Down Syndrome / Trisomy 21

1866 John Langdon Down described the phenotype. Trisomy 21 described in 1959

Epidemiology
• one in 600-800 births
• > 50% of Tris 21 conceptions abort

Genetics

• not affected by paternal age; risk increases with maternal age
• (related link: Advanced paternal age)
• usually meiotic nondisjunction (94%)
• 95% of cases have regular trisomy 21; 3% with mosaicism, 2% with translocations
  • of the translocations, 14;21 Robertsonian translocation is the most common (if mother carries this translocation, recurrence risk is 10%; if father carries it, recurrence risk is 2%)
  • recurrence risk is 100% in the rare t(21q;21q) translocation where one parent carries the translocation chromosome
• Risk of recurrence after one affected child with a standard trisomy is 1% for a baby with some form of trisomy (trisomy 21 would be the most common)

Liveborn risk of Down Syndrome (maternal age - risk)
25 yrs - 1 in 1300
35 years - 1 in 380
38 years - 1 in 180
40 years - 1 in 100
45 years 1 in 45

Prenatal Dx
• 10 weeks amniocentesis
• 10-12 weeks chorionic sampling
• Triple screen: increased HCG, decreased maternal serum AFP, decreased unconj. estriol

Features
• IQ 35-65, mean 54 ... by age 40, mean IQ is 24
• intelligence deteriorates in childhood, with clinical and pathologic findings consistent with Alzheimer's
• Personality: affectionate, docile, tend toward mimicry and enjoy music. Good sense of rhythm.
• But 13% have serious emotional problems
• Coordination usually poor

Physical Features and associations
• Overall: hypotonia (be vigilant during nbn exam), short stature, Cutis Marmorata
• Eyes: cataracts, strabismus, upslanted palpebral fissures (lateral sides are up), epicanthal folds, speckled irises (Brushfield spots, in 10% of nl, 75% of kids w/ Down), associated with Glaucoma
• Face: flat face, small ears, flat/wide nasal bridge; may be three fontanelles
• Mouth: flattened philtrum, high arched palate, macroglossia,
• Extr: simian crease (nonspecific), short broad hands, short middle phalanx of 5th digit, sandal toe
• Inside: atlantoaxial subluxation, short neck, pelvic dysplasia, intestinal atresia (Duodenal atresia is common).
Increased congenital heart disease  (in 40%) therefore do routine echo at time of dx. Endocardial cushion defects. (i.e. do echo at birth)

Disease Associations
• Leukemia: ALL especially. (i.e. do CBC at birth and qyear from age 13)
• Hirschsprungs, Hypothyroidism
• Diabetes mellitus
• Alzheimers
• Glaucoma

Protection against atherosclerotic heart disease!
• CBS (cystathione B-synthetase) is on chrom 21. This enzyme catalyzes homocysteine to cystathione.
• if CBS enzyme is low, homocysteine (reagent) builds up -> homocystinuria, premature atherosclerosis
• since there is an extra chrom 21, CBS activity is increased! and the reaction proceeds normally to produce cystathione from homecysteine and serine.

AAP recs for Health Screening:

* CBC at birth and yearly from age 13
* Hearing screening: ABR at birth, behavior audiogram at 1 year, then if can't see TM, audiogram q6 months until 3 y/o, then audiology eval annually
* TFT at 6 mos, 1 y/o and then annually
* ophtho eval by 6 m/o, then q2 years until age 5, then annually.
* c-spine XR at 3-5 years

Birth-1month
*       cardiology consult and echocardiogram (vs Turner: also need immediate endo consult and renal US)
*       CBC (not necessary in Turner)
*       ABR

1 month-1year
*       behavior audiogram at 1 year
*       check for strabismus, cataracts, nystagmus by 6 months
*       optho referral by 6 months
*       repeat TFTs at 6 months and 12 months (vs Turners: TFT's are started later at age 4)

1-5 years
*       if can't see TM- audiogram Q6 months up to 3 years
*       ophtho evaluation Q2 years
*       C-spine X-ray at 3-5 years to r/o atlanto-axial subluxation
*       TFTs annually
*      (vs turners: checking BPs and peripheral pulses, FT4 and TFT's start later, at age 4)

5-13 years
*       audiology annually
*       ophtho evaluation annually
*       TFTs annually (q1-2 yrs in Turners)

13-21 years
*       CBC and TFTs anually
*       audiology annually
*       ophtho evaluation annually
*      (vs Turner: do fasting lipid profile, second referral to cardiology and endo referral for sex hormone replacement)

Trisomy 13 (Patau)
Trisomy 18 (Edwards)

Chief Resident Pearl, 2004