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Down Syndrome
Michele Roberts, MD, PhD
Brian G. Skotko, MD, MPP
image BASICS
  • Down syndrome (DS) is a congenital condition associated with intellectual disability and an increased risk of multisystem medical problems.
  • System(s) affected: neurologic (100%), cardiac (40-50%), GI (8-12%)
  • Synonym(s): 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 Congress 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), although conventional screening tests remain most appropriate for most women. Amercian College of Medical Genetics and Genomics (ACMG) recommends all women be offered NIPS.
  • 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.
In the United States, 1 per 792 live births, ˜5,300 births/year (1)
˜250,000 persons in the United States (2)
  • 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%
  • DS believed to occur 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 electively terminated.
  • 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.
  • 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 (13-63%) (3)
    • 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%); autism (<6%)
    • Seizures: (8%), typically occurring <1 year of age 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), oppositional-defiant disorder (ODD), 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%): mostly strabismus (refractive errors, 15%), nystagmus, cataracts (15%)
  • Dermatologic
    • Xerosis, eczema, palmoplantar hyperkeratosis, atopic or seborrheic dermatitis, onychomycosis, syringomas, furunculosis/folliculitis
  • Typical growth curves should be used (4).
  • Infants and children
    • Brachycephaly (100%)
    • Hypotonia (80%)
    • Small ears, often low set and simplified
    • Upslanting palpebral fissure (90%)
    • Epicanthic folds (90%)
    • Brushfield spots
    • Depressed nasal bridge
    • Short neck, often with increased nuchal folds
    • Single palmar crease, single flexion crease on fifth finger
    • Increased space between toes 1 and 2, fifth finger clinodactyly, brachydactyly
Initial Tests (lab, imaging)
  • Maternal prenatal screening includes the following:
    • 1st trimester: combined screen (maternal age, &bgr;-human chorionic gonadotropin [&bgr;-hCG], pregnancy-associated plasma protein A [PAPP-A], and nuchal translucency)
    • 2nd trimester: quad screen (&agr;-fetoprotein, &bgr;-hCG, estriol, inhibin-A)
    • Sequential screen (combined screen in 1st trimester, if abnormal, obtain amniocentesis or await 2nd trimester quad screening)
    • Integrated screen (combined screening in 1st trimester plus quad screen in 2nd trimester)
    • NIPS with cell-free DNA (beginning at 10 weeks' gestation)
  • P.311

  • Prenatal diagnosis includes the following:
    • Chorionic villus sampling: 1st trimester, ˜99% accurate, ˜1% miscarriage
    • Amniocentesis: 2nd trimester, ˜99% accurate, ˜0.25% miscarriage rate
  • Postnatal diagnosis
    • Fluorescence in situ hybridization (FISH) can be performed at time of clinical suspicion, but karyotype should always be done to differentiate type of DS.
    • Parental (and adult-aged sibling) karyotype is indicated only if translocation DS found in child.
  • Labs for newborns
    • Echo, with or without murmur (4)
    • CBC with differential (to look for transient myeloproliferative disorder) (4)
    • Thyroid-stimulating hormone (TSH) (4)
    • Audiogram (4)
    • Ophthalmologic exam (look for red reflex) (4)
    • Swallowing study for those with feeding difficulties (4)
Follow-Up Tests & Special Considerations
  • After delivering a prenatal diagnosis, the physician should offer “Understanding a Down Syndrome Diagnosis” (www.lettercase.org) (5).
  • If the diagnosis is postnatal, the mother and her partner should be informed of the diagnosis promptly by a physician (preferably the obstetrician and pediatrician or family physician), on the basis of clinical observations and before the karyotype is available, but with consideration of extenuating circumstances (e.g., mother's medical condition). The spouse/partner and infant should be present unless this would cause undue delay. The meeting should be private. Refer to the baby by name (6).
  • In the postnatal setting, the physician should be knowledgeable on the subject of DS and should conduct a discussion with content that is current, respectful, balanced, informative, and realistic, but not overly pessimistic, concentrating on what is relevant to the first year of life (6,7).
  • Cardiac follow-up, as indicated (4).
Genetic evaluation and counseling
  • Infant stimulation programs (early intervention) (8)[A]
  • Lactation consultant
  • Physical/occupational/speech therapy (8)[A]
  • Educational inclusion often successful.
  • Pediatric cardiologist, if indicated.
  • DS specialty clinics can improve medical outcomes (9)[B].
Repair of congenital anomalies is appropriate. Plastic surgery for facial features is not recommended.
  • There is no evidence to support the use of antioxidant or folinic acid supplements in children with DS.
  • Craniosacral manipulation is dangerous due to potential atlantoaxial instability.
  • Sicca is illegal in United States, potentially dangerous, and without any evidence of benefit.
