1. Medical & Genetic characteristics of Down’s syndrome
Wayne Huttly
Wolfson Institute of Preventive Medicine

2. What is Down’s syndrome ?

4. Milestones that led to antenatal screening
In 1866 J Langdon Down ( ) published
Observations on an ethnic classification of idiots. Clinical Lecture Reports, London Hospital, 3:259, 1866
‘a large number of congenital idiots
are typical mongols’

5. In 1933 Lionel S Penrose (1898 - 1972) published
Milestones that led to antenatal screening
In 1933 Lionel S Penrose ( ) published
The relative effect of paternal and maternal age in mongolism. J. Genet. 27: (1933b)
“the father’s age is an insignificant factor in the aetiology of mongolism, the emphasis being entirely on the age of the mother”

6. Milestones that led to antenatal screening
In 1959 Jerome Lejeune ( ) published
Lejeune J, Gautier M, Turpin R (1959). "Etude des chromosomes somatiques de neuf enfants mongoliens". Comptes Rendus Hebd Seances Acad Sci 248 (11): 1721–1722.
‘the study of two other cases permitted the existence of
the supernumerary to be affirmed’

7. How does Down’s syndrome occur ?
Usually two copies pairs of alleles and 1 pair of sex chromosomes – total 46 chromosomes
Presence of an extra chromosome 21 – trisomy 21 – giving a total of 47 chromosomes
Occurs during formation of the parental germ cell – known as non-disjunction

8. 46 46
1st meiotic
division 24 22 23 23
2nd meiotic
division 24 24 22 22 23 23 23 23

9. 46 46
1st meiotic
division 24 22 23 23
2nd meiotic
division 24 24 22 22 23 23 23 23 47

10. Where does the extra chromosome originate ?
Number of cases
Maternal origin
Paternal origin
Hassold (1984) - 95 5
Ballesta (1999)
139 92 8
Hassold (2000)
711 91 9
Muller (2000)
110 89 11
Gomez (2000) 38 94 6
Jyothy (2001)
1,001 79 21

11. At what stage of meiosis does non-disjunction occur ?
Origin
Meiotic Division
First
Second
Maternal 75 25
Paternal 46 54
Source Hassold (2000)

12. What types of Down’s syndrome occur ?
Based on over 17,000 cases of Down’s syndrome reported to the National Down’s Syndrome Cytogenetic Register (NDSCR) between 1989 and 2002
Regular trisomy 95%
Mosaic %
Translocation
(usually Robertsonian) 4%
Multiple chromosome 0.5%

13. What is a Robertsonian translocation ?p q 21 14
14;21

14. How can a translocation cause Down’s syndrome ?
Carrier of
balanced
translocation
Normal
spouse
Carrier of
balanced
translocation
Normal
Monosomy 21
(Lethal)
Down’s
syndrome

15. How can a translocation cause Down’s syndrome ?
Carrier of
balanced
translocation
Normal
spouse
Carrier of
balanced
translocation
Normal
Monosomy 21
(Lethal)
Down’s
syndrome

16. What are the common features of Down’s syndrome
Severe intellectual disability
Congenital abnormalities
Other medical problems

17. Intellectual Disability
Down’s syndrome is the most common cause of severe intellectual disability
Intellectual disability defined by an IQ score less than 70

18. Distribution of IQ in 21 year olds with and without Down’s syndrome
Mean = 42

19. Can IQ level be predicted?
Studies have reported that individuals affected with mosaic type Down’s syndrome have, on average, higher IQ than individuals with complete Down’s syndrome
Also reported that individuals with translocation type DS have less severe learning difficulties than individuals with complete DS

20. Congenital abnormalities
About 1 in 5 liveborn children with Down’s syndrome die before the age of 5
About 2 in 5 have major health problems

21. What congenital abnormalities occur ?
Data based on births between 1980 and 1989 in Dublin
225,808 births
398 cases of Down’s syndrome

22. What congenital abnormalities occur ?
58% had one or more abnormalities
46% had a heart defect
11% had gastrointestinal defects

23. What type of heart defects ?
Atrioventricular canal defects (28%)
Ventricular septal defects (28%)
Patent ductus arteriosis (21%)

24. Likelihood ratio associated with Congenital Heart Defect (CHD)
Major
CHD
Down’s syndrome births
All births
Likelihood Ratio
Any
46%
0.8% 60
Atrioventricular canal defect
17%
0.04%
420

25. What type of Gastrointestinal defects occur ?
Duodenal atresia 47%
Hirschsprung’s disease 24%
Tracheo-oesophageal fistula 13%

26. Likelihood ratio associated with Congenital Abnormality
Down’s syndrome births
All births
Likelihood Ratio
Congenital Heart Defect (CHD)
46%
0.8% 60
Atrioventricular canal defect
17%
0.04%
420
Duodenal atresia 6%
0.018%
300

27. What other medical problems are associated with Down’s syndrome ?
Leukemia
Thyroid disorders
Epilepsy
Alzeheimer’s Disease

28. Leukaemia
A study of 2,033 people with Down’s syndrome in 1962 reported an 18 fold excess mortality due to leukaemia
1989 study of 766 children with Down’s syndrome reported a 1.7% rate of leukaemia – a 43 fold increase over general population

29. Thyroid Disorders
Hypothyroidism has been reported more frequently than hyperthyroidism
Studies suggest the percentage of individuals with DS affected with hypothyroidism increases with age
0.7% at birth, 7% among children, 12% among adults
Compares with 0.03% rate among general population at birth

30. Epilepsy
Belfast study of 191 adults with Down’s syndrome found 9% had epilepsy
Prevalence increased with age – reaching 46% in those over 50
About 0.8% of general population have epilepsy

