Description

• Down syndrome (DS) is a congenital condition associated with intellectual disability and an increased risk of multisystem medical problems.
• Systems affected: neurologic (100%), cardiac (40–50%), GI (8–12%)
• Synonym: trisomy 21

Pediatric Considerations
Murmur may not be present at birth. Delay in recognition of heart condition may lead to irreversible pulmonary hypertension.

Geriatric Considerations

• Life expectancy has increased to ~60 years.
• Age-related health issues occur at earlier age than in the general population.
• Communication difficulties may interfere with prompt recognition of some medical issues.

Pregnancy Considerations

• American College of Obstetricians and Gynecologists (ACOG) recommends all pregnant women be offered traditional prenatal screening and diagnostic testing for DS.
  • Maternal prenatal screening may be performed in the 1st or 2nd trimester.
  • Prenatal diagnostic tests include chorionic villus sampling or amniocentesis.
• ACOG and the Society for Maternal-Fetal Medicine (SMFM) acknowledge that any women may choose noninvasive prenatal screening (NIPS). American College of Medical Genetics and Genomics (ACMG) recommends all women be offered NIPS (1,2).
• Most, but not all, men with DS are believed to be infertile.
• Most women with DS are subfertile but can conceive children with and without DS.

Epidemiology

Incidence
In the United States, 1/792 live births, ~5,300 births per year (3)

Prevalence
~206,000 persons in the United States (4)

Etiology and Pathophysiology

• Etiology: presence of all or part of an extra chromosome 21
• Trisomy 21: 95% of DS, an extra chromosome 21 is found in all cells due to nondisjunction, usually in maternal meiosis.
• Translocation DS: 3–4% of DS, extra chromosome 21q material is translocated to another chromosome (usually 13, 14, or 21); ~25% have parental origin.
• Mosaic trisomy 21: 1–2% of DS, manifestations may be milder.

• Online Mendelian Inheritance in Man (OMIM) 190685
• Inheritance: most commonly sporadic nondisjunction resulting in trisomy 21
• Chance of having another child with DS is
  • 1% (or age risk, whichever is greater) after conceiving a pregnancy with nondisjunction trisomy 21
  • 10–15% for mothers/sisters and 3–5% for fathers/brothers who carry balanced translocation with chromosome 21
  • 100% if the parental balanced translocation is 21;21 (45,t[21;21])
  • Unclear after child with mosaic DS but ~1%

Risk Factors

• DS believed to occur in all races and ethnicities with equal frequency
• Chance of having an infant with DS increases with mother’s age
• Relatively more infants with DS are born to younger mothers because younger women are more likely to become pregnant.
• Prenatal diagnosis of DS is more common in older women, and a high percentage of such pregnancies are electively terminated.

General Prevention

• No prevention for nondisjunction trisomy 21
• Preimplantation diagnosis with in vitro fertilization (IVF), prenatal diagnosis followed by termination, and adoption are current options for expectant parents who do not wish to raise a child with DS.

Commonly Associated Conditions

• Cardiac
  • Congenital heart defects (40–50%)
• GI/growth
  • Feeding problems are common in infancy.
  • Structural defects (~12%)
  • Gastroesophageal reflux
  • Constipation
  • Celiac disease (~5%)
• Pulmonary
  • Tracheal stenosis/tracheoesophageal fistula
  • Pulmonary hypertension
  • Obstructive sleep apnea (50–75%)
• Genitourinary
  • Cryptorchidism, hypospadias
• Hematologic/neoplastic
  • Transient myeloproliferative disorder (~10%): generally resolves spontaneously; can be preleukemic (acute megakaryoblastic leukemia [AMKL]) in 20–30%
  • Leukemia (AMKL or acute lymphoblastic leukemia [ALL]) in 0.5–1%
  • Decreased risk of most solid tumors; increased risk of germ cell tumors/testicular cancer
• Endocrine
  • Hypothyroidism: congenital or acquired (13–63%)
  • Diabetes
• Skeletal
  • Atlantoaxial instability (15%): ~2% symptomatic
  • Short stature is common.
  • Scoliosis (some cases have adult onset)
  • Hip problems (1–4%)
• Immune/rheumatologic
  • Abnormal immune function with increased rate of respiratory infections
  • Increased risk of autoimmune disorders, including Hashimoto thyroiditis, celiac disease, and alopecia
• Neurologic
  • Intellectual ability ranging from mild to severe disability. Average is moderate intellectual disability.
  • Autism spectrum disorder (<18%)
  • Seizures (8%); typically occurring <1 year of age (infantile spasms) or >30 years of age
  • Alzheimer disease: At least 40% at age 40 years develop signs of dementia; percentage increases with age.
• Psychiatric
  • Attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and autism spectrum disorder increased frequency in children.
  • Generalized depression and anxiety with increased frequency in young adults/adults
• Sensory
  • Hearing loss (75%): mostly conductive due to high frequency of asymptomatic middle ear effusion; otitis media (50–70%)
  • Visual impairment (60%): strabismus (refractive errors, 15%), myopia, hyperopia, nystagmus, cataracts (15%)
• Dermatologic
  • Xerosis, eczema, palmoplantar hyperkeratosis, atopic or seborrheic dermatitis, onychomycosis, syringomas, furunculosis/folliculitis, hidradenitis suppurativa