Community: Down's Syndrome Flashcards
What is the normal number of chromosomes for a human?
46
23 pairs (one from mother and one from father)
How many chromosomes does someone with Down syndrome have?
47
It is the most common autosomal trisomy. True or false?
True
It is the most common cause of severe learning difficulties. True or false?
True
What chromosome do people with Down syndrome have an extra copy of?
Chromosome 21 - they have 3 of them ie trisomy 21
The extra chromosome 21 may result from what processes?
Meiotic nondisjunction, translocation or mosaicism
What is the most common way to get an extra chromosome 21?
Meiotic nondisjunction - 94% of cases
What does meiosis produce?
Sex cells
Describe the process of nondisjunction
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
The incidence of trisomy 21 due to nondisjunction is related to what?
Maternal age
However as the proportion of pregnancies in older mothers is small, most affected babies are born to younger mothers
Can meiotic nondisjunction occur in spermatogenesis?
Yes - the extra copy of chromosome 21 can be of parental origin
Translocation (Robertsonian) trisomy 21 is the cause of what percent of those with Down syndrome?
4%
Is translocation trisomy 21 related to maternal age?
No
Describe the translocation process
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)
If translocation is the cause, why is parental chromosome analysis recommended?
One of the parents may carry the translocation in balanced form (in 25% of cases)
In translocation Down syndrome, the risk of recurrence is what percentage if the mother is the carrier?
10-15%
In translocation Down syndrome, the risk of recurrence is what percentage if the father is the carrier?
2.5%
What happens if the parent carries the rare 21:21 translocation?
All the offspring will have Down syndrome
If neither parents carry a translocation (75%) what is the risk of recurrence?
Less than 1%
How does translocation occur?
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.
What percentage of people with Down syndrome have inherited the condition?
About 1%
Only 4% have translocation type and 1/3 of this group have inherited it
What is mosaic Down syndrome?
The extra chromosome 21 is only in some of the cells
- the mixture can vary from very few to nearly 100% trisomic cells
What percentage of those with Down syndrome have the mosaic type?
1%
How does mosaicism occur?
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
Is the phenotype milder with Down syndrome mosaicism?
Yes in some cases
What is the risk of Down syndrome with increasing maternal age?
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
What are the typical craniofacial features?
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
What are Brushfield spots?
Pigmented spots in iris
What other anomalies can occur (other than craniofacial)?
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%
What percentage have congenital heart defects?
40-50%
What cardiac complications can occur?
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%
What is the most common cardiac complication?
Atrioventricular septal canal defect 40%
What later complications can occur?
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
If not diagnosed antenatally, is Down syndrome usually suspected at birth?
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
How can the baby’s blood be analysed after birth if Down syndrome suspected?
Real time PCR or rapid fluorescence in situ hybridisation FISH
What percentage survive to 1 year of age?
85%
What is a major cause of early mortality?
Atrioventricular canal defects
How many affected individuals live longer than 50?
50%
Children with Down syndrome should be screened periodically for what?
Impairment of vision and hearing
Hypothyroidism
Coeliac disease
Atlantoaxial instability
How is fertility affected?
Males almost always infertile due to impaired spermatogenesis
Females usually subfertile - increased incidence in problems with pregnancy and labour
What are the 5 A’s of Down syndrome?
Advanced maternal age Duodenal atresia Atrioventricular septal defect AML/ALL Alzheimer’s disease
Why is their height reduced?
Shortening of long bones
All pregnant women are offered screening tests. What does this involve?
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
When an increased risk is identified after screening, what is offered?
Amniocentesis or chronic villus sampling (CVS)
What is non invasive prenatal testing NIPT?
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)
When does the combined screening test occur?
Between 10-14 weeks of pregnancy
Obtaining a nuchal translucency measurement depends on position of baby. If it’s not possible, what will be offered?
The quadruple test when 14-20 weeks pregnant
What other syndromes does the combined test also screen for?
Edwards’ syndrome (trisomy 18)
Patau’s syndrome (trisomy 13)
Does the screening test tell you if the baby has Down syndrome?
No - it tells you if you have a higher or lower chance
Describe chronic villus sampling
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
Describe amniocentesis
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
What is the current cut off level in England for being offered diagnostic testing?
1 in 150 chance
