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A. Etiology navigator

  1. Overall, chromsomal abnormalities occur in 0.1-0.2% of live births
  2. Down Syndrome is the most common of these entities
  3. Down's is due to Trisomy of chromosome 21 (or part of chr 21)
  4. Chromosome 21 Gene Groups Play a Role in Down Syndrome
    1. Mitochondrial energy and oxygen metabolism genes (16 genes)
    2. Brain development, neuronal loss, neuropathology associated genes (9 genes)
    3. Genes with role in folate and methyl group metabolism (6 genes)
  5. There is increased expression of amyloid A protein (and others)
  6. REST-Related Genes [11]
    1. Repressor Element 1 Silencing Transcription (REST) Factor
    2. REST is a transcriptional repressor, regulates genes involved in neural development
    3. REST dysregulation, probably overexpression, occurs in Down Syndrome cells
    4. REST appears to reduce expression of many genes critical to neural development in Down Syndrome cells
    5. REST dysregulation may play a key role in nervous system anomalies in Down Syndrome
    6. REST may control genes on chromosome 21 involved in brain development, neuronal loss

B. Epidemiology navigator

  1. ~1:800 live births
  2. Incidence increases with increasing maternal age
    1. ~50% of cases are to mothers >35 years of age
    2. Risk for >34 year olds is ~1/200
    3. Risk for 26 year olds is ~1/1500
  3. Risk of second Down's Child: ~1% (if due to chromosomal non-disjunction)
  4. Increased risk of neural tube defects in Down Syndrome [13]
  5. Folate supplementation may reduce risk of Down Syndrome [13]

C. Down Syndrome Risk Prediction [2] navigator

  1. Maternal blood screening using biochemical tests is most effective screening strategy
    1. Advanced maternal age alone may warrent amniocentesis and fetal karyotyping
    2. However, biochemical screening is more sensitive and specific
  2. PCR analysis of amniotic fluid cells is informative in >99% of cases [3]
  3. First Trimester Screening [16]
    1. Combination of ß-HCG and Pregnancy-Associated Protein A (PAPA) in first trimester detects 60-87% of Down Syndrome (95% specificity) [5,18]
    2. First trimester screening at 11 weeks with ß-HCG and PAPA is superior to 12-13 weeks [18]
    3. Testing using PAPA, HCG, and AFP during first two trimesters may be optimal [6]
    4. Age, maternal levels free ß-HCG, and PAPA in 35 year olds identified 90% of trisomy 21 with 15.2% false positive rate, and 100% of trisomy 18 [16]
  4. Quadruple Second Trimester Testing [2]
    1. Four maternal serum biochemical markers can be assessed in 2nd trimester
    2. alphafetoprotein (AFP)
    3. Human chorionic gonadotropin (HCG)
    4. Unconjugated estriol (estradiol)
    5. Inhibin [4]
    6. Sensitivity of Down Syndrome detection ~60% with 95% specificity with first 3 tests only
    7. Adding dimeric inhibin A to first three tests increases detection to 75-80% [2,4,18]
    8. False positive rate of quadruple test 5-7%
  5. Ultrasound [7]
    1. Thickened nuchal fold in second trimester is specific but not sensitive
    2. Measurement of 1st trimester nuchal translucency requires specialized interpretation [5]
    3. Fetal nuchal translucency thickness and maternal age predict ~80% of trisomy 21 [8]
    4. Having a thickened nuchal fold carries ~17X increased risk for Down's
    5. Absence of fetal nasal bone at 11-14 weeks is extremely sensitive and specific [10]
    6. Combination of nasal bone, fetal nuchal translucency and maternal age provides 85% sensitivity and 99% specificity [10]
    7. Ultrasound should not be used to determine who should undergo amniocentesis