31. Alzeheimer’s Disease
Association between Alzeheimer’s and Down’s syndrome has long been known
In 1987 a gene that codes for the Amyloid precursor protein (APP) involved in the pathogenesis of Alzeheimer’s was located on chromosome 21

32. Alzeheimer’s Disease
Study of 307 institutionalised people with Down’s syndrome
Dementia increased from 11% among ages 40 – 49 to 77% between ages 60 and 69
Mean onset was 56 and all over 70 had dementia
General population – 2% between 65 and 70

33. How has life expectancy changed ?

34. How likely is a Down’s syndrome birth ?
Maternal age at EDD
Risk of Down’s syndrome
<25
1 in 1,500 30
1 in 900 40
1 in 110
All
1 in 700

35. Maternal age and Down syndrome : predicted risks prior to 2002.5 1 5 10 50
100
500
Risk of Down syndrome birth per 1000 births 15 20 25 30 35 40 45 55
Maternal age (years)
Cuckle, Wald & Thompson. Journal of Obstetrics and Gynaecology. 1987;94:

36. Maternal age and Down syndrome.5 1 5 10 50
100
500
Risk of Down syndrome birth per 1000 births 15 20 25 30 35 40 45
Estimate pre 2002
register data 55
Maternal age (years)
Morris JK et al. Journal of Medical Screening 2002;9:2-6.

37. Maternal age and Down syndrome.5 1 5 10 50
100
500
Risk of Down syndrome birth per 1000 births 15 20 25 30 35 40 45
Estimate pre 2002
Revised estimate 50 55
Maternal age (years)
Morris JK et al. Journal of Medical Screening 2002;9:2-6.

38. Maternal age and Down syndrome
500
Estimate pre 2002
100
Revised estimate 50
Maternal age
Risk of a DS birth per 1,000 births 20
0.67 30 1 40 10 50
Risk of Down syndrome birth per 1000 births 10 5 1 .5 15 20 25 30 35 40 45 50 55
Maternal age (years)
Morris JK et al. Journal of Medical Screening 2002;9:2-6.

39. Maternal age and Down syndrome
500
Estimate pre 2002
100
Revised estimate 50
Maternal age
Risk of a DS birth per 1,000 births
Risk of a DS birth 20
0.67
1 in 1500 30 1
1 in 1000 40 10
1 in 100 50
1 in 30
Risk of Down syndrome birth per 1000 births 10 5 1 .5 15 20 25 30 35 40 45 50 55
Maternal age (years)
Morris JK et al. Journal of Medical Screening 2002;9:2-6.

40. Maternal age and Down syndrome
Maternal age (years)
Risk of a Down syndrome birth
per 1,000 births
Pre (a)
Post (b)
Difference in risk
(a) – (b) 25
0.7
0.0 35
2.6
2.8
-0.2 45
35.0
28.1
+6.9 47
61.6
33.2
+28.4
In England and Wales in :
901 mothers 45 and over (0.2% of all mothers)
272 mothers 47 and over (0.05% of all mothers)

41. But why is the risk different during pregnancy ?
Time of pregnancy
Age
12 weeks
16 weeks
Term 30
1 in 520
1 in 700
1 in 900 40
1 in 65
1 in 85
1 in 110

42. The effect of miscarriage
Between 10 weeks of pregnancy and term it is expected that 43% of Down’s syndrome pregnancies will miscarry
Between 16 weeks of pregnancy and term it is expected that 23% of Down’s syndrome pregnancies will miscarry

43. What else can affect the chance of a Down’s syndrome pregnancy ?
A previous pregnancy affected with Down’s syndrome
Estimated that there is a recurrence risk
This is added to the unaffected risk at term

44. Risk of DS recurrence Practice prior to 2005 :
Add 4.2 per 1,000 to a woman’s risk of a Down syndrome birth
Maternal age (years)
Risk of a Down syndrome birth per 1,000 births for a woman with
No previous DS pregnancy
A previous DS pregnancy 25
0.7
4.9 35
2.6
6.8 45
35.0
39.2

45. Recurrence risk of Down syndrome5 10 20 30 40 50
Risk of Down syndrome birth per 1000 births 15 25 35 45 55
Maternal age (years)
Risk in a woman who has had a previous DS pregnancy
Risk in a woman who has NOT had a previous DS pregnancy

46. Register data
11,281 women with a Down syndrome pregnancy who had at least one previous pregnancy
95 Women in register with two or more trisomy 21 pregnancies that were not translocations

47. 13 11 36 31 4 5 10 20 30 40 50
Risk of Down syndrome birth per 1000 births 15 25 35 45 55
Maternal age (years)
Risk of Down syndrome in women who have already had a previous Down syndrome pregnancy
Age group <

48. 5 10 20 30 40 50
Risk of Down syndrome birth per 1000 births 15 25 35 45 55
Maternal age (years)
Risk of Down syndrome in women who have already had a previous Down syndrome pregnancy
Age group <

49. Risk in a woman who has NOT had a previous DS pregnancy5 10 20 30 40 50
Risk of Down syndrome birth per 1000 births 15 25 35 45 55
Maternal age (years)
Risk of Down syndrome in women who have already had a previous Down syndrome pregnancy
Risk in a woman who has NOT had a previous DS pregnancy

50. Excess risk of Down syndrome pregnancy at birth
Maternal age at first Down syndrome pregnancy (years)
Excess risk of a Down syndrome birth per 1,000 births
< 20 5 27 4 30 3 33 2 36 1
44 +
<0.1

51. Is Down’s syndrome more common now?

52. Downs syndrome in England and Wales 1990-2001
Birth prevalence in the absence of antenatal diagnosis
1.84
1.39
Antenatal diagnosis
0.95
0.39