Community: Down's Syndrome

Question 1

What is the normal number of chromosomes for a human?

Answer 1

46

23 pairs (one from mother and one from father)

Question 2

How many chromosomes does someone with Down syndrome have?

Answer 2

47

Question 3

It is the most common autosomal trisomy. True or false?

Answer 3

True

Question 4

It is the most common cause of severe learning difficulties. True or false?

Answer 4

True

Question 5

What chromosome do people with Down syndrome have an extra copy of?

Answer 5

Chromosome 21 - they have 3 of them ie trisomy 21

Question 6

The extra chromosome 21 may result from what processes?

Answer 6

Meiotic nondisjunction, translocation or mosaicism

Question 7

What is the most common way to get an extra chromosome 21?

Answer 7

Meiotic nondisjunction - 94% of cases

Question 8

What does meiosis produce?

Answer 8

Sex cells

Question 9

Describe the process of nondisjunction

Answer 9

Nondisjunction means the chromosomes do not split apart
The chromosome 21 pair fails to separate, so that one gamete has 2 chromosome 21s and one gamete has none.
Fertilisation of the gamete with two chromosome 21s gives rise to a zygote with trisomy 21.
Nondisjunction can happen at the first step of meiosis or the second step

Question 10

The incidence of trisomy 21 due to nondisjunction is related to what?

Answer 10

Maternal age

However as the proportion of pregnancies in older mothers is small, most affected babies are born to younger mothers

Question 11

Can meiotic nondisjunction occur in spermatogenesis?

Answer 11

Yes - the extra copy of chromosome 21 can be of parental origin

Question 12

Translocation (Robertsonian) trisomy 21 is the cause of what percent of those with Down syndrome?

Answer 12

4%

Question 13

Is translocation trisomy 21 related to maternal age?

Answer 13

No

Question 14

Describe the translocation process

Answer 14

Part of one chromosome moves and switches place with another.
A fusion between the centromeres of 2 chromosomes with loss of the short arms forms a chromosome with two long arms, one derived from each chromosome.
It is usually chromosome 14 that is involved (but can be 13,15,21 or 22 - all are acrocentric ie the centromere close to one end; the short arm contains few genes)

Question 15

If translocation is the cause, why is parental chromosome analysis recommended?

Answer 15

One of the parents may carry the translocation in balanced form (in 25% of cases)

Question 16

In translocation Down syndrome, the risk of recurrence is what percentage if the mother is the carrier?

Answer 16

10-15%

Question 17

In translocation Down syndrome, the risk of recurrence is what percentage if the father is the carrier?

Answer 17

2.5%

Question 18

What happens if the parent carries the rare 21:21 translocation?

Answer 18

All the offspring will have Down syndrome

Question 19

If neither parents carry a translocation (75%) what is the risk of recurrence?

Answer 19

Less than 1%

Question 20

How does translocation occur?

Answer 20

In 2/3 of people due to a translocation that was an isolated event during the formation of the individual egg or sperm involved in the conception (no reason why it occurs and cannot be predicted) = de novo translocation

Other 1/3 the translocation is inherited from one of the parents - this parent has 2 whole number 21 chromosomes in each cell but one of them is attached to another chromosome = a balanced translocation as no loss or gain of genetic material. The parent is a carrier - no symptoms of syndrome themselves.

Question 21

What percentage of people with Down syndrome have inherited the condition?

Answer 21

About 1%

Only 4% have translocation type and 1/3 of this group have inherited it

Question 22

What is mosaic Down syndrome?

Answer 22

The extra chromosome 21 is only in some of the cells

• the mixture can vary from very few to nearly 100% trisomic cells

Question 23

What percentage of those with Down syndrome have the mosaic type?

Answer 23

1%

Question 24

How does mosaicism occur?

Answer 24

Usually after the formation of the chromosomally normal zygote by nondisjunction at MITOSIS
- number of cells affected depends on how early on the nondisjunction occurs

Can also occur when the zygote starts with trisomy 21 - mitotic nondisjunction produces a cell with 48 chromosomes (which dies) the other cell loses one of its 3 chromosome 21s, so now it has 46 chromosomes = normal

Question 25

Is the phenotype milder with Down syndrome mosaicism?

Answer 25

Yes in some cases

Question 26

What is the risk of Down syndrome with increasing maternal age?

Answer 26

``` 20 = 1 in 1500 30= 1 in 800 35 = 1 in 270 40 = 1 in 100 45= 1 in 50 ``` Approx 3 times more common for every extra 5 years of age

Question 27

What are the typical craniofacial features?

Answer 27

``` Round face Flat nasal bridge Upslanted palpebral fissures Epicanthic folds - a fold of skin running across the inner edge of the palpebral fissure Brushfield spots in iris Small mouth and protruding tongue Small ears Flat occiput and third fontanelle High arched palate ```

Question 28

What are Brushfield spots?

