Down Syndrome (Trisomy 21)

Definition and Epidemiology

Down syndrome is the most common chromosomal disorder in humans, caused by the trisomy of chromosome 21. The global incidence is approximately 1 in 700 to 1000 live births, while in India, it ranges from 1 in 800 to 1200 live births. Advanced maternal age is a primary risk factor for the condition.

Etiology and Cytogenetics

Genetic diagnosis requires karyotype analysis to determine the exact etiology, which dictates recurrence risks.

Cytogenetic Type	Frequency	Mechanism and Characteristics
Free Trisomy 21	95%	Caused by meiotic nondisjunction, primarily a maternal meiosis I error. Risk rises exponentially with advanced maternal age.
Translocation	3-4%	Robertsonian translocation, most commonly involving chromosomes 14 and 21. 75% occur de novo, while 25% are inherited from a balanced carrier parent.
Mosaicism	1-2%	Results from post-zygotic mitotic nondisjunction, leading to a mixture of normal and trisomic cells. Phenotype is often milder.

Pathophysiology

The extra chromosome 21 results in a gene dosage imbalance. Overexpression of approximately 300 genes located on chromosome 21, including APP, DYRK1A, SOD1, and RCAN1, disrupts normal cellular function. This genetic overexpression leads to impaired neurogenesis, severe oxidative stress, immune dysregulation, and defects in cardiac morphogenesis.

Clinical Features

The clinical presentation involves a recognizable pattern of dysmorphic features and multisystem anomalies.

System	Clinical Manifestations
Craniofacial	Flat facial profile, upslanting palpebral fissures, epicanthic folds, Brushfield spots, flat nasal bridge, small ears, protruding tongue, short neck with excess nuchal skin.
Cardiovascular	Present in 40-50% of patients. Atrioventricular septal defect (AVSD) is the most common, followed by ventricular septal defect (VSD), patent ductus arteriosus (PDA), and tetralogy of Fallot.
Gastrointestinal	Present in 10-15% of patients. Duodenal atresia, Hirschsprung disease, annular pancreas, and celiac disease.
Neurological	Mild to moderate intellectual disability (IQ 35-70), delayed speech, hypotonia, early-onset Alzheimer disease pathology by age 40, and seizures.
Musculoskeletal	Single transverse palmar crease, clinodactyly, sandal-gap toe, brachydactyly, generalized joint laxity, and atlantoaxial instability.
Endocrine	Congenital hypothyroidism, obesity in adolescence, and type 1 diabetes mellitus.
Hematological	Transient myeloproliferative disorder (neonates) and an increased risk of acute megakaryoblastic leukemia.
Sensory	Conductive or sensorineural hearing loss, strabismus, refractive errors, and cataracts.

Investigations and Screening

Diagnostic Confirmation: Karyotyping is the gold standard for diagnosis and identifying translocations. Fluorescence In Situ Hybridization (FISH) or Quantitative Fluorescent PCR (QF-PCR) provides rapid preliminary results.
Prenatal Screening:
- First-trimester screening shows
  - decreased Pregnancy-Associated Plasma Protein A (PAPP-A) and
  - elevated free beta-hCG,
  - alongside increased nuchal translucency and absent nasal bone on ultrasonography.
- Second-trimester quadruple markers show
  - low alpha-fetoprotein,
  - low unconjugated estriol,
  - high hCG, and
  - high inhibin-A.
- Non-Invasive Prenatal Testing (NIPT) analyzing cell-free fetal DNA offers high sensitivity.
System-Specific Surveillance:
- Echocardiography is mandatory before 9 months of age.
- Thyroid Stimulating Hormone (TSH) levels must be checked at birth, at 6 and 12 months, and annually thereafter.
- Complete blood count with differential in the neonatal period to monitor for myeloproliferative disorders.
- Lateral cervical spine radiograph at 3 to 5 years to screen for atlantoaxial subluxation.

Management Principles

Early Intervention: Implementation of physiotherapy, occupational therapy, and speech therapy starting in infancy maximizes functional independence.
Surgical Care: Early surgical correction of major cardiac anomalies, such as AVSD repair by 3 to 6 months of age, significantly improves survival.
Medical Therapy: Prompt initiation of levothyroxine for hypothyroidism and specialized dietary management for celiac disease.
Growth Monitoring: Regular plotting of parameters on specific Down syndrome growth charts to manage failure to thrive in infancy and obesity in adolescence.

Genetic Counselling and Recurrence Risk

Free Trisomy 21: The empiric recurrence risk for a mother under 35 years of age is approximately 1%. For mothers over 35, the risk corresponds to the age-related maternal risk.
Translocation Down Syndrome:
- De novo translocations carry a recurrence risk of approximately 1%.
- If the mother is a balanced carrier of t(14;21), the recurrence risk is 10-15%.
- If the father is a balanced carrier of t(14;21), the recurrence risk is less than 1%.
- Parental carriers of a balanced 21;21 Robertsonian translocation [t(21q;21q)] face a 100% recurrence risk for Down syndrome in all viable pregnancies.