Down's syndrome

Question 1

Define

Answer 1

Extra Chromosome 21

MOST COMMON autosomal trisomy and genetic cause of severe learning difficulties

May result from:
1. Meiotic non-disjunction (94%)

Error at meiosis
- Pair of chromosome 21s fails to separate so one gamete has 2 x chromosome 21s and the other has none
- Fertilisation of the gamete with 2 chromosome 21s gives rise to a zygote with trisomy 21
Translocation (5%)

2. Translocation (5%)
   - Extra chromosome 21 is joined onto another chromosome (usually 14 but occasionally 15, 22 or 21)
   - This is known as Robertsonian Translocation
   - This may result in a phenotypically normal carrier with 45 chromosomes (two being joined together) or in someone with Down syndrome as 46 chromosomes but with 3 copies of chromosome 21 material
   - Parental chromosomal analysis is recommended
3. Mosaicism (1%)

• Some of the cells are normal and some have trisomy 21
• Usually arises after the formation of the chromosomally normal zygote by non-disjunction at mitosis but can arise by later mitotic non-disjunction in a trisomy 21 conception.
• Phenotype is milder

Question 2

Risk factors

Answer 2

Advanced maternal age- errors with meiosis

Question 3

Presentation

Answer 3

Picked up on antenatal screening

**Craniofacial appearance **
1. Round face and flat nasal bridge
2. Upslanting palpebral fissures
3. Epicanthic folds
4. Brushfield spots in iris (pigmented spots)
5. Small mouth
6. Protruding tongue
7. Small ears
8. Flat occiput and third fontanelle

**Other anomalies **
1. Short neck
2. Single palmar creases, incurved 5th finger
3. Wide ‘sandal’ gap between the big and second toe
4. Hypotonia
5. Congenital heart defects (40%)
6. Duodenal atresia
7. Hirschsprung disease
8. Omphalpce;e
9. Cardiac complications (AVSD, VSD, ASD, ToF, PDA (isolated)

**Later medical problems **
1. Delayed motor milestones
2. Moderate-severe learning difficulties
3. Small stature
4. Increased susceptibility to infections
5. Hearing impairment from secretory otitis media - Vulnerable to chronic otitis media because their large adenoids, small nasopharynx and narrow Eustachian tubes make aeration of the middle ear less efficient
6. Visual impairment from cataracts, squints, myopia
7. Increased risk of leukaemia and solid tumours
8. Risk of atlanto-axial joint instability
9. Hypothyroidism > hyperthyroidism
10. T1DM
11. Coeliac disease
12. Epilepsy
13. Alzheimer’s disease

Question 4

Investigations

Answer 4

Antenatal

• Biochemical markers
• Nuchal translucency (looking at thickening of soft tissues at the back of the neck)
• Amniocentesis and foetal karyotype

Postnatal
* FISH
* cardiac echocardio- gram even if no murmur is detected.

Question 5

Management

Answer 5

Counselling services

Child Development Service
* Provide or coordinate care for parents
* Regular review of child’s development and health

MDT approach
* Parent education and support
* Genetic counselling
* IQ testing with appropriate educational input
* Physiotherapy → prevent abnormal compensatory movements for physical limitations
* OT → fine motor and self-care
* SALT → speech intelligibility and to manage language delay
* Regular follow up
* Annual hearing test, thyroid levels, ophthalmic evaluation (up to 5 years then every 2 years)
* Appropriate education placement with an individualised educational plan
* Haemoglobin level for IDA
* Monitor for symptoms of sleep apnoea (OSA)
* Monitor growth using updated Down’s syndrome growth charts

Medical
* Antibiotics for recurrent respiratory infections, levothyroxine for hypothyroidism

Surgical
* Congenital heart defects, oesophageal/ duodenal atresia

Support
* Contact local DS clinic, access to local parent support groups

Down syndrome association → helpline with lists of local groups, new parents pack, info for families and carers (www.downsyndrome.org.uk / National down syndrome society → events and support)

Question 6

Complications and prognosis

Answer 6

Complications

Congenital heart disease – present in 30%

Atrioventricular canal defect – major cause of early mortality

Hypothyroidism

Impaired vision and hearing

Atlantoaxial joint instability

Increased risk of leukaemia; transient myeloproliferative disorder and AML (mutations in GATA 1)

Prognosis

85% survive to 1 year of age

At least 50% survive > 50 years