Definition
Down syndrome (DS), also known as Trisomy 21, is a genetic disorder caused by the presence of a full or partial extra copy of chromosome 21. This chromosomal abnormality disrupts typical development and results in a spectrum of cognitive, physical, and medical challenges.
Three cytogenetic types are recognized:
- Free trisomy 21 (95% of cases) – nondisjunction during meiosis
- Translocation trisomy 21 (3–4%) – often Robertsonian
- Mosaic trisomy 21 (1–2%) – post-zygotic nondisjunction
Epidemiology
- Global incidence: Approximately 1 in 700 live births, with slight regional variation.
- Risk factors:
- Advanced maternal age remains the most significant risk factor. The estimated risk rises from ~1 in 1,500 at age 20 to ~1 in 30 at age 45.
- Emerging evidence also implicates advanced paternal age, particularly over 40, in contributing to nondisjunction errors, although this association is weaker than maternal age.
- Parental balanced translocations increase recurrence risk, especially in translocation cases.
Clinical Features
Craniofacial and Musculoskeletal:
- Brachycephaly with flat occiput
- Flat facial profile
- Upslanting palpebral fissures
- Epicanthic folds
- Brushfield spots (speckled iris)
- Macroglossia with tongue protrusion
- Small, low-set ears
- Single transverse palmar crease
- Sandal gap (increased 1st interdigital space)
- Hypotonia (neonatal and persists variably)
- Short stature and brachydactyly
Neurological and Cognitive:
- Mild to moderate intellectual disability
- Delayed milestones
- Behavioral issues, including increased risk of autism spectrum disorder (ASD)
- Alzheimer’s disease (early-onset) in >50% by age 60 due to triplication of the APP gene
Associated Medical Complications
Cardiac (40–50%)
- Atrioventricular septal defect (AVSD) – most common
- Ventricular septal defect (VSD)
- Atrial septal defect (ASD) – ostium primum
- Patent ductus arteriosus (PDA)
- Tetralogy of Fallot (TOF)
Hematologic
- Transient abnormal myelopoiesis (TAM) in neonates
- Increased risk of acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL)
Endocrine
- Congenital and acquired hypothyroidism (most common endocrine issue)
- Type 1 diabetes mellitus (increased risk)
ENT and Respiratory
- Recurrent otitis media
- Hearing loss (conductive and sensorineural)
- Obstructive sleep apnea (due to hypotonia and craniofacial structure)
- Recurrent respiratory tract infections
Gastrointestinal
- Duodenal atresia, Hirschsprung disease, celiac disease
Orthopedic
- Atlantoaxial instability (prevalence: ~10–20%)
- Joint hypermobility
Reproductive
- Infertility in males (due to azoospermia)
- Reduced fertility in females, though pregnancy is possible
Diagnosis
Prenatal Screening:
- First trimester combined test (11–13+6 weeks):
- Nuchal translucency (NT)
- PAPP-A and free β-hCG
- Second trimester quadruple test (15–22 weeks):
- AFP, hCG, estriol, inhibin A
Cell-Free Fetal DNA Testing (cffDNA):
- Highly sensitive and specific non-invasive prenatal screening test (sensitivity >99% for T21)
Diagnostic Tests (when screening is positive or in high-risk cases):
- Chorionic villus sampling (CVS): 10–13 weeks
- Amniocentesis: after 15 weeks
- Fetal karyotyping or microarray confirms diagnosis
Postnatal Diagnosis
- Based on characteristic clinical features
- Confirmed by karyotype analysis
Management
There is no cure for Down syndrome, but comprehensive care improves outcomes significantly.
Multidisciplinary Approach Includes:
- Pediatric cardiology: early echocardiography
- Endocrinology: annual thyroid screening
- Otolaryngology & Audiology: newborn hearing screening and annual reviews
- Ophthalmology: first assessment by 6 months
- Neurodevelopmental pediatrics: early intervention (speech, OT, PT)
- Orthopedics: screening for atlantoaxial instability
- Psychiatry/psychology: behavioral and cognitive support
- Education and vocational training: tailored plans for developmental delay
- Genetic counseling: for family planning and recurrence risk
Life Expectancy and Prognosis
- Significantly improved with modern medical care
- Average life expectancy (2024 data): ~60 years
- Survival trends:
- ~90% survive beyond age 10
- ~45–50% live into their 60s or longer
- Cardiac anomalies and severe infections remain leading causes of early mortality
Support and Resources
- Parent advocacy and support groups play a critical role in improving quality of life.
- Examples include the Global Down Syndrome Foundation, NDSS (National Down Syndrome Society), and Down Syndrome International.
References
- Bull MJ. “Down Syndrome.” Pediatrics, 2022;149(5):e2022057565.
- American College of Obstetricians and Gynecologists (ACOG) Committee Opinion No. 818, 2021.
- de Graaf G, et al. “The demographic and survival patterns of individuals with Down syndrome in the USA.” Genetics in Medicine, 2023.
- National Down Syndrome Society (NDSS) Clinical Guidelines 2024.
- World Health Organization (WHO): Birth Defects Surveillance Manual, 3rd Edition, 2023.