D. Symptomsnavigator

  1. Wide spectrum of severity for unknown reasons
  2. Phenotypic Abnormalities (Panel 4, Ref [1])
    1. Brachycephaly
    2. Brachydactyly
    3. Broad hands
    4. Duodenal atresia
    5. Epicanthal folds
    6. Fifth finger clinodactyly
    7. Flat nasal bridge
    8. Hypotonia
    9. Lax ligaments
    10. Mental retardation - most prominant abnormality in most cases
    11. Open mouth
    12. Short stature
    13. Wide 1-2 toe gap
  3. Associated structural defects
    1. Congenital heart disease
    2. Gastrointestinal abnormalities
  4. Premature Alzheimer's Disease
  5. Cancer Risks [8]
    1. Increased incidence of leukemia, mainly acute myeloid form
    2. Incidence of breast cancers may be reduced
  6. Myeloid Disorders
    1. Increased incidence of leukemia, mainly acute myeloid form [14]
    2. Transient myeloproliferative disorder associated with trisomy 21 also occurs [15]

E. Diagnosis [17]navigator

  1. Gold standard is full karyotyping
  2. Prenatal detection using less than full karyotyping has been instituted in some countries
  3. Rapid testing using FISH or PCR for trisomies 13, 18, and 21 after positive screen is used
  4. Rapid testing for trisomies 13, 18 and 21 is substantially less sensitive than fully karyotype

F. Evaluation of Down Syndrome Infantnavigator

  1. Intelligence testing
  2. Echocardiogram
  3. Ophthalmological assessment
  4. Hearing assessment
  5. Periodontal disease
  6. Weight control - prevent obesity
  7. Monitor for celiac disease (gluten enteropathy) and thyroid dysfunction

G. Monitoring for Complicationsnavigator

  1. Arthritis
  2. Atlantoaxial subluxation
  3. Diabetes mellitus
  4. Leukemia or transient myeloproliferative disorder
  5. Obstructive sleep apnea
  6. Seizures

G. Prognosis [12]navigator

  1. Median age at death 49 years in 1997
  2. Median age of death significantly lower in non-white patients with Down Syndrome
  3. Death usually associated with congenital heart defects, dementia (>20X versus non-Down)
  4. Leukemia also increased, but only 1.6X fold versus non-Down
  5. Overall malignancies were reduced on death certificates versus non-Down

References navigator

  1. Roizen NJ and Patterson D. 2003. Lancet. 361(9365):1281 abstract
  2. Wald NJ, Huttly WJ, Hackshaw AK. 2003. Lancet. 361(9360):835 abstract
  3. Verma L, Macdonald F, Leedham P, et al. 1998. Lancet. 352(9121):9 abstract
  4. Aitken DA, Wallace EM, Crossley JA, et al. 1996. NEJM. 334(19):1231 abstract
  5. Haddow JE, Palomaki GE, Knight GJ, et al. 1998. NEJM. 338(14):955 abstract
  6. Wald NJ, Watt HC, Hackshaw AK. 1999. NEJM. 341(7):461 abstract
  7. Smith-Bindman R, Hosmer W, Feldstein VA, et al. 2001. JAMA. 285(8):1044 abstract
  8. Snijders RJM, Noble P, Sebire N, et al. 1998. Lancet. 352(9125):343 abstract
  9. Hasle H, Clemmensen IH, Mikkelsen M. 2000. Lancet. 355(9199):165 abstract
  10. Cicero S, Curcio P, Papageorghiou A, et al. 2001. Lancet. 358(9294):1665 abstract
  11. Bahn S, Mimmack M, Ryan M, et al. 2002. Lancet. 359(9303):310 abstract
  12. Yang Q, Rasmussen SA, Friedman JM. 2002. Lancet. 359(9311):1019 abstract
  13. Barkai G, Arbuzova S, Berkenstadt M, et al. 2003. Lancet. 361(9366):1331 abstract
  14. Hasle H, Clemmensen IH, Mikkelsen M. 2000. Lancet. 355(9199):165 abstract
  15. Wolfe LC, Weinstein HJ, Ferry JA. 2003. NEJM. 348(25):2557 (Case Record) abstract
  16. Wapner R, Thom E, Simpson JL, et al. 2003. NEJM. 349(15):1405 abstract
  17. Caine A, Maltby AE, Parkin CA, et al. 2005. Lancet. 366(9480):123 abstract
  18. Malone FD, Canick JA, Ball RH, et al. 2005. NEJM. 353(19):2001 abstract