🧬 Down Syndrome (Trisomy 21)

1. Definition

Down syndrome is a genetic disorder caused by the presence of an extra copy of chromosome 21 (Trisomy 21). It results in intellectual disability, distinctive facial features, and increased risk of various medical conditions.

2. Causes

95%: Non-disjunction Trisomy 21 (three copies of chromosome 21)
4%: Robertsonian translocation involving chromosome 21
1%: Mosaicism (some cells have 46 chromosomes, others have 47)

3. Risk Factors

Advanced maternal age (>35 years)
Previous child with Down syndrome
Parental balanced translocation involving chromosome 21
Spontaneous occurrence in most cases (especially non-disjunction)

4. Types

Type	Description
Trisomy 21	Full extra chromosome 21 in all cells (most common)
Translocation	Extra chromosome 21 material attached to another chromosome
Mosaicism	Some cells normal, some have Trisomy 21 (usually milder features)

5. Pathogenesis

Extra chromosome 21 → overexpression of genes → altered fetal development
Affects neural, cardiac, GI, hematologic, and skeletal systems
Impaired brain development → cognitive and motor delay
Increased risk of early-onset Alzheimer’s and certain cancers (e.g., leukemia)

6. Clinical Presentation

Symptoms

Hypotonia (floppy baby)
Feeding difficulties in infancy
Developmental delay (motor, speech)

Physical Signs

Flat facial profile
Up-slanting palpebral fissures
Epicanthic folds
Small ears, flat nasal bridge
Single palmar crease
Clinodactyly: abnormal curved finger
Wide gap between 1st and 2nd toes
Brushfield spots (iris)

Physical Exam Findings

Hypotonia
Poor Moro reflex
Heart murmur (due to congenital heart disease)
Growth below average (use Down syndrome growth charts)

7. Organ & System Complications

System	Complications
Cardiac	AV septal defect, VSD, ASD
GI	Duodenal atresia, Hirschsprung disease, constipation
Neurodevelopment	Intellectual disability, speech/language delay
Vision	Cataracts, refractive errors, strabismus
Hearing	Otitis media, conductive hearing loss
Endocrine	Congenital hypothyroidism, diabetes mellitus
Immune	Increased risk of infections, autoimmune thyroiditis
Hematologic	Leukemia (especially Transient Myeloproliferative Disorder (TMD) and ALL)
Musculoskeletal	Atlantoaxial instability, scoliosis
Sleep	Obstructive sleep apnea

8. Diagnostic Investigations

Prenatal

Non-invasive prenatal testing (NIPT): cell-free fetal DNA
Chorionic villus sampling / Amniocentesis: karyotyping

Postnatal

Clinical features + karyotype confirmation

9. Other Relevant Investigations

Echocardiogram (for congenital heart disease)
TSH/T4 (thyroid screening at birth, then yearly)
Eye exam by 6 months
Hearing screen at birth, then 6–12 monthly
Neck X-ray if neurologic symptoms (atlantoaxial instability)
Sleep study by age 4 or if snoring/sleep issues
CBC and blood film (rule out TMD or leukemia in neonates)

10. Treatment

Empirical

Antibiotics for infections, thyroid hormone replacement if hypothyroid

Supportive

Early Intervention Programs (speech, physio, occupational therapy)
Educational support (special education, inclusion programs)
Hearing aids, glasses, cardiac surgery if needed

11. Long-Term Medications Side Effects

Children with Down syndrome may be on long-term medications for:

Hypothyroidism: Levothyroxine
Seizures: Anticonvulsants
Leukemia: Chemotherapy (if affected)

Medication	Side Effects	Monitoring Tests	Expected Results
Levothyroxine	Over/under-replacement symptoms	TSH/T4 every 6 to 12 months	TSH normal range
Anticonvulsants	Liver toxicity, sedation, gum hypertrophy	LFTs, drug levels	Stable ALT/AST
Chemotherapy	Myelosuppression, infection risk	CBC, liver, kidney tests	WBC, Hb in normal range

12. Surveillance for Down Syndrome

System / Domain	When	What to Monitor / Do
Cardiac	At diagnosis (newborn period)	Echocardiogram to detect congenital heart defects (e.g., AVSD, VSD)
Vision	By 6 months, then yearly	Ophthalmology exam – screen for cataracts, strabismus, refractive errors
Hearing	Newborn, then every 6–12 months	Audiology screen – detect conductive/sensorineural hearing loss, otitis media
Thyroid function	At birth, 6 months, 12 months, then yearly	TSH and Free T4 – screen for congenital and acquired hypothyroidism
Hematologic (Leukemia)	- At birth (CBC) - Monthly for 1st year if TAM - Symptom-based after infancy	CBC + peripheral blood film to detect Transient Abnormal Myelopoiesis (TAM) Follow-up CBC monthly if TAM is detected Monitor for symptoms of leukemia (pallor, bruising, fever, hepatosplenomegaly)
Growth	Every clinic visit	Monitor height, weight, and head circumference using Down syndrome-specific growth charts
Neurodevelopment	At diagnosis, then every 3–6 months	Screen for motor, speech, cognitive delays; refer to early intervention programs
OSA	By 4 years or earlier if symptomatic	Polysomnography (sleep study) to detect obstructive sleep apnea
Cervical spine stability	Before high-risk sports or if symptomatic	Lateral neck X-ray (flexion/extension) – check for atlantoaxial instability
Gastrointestinal	If symptoms suggestive or by age 2–3	Screen for celiac disease (TTG-IgA, total IgA); monitor for constipation or Hirschsprung

13. Malaysia Support Group for Parents

Support Group	Description	Contact/Link
Down Syndrome Association of Malaysia (PSDNM)	Parent advocacy, training, education	Facebook: @psdnmalaysia
Kiwanis Down Syndrome Foundation (KDSF)	Early intervention, therapy, and support	www.kdsf.org.my
Malaysia Rare Disorders Society (MRDS)	National support for genetic conditions	www.rare.org.my
Hospital-based developmental clinics	Multidisciplinary support & follow-up	Available at HKL, HUKM, HUSM, Penang GH, and others