  • Piracetam is much publicized, without scientific evidence of benefit.
Admission Criteria/Initial Stabilization
If the social situation indicates adoption, consider the National Down Syndrome Adoption Network (NDSAN) (www.ndsan.org), national registry of families seeking to adopt a child with DS.
Patient Monitoring
The American Academy of Pediatrics recommends ongoing assessment and review, at least annually, the following surveillance (4)[C]:
  • Vision: Assess for strabismus, cataracts, and nystagmus by ophthalmologist by 6 months, annually between ages 1 and 5 years; every 2 years ages 5 to 13 years; every 3 years ages 13 to 21 years.
  • Hearing: neonatal screen with auditory brainstem response (ABR) or otoacoustic emissions (OAE), then audiogram every 6 months until age 3 years, then annually
  • Thyroid: initial newborn screen. Repeat TSH at 6 months, 12 months, and then annually (4)[C]
  • Screening for celiac disease (total IgA and tissue transglutaminase [TTG]-IgA) annually, if symptomatic
  • Three-view cervical spine films if patient symptomatic, beginning at 3 to 5 years of age
  • Hemoglobin annually to screen for iron deficiency anemia
  • Repeat echocardiogram in teens if with murmur or fatigue.
  • No special diet, but caloric needs are lower in adolescents/adults with DS than their peers.
  • Obesity is prevalent at all ages.
  • No scientific evidence supports megavitamin therapy or dietary supplements.
  • National Down Syndrome Congress 800-232-NDSC; www.ndsccenter.org
  • National Down Syndrome Society 800-221-4602; www.ndss.org
  • The LuMind Down Syndrome Research Foundation provides information on the latest research for people with DS: www.lumindfoundation.org
  • www.lettercase.org provides peer-reviewed booklet for parents who have received a prenatal diagnosis of DS and have not yet made a decision about their pregnancy.
  • downsyndromepregnancy.org provides a free downloadable book for expectant mothers who have decided to continue their pregnancies after a prenatal diagnosis of DS.
  • www.downsyndromediagnosis.org
  • Associated congenital anomalies are the immediate concern during the newborn period.
  • 99% of young adults/adults with DS report being happy with their lives (10).
  • Life expectancy ˜60 years
1. de Graaf G, Buckley F, Skotko BG. Estimates of the live births, natural losses, and elective terminations with Down syndrome in the United States. Am J Med Genet A. 2015;167A(4):756-767.
2. Parker SE, Mai CT, Canfield MA, et al. Updated national birth prevalence estimates for selected birth defects in the United States, 2004-2006. Birth Defects Res A Clin Mol Teratol. 2010;88(12):1008-1016.
3. Purdy IB, Singh N, Brown WL, et al. Revisiting early hypothyroidism screening in infants with Down syndrome. J Perinatol. 2014;34(12):936-940.
4. Bull MJ, Saal HM, Braddock SR, et al. Health supervision for children with Down syndrome. Pediatrics. 2011;128(2):393-406.
5. Skotko BG, Kishnani PS, Capone GT, et al. Prenatal diagnosis of Down syndrome: how best to deliver the news. Am J Med Genet A. 2009;149A(11):2361-2367.
6. Sheets KB, Crissman BG, Feist CD, et al. Practice guidelines for communicating a prenatal or postnatal diagnosis of Down syndrome: recommendations of the national society of genetic counselors. J Genet Couns. 2011;20(5):432-441.
7. Skotko BG, Capone GT, Kishnani PS, et al. Postnatal diagnosis of Down syndrome: synthesis of the evidence on how best to deliver the news. Pediatrics. 2009;124(4):e751-e758.
8. Blauw-Hospers CH, Hadders-Algra M. A systematic review of the effects of early intervention on motor development. Dev Med Child Neurol. 2005;47(6):421-432.
9. Skotko BG, Davidson EJ, Weintraub GS. Contributions of a specialty clinic for children and adolescents with Down syndrome. Am J Med Genet A. 2013;161A(3):430-437.
10. Skotko BG, Levine SP, Goldstein R. Self-perceptions from people with Down syndrome. Am J Med Genet A. 2011;155A(10):2360-2369.
Additional Reading
University of Kentucky's Human Development Institute. National Center for Prenatal and Postnatal Down Syndrome Resources. Lexington, KY: University of Kentucky's Human Development Institute; 2012. www.downsyndromediagnosis.org
See Also
Algorithm: Intellectual Disability
  • Q90.9 Down syndrome, unspecified
  • Q90.1 Trisomy 21, mosaicism (mitotic nondisjunction)
  • Q90.0 Trisomy 21, nonmosaicism (meiotic nondisjunction)
Clinical Pearls
  • 99% of young adults/adults with DS report being happy with their lives.
  • DS specialty clinics can improve medical outcomes.