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Down Syndrome

Dr.K.V.GiridharAssociate Prof. of Pediatrics

GMC. Ananthapuramu, A.P.,India.

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History• Named after a physician, “John

Langdon Down” in 18th century.• Described as Mongoloid child of

European parentage-”Mongolism”• In 1959 a French doctor, named

“Jerome Lejeune”, discovered it was caused by the inheritance of an extra chromosome 21.

• Also known as “trisomy 21”

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Incidence

• Incidence classified according to 3 major ethnic groups•Malay - 1 in 981•Chinese - 1 in 940• Indians - 1 in 860

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Introduction

• Down syndrome is an autosomal disorder because it affects chromosome 21, which is an autosome.

• Down syndrome is neither a dominant nor recessive trait because it is just an error in the “translation” process of chromosome 21.

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Genetics of DS• It is believed that the ‘amyloid precursor

protein gene (App)’ is the cause of ‘Down syndrome’, and it is located on chromosome 21.

• A mutation in this gene usually results in Alzheimer’s disease . Similarly three copies of this gene has a huge effect on the brain & other tissues of body.

• Scientists believe that excess ‘App’ gene is causing the cells to die (apoptosis), because it interfere with the normal cell division (mitosis).

• Therefore people with down syndrome tend to develop the brain with signs of Alzheimer’s and abnormalities other parts of the body.

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92% -94% Trisomy 21- nondisjunction during fertilisation

2-4% Mosaicism- error in cell division after fertilisation

3-4% Translocation of chromosome 21- breaking and attaching to other chromosomes (14) during cell division

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Down Syndrome & Maternal Age

A study done in Mysore, India - paternal age and maternal grandmother’s age influences Down Syndrome in neonates.

Age Incidence of Down Syndrome

< 30303536373839404244464849

Less than 1 in 10001 in 9001 in 4001 in 3001 in 2301 in 1801 in 1351 in 1051 in 601 in 351 in 201 in 161 in 12

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Risk factors

• Advancing maternal age – usually women of age 35 and above

• Mothers who already have one child with Down syndrome – increased risk for subsequent pregnancies

• Parents who are carriers of the genetic translocation for Down syndrome

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Clinical features• Life expectancy : 55 years

(National Down Syndrome Society)

• Physical appearances– flat facial profile and an upward

slant to the eye – short neck– abnormally shaped ears– white spots on the iris of the eye

(called Brushfield spots)– single, deep transverse crease on

the palm of the hand.

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- relatively late development ofdeciduous and permanent teeth as

compared with other children- Teeth could appear in a different

sequence and positions - Teeth are often are rounded,

pointed or cone-shaped. Smaller with gaps

- Fewer teeth. - Maxilla is narrow, the tongue

appears too big for the mouth and the teeth may be pushed out of place, as the child grows older.

- Habit of breathing through the mouth- Mental retardation varied from mild to

moderate – some even have special abilities after training and early interventions

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Neonatal features

• Flat facial profile• Poor Moro reflex• Excessive skin

at the nape of neck

• Slanted palpebral fissures

• Hypotonia • Hyper flexibility

of joints

• Dysplasia of pelvis

• Anomalous ears• Dysplasia of

midphalanx of fifth finger

• Transverse palmer crease(simian)

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Percentage of dysmorphic features and physical abnormalities in ‘Down syndrome’ children

Dysmorphic features

Current study (%)

Kava et al (%)

Kumar et al

(%)

Jones (%)

Fryns (%)

Upslanting palpebral fissuresFlat facial profileEars abnormalityHypotoniaSimian creaseSandle signHypertelorismShort stubby fingersProtruding tongueClinodactylyEpicanthic foldsExcessive skin fold on neck

89.364.956.152.636.833.333.324.519.219.217.512.2

83.950.966.976.333.246.233.9

-29.936.156.936.8

---

8040----

5060-

8090608045----

50-

80

809050

21-774845---

6240

81/85

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• Other Health-related problems– Cardiovascular problems • ventricular spetal defect, atrial septal defect,

patent ductus arteriosus

– Endocrine problems• thyroid problems, diabetes mellitus

– Gastrointestinal problems – duodenal, esophageal and anal

atresia,Hirschprung’s disease– Haematological problems • Acute leukemia, transient myeproliferative

disease

– Neurological problems • Epilepsy, severe behavioral problems,

Alzheimer’s, memory problems

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– Sleep problems• Sleep apnoea, other sleep disturbance

– Skeletal problems• Flat foot, atlantoaxial subluxation

– Visual problems • Refractive disorder, squint, nystagmus

– Hearing problems• Hearing loss, conductive hearing loss, chronic otitis media

- Obesity and nutrient deficiency- Malabsorption (probably linked with celiac disease) due to intestinal damage

- Some has lack of vitamin B12, folic acid and zinc

- Need for antioxidants i.e. vitamin E

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Mental Retardation

• Almost all DS babies have MR.• Mildly to moderately retarded .• Starts in the first year of life.• Average age of sitting(11 mon), and

walking (26 mon) is twice the typical age.

