Down Syndrome

Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Characteristic traits include upslanting, almond-shaped eyes with skin covering the inner aspects, broad flattened nasal bridge, small rounded ears, and small mouth with large tongue. Screening for Down syndrome occurs during the 1st and 2nd trimesters of pregnancy and includes both blood tests and prenatal ultrasonography. Ultimately, karyotyping confirms diagnosis in the prenatal or postnatal period. There is no cure for Down syndrome. Treatment is based on the clinical manifestations present; it includes a strong support system and early intervention programs to help with education and development.

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Epidemiology and Genetics


  • Incidence: 1 in 700 live births
  • ↑ Risk with ↑ maternal age:
    • Incidence: 1 in 100 with maternal age of 40 years
    • Incidence: approximately 1 in 30 with maternal age of 45 years
    • Incidence: approximately 1 in 6 with maternal age of 50 years
  • 80% of affected children are born to women < 35 years of age—the group that has most of the children.
  • One of most common autosomal chromosomal aberrations
  • Most frequent genetic cause of developmental delay
  • Life expectancy: approximately 50 years


There are 3 genotypes that result in Down syndrome.

  • Full trisomy 21:
    • 90%–95% of cases
    • Each cell in the body has an extra chromosome 21.
    • Occurs spontaneously, not inherited
    • Most commonly due to nondisjunction in meiosis I (70%) 
    • May also be due to nondisjunction in meiosis II (20%)
    • Nondisjunction typically of maternal origin
    • Rarely due to paternal nondisjunction during spermatogenesis (approximately 5%)
    • Karyotype: 47,XX,+21 (girls) and 47,XY,+21 (boys)
  • Translocation trisomy 21: 
    • Approximately 2%–4% of all cases
    • Part or an extra or a whole extra chromosome 21 is attached (translocated) to another acrocentric chromosome (often chromosome 14).
    • Translocation may occur spontaneously or be inherited from an unaffected parent with balanced translocation (parent is carrier).
    • Advanced maternal age is not a risk factor for translocation trisomy 21.
    • Balanced Robertsonian translocation:
      • Long arm of chromosome 21 is translocated and fused to long arm of chromosome 14 (short arms of both chromosomes are deleted).
      • Karyotype: 45,XX,t(21;14) or 45,XY,t(21;14)
      • Necessary genetic material resides on long arm of chromosomes; all needed genetic material is present, thus the phenotype is normal.
    • Unbalanced translocation: 
      • Results in trisomy 21 phenotype
      • 2 normal copies of chromosome 21 are present along with translocated t(21;14) chromosome, resulting in 3 copies of chromosome 21.
      • Karyotype: 46,XX,+21,t(21;14) or 46XY,+21,t(21;14)
      • Spontaneous t(21;14) translocations are typically of maternal origin.
      • Risk of fetus with Down syndrome is 25% in parent who is a carrier of the t(21;14) balanced translocation.
    • A t(21;21) Robertsonian translocation also occurs infrequently between homologous chromosomes (in most cases, t(21;21) is actually an isochromosome (dup21q), meaning 1 arm of chromosome 21 duplicates itself, creating a partial trisomy in and of itself):
      • Occurs spontaneously
      • Isochromosome (dup21q) is equally likely to be of maternal or paternal origin.
      • Robertsonian translocation typically of maternal origin
      • Risk of fetus with Down syndrome rises to 100% in carriers of t(21;21) translocation.
  • Mosaic trisomy 21: 
    • 1%–2% of all cases
    • Simultaneous existence of normal cell line with normal number of chromosomes and another cell line with 3 copies of chromosome 21 (trisomy 21)
    • Caused by nondisjunction during mitosis
    • Timing of mitotic error affects ratio of trisomic to normal cells.
    • Phenotype depends on ratio of normal cells to trisomic cells.
    • Karyotype: 46,XX/47,XX,+21 or 46,XY/47,XY,+21

Clinical Presentation

Down syndrome presentation

Clinical presentation of Down syndrome

Image by Lecturio.


