染色體異常 鄭博仁副教授

人類正常染色體組成於 1956 年正式確立 , 第一批染色體異常 (Down’s ， Tunner’s ， Klinefelter’s 症候群 ) 則定義於 1959 年。自此，由於培養與檢驗之遺傳科技日益精進，因染色體異常導致的數百種異常也逐一被發現。

人類正常染色體組成於 1956 年正式確立 , 第一批染色體異常 (Down’s ， Tunner’s ， Klinefelter’s 症候群 ) 則定義於 1959 年。自此，由於培養與檢驗之遺傳科技日益精進，因染色體異常導致的數百種異常也逐一被發現。

定義： 整倍體（ Euploid ） 染色體數目是單倍體的倍數 （ 2n ） 多倍體（ Polyploid ） 染色體數目超過二倍體（ 3n, 三倍體 ） 非整倍體（ Aneuploid ） 染色體數目非單倍數的倍數 （ 2n ＋ 1 三體症， 2n － 1 單體症 ） 嵌合體（ Mosaic ） 出現來自同一配子的二種不 同細胞來源（ 46XX/45X ， Turner’s 嵌合體） 交移體（ Chimaera ） 出現來自二個配子融合形成 的二種不同細胞來源 （ 46XX/46XY ，真性陰陽人）

整倍體（ Euploid ） 染色體數目是單倍體的倍數 （ 2n ）

多倍體（ Polyploid ） 染色體數目超過二倍體（ 3n, 三倍體 ）

非整倍體（ Aneuploid ） 染色體數目非單倍數的倍數 （ 2n ＋ 1 三體症， 2n － 1 單體症 ）

嵌合體（ Mosaic ） 出現來自同一配子的二種不 同細胞來源（ 46XX/45X ， Turner’s 嵌合體）

交移體（ Chimaera ） 出現來自二個配子融合形成 的二種不同細胞來源 （ 46XX/46XY ，真性陰陽人）

染色體報告形式 染色體總數後列出性染色體形式 46,XX ，正常女性 47,XXY ， Klinefelter’s 症男性 47,XXX ，三 X 症女性 增加或缺少的染色體以”＋”或” －”表示 47,XY, ＋ 21 ， 21 三染色體男性（ Down’s 症） 46,XX, 12 p ＋ ， 12 染色體短臂多出一段不明染 色體 嵌合體列出所有的細胞來源 46,XX/47,XX, ＋ 21 ， Down’s 嵌合體症 46,XY/47,XXX/45,X ， Turne’s/ 三 X 嵌合體症 描述構造上的異常，指出 p ， q 及異常的部位 46,XY,del 11(P13) 11 染色體短臂的 13 顯帶處缺失 46,XX,t (X;7) (P21;q23) X 與 7 染色體在 P21 及 q23 顯帶處 裂開而移位

染色體總數後列出性染色體形式 46,XX ，正常女性 47,XXY ， Klinefelter’s 症男性 47,XXX ，三 X 症女性

增加或缺少的染色體以”＋”或” －”表示 47,XY, ＋ 21 ， 21 三染色體男性（ Down’s 症） 46,XX, 12 p ＋ ， 12 染色體短臂多出一段不明染 色體

嵌合體列出所有的細胞來源 46,XX/47,XX, ＋ 21 ， Down’s 嵌合體症 46,XY/47,XXX/45,X ， Turne’s/ 三 X 嵌合體症

描述構造上的異常，指出 p ， q 及異常的部位 46,XY,del 11(P13) 11 染色體短臂的 13 顯帶處缺失 46,XX,t (X;7) (P21;q23) X 與 7 染色體在 P21 及 q23 顯帶處 裂開而移位

