Description

• Congenital condition associated with intellectual disability and an increased risk of multisystem medical problems
• System(s) affected: Neurologic (100%); Cardiac (40–50%); Gastrointestinal (GI) (8–12%)
• Etiology: Presence of all or part of an extra chromosome 21
• Synonym(s): Trisomy 21; Down syndrome (DS)

• Congenital heart disease is major cause of morbidity/mortality.
• Murmur may not be present at birth. Delay in recognition may lead to irreversible pulmonary hypertension.

• 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.

• The ACOG and ACMG recommend all pregnant women be offered prenatal screening and testing for DS:
  • Maternal prenatal screening may be performed in the 1st or 2nd trimester.
  • Prenatal diagnosis includes chorionic villus sampling or amniocentesis.
• Most, but not all, men with DS are believed to be infertile.
• Most women with DS are subfertile, but can conceive.

Epidemiology

Incidence
In the US, 1/691 live births, ~6,000 births/year (1)

Prevalence
~400,000 persons in the US

Risk Factors

• DS occurs in all races 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 terminated.

• 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 translocation is 21:21 (45,t[21:21])
  • Unclear after child with mosaic DS, but ~1%

General Prevention

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

Etiology

• 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.

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
• Endocrine:
  • Hypothyroidism: Congenital or acquired (4–18%)
  • 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, alopecia
• Neurologic:
  • Intellectual disability ranging from near-normal to severe. Average is moderate intellectual disability.
  • Autism spectrum disorder (<18%); autism (<6%)
  • Seizures: (8%), typically occurring <1 year of age or >30 year of age
  • Alzheimer disease: At least 25% at age 35 develop signs of dementia; percentage increases with age
• Psychiatric:
  • ADHD, obsessive-compulsive disorder (OCD), oppositional-defiant disorder, autism spectrum disorder increased frequency in children
  • Generalized depression and anxiety more common 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%): Mostly strabismus (refractive errors, 15%), nystagmus, cataracts (15%)
• Dermatologic:
  • Xerosis, eczema, palmoplantar hyperkeratosis, atopic or seborrheic dermatitis, onychomycosis, syringomas, furunculosis/folliculitis