Down Syndrome
(Trisomy 21(
Trisomy 13 & 18
Dr Pupak Derakhshandeh, PhD
Ass Prof Medical Science of
Tehran University
What are chromosomes?
Chromosomes are the structures that hold
our genes
 Genes are the individual instructions that
tell our bodies how to develop and function
They govern our physical and medical
characteristics, such as hair color, blood
type and susceptability to disease.
 Each chromosome has a p and q arm; p is
the shorter arm and q is the longer arm.
 The arms are separated by a pinched
region known as the centromere

How many chromosomes do humans have?
The typical number of chromosomes in
a human cell is 46 - two pairs of 22
+ XX/XY
Holding an estimated 30,000 to
35,000 genes.
One set of 23 chromosomes is
inherited from the biological mother
(from the egg), and the other set is
inherited from the biological father
(from the sperm).
study of the chromosomes
with a microscope , then Stainning
The chromosomes look like strings
with light and dark "bands"
 A picture, or chromosome map, of
all 46 chromosomes is called a
karyotype
The karyotype can help identify
chromosome abnormalities that are
evident in either the structure or the
number of chromosomes.
 The pairs have been numbered from 1 to 22,
with the 23rd pair labeled "X" and "Y."
 In addition, each chromosome arm is defined
further by numbering the bands that appear
after staining
 The higher the number, the further that area
is from the centromere.
 The first 22 pairs of chromosomes are called
"autosomes"
 Final pair is called the "sex chromosomes."
 The sex chromosomes an individual has
determines that person's gender; females have
two X chromosomes (XX), and males have an X
and a Y chromosome (XY).
Karyotype )46, Xy)
How Chromosome
Abnormalities Happen?
Meiosis
Mitosis
Maternal Age
Environment
Meiosis
Chromosome abnormalities :
 happen as a result of an error in cell
division. “Meiosis” is the name used to
describe the cell division that the egg and
sperm go through when they are
developing.
Normally, meiosis causes a halving of
chromosome material, so that each parent
gives 23 chromosomes to a pregnancy
Meiosis
Meiosis
Chromosome abnormalities
Abnormality of chromosome
number or structure:
Numerical Abnormalities
Structural Abnormalities
Numerical Abnormalities
When an individual is missing
either a chromosome from a pair
(monosomy) or has more than two
chromosomes of a pair (trisomy).
 An example: Down Syndrome,
also known as Trisomy 21 (an
individual with Down Syndrome has
three copies of chromosome 21,
rather than two).
Numerical Abnormalities
Kleinfelter Syndrome is an
example of trisomy the
individual is born with three
sex chromosome, XXY.
Turner Syndrome is an
example of monosomy the
individual is born with only
one sex chromosome, an X.
Down
Syndrome
(Trisomy 21(
Down Syndrome (Trisomy 21(
Trisomy 2(
Down syndrom )Trisomy 21, 47)
critical region:
 A region on the long (q) arm of
chromosome 21
 Down syndrome causes mental
retardation
 a characteristic facial appearance
 multiple malformations
critical region:
 Associated with a major risk for
heart malformations
 a small but still significant risk of
acute leukemia
 3 copies of chromosome number 21
 incidence of 1 in 660 and is by far the
most common chromosomal abnormality
Slight flattening of the face
 A low bridge of the nose (lower than
the usually flat nasal bridge of the
normal newborn)
 An epicanthal fold (a fold of skin over
top of the inner corner of the eye,
which can also be seen less frequently
in normal babies)
 A ring of tiny harmless white spots
around the iris
 mental retardation
Down Syndrome: Prenatal Risk
 The risk of trisomy 21 is
directly related to maternal
age
 Patients who will be 35
years or older on their due
date should be offered
chorionic villus sampling or
second-trimester
amniocentesis
 Women younger than 35
years should be offered
maternal serum screening
at 16 to 18 weeks of
gestation
 The maternal serum
markers used to screen for
trisomy 21 are alphafetoprotein, unconjugated
estriol and human chorionic
gonadotropin
The use of ultrasound to
estimate gestational age
improves the sensitivity
and specificity of
maternal serum
screening. (Am Fam
Physician 2000;62:82532,837-8.)