自然流產及死胎的染色體異常發生率 % 自然流產 所有 50 12 週以內 60 12~20 週 20 死胎 5

%

自然流產

所有 50

12 週以內 60

12~20 週 20

死胎 5

自然流產的染色體異常種類 % 三體症 52 X 單體症 18 三倍體 17 移位 2-4

%

三體症 52

X 單體症 18

三倍體 17

移位 2-4

新生兒染色體異常比例 % 所有 91 常染色體三體症 14 常染色體重組 平衡性 52 非平衡性 6 性染色體異常 19

%

所有 91

常染色體三體症 14

常染色體重組

平衡性 52

非平衡性 6

性染色體異常 19

常見的染色體異常 常染色體 21 三體症— Down’s 症 18 三體症— Edward’s 症 13 三體症— Patau’s 症 性染色體 XO —Turner’s 症 XXX — 三 X 症 XXX —Klinefelter’s 症 XYY —XYY 男性

常染色體

21 三體症— Down’s 症

18 三體症— Edward’s 症

13 三體症— Patau’s 症

性染色體

XO —Turner’s 症

XXX — 三 X 症

XXX —Klinefelter’s 症

XYY —XYY 男性

Down Syndrome (Trisomy 21) 唐氏症 ( 蒙古痴呆症 ) MCA/MR caused by an extra copy of chromosome 21 First described by Langdon Down in 1866 Discovery of +21 by Lejeune in 1959

MCA/MR caused by an extra copy of chromosome 21

First described by Langdon Down in 1866

Discovery of +21 by Lejeune in 1959

DS: Epidemiology Incidence: 1/800 to 1/1,000 live births Prevalence: 1/3,000 in general population, reflecting high infant mortality rate Advanced maternal age effect

Incidence: 1/800 to 1/1,000 live births

Prevalence: 1/3,000 in general population, reflecting high infant mortality rate

Advanced maternal age effect

DS Fetuses: Natural History Highly lethal in fetal life (65% of conceptuses aborted) Recognizable fetal phenotype: IUGR, thickened nuchal fold, septal cardiac defects, duodenal atresia, simian crease, clinodactyly, & short cord Decreased motor activity

Highly lethal in fetal life (65% of conceptuses aborted)

Recognizable fetal phenotype:

IUGR, thickened nuchal fold, septal cardiac defects, duodenal atresia, simian crease, clinodactyly, & short cord

Decreased motor activity

DS: Cardinal Signs Hypotonia Sloping forehead, brachycephaly Slanting palpebral fissures, small dysplastic ears, flattened facies Excess nuchal skin Simian crease with dysplastic middle phalanges of 5th finger Hyperextensible joints Dysplastic pelvis

Hypotonia

Sloping forehead, brachycephaly

Slanting palpebral fissures, small dysplastic ears, flattened facies

Excess nuchal skin

Simian crease with dysplastic middle phalanges of 5th finger

Hyperextensible joints

Dysplastic pelvis

DS: Infant Sloping forehead Upslanting eyes Epicanthal folds Flat nasal bridge Small nose Protruding tongue Small chin Small ears Proximated nipples

DS: Infant

Sloping forehead

Upslanting eyes

Epicanthal folds

Flat nasal bridge

Small nose

Protruding tongue

Small chin

Small ears

Proximated nipples

DS Brachycephaly Sloping forehead Woolley sign Flat nasal bridge Small nose Protruding tongue Cutis mamorata

Brachycephaly

Sloping forehead

Woolley sign

Flat nasal bridge

Small nose

Protruding tongue

Cutis mamorata

DS child Upslant eyes Brushfield spots Epicanthal folds Flat nasal bridge Small nose Open mouth Protruding tongue Small chin Small ears

DS child

Upslant eyes

Brushfield spots

Epicanthal folds

Flat nasal bridge

Small nose

Open mouth

Protruding tongue

Small chin

Small ears

DS Ear Typical DS small ear Overfolded helix

Typical DS small ear

Overfolded helix

Dermatoglyphics

DS Hand Transverse palmar crease (simian crease) Clinodactyly

Transverse palmar crease (simian crease)

Clinodactyly

DS: Adult MR Upslanting eyes Mid-facial hypoplasia Mandibular prognathism

DS: Adult

MR

Upslanting eyes

Mid-facial hypoplasia

Mandibular prognathism

DS: Major Malformations Congenital heart disease (29% of newborn; 64% of necropsies) AV canal/endocardial cushion defect (most common), VSD, ASD, TOF, PDA, others Duodenal obstruction (2-3%) Hirschprung disease Others Cub foot, cataracts, imperforate anus, cleft lip/palate

