Lecture - Down Syndrome
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Transcript of Lecture - Down Syndrome
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Down Syndromeby
Dr. Muhammad Rafique Assistant Professor
Paediatrics College of Medicine, KKU
Abha
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Human cell and chromosome
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DOWN SYNDROME (DS) Most common chromosomal number abnormalityMost 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 varitiesMale: female ratio equal.
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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.
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Characteristics (%) Characteristicss(%)
Mental retardation 100Stunted growth 100Short stature 100Flexible ligaments 80Hypotonia 80Brachycephaly 75Short extremities 70Low set/round ears 60Flattened nose 60Small teeth 60
Clinodactyly 52Umbilical hernia 51Short neck 50Shortened hands 50Cong. heart disease 45 Simian crease 45Macroglassia 43Epicanthic fold 42Strabismus 40Brushfield spots 35
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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.
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60% translocation-between D (13,14,15) &21of G40% - 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….
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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.
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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
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Clinical Features
PATHOGNOMIC FEATURES:
Mental Retardation (100%)
Short Stature (100%)
Generalized gross hypotonia (80%)
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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. 35-50In mosaic, IQ usually 10-30 points higher Family support, enrichment therapies, some
graguated from school, enjoy jobs in work forceHigh incidence-epilepsy, Alzhemeir’s dis.10-25%Speech delay, mostly global developmental delay. Gross motor variable e.g. walking 2-4 yr.
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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.Hypospadias in males about 6%
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Clinical Features CHD:About 40-45% in DSAVSD / 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
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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….
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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
/aspermatogenesis3 examples of being father in literature.
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Clinical Features cont ….Growth retardation especially - having CHD.Obesity-BMR low, less active, indoor activitiesShort stature-male Ht. 157 cm & female 144 cmLimbs 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
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GIT: Anomalies 5-7%, duodenal atresia/stenosis 2.5% Less common - TEF, esophageal atresia, imperforate
anus, Hirschsprung’s disease and annular pancreas2% 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,
fissured, geographical tongue
Clinical features cont….
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EYE PROBLEMS:Upward slanted lateral pelpebral fissure, medial epicanthic
fold, hypertelorism, glaucoma, brush field's (iris)spotsRefractive 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….
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Clinical Features cont….RESP:Repeated aspiration and breathing difficulties
due to hypotonia.Repeated LRTI esp. with mycoplasma is
common due to immunodeficncy & CHDRecurrent 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.
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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….
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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.
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Immune Deficiency:
Chemotactic defects,Low IgG4, Quantitative & qualitative defects of T & B
cells
Clinical features cont….
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ENDOCRINE:Hypothyroidism 2-5% in institutional D.S. may
be congenital/acquired due to autoimmunityDiabetes Mellitus Reproduction
- Females are fertile.
- Males are sterile due to poor/aspermatogenesis
Clinical features cont….
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SKIN DISORDERS: Palmar hyperkeratosis 41% Seborrhic dermatitis 20% Cutis mormorata 13% Geographic tongue 11% Xerosis 10% In adolescents folliculitis is common .
Clinical Features cont….
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BEHAVIOR DISORDERS:
Attension deficit hyperactivity Disorder (ADHD). 25%
Aggressive behavior 7%Autism
Clinical features cont….
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Diagnosis
Mainly ClinicalKaryotyping study. If baby has translocation,- parents karyotying.
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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
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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
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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.
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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
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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.
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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
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Quadruple test
Triple test+ Inhibin A estimationThis test + maternal age detects
76% DS
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Maternal s screening in the 2nd trimester:
detection rate at a fixed 5% false positive rate.
Marker Detection rate (%)
Maternal age alone 30Double test 58Triple test 69Quadruple test 76
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Antenatal ScreeningFuture 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.
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Antenatal ScreeningFuture 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.
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ManagementPrevention-avoiding late child bearing (esp.>35 yr)
Examination & investigations at birth:Red reflex to detect congenital cataractEye exam for strabismusExam for imperforate anusEcho to R/O CHDCBC to R/O cong./transient leukemia Hearing test (BAER) brainstem auditory
evoked responseThyroid functions to R/O c. hypothyroidism
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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-adolescentEarly 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 activities together
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Avoid risky athletics&games-AA joint dislocationFor hypothyroidism, D/M, hearing loss and eye
problems, annual check up and investigationsIf develops s/s of malignancy, investigate and treat If develops coeliac disease– gluten free dietTo avoid repeated RTI:
- If CHD,echo, cardiologist opinion/ surgery
- Prophylactic drugs
- Specific additional vaccines
Management cont….
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Management cont….Plastic surgery-partial glossectomy improve
1/3 for oral competence& 2/3 for speech improv Surgery-GIT, heart &other repairable anomalieSpeech delay Mx. - speech augmentataive &
alternative communication methods e.g. pointing, body language.
Speech therapy for speech delayGlasses for refractive errorsEarly Dx.&Mx . for recurrent RTI and SOM etc.Hearing aids for hearing lossSupport for parents
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