Basics
Description
Syndrome first described by John Langdon Down in 1866 consisting of multiple abnormalities, including hypotonia, flat facies, upslanting palpebral fissures, and small ears; also called "trisomy 21"
Other abnormalities include the following:
- Congenital heart disease (40-50%; most not symptomatic as a newborn)
- Atrioventricular (AV) canal (60% of those with congenital heart disease)
- Ventriculoseptal defect (VSD)
- Patent ductus arteriosus (PDA)
- Atrioseptal defect (ASD)
- Aberrant subclavian artery
- Tetralogy of Fallot
- Hearing loss (66-75%): sensorineural and conductive
- Strabismus (33-45%)
- Nystagmus (15-35%)
- Fine lens opacities (by slit-lamp examination 59%), cataracts (1-15%)
- Refractive errors (50%)
- Nasolacrimal duct stenosis
- Delayed tooth eruption
- Tracheoesophageal fistula
- Gastrointestinal atresia (12%)
- Celiac disease
- Meckel diverticulum
- Hirschsprung disease (<1%)
- Imperforate anus
- Renal malformations
- Hypospadias (5%)
- Cryptorchidism (5-50%)
- Testicular microlithiasis
- Thyroid disease (15%): hypothyroidism, hyperthyroidism
- Transient myeloproliferative disorder (3-10%), neonatal (leukemoid reaction)
- Transient neonatal polycythemia, neutrophilia, thrombocytopenia
- Leukemia (<1%; 10-20 times greater risk than in general population, acute lymphoblastic and myeloid leukemias)
- Decreased T and B lymphocytes
- Testicular germ cell tumors
- Airway anomalies, including tracheo- and laryngomalacia
- Infertility, especially in males
- Obesity
- Alopecia areata (10-15%)
- Seizures (5-10%), usually myoclonic
- Alzheimer disease (nearly all older than age 40 years show neuropathologic signs)
- Mild to moderate mental retardation (IQ range 25-70)
- Dry, hyperkeratotic skin (75%)
Epidemiology
- Male > female (1.3:1)
- Best recognized and most frequent chromosomal syndrome of humans
- 1 of the 3 most common autosomal trisomies in humans (others are trisomies 18 and 13)
- Most common autosomal chromosomal abnormality causing mental retardation
- >50% of trisomy 21 fetuses are spontaneously aborted in early pregnancy.
Incidence
1/600-1/800 live births, although incidence varies with maternal age:
- 1/1,500 for maternal ages 15-29 years
- 1/800 for maternal ages 30-34 years
- 1/270 for maternal ages 35-39 years
- 1/100 for maternal ages 40-49 years
Genetics
- Approximately 90% of cases are the result of chromosomal nondisjunction (failure to segregate during meiosis) in the maternal DNA.
- <5% of cases are the result of paternal nondisjunction.
- 3-4% of cases are the result of translocations; mostly chromosomes 21 and 14 [t(14q21q)]; rarely between 21 and 13 or 15; 75% of translocations are sporadic de novo events; the others result from balanced translocations in one parent.
- Of live births, 1-2% are mosaic (nondisjunction occurs after conception; 2 cell lines are present); generally less severely affected
Diagnosis
History
- Check for previous history of infant with Down syndrome in the family.
- Growth and developmental status
- Feeding problems
- Snoring, signs of sleep apnea (e.g., restless sleep)
- Stool habits
- Hearing concerns
Physical Exam
The phenotype is variable from person to person.
- General
- Short stature
- Hypotonia (80-100%), with an open mouth and a protruding tongue
- Midface hypoplasia
- Head
- Brachycephaly with a flattened occiput
- Microcephaly
- False fontanelle (95%)
- Late closure of fontanelles
- Eyes
- Upslanting palpebral fissures (98%)
- Inner epicanthal folds
- Brushfield spots (speckling of the iris)
- Fine lens opacities on slit-lamp examination
- Cataracts, refractive error, strabismus, and nystagmus
- Ears
- Small, prominent, low set; overfolding of upper helix and small canals
- Nose: small (85%); flat nasal bridge
- Tongue
- Relative but not true macroglossia (tongue mass is normal)
- Fissuring of tongue
- Mouth: high-arched or abnormal palate
- Teeth
- Missing (50%), small, hypoplastic
- Irregular placement
- Neck
- In infancy, excess skin at the nape
- Short appearance
- Occasionally webbed
- Heart: murmur, arrhythmia, cyanosis
- Abdomen
- In neonate, distention may be present owing to obstruction or atresia.
- Diastasis recti
- Genitals
- In adolescents, straight pubic hair
- In males, small penis, cryptorchidism
- Extremities
- Broad hands, with short metacarpals and phalanges
- 5th finger with hypoplasia of the midphalanx (60%) and clinodactyly (50%)
- Simian crease (single transverse palmar crease) in ~50%. A newborn with a simian crease has a 1 in 60 chance of having Down syndrome.
