Down Syndrome Trisomy 21 Trisomy 13

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Down Syndrome (Trisomy 21(Trisomy 13 18

• Dr Pupak Derakhshandeh, PhD
• Ass Prof Medical Science of Tehran University

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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

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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).

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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.

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• 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).

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Karyotype 46), Xy)
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How Chromosome Abnormalities Happen?

• Meiosis
• Mitosis
• Maternal Age
• Environment

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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

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Meiosis
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Meiosis
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Chromosome abnormalities

• Abnormality of chromosome number or structure
• Numerical Abnormalities
• Structural Abnormalities

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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).

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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.

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• Down Syndrome (Trisomy 21(

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Down Syndrome (Trisomy 21(
Trisomy 2(
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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

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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

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• 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

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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

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• 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 alpha-fetoprotein, unconjugated
  estriol and human chorionic gonadotropin

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• The use of ultrasound to estimate gestational age
  improves the sensitivity and specificity of
  maternal serum screening. (Am Fam Physician
  200062825-32,837-8.)

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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.

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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.

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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 non-acrocentric
  chromosomes undergo Robertsonian translocation

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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.

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Robertsonian translocation
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TRANSLOCATIONS
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Balanced reciprocal translocation
Balanced reciprocal translocation
Balanced reciprocal translocation
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Frequency of Dysmorphic Signs in Neonates with
Trisomy 21

• Dysmorphic sign Frequency ()
• Flat facial profile 90
• Poor Moro reflex 85
• Hypotonia 80
• Hyperflexibility of large joints 80
• Loose skin on back of neck 80
• Slanted palpebral fissures 80

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Frequency of Dysmorphic Signs in Neonates with
Trisomy 21

• Dysmorphic sign Frequency ()
• Dysmorphic pelvis on radiograph 70
• Small round ears
  60
• Hypoplasia of small finger,
• middle phalanx 60
• Single palmar crease 45

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• 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

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Down Syndrome
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Incidence of Some Associated Medical
Complications in Persons with Down Syndrome
Disorder Incidence ()

• Mental retardation gt95
• Growth retardation gt95
• Early Alzheimer's disease 75
• by age 60
• Congenital heart defects
• (atrioventricular canal defect,
• ventricular septal defect, atrial septal
• defect 40

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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

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Disorder Incidence ()

• Increased susceptibility to
• infection (pneumonia, otitis media, sinusitis,
  pharyngitis( 1-6
• Infertility gt99 in men
• anovulation in 30 of women

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.
.
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Estimated risk of Down syndrome according to
maternal age

Maternal Serum Screening
Maternal Serum Screening
Maternal Serum Screening
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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

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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

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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.

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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

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"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.

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"Multiples of the Median (MoM)"

• With trisomy 21, second-trimester 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

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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 false-positive rate of about 5
  percent.

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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.

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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

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• Diagnosis of a chromosome-21 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

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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

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a woman having amniocentesis
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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.

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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 fetuss
  neck, known as the nuchal translucency or NT The
  increasing size of the NT indicates a greater
  risk of the fetus having Downs syndrome.

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Ultrasound
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Fluorescent In Situ Hybridisation techniques
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female fetus with trisomy-21

• chromosomes 18 (aqua), X (green), and Y (red).

• chromosomes 13 (green), and 21 (red)

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Quantitative fluorescent polymerase chain
reaction
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Trisomy 18, 47 Ch.
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Trisomy 18, 47 Ch.

• incidence of about 1 in 3,000
• There is a 31 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.

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Trisomy 18, 47 Ch.
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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.

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Turner Syndrome ( 45, X)
45, X
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• Turner Syndrome (45, X)

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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

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• Kleinefelter
• XXY

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Kleinefelter/47XXY