This document provides information on Down syndrome (DS), including its causes, genetics, clinical features, diagnostic tests, and risk factors. DS, also known as trisomy 21, is caused most commonly by non-disjunction resulting in a third copy of chromosome 21. It causes intellectual disability and physical features such as a flat facial profile, upslanted eyes, and loose skin at the neck. Diagnosis is usually based on clinical features and confirmed through karyotyping, FISH, or prenatal screening/diagnostic tests. The risk of DS increases with maternal age and for mothers who previously had a child with DS.

1. Dr Ebin Roshan Paul

2. Dysmorphology and Syndrome
 Dysmorphology - study of abnormal body shape and
defects. { Dys= abnormal ; morph= shape }
 Syndrome – recognizable pattern of dysmorphic signs
that have a common cause.

3. Introduction
Most common genetic cause of intellectual disability.
 First described by John Langdon Down in 1866,
physician from England.
 Incidence 1 in 800 worldwide. But incidence at
conception is twice that rate , which accounts for early
pregnancy losses.
Previously called as ‘Mongolism’ not used now.

5.  1515 the painting “The Adoration of the Christ Child”.

6. Risk factors
 1. Increased maternal age : older eggs have greater risk
of improper chromosomal division ( spindle fibres
deterioration ) causing Non disjunction.
 >35 years. Risk is non linear
 2. Mothers who already have a child with DS.
 3. Parents who are carriers for translocation – can
pass it to baby. ( familial DS )

7. Genetics
 First described by French doctor Jerome Lejeune in 1959.
 Presence partial or complete third copy of chromosome 21.
 200-300 genes in chromosome 21 together with other epigenetic
factors produce clinical features of DS.
Trisomy 21 occurs by
 1. Non disjunction (95%)
 2. Translocation (3-4 %)
 3. Mosaicism ( 1-2 % )
 4. Partial trisomy ( <1 % )

8. Non disjunction
 95 % . Non familial.
 Meiotic non disjunction ( free Trisomy )
 47 chromosomes seen instead 46 { 47 ,XX/XY,+21 }
 90% maternal non disjunction and 10 % paternal non
disjunction.
 Risk increases with maternal age. Especially > 35
years.

9.  hghagxh

10. Translocation
 3-4 %
 Robertsonian translocation between 21q and other
acrocentric chromosomes ( 13,14,15,21 and 22 ).
 Can be denovo (75%) or inherited (25%) .
 25% of these cases can be due to inheritance from a
balanced translocation carrier parent. So parental
evaluation is a must, if carrier high recurrence rate.
 Usually called as “familial DS”.

12. Robertsonian translocation

13. Mosaic
 1-2 %
 the result of an early “trisomy rescue” or early
somatic non disjunction error.
 Difficult to predict DS phenotype due to variable
percentage of mosaicism in different tissues.
 Usually mildly affected.

14. Partial Trisomy
 Duplication of the delimited segment ( a region ) of
chromosome 21.
 Produce some extra copies but not all genes on
chromosome 21. [ 46, XY/XX, dup (21q) ]
 If duplicated part have genes which produce features
of Down syndrome they will express in Phenotype.
 Rare < 1 %

16. Pathophysiology
 Presence of extra genetic material causes over
expression of genes in chromosome 21 ( Dosage
Imbalance )
 Length of 21 q is 33.5 Mb and 21 p is 5-15 Mb.
 DS critical regions (DSCR) : few regions of
chromosome 21 is responsible for majority of DS
phenotype.
 Mainly within 21q22 region.

17. Some common genes located in
chromosome 21
 AAP ( Amyloid beta precursor protein ) implicated in
Alzheimer’s disease.
 SOD 1 ( superoxide dismutase 1 )
 DYRK1A ( Dual Specificity tyrosine – (Y)-
phosphorylation regulated kinase 1A )
 S100B ( calcium binding protein )
 DSCR 1 ( Down syndrome critical region 1 )
 LAD ( Leukocyte Adhesion Deficiency )
 KCNE 1 and 2 ( Potassium voltage gated channel )
 CBS ( Cystathionine Beta synthase )

19. Clinical features of DS

25. Brushfield spots

27. Reproductive function
 Women with DS are fertile
 Nearly all males with DS are infertile due to impaired
“spermatogenesis”

28. Hall’s criteria ( ≥ 4 /10 )
 10 cardinal signs – Bertil Hall in Clinical paediatrics.
 1. Poor Moro Reflex
 2. Hypotonia
 3. Flat facial profile
 4. Up slanting palpebral fissures
 5. Dysplastic ears
 6. Redundant loose neck skin
 7. Simian crease
 8. Hyper extensible joints
 9. Pelvis dysplasia
 10. Hypoplasia of fifth finger middle phalanx

29.  Preterm newborn not showing typical features of
down syndrome

30. Dermatoglyphics in Down
syndrome
 Digital and Palmar dermatoglyphics are considered.
No feature is alone diagnostic, because seen in
common population also.
 But when several features are there, can be an
indicative of an associated syndrome.

