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

What is Down’s syndrome ?

Milestones that led to antenatal screening In 1866 J Langdon Down (1828 -1896) 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’

In 1933 Lionel S Penrose (1898 - 1972) published Milestones that led to antenatal screening In 1933 Lionel S Penrose (1898 - 1972) published The relative effect of paternal and maternal age in mongolism. J. Genet. 27:219-224. (1933b) “the father’s age is an insignificant factor in the aetiology of mongolism, the emphasis being entirely on the age of the mother”

Milestones that led to antenatal screening In 1959 Jerome Lejeune (1926 -1994) 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’

How does Down’s syndrome occur ? Usually two copies - 22 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

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

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

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

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

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 1.1% Translocation (usually Robertsonian) 4% Multiple chromosome 0.5%

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

How has life expectancy changed ?

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

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: 387-402

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.

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.

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.

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.

Maternal age and Down syndrome Maternal age (years) Risk of a Down syndrome birth per 1,000 births Pre 2002 (a) Post 2002 (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 2002 : 901 mothers 45 and over (0.2% of all mothers) 272 mothers 47 and over (0.05% of all mothers)

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

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

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

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

Recurrence risk of Down syndrome 5 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

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

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 <30 30-34 35-39 40-44 45+

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 <30 30-34 35-39 40-44 45+

Risk in a woman who has NOT had a previous DS pregnancy 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 Risk in a woman who has NOT had a previous DS pregnancy

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

Is Down’s syndrome more common now?

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