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CYTOGENETICS > CLINICAL CYTOGENETICS > Flashcards

CLINICAL CYTOGENETICS Flashcards

1
Q
  • An abnormal amount of DNA
  • Usually used in reference to an abnormal number of chromosomes
A

Aneuploidy

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2
Q

Number of chromosomes in the normal diploid cell, as well as their size distribution

A

Karyotype

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3
Q
  • Can be found in apparently normal looking individuals
  • Patients with phenotypic/trait anomalies
  • Patients with diagnosed genetic disorders
A

Cytogenetic Abnormalities

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4
Q
  • advanced maternal age
  • multiple pregnancy losses (>3)
  • known or suspected family history of genetic disease or multifactorial disorder
  • ethnicity at increased risk for genetic disease
  • teratogen
  • abnormal ultrasound findings
  • abnormal maternal serum screen results
A

indications for prenatal diagnosis

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5
Q
  • Responsible for 50%-60% spontaneous abortion
  • 52% due to autosomal trisomies
  • 1 for every 3 spontaneous abortions have chromosomal abnormalities
  • Seen in 6:1000 live births
  • 90% of 1st month death? – Trisomy 18
  • Remain at 6 months level
  • Trisomy 13 – Not compatible with life
  • Striking – cyclops
  • Trisomy 16 – fetal loss in 1st trimester
A

Prenatal Cytogenetic Abnormalities

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6
Q
  • 95% of 45,X
  • 90% of Trisomy 13
  • 80% of Trisomy 18
  • 65% of Trisomy 21
  • 15% of recognized genetically abnormal pregnancy end in spontaneous fetal loss
  • 80% occur during the 1st trimester
A

Rate of biological elimination:

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7
Q
  • Done to screen for any possible genetic alterations
  • Usually done for those who become pregnant at an older age
  • Advanced maternal age = incidence of chromosomal abnormalities
A

Prenatal Chromosomal Analysis

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8
Q

Types of Prenatal Chromosomal Analysis

A
  1. Amniocentesis
  2. Chorionic villus biopsy
  3. Umbilical cord blood
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9
Q
  • Collecting amniotic fluid and culturing the cells to create a karyotype of the growing fetus inside
  • Can also be done by measuring the amount of Alpha fetoprotein (AFP) in the fluid
A

Amniocentesis

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10
Q
  • Transcervical/transabdominal chorionic venous sampling
  • The chorionic villi are wispy projections of placental tissue that share the baby’s genetic makeup
A

Chorionic villus biopsy

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11
Q
  • Aka Cordocentesis
  • Fetal blood is extracted, cultured, and assessed for any abnormalities
A

Umbilical cord blood biopsy

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12
Q
  • Detects neural tube defects which occur in 2:1000 pregnancies
  • Not related to mother’s age
  • Can also predict Down’s syndrome
A

Alpha fetoprotein (AFP)

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13
Q

Indications for Prenatal Chromosomal Analysis

A
  • Screening for maternal age-related risk
  • Family history of previous child with chromosomal abnormality
  • Abnormal levels of AFP in a screening test
  • A fetal abnormality detected on ultrasound
  • A parent who is carrier of unbalanced gametes
  • A parent who is a carrier of X-linked genetic disorder
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14
Q
  • 0.6% - 1.0% newborns have gross chromosomal abnormality
  • Karyotype analysis is needed
  • Indications:
  • Presence of multiple congenital anomalies
  • Suspected aneuploidy e.g. features of Down Syndrome
A

Postnatal Chromosomal Analysis

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15
Q
  • Indications:
  • Unexplained mental retardation or developmental delay
  • Suspected sex chromosomal abnormality (Turner Syndrome)
  • Suspected unbalanced autosome (Prader-Willi Syndrome)
  • Loss of function of genes in Chromosome 15
  • Begins as hypotonia, feeding difficulties, delayed development
  • During childhood, insatiable appetite, overeating, obesity
  • During adulthood, Diabetes mellitus type 2
  • Indications:
  • Suspected Fragile-X Syndrome
  • Infertility
  • Multiple spontaneous abortions
A

Childhood and Adult Cytogenetics

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16
Q

Trisomy 21 or Down Syndrome
Trisomy 13 or Patau Syndrome
Trisomy 18 or Edwards Syndrome

A

Autosomal Aneuploidies

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17
Q

47XXX females and 47XYY males
Klinefelter Syndrome
Turner Syndrome
Pseudo-hermaphroditism

A

Sex Chromosome Aneuploidies

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18
Q
  • Most common of the chromosomal disorder
  • Major cause of mental retardation
  • US – 1:700 live births
  • Risk increases with the mother’s age
A

Trisomy 21 or Down Syndrome

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19
Q

92.5% - 95% of Trisomy 21 are

A

47,XX+21

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20
Q

<3% of Trisomy 21 are:

A

mosaic with 2 cell lines
(47,XX+21/46,XX or 47XY+21/46XY)

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21
Q

5% of Trisomy 21 have:

A

46 chromosomes, extra 21 part of Robertsonian or other translocation

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22
Q
  • average life expectancy 30 years
  • characteristic phenotype
  • learning disability (IQ 20-60)
  • developmental delay / hypotonia
  • delayed puberty / early menopause
A

Clinical Features of Trisomy 21

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23
Q
  • 96% portal tract anomalies / duodenal atresia
  • 50% congenital cardiac lesions
  • 60% pre-senile dementia
A

Major Causes of Morbidity and Mortality of Trisomy 21

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24
Q
  • Transverse palmar creases (simian crease)
  • Heart defects (40%)
  • Ostium primum
  • Atrial septal defects
  • A-V valve malformations
  • Ventricular septal defects
  • Hypogonadism
A

Symptoms of Trisomy 21

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25
Q
  • Acute Leukemia
  • Acute lymphoblastic leukemia
  • Acute myeloblastic leukemia
  • Infections
  • Alzheimer’s Disease
A

Risks of Trisomy 21

26
Q
  • Triple copies of chromosome 13
  • Incidence = 1:4000 to 1:15000 live births
  • Caused by: Meiotic nondisjunction
  • Associated with increase in Maternal age
A

Trisomy 13 or Patau Syndrome

27
Q

Translocation type of Trisomy 13

A

(46XX,+13,del(13,14)(q10;q10))

28
Q

Mosaic type of Trisomy 13

A

(46,XX/47,XX+13)

29
Q
  • Microcephaly
  • Mental retardation
  • Microphthalmia
  • Cleft lip and/or cleft palate
  • Cyclopia
  • Transverse palmar crease
  • Polydactyly of hands and/or feet
  • Cardiac defect – VSD
  • Renal defect
  • Rocker-bottom feet
  • Punched-out scalp
A

Signs and Symptoms of Trisomy 13

30
Q
  • Incidence = 1:8000 live births
  • Caused by Meiotic nondisjunction
  • Associated with increase in maternal age
A

Trisomy 18 or Edwards Syndrome

31
Q

Karyotype of Trisomy 18

A

Trisomy type (47,XX+18)

32
Q

Mosaic type of Trisomy 18

A

(46,XX/47,XX+18)

33
Q
  • Low birth weight
  • Mental retardation
  • Micrognathia
  • Hypoplasia of the muscles
  • Prominent occiput
  • Low-set malformed ears
  • Short neck
  • Overlapping fingers
  • Heart defects – VSD
  • Renal malformations
  • Hip abduction
  • Rocker bottom feet
  • Note: rarely survive beyond 1 year
A

Signs and Symptoms of Trisomy 18

34
Q
  • Trisomy 13 & 18 less compatible with life, die within the 1st month of life
  • Survive: cannot walk, talk or care for themselves
  • Option: termination of pregnancy
  • Counseling
A

Summary

35
Q
  • People with sex chromosome aneuploidy have extra or missing sex chromosomes
  • 1:500 live births
  • Phenotypically milder
  • Chronic problems associated with sexual development and fertility
  • Recognized at puberty
A

Sex Chromosome Aneuploidies

36
Q
  • Incidence = 1:1000
  • Features: Taller than average
  • Generalized learning difficulties
  • XXX female and XYY males are fully fertile and have chromosomally normal children
  • XYY male
A

47, XXX females, 47, XYY males

37
Q
  • Incidence = 1:500 live male births
  • One of the most common cause of hypogonadism in male
  • Cause is meiotic non-disjunction (maternal)
  • Clinical features are rarely diagnosed before puberty
A

Klinefelter Syndrome

38
Q

Karyotype of Klinefelter Syndrome

A

47,XXY = 82%

39
Q

Mosaic type of Klinefelter Syndrome

A

46,XY/47,XXY or 47,XXY/48XXXY = 15%

40
Q
  • Tall and thin with relatively long legs
  • Postpubertal hypogonadism
  • Infertility – atrophic testicles
  • Hyalinized seminiferous tubules
  • Azoospermia
  • Small penis
  • Absent 2 male sex characteristics
  • Gynecomastia
  • Lower IQ
  • Increased FSH and Estradiol
A

Signs and Symptoms of Klinefelter Syndrome

41
Q
  • 46,XY/47,XXY mosaic – presents with milder form of abnormality
  • Normal testicular development depending on the relative proportion of XXY to XY
  • Increased likelihood of fertility with greater increase in XY cells than XXY cells
A

Karyotype of Klinefelter Syndrome

42
Q
  • More physical abnormalities
  • Cryptorchidism - Inability of testes to descend
  • Hypospadias - Lack of development of penis
  • Prognathism - Extension of lower jaw
  • Severe testicular hypoplasia
  • Radioulnar synostosis
A