• First words at 18 months.• IQ declines through the first 10 years of

age, reaching a plateau in adolescence that continues into adulthood.

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Heart Disease• 50 % of Down Syndrome pts have

heart disease• Endocardiac cushion defects• VSD• Secundum ASD• PDA• Tetrology of Fallot• Mitral valve prolapse• AR, MR

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GI abnormalities

• 5% of cases• Duodenal atresia or stenosis,

sometimes assoc with annular pancreas in 2.5 % of cases

• Imperforate anus• Esophageal atresia with TE fistula is

less common• Hirschsprung’s disease• Strong assoc with celiac disease

between 5 – 16 % ,

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Growth• Weight, length and HC are less in DS • Reduced growth rate• Prevalence of ‘obesity’ is greater in

DS• Weight is less than expected for

length in ‘infants’ with DS, and then increases disproportionally so that they are obese by age 3-4 yrs

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Eye problems

Most common disorders are Refractory error – 35 to 76 %Strabismus – 25 to 57 percent Nystagmus – 18 to 22 percentCataract occur in 5 % of

newborns, Frequency increases with age.

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Brush field spots

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Hearing loss

• Unilateral or bilateral• Conductive, sensorineural or

mixed• Otitis media is a frequent

problem

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Hematologic disorders• The risk of leukemia is 1 to 1.5 percent.• 65% of newborn have polycythemia

resulting in hypoglycemia.• Risk of AML and ALL is also much higher

than the general population.• Transient leukemia – exclusively affects

NB. - It is asymptomatic with spontaneous

resolution in 2-3 months.

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Endocrine disorder• Thyroid disease –

Hypothyroidism occurs more frequently than hyperthyroidism.

• Diabetes – The risk of type 1 diabetes is

three times greater than that of the general population.

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Reproduction

• Women with DS are fertile and may become pregnant.

• Nearly all males with DS are infertile. Due to impaired ‘spermatogenesis’.

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Skeletal abnormalities

• Excessive mobility of atlas (C1) and the axis (C2), may lead to subluxation of the cervical spine. (Atlantoaxial instability )

• Diagnosis made by lateral neck radiograph.

• flat foot, dysgenesis of middle phalax in little finger, narrow maxilla, clindactyly.

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Skin disorder

• Palmoplantar hyperkeratosis• Seborreic dermatitis• Fissured tongue• Cutis marmorata• Geographical tongue• Xerosis

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Diagnosis

• Prenatal screening

• If no screening – It can be recognized by the characteristic phenotypic features.

• Confirmed by genetic Karyotyping.

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Management1. Growth – Measurements should be

plotted on the appropriate growth chart for children with DS.

• This will help in prevention of obesity and early diagnosis of celiac disease and hypothyroidism.

2. Cardiac disease – All newborns should be evaluated by cardiac ECHO for CHD in consultation with pediatric cardiologist.

3. Hearing – Screening to be done in the newborn period, every 6 months until 3 yrs of age and then annually.

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Management (cont.)4. Eye disorders - An eye exam should

be performed in the newborn period or at least before 6 months of age to detect strabismus, nystagmus, and cataracts.

5. Thyroid Function – Should be done in newborn period and should be repeated at six and 12 months, and then annually.

6. Celiac Disease – Screening should begin at 2 yrs. Repeat screening if signs develop.

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Management ( cont)7. Hematology – CBC with DLC at birth to

evaluate for polycythemia as well as leukemia.

8. Atlanto-axial instability – X ray for evidence of AAI or sub-luxation at 3 to 5 years of age.

9. Alzheimer’s disease – Adult with a Down Syndrome has earlier onset of symptoms. When diagnosis is considered, thyroid disease and possible depression should be excluded.

10.Rehabilitation

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Prevention

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Counseling

• May begin when a prenatal diagnosis is made.

• Discuss the wide range of variability in manifestation and prognosis.

• Medical and educational treatments and interventions should be discussed.

• Initial referrals for early intervention, and ‘rehabilitation’.

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Mortality

Avarage life span is 25yrs. To 50 yrs.Most likely cause of death is CHD, AAI, Hypothyroidism and Leukemia.Improved survival is because of increased placements of infants in ‘rehabilitation homes’ and changes in treatment for common causes of death.Survival is better for males

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Thank you