  • Brachycephaly (flattened back of skull)
  • Almond-shaped eyes
  • Upslanting palpebral fissures
  • Epicanthal folds
  • Ocular hypertelorism (↑↑ distance between eyes)
  • Brushfield spots (small white or grayish-brown spots on periphery of iris)
  • Flattened, broad nasal bridge
  • Low-set, small, rounded, folded, and/or dysplastic ears
  • Small mouth and chin
  • High-arched palate (roof of mouth)
  • Abnormal teeth
  • Large, protruding, and/or fissured tongue
Brushfield spots

The eyes of a baby with Down syndrome:
Brushfield spots are visible between the inner and outer circles of the iris.

Image: “Brushfield spots” by Szymon Tomczak. License: CC0


High prevalence of ocular disorders: Frequency increases with age.

  • Refractive errors, such as myopia, hyperopia, and astigmatism (approximately 35%–76%)
  • Strabismus (crossed eyes) 
  • Nystagmus 
  • Cataracts
  • Corneal opacities
  • Glaucoma
  • Keratonus (abnormal shape and thinning of cornea)


  • Recurrent otitis media
  • Hearing loss:
    • May be congenital or secondary to otitis media
    • Conductive hearing loss most common, but may also be sensorineural or mixed
    • May be unilateral or bilateral


  • Hypotonia 
  • Short neck with excessive skin at nape
  • Dysplasia of middle phalanx of 5th finger
  • Single transverse palmar crease
  • Shortened and broad hands and feet
  • Separation of first and second toes (sandal gap)
  • Hypermobility of joints
  • Atlantoaxial instability (ligamentous instability between atlas C1 and axis C2 vertebrae)
  • Clinodactyly (abnormal curvature of finger, typically inward curve of 5th finger)
  • Brachydactyly (abnormal shortness of fingers or toes)
  • Diastasis recti
  • Surplus ribs
  • Abnormal vertebral bodies
  • Pelvic dysplasia with leveled angle of acetabulum and ilium
Feet of a boy with Down syndrome

Feet of a 10-year-old boy with Down syndrome, with the typical large space between the large toe and the second toe

Image: “Feet of a boy with Down syndrome” by Loranchet. License: CC BY 3.0


  • Congenital heart defects present in approximately 50% of patients, with > 20% having more than 1 anomaly:
    • Atrioventricular septal defect (approximately 40%)
    • Ventricular septal defect (approximately 30%)
    • Isolated atrial septal defects (approximately 15%)
    • Tetralogy of Fallot 
    • Patent ductus arteriosus 
  • Valve abnormalities found in adolescents/adults, most commonly mitral valve prolapse and aortic regurgitation 
  • Pulmonary hypertension also common (> 25%) and may be transient or persistent


  • GI tract anomalies occur in approximately 5% of cases:
    • Duodenal atresia/stenosis + annular pancreas most common
    • Atresia of esophagus + tracheoesophageal fistula
    • Atresia of anus 
    • Rectal prolapse
    • Malformation of bile duct 
  • Umbilical/inguinal hernia
  • Hirschsprung’s disease (congenital defect involving nerve cells of colon causing functional bowel obstruction)
  • Celiac disease (intolerance to gluten affecting small intestine)


  • Polycythemia (↑ RBCs) 
  • Leukopenia (↓ WBCs)
  • Thrombocytosis 
  • Transient myeloproliferative disorder, also known as transient leukemia:
    • Found almost exclusively in newborns with Down syndrome
    • Majority asymptomatic and have spontaneous resolution within 2–3 months
    • Rarely progresses to serious condition, which can cause organ damage and death
  • ↑ Risk of leukemia (ALL, AML)


  • Hypothyroidism
  • Type 1 diabetes


  • Hypogonadism
  • Cryptorchidism (undescended testes)
  • Impaired fertility, more so in men


  • ↑ Risk of early-onset Alzheimer disease (typically by age 40)
  • ↑ Risk of development of epilepsy