- Wide gap between the 1st and 2nd toes (96%)
- Syndactyly of 2nd and 3rd toes
- Hyperflexibility of joints
- Skin
- Cutis marmorata (43%)
- In older children, hyperkeratotic dry skin (75%)
- Fine, soft, sparse hair
Diagnostic Tests & Interpretation
Prenatal
- 2nd-trimester prenatal quad screen test (alpha-fetoprotein [AFP], unconjugated estriol, human chorionic gonadotropin [hCG], and inhibin A):
- Performed at 15-18 weeks
- These serum markers together can detect 67-76% of pregnancies affected by trisomy 21, with a false-positive rate of ~5%.
- A positive test is an indication for karyotyping with amniocentesis.
- 1st-trimester maternal serum screening (pregnancy-associated plasma protein A and free β-hCG)
- When 1st- and 2nd-trimester tests are combined, there is a detection rate of 95%.
- New 2nd-trimester noninvasive prenatal screening (NIPS) tests are available to assess fetal DNA in the maternal circulation as a supplement to other tests.
Postnatal
- Chromosomal karyotype on cultured lymphocytes from peripheral blood: may be performed postnatally for confirmation if there is a clinical suspicion of Down syndrome
- Complete blood count (CBC)
- In the newborn period to check for polycythemia and transient myeloproliferative disorder; repeat test in adolescence.
- Down syndrome patients may have an increased mean corpuscular volume (MCV), making the diagnosis of iron deficiency anemia difficult.
- Thyroid function tests: to rule out hypothyroidism or hyperthyroidism
Imaging
- 1st-trimester ultrasound measurement of nuchal translucency: performed in the 1st trimester along with maternal serum screening
- Fetal ultrasound
- May show polyhydramnios if bowel obstruction is present
- A thickened nuchal fold, an absent nasal bone in the 1st trimester, and echogenic intracardiac foci have been associated with an increased risk for Down syndrome.
- Echocardiography and chest radiography: done in the 1st month of life to rule out cardiac disease
- When symptoms suggestive of atlantoaxial instability (e.g., neck and/or radicular pain, weakness, change in tone, difficulties walking, or changes in bowel and bladder function) are present, lateral cervical spine radiographs in flexion, neutral, and extension: to rule out atlantoaxial instability, defined as >5-mm space between atlas and odontoid process of the axis. Important measures include the following:
- Atlantodens interval (ADI; normal <4.5 mm): the distance between the posterior surface of the anterior arch of C1 and the anterior surface of the dens
- Neural canal width (NCW; normal ≥14 mm): the distance between the posterior surface of the dens and the anterior surface of the posterior arch of C1
- Distance of subluxation at the occipitoatlantal joint: normally ≥7 mm
Diagnostic Procedures/Other
- Prenatal karyotyping via amniocentesis (16-18 weeks' gestation) or chorionic villus sampling (9-11 weeks' gestation)
- Performed for any woman who presents with a positive triple or quad screen
- May be offered if prenatal ultrasound reveals a finding associated with Down syndrome
- Because this test fails to detect 10-15% of Down syndrome in older women, amniocentesis is typically offered to all women >35 years of age.
- Tissue sample other than blood (usually skin): to check for mosaicism
Follow-Up Recommendations
- Genetic counseling and evaluation is recommended.
- Referral to organizations (e.g., Down Syndrome International), parent-to-parent support groups, and other community supports available to families of children with Down syndrome
Prognosis
- Life expectancy is mildly decreased, with many living into the 6th decade; median age of death is 49 years.
- Clinical signs of Alzheimer disease occur later in life, with reports as high as 51% in the 4th decade.
- As adults, most patients with Down syndrome can work in supported positions.
Complications
- Otitis media with effusion (50-70%)
- Sinusitis
- Tonsillar and adenoidal hypertrophy
- Obstructive airway disease with associated sleep apnea (50-79%), cor pulmonale
- Obstructive bowel disease (12%, newborn period)
- Constipation (owing to low tone and decreased gross motor mobility)
- Subluxation of the hips (secondary to ligamentous laxity)
- Atlantoaxial instability (10-30%; secondary to ligamentous laxity, which is most severe prior to age 10 years)
Patient Monitoring
- Annually: growth and development:
- Current recommendations by the American Academy of Pediatrics (AAP) are to use standard growth charts for all children including those with Down syndrome because the previously used Down syndrome growth charts are no longer felt to represent the current body proportion.
- Average age for acquiring developmental milestones differs from normal population.
- Early intervention program for hypotonia and developmental delay is recommended.
- Review need for physical, occupational, and speech therapy at each health maintenance visit.
- Discuss psychosocial and behavioral progress and concerns and screen for mental health disorders (e.g., autism, ADHD).
- Assessment of nutrition and activity for obesity prevention/counseling
- Evaluation/referrals for available family support including medical, financial, and social services and school transitions
- Injury and abuse prevention
- Cardiac: Early evaluation in newborn period, with follow-up until the presence or absence of disease is evident. Subacute bacterial endocarditis prophylaxis for patients with certain types of cardiac disease.