Etiology and Clinical
Manifestations
 Trisomy 21 is present in 95
percent of persons with Down
syndrome.
 Mosaicism, a mixture of normal
diploid and trisomy 21 cells,
occurs in 2 percent.
Etiology and Clinical
Manifestations
 The remaining 3 percent
have a Robertsonian
translocation in which all or
part of an extra
chromosome 21 is fused
with another chromosome.
Robertsonian translocation
The reciprocal transfer of the
long arms of two of the
acrocentric chromosomes: 13,
14, 15, 21 or 22
On rare occasions, other nonacrocentric chromosomes
undergo Robertsonian
translocation
Robertsonian translocation
 a reciprocal transfer of the whole
long or short arms close to the
centromere
 A relatively common Robertsonian
translocation is between
chromosome 14 and chromosome
21
 In meiosis, a trivalent is formed.
Robertsonian translocation
TRANSLOCATIONS
Balanced reciprocal translocation
Balanced reciprocal translocation

Frequency of Dysmorphic Signs
in Neonates with Trisomy 21
Dysmorphic sign
Frequency (%)
Flat facial profile
Poor Moro reflex
Hypotonia
Hyperflexibility of large joints
Loose skin on back of neck
Slanted palpebral fissures
90
85
80
80
80
80
Frequency of Dysmorphic Signs
in Neonates with Trisomy 21
Dysmorphic sign
Frequency (%)
Dysmorphic pelvis on radiograph
Small round ears
Hypoplasia of small finger,
middle phalanx
Single palmar crease
70
60
60
45
 Persons with Down
syndrome usually have mild
to moderate mental
retardation
 School-aged children with
Down syndrome often have
difficulty with language,
communication
 Adults with Down syndrome
have a high prevalence of
early Alzheimer's disease
Down
Syndrome
Incidence of Some Associated Medical
Complications in Persons with Down
Syndrome
Disorder
Incidence (%)
Mental retardation
>95
Growth retardation
>95
Early Alzheimer's disease
75%
by age 60
Congenital heart defects
(atrioventricular canal defect,
ventricular septal defect, atrial septal
defect
40
Disorder
Incidence (%)
Hearing loss
40 to 75
Ophthalmic disorders
(congenital cataracts,
glaucoma(
60
Epilepsy
5 to 10
Gastrointestinal malformations
(duodenal atresia,
Hirschsprung disease)
5
Hypothyroidism
5
Leukemia
5
Disorder
Incidence (%)
Increased susceptibility to
infection (pneumonia, otitis media,
sinusitis, pharyngitis(
1-6
Infertility
>99% in men
anovulation in
30% of women
Estimated risk of Down syndrome
according to maternal age
The risk of having a child with
Down syndrome
 1/1,300 for a 25-year-old
woman;
 at age 35, the risk increases
to 1/365
 At age 45, the risk of a
having a child with Down
syndrome increases to 1/30
Maternal Serum Screening
 If all pregnant women 35 years or
older chose to have amniocentesis
 about 30 percent of trisomy 21
pregnancies would be detected
 Women younger than 35 years give
birth to about 70 percent of infants
with Down syndrome
The risk of having a child with
Down syndrome
 Maternal serum screening
(multiple-marker screening)
can allow the detection of
trisomy 21 pregnancies in
women in this younger age
group.
Maternal Serum Screening
"triple test" or "triple screen"
"Multiples of the Median (MoM)"
 Alpha-fetoprotein (AFP)
 unconjugated estriol
 human chorionic gonadotropin
(hCG)
 the serum markers most widely
used to screen for Down syndrome
"Multiples of the Median
(MoM)"
 AFP is produced in the yolk sac and
fetal liver.
