1/650 live births; increased in mothers age >35 yr. Associated Alzheimer’s disease in families, esp premature Alzheimer’s (Ann IM 1985;103:566) and correlates with amyloid A₄ protein excess production and deposition (Nejm 1989;320:1446)

Sx:Flat face (90%), poor Moro (85%), hypotonia (80%)

Si:Findings subtle at birth and become more apparent late: hypotonia; developmental delay; short, brachycephalic with excess skin on the back of the neck; hypoplastic midface bones; single palmar crease, epicanthal fold (50%); Brushfield’s spots (white) on iris (present in 10% normals too); short 5th finger and toes; duodenal obstruction in many, esp from atresia and ring pancreas; low-set, hypoplastic ears; heart murmurs and congenital heart disease, esp atrial septal defect (in 25%); imperforate anus (3%); umbilical hernia; tachycardia

Odontoid ligament laxity causing C₁ on C₂ dislocation as in rheumatoid arthritis (Peds 1992;89:1194); leukemia; increased infection rates; incr Hashimoto’s thyroiditis (get TSH q 1 yr); incr gluten enteropathy

r/o D-1 (13-15) trisomies with elevated fetal hemoglobin, decreased A₂ hemoglobin, polydactyly, cleft palate; E (17-18) trisomy with many Down’s-type changes and associated with congenital biliary atresia

Lab:

Hem:Chromosome prep shows trisomy or translocation

Serol:SPEP shows diffuse increased globulin

Xray:Hip films show horizontal acetabulum. Skull films, facial and sphenoid views show hypoplasia; bronchogram shows “pig bronchus,” ie, one ending in a blind pouch

Rx:

Prevention (Nejm 2005;353:2001; 2003;349:1405); many of these tests can be used in combination (Nejm 1999;341:461, 521) to incr sens and specif; positive results = <1/250 chance of trisomy resulting in amnio or chorionic sampling. At 15 wk gestation, 5% sens and 90% specif of first 3 in combo

Screening strategies (Nejm 2009;360:2556; 2005;353:2001):

• 1st trimester combined screening (wk 10-11) 83-87% sensitive, earlier is better.
• Nuchal translucency
• HCG
• Pregnancy associated plasma protein A (PAPP-A)
• 2nd trimester quadruple screening (wk 15-18) 81% sensitive.
• Alpha fetoprotein
• HCG
• Unconjugated estriol
• Inhibin A
• Stepwise sequential screening: offer chorionic villus sampling after each round of screening. 95% sensitivity, 4.9% false positives.
• Integrated screening: offer risk stratification after 1st and 2nd trimester screenings. 96% sensitivity, 4% false positives.
• Fetoprotein (low in Down’s) under age 35 yr, w 2nd trimester, alone, or as “quadruple screen” w a fetoprotein
• HCG subunit and
• Unconjugated estriol
• Protein (inhibin) A levels perhaps combined w above and US of neck, in 1st trimester (Nejm 2003;349:1405; 1998;338:955);
• Karyotype analysis by amniocentesis if over 35 yr or when risk calculated from these results is >1/250 (equivalent to risk at age 35 yr); this strategy equalizes risk of Down’s vs abortion from amnio (Nejm 1994;330:1114, 1151).
• High risk:
• Ultrasound in 2nd trimester, which can detect 60-75% by neck skin thickness but specif ~25% (Nejm 1997;327:1654) or as low as 0.00015% in normal women or 0.002% in high-risk women! (Jama 2001;285:1044); and by femur length (Nejm 1987;317:1371)
• Karyotype analysis by amniocentesis if over 35 yr or when risk calculated from these results is >1/250 (equivalent to risk at age 35 yr); this strategy equalizes risk of Down’s vs abortion from amnio (Nejm 1994;330:1114, 1151).
• Chorionic villus sampling now almost as safe as amnio, and abortion can be done much earlier, eg, in 1st trimester (Nejm 1989;320:7), then w 2nd trimester abortion (Nejm 1979;300:157—useful table of incidence by maternal age); amniocentesis has a 0.3% false-positive (error) rate. Half of fetuses with Down’s at 15 wk gestation will spontaneously abort or die perinatally; 1.5% abort after amniocentesis (Nejm 1979;300:118—ethical discussion)

Primary care: of newborn, confirm clinical suspicion w karyotype; cardiac consultation on all; hearing screen, thyroid studies, CBC; early intervention program and parental support group referral

• of child, annual thyroid screen, cervical spine films at 3 and 12 yr prn long tract si’s or sx; periodic hearing and ENT assessment; periodic ophthalmologic exam; dental visits begin at age 2 yr