeFlat nosal bridgenLow set earLow set earnOpen mouth with
2、 Open mouth with protruding tongueprotruding tonguenShort and broad hand Short and broad hand with a single with a single transverse palmar transverse palmar creasecreaseTrisomy 21 Downs syndrome20-291;150030-341:100035-401:10040-451:40Age of WomenBirth RateRelated with advanced maternal ageRelated
3、with advanced maternal ageTrisomy 21 Downs syndromeTrisomy 18 Edwards syndromen1:7500 in liveborn 1:7500 in liveborn and more common in and more common in abortion and abortion and stillbirthstillbirthnSever mental Sever mental retardation and retardation and multiple multiple structural structural
4、anomaliesanomalies18-green, X-aquaTrisomy 18 Edwards syndrome47, XY, +18Trisomy 13Pataus syndromen1:20,000 in 1:20,000 in liveborn and more liveborn and more common in abortion common in abortion and stillbirthand stillbirthnSever structural Sever structural anomalies lead to anomalies lead to death
5、 in one monthdeath in one monthTrisomy 13Pataus syndrome13-green, 21-orange47, XY, +13XXY, Klinefelters syndromen1:1,000 in 1:1,000 in male livebornmale livebornnHypogonadism Hypogonadism and and Infertility:Infertility:1.1.Tall statureTall stature2.2.Long limbsLong limbs3.3.Small Small genitaliagen
6、italia4.4.GynecomastiaGynecomastiaXXY, Klinefelters syndromeX-green, Y-red47, XXY47, XYY syndromen1:1,000 in male live birth1:1,000 in male live birthnNormal intelligence and normal Normal intelligence and normal appearance but:appearance but:1.1.Educational problem: language delays Educational prob
7、lem: language delays and spelling difficultiesand spelling difficulties2.2.Behavioral problems: attention deficits, Behavioral problems: attention deficits, hyperactivity and impulsivenesshyperactivity and impulsiveness3.3.Fertility problem: increase risk of Fertility problem: increase risk of chrom
8、osomal abnormal childchromosomal abnormal child47, XYY syndrome47, XYY47, XXX syndromen1:1,000 in Female live birth1:1,000 in Female live birthnNormal intelligence and normal Normal intelligence and normal appearanceappearancenA significant deficit in A significant deficit in performance on IQ tests
9、performance on IQ testsn70 % with some learning problems70 % with some learning problemsnInfertility: 50%Infertility: 50%47, XXX syndrome47, XXXXXXXX SyndromeWhy? Autosome: only Autosome: only trisomy 21, 18 trisomy 21, 18 and 13 found in and 13 found in live-birth, no live-birth, no monsomymonsomyS
10、ex chromosome in Sex chromosome in livebirth: XO, livebirth: XO, XXX, XXY, XYY, XXX, XXY, XYY, XXXX, XXXXXXXXX, XXXXX50, XXXXXX chromosome inactivation and XISTnGene dosage compensation is achieved in all Gene dosage compensation is achieved in all persons with two or more X chromosomes in persons w
11、ith two or more X chromosomes in their genetic constitution by partial their genetic constitution by partial inactivation of all X chromosomes except inactivation of all X chromosomes except one. one. nThe process is controlled by XIST (X The process is controlled by XIST (X inactive specific transc
12、ripts) gene in inactive specific transcripts) gene in Xq13.2, which encodes a large RNA that Xq13.2, which encodes a large RNA that appears to coat the X chromosome and appears to coat the X chromosome and facilitate inactivation of genes on the X facilitate inactivation of genes on the X chromosome
13、.chromosome.nDuring the late blastocyst stage, all X During the late blastocyst stage, all X chromosomes except one undergo chromosomes except one undergo heterochromatinization and form X chromatin heterochromatinization and form X chromatin bodies in each cell.bodies in each cell.nThe balance of g
14、ene dosage on X chromosome is The balance of gene dosage on X chromosome is achieved. achieved. The explanation of The explanation of various kinds of X polysomies in live-birth. various kinds of X polysomies in live-birth. Barr body(3) Mosaic and chimeraMosaicChimeraAberrationAberrationMosaic and c
15、himera45,X/47,XXXnResulted from chromosome breakage and Resulted from chromosome breakage and reunion.reunion.nBalanced structural abnormality Balanced structural abnormality With normal complement of With normal complement of chromosomal materialchromosomal materialnUnbalanced structural abnormalit
16、yUnbalanced structural abnormality With loss or gain of chromosomal With loss or gain of chromosomal materialmaterial(2). Abnormalities of chromosome structurea. Unbalanced structure abnormalitynDeletion: Loss of a chromosome Loss of a chromosome segment segment Resulted from breakage Resulted from
