lecture

1. Down Syndrome
by
Dr. Muhammad
Rafique
Assistant Professor
Paediatrics
College of Medicine, KKU Abha

2. Human cell and chromosome

3. DOWN SYNDROME (DS)
Most common chromosomal number abnormality
Most common cause of mental retardation (MR)
Named after British Dr. Jhon Langdon Down
who describe its features in 1862.
80% diagnosis in NNU but 20% are missed b/c
most - clinical features in normal babies.
DS is an umbrella term, used collectively for
trisomy, translocation and mosaic varities
Male: female ratio equal.

4. INCIDENCE
Non-disjunction increases with maternal age.
Generally (0.01%) 1: 700 -1000 (live
births)
At younger age - <20yr 1: 4000
At ---------------- - 35yr 1: 400
At ----------------- 40yr 1: 110
At ----------------- 45yr 1: 35
Maternal age - no effect on translocation variety.
rather opposite effect - high fertility at lower age
Paternal age - mild effect esp. after 42 yr.

6. Characteristics (%) Characteristicss(%)
Mental retardation 100
Stunted growth 100
Short stature 100
Flexible ligaments 80
Hypotonia 80
Brachycephaly 75
Short extremities 70
Low set/round ears 60
Flattened nose 60
Small teeth 60
Clinodactyly 52
Umbilical hernia 51
Short neck 50
Shortened hands 50
Cong. heart disease 45
Simian crease 45
Macroglassia 43
Epicanthic fold 42
Strabismus 40
Brushfield spots 35

13. VARITIES
(i) Trisomy 21 : 95% of DS
 Due to non- disjunction of chromosome pair during
meiosis-I. Fully developed phenotype.
Majority(>3/4) extra ch.- from egg,<25% - sperm
(ii) Translocation:
4% of DS. A part of one chr. is attached to other one
and vise versa. Less clear phenotype
Young maternal age, translocation chances high e.g.
9% of DS at <30 yr age.

17. 60% translocation-between D (13,14,15) &21of
G
40% - translocation is between G and G (21,22)
25 – 50% translocations are due to new mutation.
50 -75% are due to translocation carrier parents.
(iii)MOSAIC:
1% of DS. Less sever S/S. Phenotype normal
2 cell lines - normal and abnormal chr. No.
Sperm/egg normal. After fertilization ,during
rapidly dividing cell phase. Some cells revert to
normal chr. re-arrangement, so mixed cells.
Varities cont….

18. Example of a Robertsonian translocation in which the long arms of one chromosome 14 and one chromosome 21 are fused
in the carrier parent (upper panel) is a cause of Down syndrome in the offspring. One of the three viable gametes will be
normal, one will have a balanced rearrangement, and one will contain the fused chromosome [der(14;21)] as well as the
unaffected chromosome 21. Normal fertilization of this gamete results in a fetus with trisomy 21. Other possible segregation
products are gametes lacking a chromosome 21, gametes lacking a chromosome 14, and gametes with one chromosome 14
and a derivative chromosome der(14;21), all of which are not viable. Courtesy of Iris Schrijver, MD.

19. Recurrence Rate
(i) Trisomy -21: 1% + maternal age effect
(ii) Translocation:
D Group (13,14,15) & 21 chr. of G group
- mother carrier - 15%
- father carrier - 5%
t(21, 22)
- mother carrier - 10%
- father carrier - 2%
t(21,21)
lethal or 100% recurrence

20. Clinical Features
PATHOGNOMIC
FEATURES:
Mental
Retardation
(100%)
Short Stature
(100%)
Generalized gross
hypotonia (80%)

21. Clinical Features
Initially IQ is better 50-75. Reduce with
increasing age. Usually it is 50/100.
 Usually max. developmental age is 8-10 yrs.
Mild intellectual disability -IQ 50-70, mod. 35-
50
In mosaic, IQ usually 10-30 points higher
Family support, enrichment therapies, some
graguated from school, enjoy jobs in work force
High incidence-epilepsy, Alzhemeir’s dis.10-25%
Speech delay, mostly global developmental
delay.

23. Clinical Features
Brachycephaly, short neck, excessive skin at
neck
Flat, round face, depressed bridge of nose, ear
anomalies like small and folded ears
Poor or absent morro reflex- 80%
Physical changes rapid (premature aging)
Average age is 50-55 yr.
Mild to moderate MR - trainable for self care
Low risk-solid tumours, hardening of vessels
and diabetic retinopathy.