  • Developmental delay is universal.
  • Cognitive impairment is often present.
  • ↑ Prevalence of behavioral disorders: 
    • ADHD
    • Conduct/oppositional disorder
    • Aggressive behaviors
  • Depression and aggressive behavior most common in adults
  • Autism diagnosed as comorbidity in about 7% of cases
  • Down syndrome is a disintegrative disorder.
    • New or worsening autism-like symptoms in school-aged children
    • Cognitive decline/dementia
    • New-onset insomnia


  • Impaired development noted in 1st year of life: 
    • Impaired motor development: milestones achieved at approximately twice the normal age
    • Impaired language development: Average age for 1st word is 18 months.
  • Cognitive impairment varies from mild to severe, with most having mild to moderate intellectual disability.
  • Growth retardation/↓ growth rate

Other associated conditions

  • Obesity
  • Sleep apnea 
  • ↑ Prevalence of infections, particularly respiratory infections


Prenatal diagnosis

Screening is recommended prior to 20th week of gestation.

  • 1st-trimester combined test at 11th–13th week detects < 90% of cases: 
    • Maternal serum testing:
      • ↑ β-hCG
      • ↓ Pregnancy-associated plasma protein A
    • Ultrasound:
      • ↑ Nuchal translucency measurement (edema of posterior neck)
      • Absent or hypoplastic nasal bone
      • Shortened long bones (humerus, femur)
      • Shortened middle phalanges of 5th digits with abnormal curvature
  • 2nd-trimester triple test (triple screen) between 16th and 20th weeks:
    • ↑ β-hCG
    • ↓ α-fetoprotein
    • ↓ Free estriol
  • 2nd-trimester quadruple test (quad-screen) between 15th and 18th weeks:
    • ↓ Free estriol
    • ↓ α-fetoprotein 
    • ↑ Inhibin A
    • ↑ β-hCG
  • Sequential integrated test: combination of 1st-trimester combined test and 2nd-trimester quadruple test
  • Full integrated test between 10th and 13th weeks includes measurement of maternal serum pregnancy-associated plasma protein A and nuchal translucency
  • Cell-free fetal DNA test may be done any time after 10 weeks of gestation.
    • Fetal DNA is isolated from maternal blood and evaluated for chromosomal abnormalities
    • Noninvasive procedure for fetus
    • May be more accurate than traditional screening tests
    • Also tests for sex of baby
  • Diagnostic tests: 
    • Indicated if: 
      • Positive screening test
      • Previous pregnancy with child with trisomy 21
      • Known chromosomal translocation or aberration in parent
    • Procedures:
      • Chorionic villus sampling: takes sample of placenta for testing between 10th and 13th weeks
      • Amniocentesis: samples amniotic fluid for testing between 15th and 20th weeks
      • Percutaneous umbilical blood sampling: blood sample from umbilical cord between 18th and 22nd weeks (most accurate diagnosis during pregnancy)
    • Risks include bleeding, infection, fetal injury, and, rarely, fetal loss.
  • Fetal karyotyping is confirmatory.
Trisomy 21 ultrasound

Trisomy 21 on ultrasound:
Ultrasound image of fetus at 12 weeks, showing nuchal translucency and presence of nasal bone

Image: “Ultrasound image of the second fetus at 12 weeks” by The 2nd University Department of Obstetrics and Gynecology, Hippokratio General Hospital, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642 Thessaloniki, Greece. License: CC BY 2.0

Postnatal diagnosis

  • History and clinical examination
  • Screening for associated conditions:
    • Pediatric cardiology evaluation and echocardiography to evaluate for congenital heart disease
    • Hearing screen
    • Pediatric ophthalmology exam
    • Routine labs: CBC with differential, thyroid function testing, glucose screening 
  • Confirmed via karyotype analysis


Given the pervasive nature of Down syndrome and the lack of a cure, the majority of management focuses on screening and prevention of the various clinical manifestations and complications associated with the syndrome.