31.  1. Excess ulnar loops
 2. Radial loops mainly in 4th and 5th digit
 3. Wide ATD angle
 4. Simian crease
 5. Digital loop between the base of the index finger &
middle finger / middle finger & ring finger opening to
inter digital space.

32. Tri radius
 Point of convergence of 3 regions that separate almost
parallel ridges.

33. Radial Loop opening

34. Wide ATD angle and Loop

35. Simian and Sydney crease
 Based on PTC and DTC
 Simian – fusion of PTC and DTC
 Sydney – very long PTC which crosses the whole width
of palm. DTC appears normal.

36. Why Dysmorphology important ?
Genetic Tests are mainly
 1. Costly.
 2. Time consuming.
 3. Cannot be easily accessed in remote area limited
settings.
Physical examination is the most accurate initial
diagnostic tool in practise.

37. Diagnostic tests in DS
1. Prenatal diagnosis – screening test and invasive
diagnostic testing.
2. Post natal diagnosis.
 Why need screening ? – frequency, increased maternal
age related risk, availability of diagnostic test.
 ACOG : All pregnant women must be provided with
options of screening with less invasive method.

38. 1 st TM screening
 Detection rate 82-87%
 1. NT scan + soft markers
 2. Maternal serum B- HCG level
 3. PAPP-A level ( Pregnancy associated Plasma protein )
Plus “Maternal age related risk”

39. 2 nd TM screening
 “Quad screen”
 1. Maternal serum B- HCG level
 2. Unconjugated estriol
 3. AFP levels
 4. Inhibin level
Plus “maternal age related risk”

40.  Combining 1 and 2nd TM screening detection rate is
95 % called “ integrated screening ”
 Screening test are reported to have 5% FPR.
 Confirmation is done by Invasive testing but
miscarriage risk is 0.5 -1 %
 Chorionic Villus Sampling ( >11 weeks )and
Amniocentesis ( >16 weeks )

41. Karyotype analysis
 99 % accurate
 Metaphase karyotype G banding is done on fetal cells.
 Other than Trisomy 21, other aneuploidy and Balanced
translocations can be detected.
 Cost low
 4 week time needed. Time consuming.
 < 4 Mb ( sub microscopic ) deletions are missed.

44. SKY ( Spectral Karyotyping )
 Painting 24 chromosomes with colours.
 5 basic dyes used , mixed to produce various colours
(31colours )
 Clinical use – 1. when origin of chromosome not clear
2. helps to identify parental origin
or carrier state without screening.
Limitation : detection within same chromosome
difficult. Resolution limit is 1-2 Mb and less than 1 Mb
cannot detected.

45. SKY

46. FISH
 2 types –Interphase FISH ( simple uncultured blood)
and Metaphase FISH ( Karyotype FISH ).
 Rapid turn around ( 1 week )
 Fluorescent tagged centromere probes are used, so
signals appears as distinct dots.
 Since large number of nucleus used in Interphase
FISH mosaicism is not missed.
 <4 Mb deletions are noted.

47. Disadvantages of FISH
 Since Interphase chromosomes are less dense so
diffuse signals may produced.
 Translocations are missed so need karyotype
confirmation.

48. Interphase FISH Trisomy 21

49. NIPT ( Non Invasive Prenatal
testing )
 Cell free fetal DNA (cf DNA) circulating in maternal
blood is used for sequencing.
 5-10 % of total cell free DNA in maternal plasma.
 Increased during gestation age and rapid clearance
after delivery.
 Looked for aneuploidy, extra chromosomes.
 NIPT still considered as screening test and need
Invasive test for confirmation.

51. Post natal diagnosis
 Based on clinical features and followed by
confirmatory genetic tests.
 Physical examination is the most accurate initial
diagnostic tool in practise.
 Confirmatory test include Karyotype and FISH.
 Followed by parental testing if indicated.

52.  Risk assessment of next child with DS depends on
 1. Maternal age related risk
 2. Karyotype result of affected baby
 3. Parental carrier status and translocation.