Congenital heart disease (29% of newborn; 64% of necropsies)

AV canal/endocardial cushion defect (most common), VSD, ASD, TOF, PDA, others

Duodenal obstruction (2-3%)

Hirschprung disease

Others

Cub foot, cataracts, imperforate anus, cleft lip/palate

DS: Growth & Development Developmental delay (MR) Atlantoaxial joint instability Males: Infertile due to testicular interstitial fibrosis and hypoplasia of seminiferous tubules Females: about 1/2 of offspring with Down syndrome

Developmental delay (MR)

Atlantoaxial joint instability

Males: Infertile due to testicular interstitial fibrosis and hypoplasia of seminiferous tubules

Females: about 1/2 of offspring with Down syndrome

DS: Immune System & Aging Increased incidence of hypothyroidism, thyroiditis, diabetes mellitus, and leukemia (10- to 30-folds) Depressed immune system Premature aging (Alzheimer)

Increased incidence of hypothyroidism, thyroiditis, diabetes mellitus, and leukemia (10- to 30-folds)

Depressed immune system

Premature aging (Alzheimer)

Trisomy 21 Karyotype

活產及羊膜穿刺檢查唐氏症發生率 孕婦年齡 ( 生產時 活產發生率 羊膜穿刺術發生率 或羊膜穿刺術時 ) 所有年齡 650 分之 1 30 歲 900 分之 1 35 歲 385 分之 1 256 分之 1 36 歲 305 分之 1 200 分之 1 37 歲 240 分之 1 156 分之 1 38 歲 190 分之 1 123 分之 1 39 歲 145 分之 1 96 分之 1 40 歲 110 分之 1 75 分之 1 44 歲 37 分之 1 29 分之 1

孕婦年齡 ( 生產時 活產發生率 羊膜穿刺術發生率

或羊膜穿刺術時 )

所有年齡 650 分之 1

30 歲 900 分之 1

35 歲 385 分之 1 256 分之 1

36 歲 305 分之 1 200 分之 1

37 歲 240 分之 1 156 分之 1

38 歲 190 分之 1 123 分之 1

39 歲 145 分之 1 96 分之 1

40 歲 110 分之 1 75 分之 1

44 歲 37 分之 1 29 分之 1

I(21q) Karyotype

FISH: Trisomy 21

DS: Cytogenetic Basis Full trisomy (94%) Translocation trisomy (4%) Translocation between 21 & other chromosome Mosaic trisomy (2%) Most commonly due to maternal non-disjunction (95% by molecular studies) 21q22 to qter is responsible for the phenotype

Full trisomy (94%)

Translocation trisomy (4%)

Translocation between 21 & other chromosome

Mosaic trisomy (2%)

Most commonly due to maternal non-disjunction (95% by molecular studies)

21q22 to qter is responsible for the phenotype

DS: Genetic Counseling (Recurrence Risk) Full trisomy 21 (irrespective of maternal age) - 1% Siblings, nieces, nephews, a aunts, or uncles of the proband with trisomy 21 – probably no increased risk Mother with balanced D/G translocation - 10% Father with balanced D/G translocation - 4% Mother with 21/22 carrier - 6% Father with 21/22 carrier - 3% Parent with 21/21 carrier - 100% A DS child with de novo translocation - 1%

Full trisomy 21 (irrespective of maternal age) - 1%

Siblings, nieces, nephews, a aunts, or uncles of the proband with trisomy 21 – probably no increased risk

Mother with balanced D/G translocation - 10%

Father with balanced D/G translocation - 4%

Mother with 21/22 carrier - 6%

Father with 21/22 carrier - 3%

Parent with 21/21 carrier - 100%

A DS child with de novo translocation - 1%

羊膜穿刺判讀錯誤 新光判賠七百多萬 婦人朱秀蘭高齡懷孕，到台北新光醫院作羊膜穿刺篩檢，因醫院僱用非專業的檢驗員判讀資料錯誤，致生下患有唐氏症的男孩，朱女經過八年訴訟，最近獲得確定勝訴判決，最高法院前天判決新光醫院應賠償朱女七百廿五萬餘元。