25. Clinical Features
CHD:
About 40-45% in DS
AVSD / endocardial cushion defect (most
common 33-40%) with or without other CHD.
VSD about 30%
CHD/ its complications are the most common
cause of death.
CCF & pul. V Disease increase mortality in F up

26. Unsexual, playful, affectionate, mischievous
friendly, imitative, music liking-called good babies
JRA and other autoimmune diseases common
Atlanto axial joint dislocation/instability (10-20%)
due to ligament over-laxity and shallow axial
foramen, may leads to spinal cord complications.
 Sometimes degenerative changes in cervical spines.
hyper flexibility of ligaments & joints.
Gall stone 3.5%. rarely congenitally present.
Clinical Features cont….

28. Clinical Features cont….
INFERTILITY:
Females are also less fertile.
Females after conception have difficulties like
miscarriage, premature birth, difficult labour.
Outcome babies are 50% DS.
Males are sterile due to poor
/aspermatogenesis
3 examples of being father in literature.

29. Clinical Features cont ….
Growth retardation especially - having CHD.
Obesity-BMR low, less active, indoor activities
Short stature-male Ht. 157 cm & female 144 cm
Limbs are short.
Short staby hand, simion crease 40%.
Clinodactyly of 5th
finger due to hypoplasia of
middle phalynx and single flexure crease 20- 45%
Dysplasia of pelvis
Sandal sign-increase space between 1st
& 2nd
toe

31. GIT:
Anomalies 5-7%, duodenal atresia/stenosis 2.5%
 Less common - TEF, esophageal atresia,
imperforate
anus, Hirschsprung’s disease and annular pancreas
2% Hirschsprung’s disease patients are D.S.
5-16% D.S. are having coeliac disease.
Poor swallowing due to hypotonia
Semi open small mouth /oral cavity, GERD
Cleft/oval palate. Large, protruded, furrowed,
Clinical features cont….

32. EYE PROBLEMS:
Upward slanted lateral pelpebral fissure, medial
epicanthic fold, hypertelorism, glaucoma, brush
field's (iris)spots
Refractive errors 35-75%
(Myopia, hypermetropia, astigmatism )
Strabismus 25- 57%
Nystagmus 18- 22%
Cataract 5% (starts in 2nd
decade)
 Frequency of ocular disorders increase with age.
Clinical Features cont….

34. Clinical Features cont….
RESP:
Repeated aspiration and breathing difficulties
due to hypotonia.
Repeated LRTI esp. with mycoplasma is
common due to immunodeficncy & CHD
Recurrent ear infections (otitis media 50–70%)
Obstructive sleep apnea 30-75% due to
hypotonia, laryngomalacia, large tongue, mid face
hypoplasia, increased size of tonsils and adenoids.

35. HEARING LOSS:
Hearing impairment initially 38-78 (2mo–3.5
yr)
Now aggressive & meticulous Dx. and Mx. of
SOM (50-70% in DS) it has reduced to 2%
Frequent monitoring is important to prevent
hearing loss.
Clinical features cont….

36. Clinical Features cont….
HEMATOLOGICAL PROBLEMS:
Leukemia 1- 1.5% in DS. ALL, 10 times and
AML is 50 times more common
< 2 yr AML and >2 yr ALL is common
 Polycythemia 65%, -high erythropoitin level.
 Solid tumours less common – tumour suppressor
gene on genetic material of extra chr. 21
Transient leukemia:affect newborns 20%,
majority – asymptomatic-spontaneous resolution
in 2 – 3M.

37. Immune Deficiency:
Chemotactic defects,
Low IgG4,
Quantitative & qualitative defects of T & B
cells
Clinical features cont….

38. ENDOCRINE:
Hypothyroidism 2-5% in institutional D.S. may
be congenital/acquired due to autoimmunity
Diabetes Mellitus
Reproduction
- Females are fertile.
- Males are sterile due to poor/aspermatogenesis
Clinical features cont….

39. SKIN DISORDERS:
 Palmar hyperkeratosis 41%
 Seborrhic dermatitis 20%
 Cutis mormorata 13%
 Geographic tongue 11%
 Xerosis 10%
 In adolescents folliculitis is common
.
Clinical Features cont….

41. BEHAVIOR DISORDERS:
Attension deficit hyperactivity Disorder
(ADHD). 25%
Aggressive behavior 7%
Autism
Clinical features cont….