17、breakage or unequal cross-over or unequal cross-over or segregation of or segregation of balanced abnormalitybalanced abnormalityCri Du Chat (5p-) syndrome nDeletion: 5p15Deletion: 5p15nCrying sounds like a Crying sounds like a newing catnewing catnTypical features: Typical features: hypertelorism,
18、hypertelorism, epicanthus and epicanthus and retrognathiaretrognathiaCri Du Chat (5p-) syndrome 5-p-telomere -green 46,XY,5p-; 46, XY, del(5p15:)46, XY, del(5)(p15:)46, XY, del(5)(qter-cen-p15:)4p- syndrome46, XX, del(4)(p16:)Deletion of 22q-, Mosaic 46, XY (40) / 46, XY, del(22)(q13:) (10) Duplicat
19、ionnGain of a extract Gain of a extract chromosome segment in the chromosome segment in the same chromosomesame chromosomenResulted from unequal Resulted from unequal cross-over or segregation cross-over or segregation of balanced abnormalityof balanced abnormality18q2318 Dup (18)46,XY,dup (18)(q23)
20、 46, XY, dup(18)(pter -cen-q23:q23:qter)46,X, dup(X)(q13q26)46, X, dup(X)(pter-q26:q13q26:q26-qter)InsertionnGain of a extract chromosome segment from Gain of a extract chromosome segment from the different chromosomethe different chromosomenResulted from segregation of balanced Resulted from segreg
21、ation of balanced abnormalityabnormalityFather46, XY, t(3;11)(q27;q13), ins(11;3)(q13;p26p13)Son46, XY, der(11) ins(11;3)(q13;p26p13)Isochromosomes One arm is deleted One arm is deleted and the other and the other duplicatedduplicated One arm is monosomy One arm is monosomy and other is trisomyand o
22、ther is trisomy The most common The most common isochromosome is isochromosome is i(Xq)i(Xq)46, X, i(Xq)Ring chromosomesFormed when a chromosome undergoes two Formed when a chromosome undergoes two breaks and broken ends of the chromosome breaks and broken ends of the chromosome reunite in a ring st
23、ructurereunite in a ring structure46, X, r(X)Ring chromosome, unstableSummary of chromosome number abnormalitynDeletionDeletionnDuplicationDuplicationnInsertionInsertionnRing chromosomeRing chromosomenIsochromosomeIsochromosomenWith normal complement of chromosomal With normal complement of chromoso
24、mal materialmaterialnUsually have no phenotypic effectsUsually have no phenotypic effectsnRepeated abortion, intrauterus fetal Repeated abortion, intrauterus fetal death, stillbirth and birth defects death, stillbirth and birth defects due to the abnormal segregation of due to the abnormal segregati
25、on of involved chromosomes in meiosisinvolved chromosomes in meiosisb. Balanced structure abnormality (a) InversionsnA single chromosome undergoes two A single chromosome undergoes two breaks and is reconstituted with the breaks and is reconstituted with the segment between the breaks inverted.segme
26、nt between the breaks inverted.Inversion of Chromosome 146, XX, inv(1) 46, XY, inv(1)46, XX, inv(1)(q24q32)nPericentric: involving centromerePericentric: involving centromerenParacentric: not involving centromereParacentric: not involving centromerenUsually no abnormal phenotype Usually no abnormal
27、phenotype nA inversion loop is formed between the A inversion loop is formed between the pair of chromosomes and may lead to pair of chromosomes and may lead to produce unbalanced gametes or produce unbalanced gametes or offspring:offspring:InversionsPericentric inversionThe products of meiosis1/4：N
28、ormal1/4：Inversion1/2：Partial trisomy and partial monosomyA inversion loopParacentric inversionThe products of meiosis1/4：Normal1/4： Bicentric ch.1/4： Acentris frag.1/4：InversionA inversion loopnReciprocal Resulted Resulted from from breakage breakage of of nonhomologous nonhomologous chromosomes, c
29、hromosomes, with with reciprocal reciprocal exchange exchange of of the the broke-off broke-off segmentssegmentsTranslocationReciprocal Translocation (9;22)t(9;22)(q34;q12)t(9;22)(9pter-cen-9q34:22q21-22qter; 22pter-cen-22q21:9q34-9qter)Reciprocal translocation in meiosis2:2 separationHigh Risk to p
30、roduce High Risk to produce unbalanced offspringunbalanced offspring2:2Abortion, Fetal death, Birth defects 1/18 Normal, 1/18 carrier，8/9 various kinds of unbalancedPossible offsprings of Reciprocal translocation Abortion, Fetal death, Birth defects Mother: 46, XX, t(11;22)(q24;q12)Normal phenotypeS
31、on: 47, XX, +der(22) t(11;22)(q24;q12)matMental retardation Multiple structural abnormalitiesUnbalanced derivated from reciprocal translocation of the parents45,XY,-22,der(6)t(6;22)(p25.3;q11.2)45,XY,-22,der(6)t(6;22)(6qter-cen-6p25.3:22q11.2-22qter)Robertsonian TranslocationnTwo acrocentric Two acr