婦人朱秀蘭高齡懷孕，到台北新光醫院作羊膜穿刺篩檢，因醫院僱用非專業的檢驗員判讀資料錯誤，致生下患有唐氏症的男孩，朱女經過八年訴訟，最近獲得確定勝訴判決，最高法院前天判決新光醫院應賠償朱女七百廿五萬餘元。

Trisomy 18 (Edwards Syndrome) MCA/MR caused by an extra copy of 18 Epidemiology: 1/3,000 live births Natural history: Fetal wastage (95%) Intrauterine growth retardation Polyhydramnios Small placenta with single umbilical artery 90% die before 1 year of age Severe growth and mental retardation

MCA/MR caused by an extra copy of 18

Epidemiology: 1/3,000 live births

Natural history:

Fetal wastage (95%)

Intrauterine growth retardation

Polyhydramnios

Small placenta with single umbilical artery

90% die before 1 year of age

Severe growth and mental retardation

Trisomy 18: Cardinal Signs Hyotonia, followed by hypertonia, apnea, seizures Microcephaly, prominent occiput Hypertelorism, epicanthal folds, microphthalmia, iris coloboma, micro/retrognathia, low set/malformed ears, choanal atresia Cardiac defects (polyvalvular, VSD) Renal/GI anomalies (cystic kidneys; TE fistula) Abnormal finger grasping pattern, increased digital arches, rocker-bottom feet, short sternum

Hyotonia, followed by hypertonia, apnea, seizures

Microcephaly, prominent occiput

Hypertelorism, epicanthal folds, microphthalmia, iris coloboma, micro/retrognathia, low set/malformed ears, choanal atresia

Cardiac defects (polyvalvular, VSD)

Renal/GI anomalies (cystic kidneys; TE fistula)

Abnormal finger grasping pattern, increased digital arches, rocker-bottom feet, short sternum

Infant with trisomy 18 Microcephaly Hypertelorism Microphthalmia Micro/retrognathia Low set, malformed ears Short sternum Abnormal finger grasping pattern

Microcephaly

Hypertelorism

Microphthalmia

Micro/retrognathia

Low set, malformed ears

Short sternum

Abnormal finger grasping pattern

Trisomy 18 fetus Arthrogryposis Distinct finger grasping pattern

Arthrogryposis

Distinct finger grasping pattern

Trisomy 18 Arthrogryposis Abnormal finger grasping pattern Nail hypoplasia Increased number of digital arches

Arthrogryposis

Abnormal finger grasping pattern

Nail hypoplasia

Increased number of digital arches

Trisomy 18 Rocker-bottom feet

Rocker-bottom feet

Trisomy 13 (Patau Syndrome) Epidemiology: 1/6,000 live births Cytogenetics: Full trisomy (80%) Mosaics or translocations (20%) Natural history: 90% die before 1 year of age FTT, hypotonia, deafness, seizures Severe psychomotor retardation

Epidemiology: 1/6,000 live births

Cytogenetics:

Full trisomy (80%)

Mosaics or translocations (20%)

Natural history:

90% die before 1 year of age

FTT, hypotonia, deafness, seizures

Severe psychomotor retardation

Trisomy 13: Cardinal Signs Craniofacial: Microcephaly, trigonocephaly, glabellar hemangioma, punched-out scalp lesion Hypertelorism, anophthalmia/microphthalmia, coloboma of iris/retina, cleft lip/palate, micro/retrognathia CNS: holoprosencephaly spectrum Cardiac/renal/GI anomalies: VSD, multicystic kidneys, omphalocele Skeletal anomalies: polydactyly, talipes equinovarus

Craniofacial:

Microcephaly, trigonocephaly, glabellar hemangioma, punched-out scalp lesion

Hypertelorism, anophthalmia/microphthalmia, coloboma of iris/retina, cleft lip/palate, micro/retrognathia

CNS: holoprosencephaly spectrum

Cardiac/renal/GI anomalies:

VSD, multicystic kidneys, omphalocele

Skeletal anomalies: polydactyly, talipes equinovarus

Trisomy 13 Microcephaly Microphthalmia Cleft lip/palate Holoprosencephaly Short neck Polydactyly

Microcephaly

Microphthalmia

Cleft lip/palate

Holoprosencephaly

Short neck

Polydactyly

Trisomy 13 Infant with trisomy 13 Scalp defect Polydactyly

Infant with trisomy 13

Scalp defect

Polydactyly

Sex Chromosome Anomalies Turner syndrome Klinefelter syndrome Trisomy X syndrome XYY syndrome

Turner syndrome

Klinefelter syndrome

Trisomy X syndrome

XYY syndrome

Turner Syndrome Described by Turner in 1938 Prevalence: one in 2,500-10,000 females Phenotypic female Proportionate short stature Normal intelligence Sexual infantilism & ovarian dysgenesis

Described by Turner in 1938

Prevalence: one in 2,500-10,000 females

Phenotypic female

Proportionate short stature

Normal intelligence

Sexual infantilism & ovarian dysgenesis

Turner Syndrome: Sexual infantilism & ovarian dysgenesis The ovaries develop normally until the 15th week of gestation, but then ova begin to degenerate and disappear, so that at birth they are represented by streaks Primary amenorrhea (exception 5%) Infertility Absent secondary sex characteristics Low estrogen High gonadotropins

The ovaries develop normally until the 15th week of gestation, but then ova begin to degenerate and disappear, so that at birth they are represented by streaks

Primary amenorrhea (exception 5%)

Infertility

Absent secondary sex characteristics

Low estrogen

High gonadotropins

Turner Syndrome: Characteristic Facies Antimongoloid slant Ptosis Strabismus High-arched palate Posteriorly rotated ears

Antimongoloid slant

Ptosis

Strabismus

High-arched palate

Posteriorly rotated ears

Turner Syndrome: Lymphatic Obstruction Webbed neck Low posterior hair line Redundant skin on the nape Cystic hygroma Rotated ears Lymphedema of hands/feet Nail hypoplasia

Webbed neck

Low posterior hair line

Redundant skin on the nape

Cystic hygroma

Rotated ears

Lymphedema of hands/feet

Nail hypoplasia

Turner Syndrome Short neck Webbed neck Low posterior hair line Abnormal ears

Short neck

Webbed neck

Low posterior hair line

Abnormal ears

Turner Syndrome: Fetus Severe cystic hygroma

Severe cystic hygroma

Turner Syndrome Lymph edema Nail hypoplasia

Lymph edema

Nail hypoplasia

Turner Syndrome Nail hypoplasia

Nail hypoplasia

Turner Syndrome: Skeletal Features Short stature Short neck Cubitus valgus Short metacarpals Madelung deformity Scoliosis Genu valgum

Short stature

Short neck

Cubitus valgus

Short metacarpals

Madelung deformity

Scoliosis

Genu valgum

Growth Chart for Turner Syndrome

Turner Syndrome: Miscellaneous Defects Shield-like chest, increased inter-nipple distance (optical illusion in some cases) Multiple pigmented nevi Cardiovascular anomalies/hypertension (COA most common) Renal anomalies Horse-shoe/ectopic/absent kidney Ureteral duplications) Hearing loss

Shield-like chest, increased inter-nipple distance (optical illusion in some cases)

Multiple pigmented nevi

Cardiovascular anomalies/hypertension

(COA most common)

Renal anomalies

Horse-shoe/ectopic/absent kidney

Ureteral duplications)

Hearing loss

Turner Syndrome: Chest Shield-like chest Increased inter-nipple distance

Shield-like chest

Increased inter-nipple distance

Turner Syndrome: Associated Disorders Hashimoto thyroiditis Hypothyroidism Crohn disease Gastrointestinal bleeding (telangiectasia)

Hashimoto thyroiditis

Hypothyroidism

Crohn disease

Gastrointestinal bleeding (telangiectasia)

Turner Syndrome: Epidemiology Incidence: 1/2,500 - 1/5,000 liveborn females 45,X represents 15-20% of chromosome abnormalities seen among spontaneous abortions. The great majority (>99%) of 45,X conceptus are lost prenatally. Many chromosomal mosaicism or confined placental mosaicism do survive to term.

