??????????1956?????, ????????(Down

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?????

• ??????

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• ??????????1956?????,
  ????????(Downs,Tunners,Klinefelters???)????1959
  ????,????????????????,?????????????????????

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??

• ???(Euploid) ????????????
  (2n)
• ???(Polyploid) ??????????(3n,
  ???)
• ????(Aneuploid) ????????????
  (2n1???,2n-1???)
• ???(Mosaic) ????????????
  ?????(46XX/45X,
  
  Turners???)
• ???(Chimaera) ????????????
  ?????????
  
  (46XX/46XY,?????)

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???????

• ??????????????46,XX ,????47,XXY
  ,Klinefelters???47,XXX ,?X???
• ??????????? -?? 47,XY, 21
  ,21??????(Downs?) 46,XX, 12 p
  ,12????????????
  ??
• ????????????46,XX/47,XX, 21
  ,Downs????46,XY/47,XXX/45,X ,Turnes/?X????
• ????????,??p,q??????46,XY,del 11(P13)
  11??????13?????46,XX,t (X7) (P21q23)
  X?7????P21?q23???
  ?????

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????????????????

• 
  
• ????
• ??
  50
• 12???
  60
• 1220?
  20
• ??
  5

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????????????

• 
  
• ???
  52
• X ???
  18
• ???
  17
• ??
  2-4

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??????????

• 
  
• ??
  91
• ??????? 14
• ??????
• ???
  52
• ????
  6
• ?????? 19

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????????

• ????
• 21???Downs?
• 18???Edwards?
• 13???Pataus?
• ????
• XO Turners?
• XXX ?X?
• XXX Klinefelters?
• XYY XYY??

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Down Syndrome (Trisomy 21)???(?????)

• MCA/MR caused by an extra copy of chromosome 21
• First described by Langdon Down in 1866
• Discovery of 21 by Lejeune in 1959

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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

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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

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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

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

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DS

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

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

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DS Ear

• Typical DS small ear
• Overfolded helix

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Dermatoglyphics
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DS Hand

• Transverse palmar crease (simian crease)
• Clinodactyly

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

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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

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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

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DS Immune System Aging

• Increased incidence of hypothyroidism,
  thyroiditis, diabetes mellitus, and leukemia (10-
  to 30-folds)
• Depressed immune system
• Premature aging (Alzheimer)

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Trisomy 21 Karyotype
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???????????????

• ????(??? ????? ????????
• ???????)
• ???? 650??1
• 30? 900??1
• 35? 385??1
  256??1
• 36? 305??1
  200??1
• 37? 240??1
  156??1
• 38? 190??1
  123??1
• 39? 145??1
  96??1
• 40? 110??1
  75??1
• 44? 37??1
  29??1

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I(21q) Karyotype
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FISH Trisomy 21
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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

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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

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???????? ????????

• ?????????,??????????????,??????????????????,??????
  ?????,????????,??????????,????????????????????????
  ?

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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

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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

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Infant with trisomy 18

• Microcephaly
• Hypertelorism
• Microphthalmia
• Micro/retrognathia
• Low set, malformed ears
• Short sternum
• Abnormal finger grasping pattern

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Trisomy 18 fetus

• Arthrogryposis
• Distinct finger grasping pattern

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Trisomy 18

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

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Trisomy 18

• Rocker-bottom feet

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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

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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

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Trisomy 13

• Microcephaly
• Microphthalmia
• Cleft lip/palate
• Holoprosencephaly
• Short neck
• Polydactyly

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Trisomy 13

• Infant with trisomy 13
• Scalp defect
• Polydactyly

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Sex Chromosome Anomalies

• Turner syndrome
• Klinefelter syndrome
• Trisomy X syndrome
• XYY syndrome

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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

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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

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Turner Syndrome Characteristic Facies

• Antimongoloid slant
• Ptosis
• Strabismus
• High-arched palate
• Posteriorly rotated ears

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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

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Turner Syndrome

• Short neck
• Webbed neck
• Low posterior hair line
• Abnormal ears

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Turner Syndrome Fetus

• Severe cystic hygroma

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Turner Syndrome

• Lymph edema
• Nail hypoplasia

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Turner Syndrome

• Nail hypoplasia

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Turner Syndrome Skeletal Features

• Short stature
• Short neck
• Cubitus valgus
• Short metacarpals
• Madelung deformity
• Scoliosis
• Genu valgum

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Growth Chart for Turner Syndrome
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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

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Turner Syndrome Chest

• Shield-like chest
• Increased inter-nipple distance

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Turner Syndrome Associated Disorders

• Hashimoto thyroiditis
• Hypothyroidism
• Crohn disease
• Gastrointestinal bleeding (telangiectasia)

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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 (gt99) of 45,X conceptus are
  lost prenatally.
• Many chromosomal mosaicism or confined placental
  mosaicism do survive to term.

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Turner Syndrome Karyotype (45,X)
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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

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Turner Syndrome Cytogenetic Basis

• Karyotypes
• 45,X (gt50)
• 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)

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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

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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.

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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

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Klinefelter Syndrome Karyotype
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Klinefelter Syndrome Growth/Development

• Tall with disproportionately long arms/legs
• Poorly developed secondary sex characteristics
• Learning/speech disabilities
• Psychosocial/behavioral problems
• Subnormal intelligence

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Klinefelter Syndrome A Child

• Slightly long arms and legs
• Otherwise normal phenotype

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Klinefelter Syndrome Hypogonadism

• A common cause of primary hypogonadism in males
• Gynecomastia (1/3), with increased risk for
  breast cancer (20X)
• Small testes (lt10 ml), sterility (most patients),
  secondary to atrophic seminiferous tubules

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Klinefelter syndrome Gynecomastia
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Klinefelter Syndrome External Genitalia

• Female type distribution of pubic hair
• Testicular dysgenesis

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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

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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)

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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

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Triple X Syndrome Phenotype

• Benign phenotype
• Physically normal
• Late puberty
• Menstrual irregularity
• Majority are fertile
• Sterility
• Mild mental retardation (15-25)

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Trisomy X Karyotype (47,XXX)
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Triple X Syndrome

• Slender body habitus

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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

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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

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47,XYY Syndrome

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

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XYY Karyotype
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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!)

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XYY Syndrome

• Tall stature
• Otherwise normal phenotype

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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 (lt3)
• Diploidy/triploidy mosaicism
• Milder phenotype

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Triploidy

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

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Triploidy

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

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Objectives Students are required to study and
understand

• Classic deletion syndromes (Cri-du-chat,
  Wolf-Hirschhorn)
• Microdeletion syndromes (Williams, Miller-Dieker)

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Classic Deletion Syndromes

• Del(4p) syndrome
• Del(5p) syndrome

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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

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WHS Karyotype

• Del(4p)

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WHS-FISH

• Deletion of a WH probe signal

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WHS Face

• Microcephaly
• MR
• Characteristic facies
• Greek warrior helmet
• Short philtrum

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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)

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CCS Karyotype

• Del(5p)

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CCS Face/Cry

• A round face
• Hypertelorism
• Epicanthal folds
• Cat-like cry

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Microdeletion Syndromes

• Williams syndrome
• Miller-Dieker syndrome

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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)

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Miller-Dieker Syndrome

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

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