32、ocentric chromosomes fuse near chromosomes fuse near the centromere region the centromere region with loss of the with loss of the short arms, which short arms, which carry multiple copies carry multiple copies of genes for rRNA.of genes for rRNA.n Only 45 chromosomes with balanced Only 45 chromosom
33、es with balanced karyotype and phenotypekaryotype and phenotype 45, XX, rob t ( 13q14q)t(14q21q) 14 21Offspring of Rob. translocation Normal, Carrier, Tri 14, Mono14, Tri 21, Mono 21 Fertilized by normal gameteGametesZygotesMeoisisnLimitation of resolution of Limitation of resolution of microscopy:
34、microscopy: 4 Mb DNA 4 Mb DNAnDuplication or deletion 4 Mb DNA:Duplication or deletion 4 Mb DNA: Microdeletion Microdeletion Microduplication Microduplication nDiagnosis with Fluorescent in-situ Diagnosis with Fluorescent in-situ hybridization (FISH) with specific hybridization (FISH) with specific
35、DNA probe or cDNA probe or comparative genomic omparative genomic hybridization (CGH)hybridization (CGH)(3) Chromosomal micro-abnormality Parader-Willi Syndromes(PWS)nExcessive eating and Excessive eating and ObesityObesitynSmall hands, feet Small hands, feet and short statureand short staturenHypog
36、onadismHypogonadismnMental retardationMental retardationAngelman Syndromes(AS)nUnusual facial Unusual facial appearance,appearance,nShort statureShort staturenSpasticity,SeizureSpasticity,SeizurenS mental S mental retardationretardationPWSAS46, XX or XY, del(15)(q11-q13)70% paternal70% maternalSimil
37、ar deletion, Different origin, Similar deletion, Different origin, Associated with gene imprintingAssociated with gene imprintingDiGeorge (velo-cardio-facial, 22q11.2 deletion) syndromeCongenital heart disease (particularly Congenital heart disease (particularly conotruncal malformations) conotrunca
38、l malformations) Palatal abnormalities especially Palatal abnormalities especially velopharyngeal insufficiency (VPI) velopharyngeal insufficiency (VPI) Hypocalcemia Hypocalcemia Immune deficiency Immune deficiency Learning difficultiesLearning difficulties46, XX, del( 22q11.2)Williams syndromenChar
39、acteristic dysmorphic facies, Characteristic dysmorphic facies, frequently referred to as elfin frequently referred to as elfin facies (100%)facies (100%)nSupravalvular aortic stenosis Supravalvular aortic stenosis (80%)(80%)nVariable mental retardation (75%)Variable mental retardation (75%)nCharact
40、eristic Characteristic cognitive/behavioral profile cognitive/behavioral profile (90%)(90%)Williams syndromeDeletion of 7q11.23 or elastin gene 46, XY, del(7q11.23)Steroid Sulfatase Deficiency and X-Linked IchthyosisDeletion of Xp22.3 STS46, X, del(Xp22.3)nX-linked ichthyosis showing X-linked ichthy
41、osis showing thick, large, polygonal, thick, large, polygonal, dark-brown scales involving dark-brown scales involving the extensor.the extensor.nSteroid sulfatase Steroid sulfatase deficiency during pregnancy deficiency during pregnancy in carrier females: Leads in carrier females: Leads to an over
42、all decrease in to an overall decrease in the levels of estrogenthe levels of estrogenSteroid Sulfatase Deficiency and X-Linked IchthyosisKallmanns syndromeDeletion of Xp22.3 KALnCongenital reduced pituitary Congenital reduced pituitary gonadotropic activity with resulting gonadotropic activity with
43、 resulting association of hypogonadism, association of hypogonadism, eunuchoidism and anosmia.eunuchoidism and anosmia.46, Y, del(Xp22.3) Summary of Chromosome disorders Duplication or deletion of the certain Duplication or deletion of the certain chromosomes or the certain chromosomal chromosomes o
44、r the certain chromosomal segmentssegments Number or structure abnormality Number or structure abnormality 0.6 % in live birth and 50% in 0.6 % in live birth and 50% in spontaneous abortions in first-trimester spontaneous abortions in first-trimester in microscopic observation in microscopic observa
45、tion Summary of Chromosome disordersnInvolving the changes of a groups Involving the changes of a groups of genes: complicated symptom of genes: complicated symptom nSyndrome: Featured by serious Syndrome: Featured by serious mental retardation, structural mental retardation, structural abnormality
46、of face, body and abnormality of face, body and multiple organsmultiple organsHermaphroditismSex Differentiation nGenes, Chromosome nOvary and TesitisnHormone: female hormones, Male hormonesnMallerian duct: uterus, fallopian tubenWolffian duct: epididymis. glandula seminalis nExterior genitalianSoci
47、al, BrainSex Differentiation nTwo intact and normally functioning X chromosomes, in the absence of a Y chromosome lead to the formation of an ovarynFemale sex differentiation will occur in the presence of an ovary or streak gonads or if no gonad is present n8w: exterior genitalia in all fetus remain