Incidence: 1/2,500 - 1/5,000 liveborn females

45,X represents 15-20% of chromosome abnormalities seen among spontaneous abortions.

The great majority (>99%) of 45,X conceptus are lost prenatally.

Many chromosomal mosaicism or confined placental mosaicism do survive to term.

Turner Syndrome: Karyotype (45,X)

Monosomy X: Mechanism Monosomy X arises from non-disjunction 80% of cases have only maternal X chromosome, an error occurred in spermatogenesis or post-fertilization

Monosomy X arises from non-disjunction

80% of cases have only maternal X chromosome, an error occurred in spermatogenesis or post-fertilization

Turner Syndrome: Cytogenetic Basis Karyotypes 45,X ( > 50%) Mosaics (30-40%) Iso(Xq), r(X), iso(Xp) In general, del(Xp) is associated with the Turner phenotype, whilst del(Xq) alone produce streak ovaries without the associated dysmorphic features (Turner stigmata)

Karyotypes

45,X ( > 50%)

Mosaics (30-40%)

Iso(Xq), r(X), iso(Xp)

In general, del(Xp) is associated with the Turner phenotype, whilst del(Xq) alone produce streak ovaries without the associated dysmorphic features (Turner stigmata)

Turner Syndrome: Management Psychosocial approach Webbing resection (cosmetic) Sex hormone replacement Secondary sexual characteristics Stature Growth hormone therapy Stature Genetic counseling Recurrence risk - not increased

Psychosocial approach

Webbing resection (cosmetic)

Sex hormone replacement

Secondary sexual characteristics

Stature

Growth hormone therapy

Stature

Genetic counseling

Recurrence risk - not increased

Klinefelter Syndrome: Background In 1942, Klinefelter et al. reported 9 men who had: Enlarged breasts Sparse facial and body hair Small testes Inability to produce sperm In 1959, men with Klinefelter syndrome were discovered to have 47,XXY.

In 1942, Klinefelter et al. reported 9 men who had:

Enlarged breasts

Sparse facial and body hair

Small testes

Inability to produce sperm

In 1959, men with Klinefelter syndrome were discovered to have 47,XXY.

Klinefelter Syndrome: Epidemiology Incidence Birth – 1/1,000 male births Males in institutions for the mentally retarded - 1/100 Infertile males - 1/10 Chromosome types 47,XXY (majority) 46,XY/47,XXY (15%) 48,XXXY, 48,XXYY 49,XXXXY, 49,XXXYY

Incidence

Birth – 1/1,000 male births

Males in institutions for the mentally retarded - 1/100

Infertile males - 1/10

Chromosome types

47,XXY (majority)

46,XY/47,XXY (15%)

48,XXXY, 48,XXYY

49,XXXXY, 49,XXXYY

Klinefelter Syndrome: Karyotype

Klinefelter Syndrome: Growth/Development Tall with disproportionately long arms/legs Poorly developed secondary sex characteristics Learning/speech disabilities Psychosocial/behavioral problems Subnormal intelligence

Tall with disproportionately long arms/legs

Poorly developed secondary sex characteristics

Learning/speech disabilities

Psychosocial/behavioral problems

Subnormal intelligence

Klinefelter Syndrome: A Child Slightly long arms and legs Otherwise normal phenotype

Slightly long arms and legs

Otherwise normal phenotype

Klinefelter Syndrome: Hypogonadism A common cause of primary hypogonadism in males Gynecomastia (1/3), with increased risk for breast cancer (20X) Small testes (<10 ml), sterility (most patients), secondary to atrophic seminiferous tubules

A common cause of primary hypogonadism in males

Gynecomastia (1/3), with increased risk for breast cancer (20X)

Small testes (<10 ml), sterility (most patients), secondary to atrophic seminiferous tubules

Klinefelter syndrome: Gynecomastia

Klinefelter Syndrome: External Genitalia Female type distribution of pubic hair Testicular dysgenesis