- Ophthalmologic
- Early evaluation for cataracts and glaucoma
- Visit to ophthalmologist by 6 months, annually until age 5 years, then every 2-3 years
- Ear, nose, and throat (ENT)/audiologic
- Audiologic evaluation; if newborn evaluation was normal, repeat at 6 months of age in the first 3 years of life, then every other year.
- Obstructive sleep apnea
- Review symptoms with family in first 6 months and screen for symptoms at each well child visit.
- Refer all children for sleep study or polysomnography by 4 years of age and at any age if symptomatic.
- Orthopedic: Routine screening by x-ray for atlantoaxial instability in asymptomatic children is no longer routinely recommended by the AAP, although it is still required for participation in the following Special Olympics activities: butterfly stroke and diving starts in swimming, diving, pentathlon, high jump, equestrian sports, artistic gymnastics, soccer, alpine skiing, and any warm-up exercise placing undue stress on the head and neck.
- Endocrine: thyroid function tests in newborn period, ages 6 months and 12 months, then yearly
- Gastrointestinal: Screen for symptoms of celiac disease (i.e., diarrhea, poor growth, failure to thrive, etc.), and if symptomatic, obtain tissue transglutaminase immunoglobulin A (IgA) level and quantitative IgA.
- For adolescents, discuss personal hygiene and issues related to reproductive health.
Alert
- Use caution with endotracheal intubation if absence or presence of atlantoaxial instability is unknown in order to avoid spinal cord injury, which may be seen in rare cases.
- Hearing loss may be misinterpreted as a behavioral problem.
- Use care with atropine and pilocarpine for ophthalmologic evaluation because of possible cholinergic hypersensitivity.
Additional Reading
- Bull MJ, Committee on Genetics. Health supervision for children with Down syndrome. Pediatrics. 2011;128(2):393-406. [View Abstract]
- Bruwier A, Chantrain DF. Hematological disorders and leukemia in children with Down Syndrome. Eur J Pediatr. 2012;171(9):1301-1307. [View Abstract]
- Crissman BG, Worley G, Roizen N, et al. Current perspectives on Down syndrome: selected medical and social issues. Am J Med Genet C Semin Med Genet. 2006;142C(3):127-130. [View Abstract]
- Dykens EM. Psychiatric and behavioral disorders in person with Down syndrome. Ment Retard Dev Disabil Res Rev. 2007;13(3):272-278. [View Abstract]
- Hickey F, Hickey E, Summar KL. Medical update for children with Down syndrome for the pediatrician and family practitioner. Adv Pediatr. 2012;59(1):137-157. [View Abstract]
- Mik G, Gholve PA, Scher DM, et al. Down syndrome: orthopedic issues. Curr Opin Pediatr. 2008;20(1):30-36. [View Abstract]
- Pandit C, Fitzgerald DA. Respiratory problems in children with Down syndrome. J Paediatr Child Health. 2012;48(3):E147-E152. [View Abstract]
- Gregg AR, Gross SJ, Best RG, et al. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet Med. 2013;15(5):395-398. [View Abstract]
Codes
ICD09
ICD10
- Q90.9 Down syndrome, unspecified
- Q90.2 Trisomy 21, translocation
- Q90.1 Trisomy 21, mosaicism (mitotic nondisjunction)
- Q90.0 Trisomy 21, nonmosaicism (meiotic nondisjunction)
SNOMED
- 41040004 Complete trisomy 21 syndrome (disorder)
- 371045000 Translocation Down syndrome (disorder)
- 205616004 trisomy 21- mitotic nondisjunction mosaicism (disorder)
Patient Education
Participation by individuals with Down syndrome who have atlantoaxial instability. See: http://sports.specialolympics.org/specialo.org/special_/English/coach/coaching/basics_o/Down_syn.htm
Down syndrome. See: http://kidshealth.org/parent/medical/genetic/down_syndrome.html
FAQ
- Q: Why was Down syndrome referred to as mongolism in the past?
- A: There was a mistaken notion about a racial cause for this syndrome because of the facial appearance, which was thought to be similar to that of those of Mongoloid origin.
- Q: Do all children with Down syndrome have mental retardation?
- A: No. Although all persons with nonmosaic Down syndrome have some degree of cognitive disability, some have IQs >70 and are not considered to have mental retardation.
- Q: Can a normal cardiac examination rule out the presence of a cardiac anomaly?
- A: No. The AAP recommends that all patients with Down syndrome have a cardiology consultation within the 1st month of life. Timely surgery may be necessary to prevent serious complications.
- Q: Are patients with atlantoaxial instability symptomatic?
- A: No. Most are asymptomatic, but symptoms of cord compression may be seen in 1-2% of patients. Patients with neck and/or radicular pain, weakness, change in tone, difficulties walking, or changes in bowel and bladder function should undergo radiologic evaluation for atlantoaxial instability.