Down syndrome is caused by trisomy 21, where there is an extra copy of chromosome 21 in each cell. There are three main types of chromosome abnormalities that cause Down syndrome - trisomy 21 (95%), translocation (3-4%), and mosaicism (1%). Advanced maternal age is a risk factor, with the risk increasing from 1 in 1500 for women aged 15-29 to 1 in 50 for women aged 45 and above. Down syndrome is not inherited in a simple Mendelian pattern, and the risk of recurrence depends on the specific chromosomal abnormality involved.

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History
 First described by John Langdon Down, 1866
 Trisomy 21 described by Professor Jérôme
Lejeune & Turpin in 1959
 In 1975, NIH suggested that possessive use of
eponym should be discontinued in the USA, but
in England it remains Down’s Syndrome

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Incidence
 1 in 800 to 1000 live births
 Slight male preponderance

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Aetiology There are three main types of chromosome
abnormalities in Down syndrome
1. Trisomy 21 (95 percent)
• an extra 21 chromosome. Instead of the normal number of 46
chromosomes in each cell, the individual with Down syndrome
has 47 chromosomes.
2. Translocation (3 - 4 percent)
• extra 21 chromosome is attached or translocated on to
another chromosome, usually on chromosome 14, 21 or 22.
3. Mosaicism (1 percent)
• some cells have 47 chromosomes and others have 46
chromosomes. Mosaicism is thought to be the result of an
error in cell division soon after conception.

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Nondisjunction

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Robertsonian translocation

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Mosaicism

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Karyotype

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Advanced maternal age – Risk of Down
syndrome
Maternal Age Risk of Down Syndrome
15 – 29 yrs 1 : 1500
30 – 34 yrs 1 : 800
35 – 39 yrs 1 : 270
40 – 45 yrs 1 : 100
45 and above 1 : 50

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Advanced maternal age

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Hall’s Ten Signs of Down Syndrome in
Newborns
Neonatal sign Frequen
cy %
1 Poor Moro reflex 85
2 Hypotonia 80
3 Flat facial profile 90
4 Upward-slanting palpebral fissures 80
5 Morphologically simple, small round ears 60
6 Redundant loose neck skin 80
7 Single palmar crease 45
8 Hyperextensible large joints 80
9 Pelvis radiograph morphologically abnormal 70
10 Hypoplasia of fifth finger middle phalanx 60

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Clinical Features
 Head & Neck
 Brachycephaly
 Mongoloid slant
 Epicanthal fols
 Brushfield spots
 Flat nasal bridge
 Folded or dysplastic ears
 Open mouth
 Scrotal tongue
 Protruding tongue
 Short neck
 Excessive skin at nape of neck

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Clinical Features

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Clinical Features - Eyes:
 Up-slanting(mongoloid
slant)
 Myopia, hypermetropia
 Strabismus,
 Brushfield spots,
 Cataracts
 Glaucoma
 Keratoconus, blepharitis
 Hypertelorism
 Medial epicanthal folds
 Nystagmus

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Clinical Features
 Extremities
 Short broad
hands
 Clinodactyly
 Simian crease
 Sandal gap toes
 Hyper flexibility
of joints

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Dermatoglyphics

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System wise problems in Down
Syndrome
CNS  Intellectual disability
 Alzheimer like disease after 25 yrs
 Autistic behaviour
CVS  CHD 40% - AV cushion defects before 10 mo.
 Cor pulmonale
GIT  Atresia of gut (Duodenal atresia – 8%)
 Hirschprung’s disease
Otological  Impaired hearing (60-70% - middle ear effusion)
 Excessive Wax ( because auditory canal is narrow)

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Ocular  Congenital cataracts 1% (correct before 3 mo.)
 Nystagmus (5-30%)
 Strabismus (23-44%)
 Blepharitis (2-67%)
 Refractive Errors (70-80%)
 Tear duct stenosis
 Cataract after 25 yrs (12-86%)
Immune
system
 Frequent infections
 Hepatitis B
 Autoimmune diseases
 Celiac disease
 Trace element deficiency
System wise problems in Down
Syndrome

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Endocrine  Congenital hypothyroidism 1%
Hypo or hyperthyroidism, Thyroid antibodies
 Growth retardation
Orthopedic  Muscle hypotonia
 Joint laxity
 Dislocation of patella and hip
 Hallus valgus
 Atlantoaxial dislocation (10% radiologically)
Urogenital  Renal hypoplasia , post urethral valves
 Cryptorchidism, hypospadiasis
 Boys - Sterility
System wise problems in Down
Syndrome

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Diagnosis
 Prenatal
 U/s – Double bubble
 Echo - AV canal defects
 X- Ray – Short femur or humerus
 Echogenic small bowel - Double bubble
appearance
 Postnatal
 Physical examination
 Confirmation
 Chromosome evaluation