Medical management

  • Growth: 
    • Monitor growth throughout childhood and adolescence.
    • CDC provides specific growth charts.
  • Nutrition and obesity prevention:  
    • Attention to diet and physical activity level starting at 2 years of age
    • Monitor weight gain throughout lifespan.
    • Calcium and vitamin D supplements to minimize bone loss
  • Hearing: 
    • Hearing screens every 6 months until 5 years of age, then annually 
    • Referral to otolaryngologist if hearing screen failed
    • May require hearing aids or cochlear implants
  • Vision:
    • Annual exam for children with known ophthalmologic disorders
    • Prescription glasses for refractive errors 
    • Unaffected children should have eye exams: 
      • Annually for ages < 5 years
      • Every 2 years for ages 5–13 
      • Every 3 years for ages > 13
  • Dental: 
    • Visits every 6 months
    • Treatment and cleaning may be complicated and require sedation. 
  • Cardiovascular: 
    • Continued cardiac monitoring through adulthood 
    • Assess for development of mitral valve prolapse or aortic regurgitation.
  • GI: screening for celiac disease beginning at 1 year of age 
  • Hematologic:
    • Hemoglobin measurement annually until 13 years of age to screen for anemia
    • If transient myeloproliferative disorders detected: 
      • Repeat CBC with differential every 3 months until 3 years of age.
      • Every 6 months for ages 3–6 years
  • Endocrine: 
    • Routine thyroid function and glucose testing
    • Thyroxine for hypothyroidism treatment 
    • Insulin for type 1 diabetes
  • Musculoskeletal/neurologic:
    • Physical therapy for hypotonia
    • Atlantoaxial instability: 
      • Annual screening with thorough neurologic evaluation for signs or symptoms of spinal cord injury
      • Caution playing sports and other high-risk activities (e.g., trampoline use)
      • Cervical spine films, particularly with lateral views, starting at 3 years of age:
        • If any neurologic deficits detected on exam 
        • Screening as part of sports preparticipation exam 
        • Prior to medical procedures that require extreme head positioning 
      • If abnormalities seen on cervical spine films → place in cervical collar, refer to pediatric neurosurgeon or pediatric orthopedic spine surgeon, obtain cervical spine MRI
  • Sleep apnea:
    • Screen for symptoms beginning at 1 year of age.
    • Sleep study or pulse oximetry monitoring during sleep recommended by 4 years of age.
  • Reproductive: 
    • Pregnancy is high-risk for women with Down syndrome.
    • Contraception counseling

Surgical management

  • Correction of congenital heart defects
  • Correction of GI anomalies
  • Rarely, surgical correction for ocular disorders (e.g., strabismus, cataracts) needed to improve vision
  • Surgical fusion or stabilization for severe atlantoaxial instability 
  • Adenotonsillectomy or other surgical procedures for treatment of sleep apnea

Educational/early interventions

  • Neuropsychological, developmental, educational, and behavioral assessments/screenings 
  • Special education
  • Speech and language therapy
  • Vocational training


  • Supportive environment 
  • Genetic counseling 
  • Psychotherapy

Differential Diagnosis

  • Trisomy 18 (Edwards syndrome): genetic syndrome caused by presence of 3 copies of chromosome 18: Edwards syndrome is the 2nd most common trisomy, with predominance in girls. Characteristic features include intrauterine growth retardation, cardiac defects, clenched fists with overlapping fingers, and rocker-bottom feet. Diagnosis is made by karyotype analysis. No treatment is available, and most do not survive beyond 1 year of life.
  • Trisomy 13 (Patau syndrome): genetic syndrome caused by presence of 3 copies of chromosome 13: Patau syndrome is the 3rd most common trisomy. Clinical features include brain and spinal cord malformations, cardiac defects, eye defects, cleft lip/palate, and hypotonia. Diagnosis is made by karyotype analysis. No treatment is available, and most do not survive beyond 1 year of life.
  • Zellweger syndrome: also called cerebrohepatorenal syndrome: Zellweger syndrome is a rare autosomal recessive congenital peroxisome biosynthesis disorder and is considered an inborn error of metabolism. Characterized by reduction or absence of functional peroxisomes. Clinical features are present from birth and include craniofacial and skeletal anomalies, as well as ocular disorders, hypotonia, and seizures. No treatment is available, and most do not survive beyond 1 year of life.


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