42. Diagnosis
Mainly Clinical
Karyotyping study.
If baby has translocation,- parents karyotying.

43. Antenatal Screening
A- INVASIVE TESTS:
Detection is up to 99.8%
with rare false +ve result
(i)CVS (chorionic Villous
sampling):
At 10-12 weeks. Fetal cells
are obtained, cultured &
karyotyping is done.
(i)Amniocentesis:
At 14-16 weeks

44. B- NON INVASIVE TESTS:
(i) Biochemical tests: (assessment-
maternal blood)
a) AFP: (alpha fetoproteins)
At 14 - 16 weeks. lower in D.S.
b) B-hCG: (beta human chorionic
gonadotropin)
Possible in 1st
trimester- more
useful at 14 –16W (About 2 time
higher value in DS)
Antenatal Screening

45. NON INVASIVE TESTS cont….
c) Oestriol (uE3)
At 14 – 16 weeks, value is lower in D.S.
d) Inhibin- A
e) PAPP-A (pregnancy associated placental
protein-A)
At 8-13 weeks. Currently single best serum
marker with 42% detection rate and 5% false
+ve rate, 2.5 times low.

46. NON INVASIVE TESTS cont...
ii. USG:
Nuchal translucency (NT)
of fetus. Normal 1-2 mm,
increases with gest. age,
60% detection rate with
5% false +ve rate at
10wks. Max. 69%
detection rate with 4%
false +ve rate at 12–13 wk

47. Double Test
Low, pregnancy associated plasma
proteins-A (PAPP-A) level and raised serum
Beta-hCG during 1st
trimester
Double test+ maternal age Dx. 60% DS.

48. Triple Test
 It comprises
. AFP
. B-hCG
. uE3 (unconjugated oestriol)
 Best carried at 15-18 wks.
 AFP & uE3 are low while B-hCG is raised
 Triple test+ maternal age, diagnose 69%
DS

49. Quadruple test
Triple test+ Inhibin A estimation
This test + maternal age detects 76% DS

50. Maternal s screening in the 2nd trimester:
detection rate at a fixed 5% false positive rate.
Marker Detection rate (%)
Maternal age alone 30
Double test 58
Triple test 69
Quadruple test 76

51. Antenatal Screening
Future Development :
1- Fetal nasal bone:
In first trimester in
DS fetuses, nasal bone
was found to be
absent 76% while
1.4% normal fetuses
were also found to be
having no nasal bone.

52. Antenatal Screening
Future Development :
2- Fetal ductus venosus:
Doppler USG of DV in normal
pregnancy demonstrate a forward
biphasic flow. In fetuses with an
aneuploidy or cardiac defect, there
is reverse flow at the time of atrial
contraction . A study showed +ve in
60-93% DS fetuses but 2-21% normal
fetuses also displayed same findings.
Further work is required in this
aspect.

54. Management
Prevention-avoiding late child bearing (esp.>35 yr)
Examination & investigations at birth:
Red reflex to detect congenital cataract
Eye exam for strabismus
Exam for imperforate anus
Echo to R/O CHD
CBC to R/O cong./transient leukemia
Hearing test (BAER) brainstem auditory
evoked response
Thyroid functions to R/O c. hypothyroidism

55. Management
In UK/Europe 92% - abortion after antenatal Dx.
Parents counseling about
- Nature & problems, future antenatal screening,
family planning, karyotyping of baby & parents.
- Mx. of menstruation &contraception-adolescent
Early interventions from birth, to coordinate and
plan effective strategies for learning development.
• Special schools/institutions for education&
training In Germany/Denmark, two school teacher
system, 1- main stream& 2-special disabilities
within class sports, outing, breaks, meals&art

56. Avoid risky athletics&games-AA joint dislocation
For hypothyroidism, D/M, hearing loss and eye
problems, annual check up and investigations
If develops s/s of malignancy, investigate and treat
If develops coeliac disease– gluten free diet
To avoid repeated RTI:
- If CHD,echo, cardiologist opinion/ surgery
- Prophylactic drugs
- Specific additional vaccines
Management cont….

57. Management cont….
Plastic surgery-partial glossectomy improve
1/3 for oral competence& 2/3 for speech
improv
Surgery-GIT, heart &other repairable
anomalie
Speech delay Mx. - speech augmentataive &
alternative communication methods e.g.
pointing, body language.
Speech therapy for speech delay
Glasses for refractive errors
Early Dx.&Mx . for recurrent RTI and SOM etc.