Polysomic X (47,XXY/48,XXXY)

43
Q

Inability of testes to descend

A

Cryptorchidism

44
Q

Lack of development of penis

A

Hypospadias

45
Q

Extension of lower jaw

A

Prognathism

46
Q
  • Most common sex chromosomal anomaly in females
  • Represents the only viable born monosomy
A

Turner Syndrome

47
Q

Karyotype of Turner Syndrome

A

50% = 45, X
Mosaic 10% = 45,X/46,XX

48
Q

Structural abnormalities of Turner Syndrome

A

20% = 46,Xi (Xq)
15% = X chromosome del: (46X,del(Xq) or 46X,del(Xp))
* Rings 46,Xr(X))
* Presence of Y chromosome

49
Q
  • Critical region – region of short arm just proximal to the centromere
  • X chromosome – maternal origin
  • Paternal meiotic nondisjunction - most common cause of error
A

Turner Syndrome

50
Q
  • Short stature
  • Absent 2 female sex characteristics
  • Gonadal dysgenesis and amenorrhea
  • Normal IQ with learning difficulties
  • Bilateral neck webbing
  • Low posterior hair line
  • Heart and renal anomalies
  • Cubitus valgus
  • Shield chest
  • Autoantibody to thyroid (50%)
  • Glucose intolerance
  • **Obesity **
A

Clinical Features of Turner Syndrome

51
Q
  • SRY – Sex-Determining Region of the Y chromosome
  • TDF – Testes Determining Factor
  • SRY produces a protein called TDF that promotes the development of a testis: the primitive sex cords proliferate and penetrate into the medulla to form the testicular cords
A

Other Sex Chromosome Abnormalities

52
Q
  • XX male
  • Disagreement between:
  • Gonadal (XX) - female
  • Phenotypic (male) sex
  • Clinical Features:
  • Normal development of ovaries and internal genitalia
  • External genitalia is ambiguous or virilized
A

Female Pseudo-hermaphroditism

53
Q

Causes of Female Pseudo-hermaphroditism

A

Causes:
* Congenital Adrenal Hyperplasia (CAH)
1. Deficiency of enzyme 21-hydroxylase
2. Causing increase androgen production
* Cryptic translocation between X and Y chromosome
* Pseudoautosomal regions

54
Q
  • Homologous distal ends of the short arms of X and Y chromosomes which serves as primary site of X and Y chromosome pairing during meiosis
  • Recombination may occur between X & Y alleles resulting in the transfer of unique Y loci together with the SRY to the tip of X-chromosome (rearranged X chromosome)
A

Pseudoautosomal regions

55
Q
  • Gonadal (XY) male
  • Phenotypically female
  • Caused by:
  • Complete androgen insensitivity syndrome (Testicular Feminization)
  • Due to mutations in the gene for androgen receptor located at Xq11-Xq12 (X-linked recessive trait)
  • TDF/SRY is absent in the Y chromosome due to translocation
A

Male Pseudo-hermaphroditism

56
Q
  • Lack of any functional internal genitalia
  • Blind vagina
  • Testes in the abdomen or inguinal canal causing infertility
  • Rarely, lack of 2 intact copies of proximal X short arm
A

Clinical Features of Male Pseudo-hermaphroditism

57
Q
  • Prader-Willi Syndrome and Angelman Syndrome
  • Interstitial deletion of the proximal long arm of chromosome 15,del(15)(q11.2q13)
A

Microdeletion Syndromes

58
Q
  • Involves deletion of maternally-derived chromosome 15
  • Molecular basis – affects the gene, ubiquitin protein ligase (UBE3A gene located within the 15q12 region)
A

Angelman Syndrome

59
Q
  • Severely mentally retarded
  • Cannot carry a normal conversation, inappropriate laughter (happy puppet)
  • Hyperactive
  • Short stature
  • Microcephaly
  • Seizure and ataxia
A

Clinical Features of Angelman Syndrome

60
Q
  • Deletion of paternally-derived chromosome 15
  • No single gene has been implicated, series of gene located at 15q11.2-13 are believed to be involved
A

Prader-Willi Syndrome

61
Q
  • Small, hypotonic at birth
  • Obese because of overeating
  • Small hands and feet
  • Hypogonadism
  • Bad temper
A

Clinical Features of Prader-Willi Syndrome

62
Q
  • Routine or High-resolution cytogenetic analysis
  • Prader-Willi syndrome – 60%
  • Angelman syndrome – 10-20%
  • FISH – 80-85% of cases
  • Fluorescence In-Situ Hybridization
A

Testing for Microdeletion Syndromes

CYTOGENETICS (11 decks)

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