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During 1st and 2nd trimester serum
testing
What is measure When is it
measured
Where does it
come from
Other information
Pregnancy associated
plasma protein-A
(PAPP-A)
1st
trimester
Produced by the
baby and placenta
Very low in mother’s blood can indicate
poor placentation
Beta human chorionic
gonadotrophin (bhCG)
1st and 2nd
trimester
Produced by the
baby
High levels of bhCG in mother’s blood
indicate problems with pregnancy like fetal
growth restriction
Unconjugated oestriol
(uE3)
2nd
trimester
Produced by the
placenta
Very low levels of uE3 indicate biochemical
disorder of Smith Lemli Opitz syndrome,
steroid sulphatase deficiency
Alfa fetoprotein (AFP) 2nd
trimester
Produced by the
baby
Very high AFP in absence of structural
anomalies indicate problem of pregnancy
(fetal growth restriction)
Inhibin A 2nd
trimester
Produced by the
placenta
Very high levels indicte poor placentation

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Preventive Screening – 1st
Trimester
Maternal serum PAPP – A * Increased
Maternal free b hCG Increased
Fetal nuchal translucency
thickness
> 4 mm (USG)
*pregnancy-associated plasma protein A
* Blood collected ideally between 9 -1 2W

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Preventive Screening
1
• Serum a-fetoprotein
• Decreased
2
• Unconjugated estradiol level
• Decreased
3
• Human chorionic gonadotrophin
• Incresed
Triple Test
(Kettering test or the Bart's test)
– Done during 2nd trimester
– 65% detection rate

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Preventive Screening 2nd
trimester
1
• Serum a-fetoprotein
• Decreased
2
• Unconjugated estradiol level
• Decreased
3
• Human chorionic gonadotrophin
• Incresed
4
 Inhibin A
• Increased
Quadruple Test - 75% detection rate
* Blood collected ideally between 15 -17 W

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Iliac Index
(80% accuracy)

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3 D CT image of pelvis : Broad, laterally flattened iliac wings

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For couples who come late or opt for the initial
screening with serum markers and
ultrasonography
 Karyotyping by amniocentesis (16— 18 weeks) or
transabdominal CVS, or cordocentesis (after 18
weeks).
 The karyotype results are available within a week with
cord blood samples and direct CVS preparations.
 The results of amniotic fluid cultures take about 2- 3
weeks.
 The risk of fetal loss after CVS is about 3—4% and
with cordocentesis it is about 3%.
 Amniocentesis poses the lowest risk of about 0.5-1%.

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Non-invasive Prenatal Screening
 Analyzing cell-free fetal DNA in maternal serum is an
important advance in prenatal diagnosis of Down
syndrome.
 Next-generation DNA sequencing has reduced the cost
of this procedure, which has a high degree of accuracy
(98% detection rate) and applicability.

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Down syndrome Screening - overview
SCREENING TEST DETECTION
RATE (%)
1st
Trimester
NT measurement 64-70
NT measure + PAPP-A, free or total b-hCG 82-87
2nd
Trimester
Triple screen (metarnal serim AFP, hCG, uE3) 69
Quadruple screen (metarnal serim AFP, hCG, uE3
+ Inhibin A)
81
1st and 2nd
Trimesters
Integrated (NT, PAPP-A, quadruple screen) 94-96
Serum integrated(PAPP-A, quadruple screen) 85-88

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Treatment : Goals
 Appropriate and timely management of age-
specific Down syndrome–related medical and
developmental conditions
 Early intervention for maximal potential of
developmental skills including occupational,
speech, and physical therapy
 Injury and abuse prevention
 Identify and refer family or caregivers to
financial and medical support programs
 Develop an individual education plan before
transition to preschool

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Management
 Early stimulation : involve therapists and special educators
whose goal is to help the baby develop motor skills,
language, social skills and self-help skills
 Physiotheroapy
 Antioxidants like Zn – Alzheimer’s disease
 AEDs – for epilepsy
 CVS / GI Abnormalities : Corrective surgeries
 Refractory errors : Appropriate lenses
 Speech & Language Defects: Specialist speech therapies
 Anemia: Appropriate nutrients
 Hypothyroidism : Thyroxine
 Skin disorders : Moisteners, appropriate therapies
 Low cholesterol diet
 Immune deficiencies: Vitamin C and Antibiotics

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Management - Monitoring
 Hearing tests - at birth or by 3 months of age.
 A complete blood count (CBC).
 Check for signs of leukemia.
 Thyroid evaluation
 Heart evaluation
 X-rays to evaluate bones in the neck
 Dislocation of the neck bones (atlantoaxial dislocation).
between ages 3 and 5 to look for signs of loose ligaments that
may lead to dislocation.
 Evaluation for Sleep Apnea
 Eye testing – once in an year

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Risk of Recurrence
 Robertsonian Translocation 21 – 13, 14, 15
 Female carrier : 15%
 Male carrier : 5%
 Robertsonian Translocation 21 – 22
 Female carrier : 10%
 Male carrier : 2%
 Robertsonian Translocation 21 – 21
 Female or Male : 100%

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Life Expectations
 The typical life expectancy of people with
Down syndrome has nearly doubled in
recent decades, from 25 years in 1983 to
49 years in 1997
 About 13% of people with Down syndrome
live longer than 68 years

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 Down Syndrome is inherited as ..
A. Autosomal recessive
B. X-linked recessive
C. Autosomal dominant
D. All of the above
E. None of the above

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Than Q - Vittal