lecture - down syndrome

Down Syndromeby

Dr. Muhammad Rafique Assistant Professor

Paediatrics College of Medicine, KKU

Abha

Human cell and chromosome

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.

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.

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

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.

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….

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.

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

Clinical Features

PATHOGNOMIC FEATURES:

Mental Retardation (100%)

Short Stature (100%)

Generalized gross hypotonia (80%)

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.

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%

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

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….

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.

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

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….

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….

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.

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….

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.

Immune Deficiency:

Chemotactic defects,Low IgG4, Quantitative & qualitative defects of T & B

cells

Clinical features cont….

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….

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

Clinical Features cont….

BEHAVIOR DISORDERS:

Attension deficit hyperactivity Disorder (ADHD). 25%

Aggressive behavior 7%Autism

Clinical features cont….

Diagnosis

Mainly ClinicalKaryotyping study. If baby has translocation,- parents karyotying.

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

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

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.

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

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.

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

Quadruple test

Triple test+ Inhibin A estimationThis test + maternal age detects

76% DS

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

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.

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.

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

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

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….

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