 Unconjugated estriol and hCG are
produced by the placenta.
 The maternal serum levels of each of
these proteins and of steroid
hormones vary with the gestational
age of the pregnancy.
"Multiples of the Median
(MoM)"
 With trisomy 21, secondtrimester maternal serum
levels of AFP and unconjugated
estriol are about 25 percent
lower than normal levels
 maternal serum hCG is
approximately two times higher
than the normal hCG level
Maternal Serum Screening
"triple test" or "triple screen"
 The triple test can detect
approximately 60 percent of
the pregnancies affected by
trisomy 21, with a falsepositive rate of about 5
percent.
Maternal Serum Screening
"triple test" or "triple screen"
 In women older than 35
years, the triple test fails to
detect 10 to 15 percent of
pregnancies affected by
trisomy 21.
Recurrence Risk and Family History
If a patient has had a trisomy
21 pregnancy in the past, the
risk of recurrence in a
subsequent pregnancy
increases to approximately 1-3
percent above the baseline risk
determined by maternal age
 Diagnosis of a chromosome21 translocation in the fetus
or newborn is an indication
for karyotype analysis of
both parents
 If both parents have normal
karyotypes, the recurrence
risk is 2 to 3 percent
Ultrasonographic Findings Associated
with Fetal Down Syndrome
Chorionic villus sampling
10 to 12 weeks 0.5 to 1.5 %
Early amniocentesis
12 to 15 weeks 1.0 to 2.0 %
Second-trimester amniocentesis
15 to 20 weeks 0.5 to 1.0 %
a woman having amniocentesis
Counseling Aspects
 Women who will be 35 years or
older on their due date should
be offered chorionic villus
sampling or second-trimester
amniocentesis.
 Women younger than 35 years
should be offered maternal
serum screening at 15 to 18
weeks' gestation.
Ultrasound
 During the first trimester of the
majority of pregnancies, it is
possible to measure the size of
the fluid area at the back of the
fetus’s neck, known as the
nuchal translucency or NT The
increasing size of the NT
indicates a greater risk of the
fetus having Down’s syndrome.
Ultrasound
Fluorescent In Situ Hybridisation
techniques
female fetus with trisomy-21
• chromosomes
13 (green), and
21 (red)
 chromosomes 18
(aqua), X
(green), and Y
(red).
Quantitative fluorescent
polymerase chain reaction
2:1 ratio (Down's
Syndrome)
1:1 ratio (normal fetus)
Trisomy 18, 47 Ch.
Trisomy 18, 47 Ch.
incidence of about 1 in 3,000
There is a 3:1 preponderance of females to
males
Thirty percent of affected newborns die
within the first month
50% by two months
and 90% by one year.
severe mental retardation
microcephaly
overlapping fingers, and rocker bottom feet
Neurologically they are hypertonic
Other common malformations include
congenital heart, kidney, .... abnormalities.
Trisomy 18, 47 Ch.
Trisomy 13 (XX/XY, 47 Ch)
has an incidence of 1 in 5,000
Forty-four percent of affected newborns
succumb in the first month of life
and 69% by six months
Only 18% of the babies born with trisomy 13
survive the first year
microcephaly
microophthalmia (small eyes)
cleft lip or cleft palate
polydactyly (extra fingers)
congenital heart defects
urogenital defects
brain malformations
severe to profound mental retardation.
Turner Syndrome (45 , X)
45, X
Turner Syndrome
(45, X)
Turner syndrome
• Only females
• One X chromosome
• Or has two X chromosomes but one is
damaged
• Short stature
• Delayed growth of the skeleton
• Sometimes heart abnormalities
• Usually infertile due to ovarian failure
• Diagnosis is by blood test (karyotype)
• 1 out of every 2,500 female live births
worldwide
• Short neck with a webbed appearance
Kleinefelter
XXY
Kleinefelter47/XXY