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 functionThey 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 Karyotype 4646)), Xy), Xy)

How Chromosome Abnormalities Happen?

MeiosisMitosisMaternal AgeEnvironment

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

MeiosisMeiosis

MeiosisMeiosis

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 Down Syndrome Syndrome ((Trisomy 21(Trisomy 21(

Trisomy 2(Trisomy 2(

Down Syndrome Down Syndrome ((Trisomy 21(Trisomy 21(

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 alpha-fetoprotein, 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;62:825-32,837-8.)

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 Robertsonian translocationtranslocation

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

Robertsonian Robertsonian translocationtranslocation 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

TRANSLOCATIONSTRANSLOCATIONS

Balanced reciprocal translocation Balanced reciprocal translocation

Balanced reciprocal Balanced reciprocal translocationtranslocation

Frequency of Dysmorphic Signs in Neonates with Trisomy 21

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

Frequency of Dysmorphic Signs Frequency of Dysmorphic Signs in Neonates with Trisomy 21in Neonates with Trisomy 21

Dysmorphic sign Frequency (%)

Dysmorphic pelvis on radiograph 70Small round ears 60Hypoplasia of small finger,middle phalanx 60Single palmar crease 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 >95Growth retardation >95Early Alzheimer's disease 75% by age 60Congenital heart defects (atrioventricular canal defect, ventricular septal defect, atrial septal defect 40

Disorder Incidence (%)

Hearing loss 40 to 75Ophthalmic disorders (congenital cataracts, glaucoma( 60Epilepsy 5 to 10Gastrointestinal malformations

(duodenal atresia, Hirschsprung disease) 5Hypothyroidism 5Leukemia 5

Disorder Incidence (%)

Increased susceptibility to infection (pneumonia, otitis media,

sinusitis, pharyngitis( 1-6Infertility >99% in menanovulation in 30% of

women

Estimated risk of Down syndrome according to maternal

age

The risk of having a child with The risk of having a child with Down syndromeDown 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 The risk of having a child with Down syndromeDown 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, 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

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.

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 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

Ultrasonographic Findings Associated with Fetal Down Syndrome

Chorionic villus sampling10 to 12 weeks 0.5 to 1.5 %

Early amniocentesis12 to 15 weeks 1.0 to 2.0 %

Second-trimester amniocentesis15 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.

UltrasoundUltrasound

Fluorescent In Situ Hybridisation techniques

female fetus with trisomy-21

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

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

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 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 SyndromeTurner Syndrome ( ( 45 45, , X)X)

4545, X, X

Turner Syndrome (45, X)

Turner syndrome• OOnly femalesnly females• OOne X chromosome ne X chromosome • OOr has two X chromosomes but r has two X chromosomes but one is one is damageddamaged• SShort staturehort stature• DDelayed growth of the skeletonelayed growth of the skeleton• SSometimes heart abnormalitiesometimes heart abnormalities• UUsually infertile due to ovarian sually infertile due to ovarian failurefailure• Diagnosis is by blood test Diagnosis is by blood test (karyotype)(karyotype)• 1 out of every 2,500 female live 1 out of every 2,500 female live births births worldwideworldwide• SShort neck with a webbed hort neck with a webbed appearanceappearance

KleinefelterXXY

KleinefelterKleinefelter/47/47XXYXXY