CLINICAL CYTOGENETICS Flashcards
1
Q
- An abnormal amount of DNA
- Usually used in reference to an abnormal number of chromosomes
A
Aneuploidy
2
Q
Number of chromosomes in the normal diploid cell, as well as their size distribution
A
Karyotype
3
Q
- Can be found in apparently normal looking individuals
- Patients with phenotypic/trait anomalies
- Patients with diagnosed genetic disorders
A
Cytogenetic Abnormalities
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
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
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:
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
8
Q
Types of Prenatal Chromosomal Analysis
A
- Amniocentesis
- Chorionic villus biopsy
- Umbilical cord blood
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
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
11
Q
- Aka Cordocentesis
- Fetal blood is extracted, cultured, and assessed for any abnormalities
A
Umbilical cord blood biopsy
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)
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
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
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
16
Q
Trisomy 21 or Down Syndrome
Trisomy 13 or Patau Syndrome
Trisomy 18 or Edwards Syndrome
A
Autosomal Aneuploidies
17
Q
47XXX females and 47XYY males
Klinefelter Syndrome
Turner Syndrome
Pseudo-hermaphroditism
A
Sex Chromosome Aneuploidies
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
19
Q
92.5% - 95% of Trisomy 21 are
A
47,XX+21
20
Q
<3% of Trisomy 21 are:
A
mosaic with 2 cell lines
(47,XX+21/46,XX or 47XY+21/46XY)
21
Q
5% of Trisomy 21 have:
A
46 chromosomes, extra 21 part of Robertsonian or other translocation
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
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
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
25
* Acute Leukemia
* Acute lymphoblastic leukemia
* Acute myeloblastic leukemia
* Infections
* Alzheimer’s Disease
Risks of Trisomy 21
26
* Triple copies of chromosome 13
* Incidence = 1:4000 to 1:15000 live births
* Caused by: Meiotic nondisjunction
* Associated with increase in Maternal age
Trisomy 13 or Patau Syndrome
27
Translocation type of Trisomy 13
(46XX,+13,del(13,14)(q10;q10))
28
Mosaic type of Trisomy 13
(46,XX/47,XX+13)
29
* 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
Signs and Symptoms of Trisomy 13
30
* Incidence = 1:8000 live births
* Caused by Meiotic nondisjunction
* Associated with increase in maternal age
Trisomy 18 or Edwards Syndrome
31
Karyotype of Trisomy 18
Trisomy type (47,XX+18)
32
Mosaic type of Trisomy 18
(46,XX/47,XX+18)
33
* **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**
Signs and Symptoms of Trisomy 18
34
* 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
Summary
35
* 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
Sex Chromosome Aneuploidies
36
* 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
47, XXX females, 47, XYY males
37
* 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
Klinefelter Syndrome
38
Karyotype of Klinefelter Syndrome
47,XXY = 82%
39
Mosaic type of Klinefelter Syndrome
46,XY/47,XXY or 47,XXY/48XXXY = 15%
40
* 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
Signs and Symptoms of Klinefelter Syndrome
41
* 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
Karyotype of Klinefelter Syndrome
42
* 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
Polysomic X (47,XXY/48,XXXY)
43
Inability of testes to descend
Cryptorchidism
44
Lack of development of penis
Hypospadias
45
Extension of lower jaw
Prognathism
46
* Most common sex chromosomal anomaly in females
* Represents the only viable born monosomy
Turner Syndrome
47
Karyotype of Turner Syndrome
50% = 45, X
Mosaic 10% = 45,X/46,XX
48
Structural abnormalities of Turner Syndrome
20% = 46,Xi (Xq)
15% = X chromosome del: (46X,del(Xq) or 46X,del(Xp))
* Rings 46,Xr(X))
* Presence of Y chromosome
49
* Critical region – region of short arm just proximal to the centromere
* X chromosome – maternal origin
* Paternal meiotic nondisjunction - most common cause of error
Turner Syndrome
50
* 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 **
Clinical Features of Turner Syndrome
51
* 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
Other Sex Chromosome Abnormalities
52
* 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
Female Pseudo-hermaphroditism
53
Causes of Female Pseudo-hermaphroditism
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
* 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)
Pseudoautosomal regions
55
* 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
Male Pseudo-hermaphroditism
56
* 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
Clinical Features of Male Pseudo-hermaphroditism
57
* Prader-Willi Syndrome and Angelman Syndrome
* Interstitial deletion of the proximal long arm of chromosome 15,del(15)(q11.2q13)
Microdeletion Syndromes
58
* Involves deletion of maternally-derived chromosome 15
* Molecular basis – affects the gene, ubiquitin protein ligase (UBE3A gene located within the 15q12 region)
Angelman Syndrome
59
* Severely mentally retarded
* Cannot carry a normal conversation, inappropriate laughter (happy puppet)
* Hyperactive
* Short stature
* Microcephaly
* Seizure and ataxia
Clinical Features of Angelman Syndrome
60
* 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
Prader-Willi Syndrome
61
* Small, hypotonic at birth
* Obese because of overeating
* Small hands and feet
* Hypogonadism
* Bad temper
Clinical Features of Prader-Willi Syndrome
62
* Routine or High-resolution cytogenetic analysis
* Prader-Willi syndrome – 60%
* Angelman syndrome – 10-20%
* FISH – 80-85% of cases
* Fluorescence In-Situ Hybridization
Testing for Microdeletion Syndromes