Answer 28

Pigmented spots in iris

Question 29

What other anomalies can occur (other than craniofacial)?

Answer 29

``` Short neck Single palmar crease Incurved and short fifth finger Wide ‘sandal gap’ between first and second toes Hypotonia Congenital heart defects Duodenal atresia Hirschsprung disease <1% ```

Question 30

What percentage have congenital heart defects?

Answer 30

40-50%

Question 31

What cardiac complications can occur?

Answer 31

``` Endocardial cushion defect - also known as atrioventricular septal canal defects Ventricular septal defect 30% Secundum atrial septal defect 10% Tetralogy of Fallot 5% Isolated patent ductus arteriosus 5% ```

Question 32

What is the most common cardiac complication?

Answer 32

Atrioventricular septal canal defect 40%

Question 33

What later complications can occur?

Answer 33

Delayed motor milestones Learning difficulties - severity variable (usually mild to moderate) Short stature Increased susceptibility to infections especially respiratory Hearing impairment from secretory otitis media Visual impairment form cataracts 15%, squints, myopia 50% ALL Hypothyroidism 15% Coeliac disease Epilepsy Early onset Alzheimer’s Acquired hip dislocation and atlantoaxial instability Obstructive sleep apnoea 50-75% Subfertility

Question 34

If not diagnosed antenatally, is Down syndrome usually suspected at birth?

Answer 34

Yes because of baby’s facial features, hypotonia, flat occiput, single palmar crease etc - suspected diagnosis should be confirmed by senior paediatrician - blood sent for analysis

Question 35

How can the baby’s blood be analysed after birth if Down syndrome suspected?

Answer 35

Real time PCR or rapid fluorescence in situ hybridisation FISH

Question 36

What percentage survive to 1 year of age?

Answer 36

85%

Question 37

What is a major cause of early mortality?

Answer 37

Atrioventricular canal defects

Question 38

How many affected individuals live longer than 50?

Answer 38

50%

Question 39

Children with Down syndrome should be screened periodically for what?

Answer 39

Impairment of vision and hearing Hypothyroidism Coeliac disease Atlantoaxial instability

Question 40

How is fertility affected?

Answer 40

Males almost always infertile due to impaired spermatogenesis Females usually subfertile - increased incidence in problems with pregnancy and labour

Question 41

What are the 5 A’s of Down syndrome?

Answer 41

``` Advanced maternal age Duodenal atresia Atrioventricular septal defect AML/ALL Alzheimer’s disease ```

Question 42

Why is their height reduced?

Answer 42

Shortening of long bones

Question 43

All pregnant women are offered screening tests. What does this involve?

Answer 43

Ultrasound - nuchal thickening (thickened soft tissue on back of neck) can also look for absent or hypoplastic nasal bone, shortened middle phalanges of fifth digit with clindodactyly, shortened long bones Maternal serum: reduced pregnancy associated plasma protein-A (PAPP-A); increased beta-hCG = the combined test

Question 44

When an increased risk is identified after screening, what is offered?

Answer 44

Amniocentesis or chronic villus sampling (CVS)

Question 45

What is non invasive prenatal testing NIPT?

Answer 45

Cell free foetal DNA analysed from maternal blood - becoming part of routine screening in UK - means fewer women will go on to be offered diagnostic testing (carries a risk of miscarriage)

Question 46

When does the combined screening test occur?

Answer 46

Between 10-14 weeks of pregnancy

Question 47

Obtaining a nuchal translucency measurement depends on position of baby. If it’s not possible, what will be offered?

Answer 47

The quadruple test when 14-20 weeks pregnant

Question 48

What other syndromes does the combined test also screen for?

Answer 48

Edwards’ syndrome (trisomy 18) | Patau’s syndrome (trisomy 13)

Question 49

Does the screening test tell you if the baby has Down syndrome?

Answer 49

No - it tells you if you have a higher or lower chance

Question 50

Describe chronic villus sampling

Answer 50

A diagnostic test Usually done between weeks 11 and 14 Fine needle used to take sample of tissue from placenta Risks = miscarriage 1 in 100, infection

Question 51

Describe amniocentesis

Answer 51

Usually between 15-20 weeks Long, thin needle guided by US through abdominal wall and into amniotic sac that surrounds foetus - sample of amniotic fluid taken for analysis Risk: miscarriage 1 in 100, infection or needing procedure again

Question 52

What is the current cut off level in England for being offered diagnostic testing?

Answer 52

1 in 150 chance