Female type distribution of pubic hair

Testicular dysgenesis

Klinefelter syndrome: Management Androgen therapy (testosterone injection) for hypogonadism Mastectomy for gynecomastia Multidisciplinary team approach Speech impairments Academic difficulties Psychosocial/behavioral problems Genetic counseling Recurrence risk - not increased

Androgen therapy (testosterone injection) for hypogonadism

Mastectomy for gynecomastia

Multidisciplinary team approach

Speech impairments

Academic difficulties

Psychosocial/behavioral problems

Genetic counseling

Recurrence risk - not increased

Trisomy X Syndrome First described by Jacobs et al. in 1959 Most frequent sex chromosome abnormality present at birth in females 47,XXX (1/1,000 female births)

First described by Jacobs et al. in 1959

Most frequent sex chromosome abnormality present at birth in females

47,XXX (1/1,000 female births)

Triple X Syndrome: Origin Most 47,XXX conceptions result from maternal nondisjunction at meiosis I (AMA). Two of the three X chromosomes are inactivated. Abnormalities may result from: Three active X chromosomes early in embryonic development (prior to X inactivation) Genes on the X chromosome that escape inactivation

Most 47,XXX conceptions result from maternal nondisjunction at meiosis I (AMA).

Two of the three X chromosomes are inactivated.

Abnormalities may result from:

Three active X chromosomes early in embryonic development (prior to X inactivation)

Genes on the X chromosome that escape inactivation

Triple X Syndrome: Phenotype Benign phenotype Physically normal Late puberty Menstrual irregularity Majority are fertile Sterility Mild mental retardation (15-25%)

Benign phenotype

Physically normal

Late puberty

Menstrual irregularity

Majority are fertile

Sterility

Mild mental retardation (15-25%)

Trisomy X: Karyotype (47,XXX)

Triple X Syndrome Slender body habitus

Slender body habitus

Triple X Syndrome: Genetic Counseling A small but slightly increase risk of XXX daughter or XXY son of an XXX mother Recurrence risk – not increased unless mother is a 47,XXX or mosaic Pertinent to offer prenatal diagnosis

A small but slightly increase risk of XXX daughter or XXY son of an XXX mother

Recurrence risk – not increased unless mother is a 47,XXX or mosaic

Pertinent to offer prenatal diagnosis

Poly X Syndromes Females with 4 or 5 X chromosomes Each additional X chromosome is accompanied by increased mental retardation & physical abnormalities 48,XXXX 49,XXXXX

Females with 4 or 5 X chromosomes

Each additional X chromosome is accompanied by increased mental retardation & physical abnormalities

48,XXXX

49,XXXXX

47,XYY Syndrome Incidence: one in 1,000 males Arise through nondisjunction at paternal meiosis II Incidence in male prison populations (1/30)

Incidence: one in 1,000 males

Arise through nondisjunction at paternal meiosis II

Incidence in male prison populations (1/30)

XYY Karyotype

47,XYY Syndrome Normal birth length and weight Tall when older Subnormal intelligence Sexual orientation: heterosexual Normal fertility Minor behavioral disorders (hyperactivity, ADD, learning disabilities) Predisposition to violent, criminal behavior (controversy!)

Normal birth length and weight

Tall when older

Subnormal intelligence

Sexual orientation: heterosexual

Normal fertility

Minor behavioral disorders (hyperactivity, ADD, learning disabilities)

Predisposition to violent, criminal behavior (controversy!)

XYY Syndrome Tall stature Otherwise normal phenotype

Tall stature

Otherwise normal phenotype

Triploidy Syndrome Triploidy is a frequent cause of fetal wastage (20%) during 1st/2nd trimester. Most die within 1st few days of life. Incidence: 1/2,500 births 69,XXY (60%) 69,XXX (37%) 69,XYY (<3%) Diploidy/triploidy mosaicism Milder phenotype

Triploidy is a frequent cause of fetal wastage (20%) during 1st/2nd trimester.

Most die within 1st few days of life.