48、s like femalesFemale sex differentiationnA Y chromosome or the presence of the testis-testis-determining factordetermining factor (SRY) will lead to testicular organogenesisnDifferentiation of the external genitalia along male lines depends on the action of testosterone and particularly dihydrotesto
49、steroneMale sex differentiationSRY F m m 1. True Hermaphroditism nBoth ovarian and testicular tissue are present in one (ovotestis) or both gonads. nDifferentiation of the internal and external genitalia is highly variable, and most often they are ambiguous. nA testis and ovary or ovotestis is locat
50、ed A testis and ovary or ovotestis is located in the the labioscrotal folds, inguinal in the the labioscrotal folds, inguinal canal or the abdomen in the remainder. canal or the abdomen in the remainder. nA uterus is usually present, hypoplastic A uterus is usually present, hypoplastic or unicornuat
51、e. or unicornuate. nThe ovotestis is the most common gonad The ovotestis is the most common gonad found in true hermaphrodites (60%), found in true hermaphrodites (60%), followed by the ovary and, least commonly, followed by the ovary and, least commonly, 1.1 Phenotype: True hermaphrodites n20%: 46,
52、 XX/46, XY 20%: 46, XX/46, XY n20%: 46, XY : 20%: 46, XY : Y-to-X and Y-to-autosome translocations, hidden sex chromosome mosaicism, or chimerism can explain the pathogenesis in these patients. n60%: 46, XX60%: 46, XX1.2 Karyotype: True hermaphrodites Diagnosis depending on pathology !2. Female Pseu
53、dohermaphroditism nAffected individuals have normal ovaries and mllerian derivatives associated with ambiguous external genitalia. nIn the absence of testes, a female fetus will be masculinized if subjected to increased circulating levels of androgens derived from a fetal or maternal source. nThe de
54、gree of masculinization depends upon the stage of differentiation at the time of exposure 2.1 Congenital Adrenal Hyperplasia nMost cases of female pseudohermaphroditism and around 50% of all cases of ambiguous genitalianDefect in the synthesis of cortisol that results in an increase in ACTH and cons
55、equently in adrenal hyperplasia nFive major types: AR single gene disorder. 2.2Maternal androgens & progestogens nMasculinization of the external genitalia of a female infant can occur if the mother is given testosterone, other androgenic steroids, or certain synthetic progestational agents during p
56、regnancy. 3. Male PseudohermaphroditismnGonads are testes, but the genital ducts or Gonads are testes, but the genital ducts or external genitalia, or both, are not completely external genitalia, or both, are not completely masculinized.masculinized. (1) Testicular dysgenesis (2) Impaired secretion
57、of testosterone or antimllerian hormone(3) Failure of target tissue response to testosterone and dihydrotestosterone or antimllerian hormone (4)Failure of conversion of testosterone to dihydrotestosterone. .Testicular feminization syndrome Syndrome of complete androgen resistanceSyndrome of complete
58、 androgen resistancenFemale secondary sexual characteristics, Female secondary sexual characteristics, but menarche does not ensue. but menarche does not ensue. nBilateral testes, absent or hypoplastic Bilateral testes, absent or hypoplastic wolffian ducts, female-appearing external wolffian ducts,
59、female-appearing external genitalia with a hypoplastic clitoris and genitalia with a hypoplastic clitoris and labia minora, a blind vaginal pouch, and labia minora, a blind vaginal pouch, and absent or rudimentary mabsent or rudimentary mllerian llerian derivativesderivativesn 46,XY karyotype 46,XY
60、karyotypeMarDaughter?MotherFatherGrandfatherUncleAuntMale controlFemale secondary sexual characteristics, 46,XYTesticular feminization syndromeAndrogen receptor gene mutation4. Gonadal Neoplasms in Hermaphroditism n45,X/46,XY, structurally abnormal Y 45,X/46,XY, structurally abnormal Y chromosome,ch
61、romosome, XY gonadal dysgenesis, especially with XY gonadal dysgenesis, especially with testes located in outside of clitoris.testes located in outside of clitoris.nGonadoblastomas, germinomas, seminomas, and Gonadoblastomas, germinomas, seminomas, and teratomas are found most frequently. teratomas are found most frequently. Surgery: remove the testes or ovotestes. Homework Figure out the all possible offsprings from the couple which female with balanced reciprocal translocation of t(1p21;6q21) and male with normal male karyotype after reading some references.