Incidence: 1/2,500 births

69,XXY (60%)

69,XXX (37%)

69,XYY (<3%)

Diploidy/triploidy mosaicism

Milder phenotype

Triploidy “ Cracked egg-shell” skull Distinctive facies (beaked nose, small chin, low-set/malformed ears) Woolly hair

“ Cracked egg-shell” skull

Distinctive facies (beaked nose, small chin, low-set/malformed ears)

Woolly hair

Triploidy Syndactyly of fingers (3-4) Syndactyly of toes (3-4)

Syndactyly of fingers (3-4)

Syndactyly of toes (3-4)

Objectives: Students are required to study and understand Classic deletion syndromes (Cri-du-chat, Wolf-Hirschhorn) Microdeletion syndromes (Williams, Miller-Dieker)

Classic deletion syndromes (Cri-du-chat, Wolf-Hirschhorn)

Microdeletion syndromes (Williams, Miller-Dieker)

Classic Deletion Syndromes Del(4p) syndrome Del(5p) syndrome

Del(4p) syndrome

Del(5p) syndrome

Del(4p) (Wolf-Hirschhorn Syndrome) Deletion of 4p De novo (90%) Parental translocation or mosaicism (10%) IUGR, microcephaly, microphthamia, scalp defects Characteristic “Greek warrior helmet” facies, short philtrum Cardiac/genitourinary/skeletal anomalies Severe psychomotor retardation

Deletion of 4p

De novo (90%)

Parental translocation or mosaicism (10%)

IUGR, microcephaly, microphthamia, scalp defects

Characteristic “Greek warrior helmet” facies, short philtrum

Cardiac/genitourinary/skeletal anomalies

Severe psychomotor retardation

WHS Karyotype Del(4p)

Del(4p)

WHS-FISH Deletion of a WH probe signal

Deletion of a WH probe signal

WHS Face Microcephaly MR Characteristic facies “ Greek warrior helmet” Short philtrum

Microcephaly

MR

Characteristic facies

“ Greek warrior helmet”

Short philtrum

Del(5p) (Cri Du Chat Syndrome) Incidence: 1/50,000 live births A distinct, shrill, cat-like cry (secondary to hypoplastic larynx) Mental retardation, hypotonia, microcephaly Round face, hypertelorism, epicanthal folds, downward slanting of palpebral fissures Other defects: CHD, simian crease Most cases (de novo) 5-10% (parental translocation)

Incidence: 1/50,000 live births

A distinct, shrill, cat-like cry (secondary to hypoplastic larynx)

Mental retardation, hypotonia, microcephaly

Round face, hypertelorism, epicanthal folds, downward slanting of palpebral fissures

Other defects: CHD, simian crease

Most cases (de novo)

5-10% (parental translocation)

CCS Karyotype Del(5p)

Del(5p)

CCS Face/Cry A round face Hypertelorism Epicanthal folds Cat-like cry

A round face

Hypertelorism

Epicanthal folds

Cat-like cry

Microdeletion Syndromes Williams syndrome Miller-Dieker syndrome

Williams syndrome

Miller-Dieker syndrome

Williams Syndrome Elfin facies Full cheeks/lips, long/smooth philtrum, broad forehead DD, MR Overly friendly personality Supravalvular aortic stenosis Hypercalcemia/hypercalcinuria Musculoskeletal abnormalities Del(7)(q11.2)

Elfin facies

Full cheeks/lips, long/smooth philtrum, broad forehead

DD, MR

Overly friendly personality

Supravalvular aortic stenosis

Hypercalcemia/hypercalcinuria

Musculoskeletal abnormalities

Del(7)(q11.2)

Miller-Dieker Syndrome Lissencephaly (smooth brain) Agyria Pachygyria Profound MR Dysmorphic features Del(17)(p13.1-13.3)

Lissencephaly (smooth brain)

Agyria

Pachygyria

Profound MR

Dysmorphic features

Del(17)(p13.1-13.3)

Microcephaly, bitemporal depression, long philtrum, thin upper lip, mild micrognathia, ear dysplasia, anteverted nares Miller-Dieker Syndrome

Miller-Dieker Syndrome