A 2-day-old baby boy is brought to the emergency department for vomiting. The patient’s mother is a 25 year-old single parent who did not receive prenatal care, and the baby was born at home via vaginal delivery at 39 weeks gestation. The mother reports that the baby vomits whenever she tries to breastfeed him and that the emesis appears green and thick. The infant is noted to have epicanthal folds, upward-slanting palpebral fissures, flat nasal bridge, a single transverse palmar (simian) crease, and small ears (Figures 221-1 and 221-2). The examining physician suspects the child has Down syndrome and orders an abdominal x-ray, which reveals a “double-bubble,” consistent with duodenal atresia, and is associated with Down syndrome. (Figure 221-3). The baby undergoes surgical correction of the atresia and recovers completely. A chromosomal analysis confirms the diagnosis of Down syndrome.

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  Down syndrome (DS) is an aneuploidy that develops from excess genetic material on chromosome 21, and results in a distinctive phenotypic appearance.^1,2 Children commonly present with congenital cardiac, hematologic, musculoskeletal, visual, and/or auditory defects.³ The incidence of DS increases with maternal age.⁴

Trisomy 21.

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  DS is the most commonly occurring genetic disorder among live births, occurring in 1 in 691 of all live births in the US.⁵

  
  
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  The risk of having a prenatal diagnosis for DS is thought to be higher since it is estimated that 67 percent women (range 61% to 93%) in the US with a fetus demonstrating trisomy 21 will terminate the pregnancy.⁶

  
  
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  Compared to Caucasian mothers, the prevalence ratio of trisomy 21 live births was 0.77 among African American mothers and 1.12 among Hispanic mothers. These differences could reflect ethnic differences in accessibility to prenatal screening, variation in the decision to terminate the pregnancy, or reporting bias inherent to the design of the study.⁷

  
  
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  Although the risk of DS increases with increasing maternal age, approximately 80 percent of babies with DS are born to women <35 years of age.⁴

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  Ninety-five percent of DS cases arise from nondisjunction of chromosome 21, resulting in 3 complete copies of chromosome 21.²

  
  
  
  
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    In 86 percent of these cases, the extra chromosome originated from the mother due to nondisjunction during meiosis II (75%) rather than meiosis I (25%). Nine percent of complete trisomy 21 is derived from the father. Less than 5 percent of complete trisomy 21 is due to mitotic errors.¹

    
    
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    These nondisjunction events are associated with increasing maternal age, which is correlated with a decrease in genetic recombination.¹

  
  
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  Three to four percent of DS cases occur due to chromosome 21 translocations, including balanced Robertsonian translocations of chromosome 21q paired most commonly with chromosome 14q. In patients with balanced translocations, parents should be screened to ensure that one of them is not a phenotypically normal carrier of a balanced translocation.¹

  
  
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  One to two percent of DS cases are due to mosaicism in which two cell lines are expressed, one with trisomy 21 and the other with normal cytogenetics.¹

  
  
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  The extra genetic materials lead to the characteristic DS phenotype, the best studied of which being the central nervous system manifestations. On histopathological studies, DS patients have decreased numbers of cortical neurons, stagnation of dendritic tree development at 4 months of age, decreased number of synapses, and delayed myelination when compared to normal subjects.¹

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  Increasing maternal age is the single risk factor most associated with nondisjunction errors hypothesized to be secondary to accumulation of environmental insults to the oocyte and/or gradual attrition of the meiotic machinery.¹

  
  
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  Altered recombination pattern during meiosis, characterized by decreased recombination or pericentromeric exchange, will increase risk of DS.¹

  
  
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  Other environmental factors implicated in DS include maternal alcohol use, maternal irradiation, and low socioeconomic status. However, these associations have not been confirmed.⁷

Clinical Features

Typical physical findings characteristic of DS are:

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  Hypotonia (Figure 221-1).

  
  
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  Wide gap between first and second toes (Figure 221-1).

  
  
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  Clinodactyly (bend or curvature of one finger toward the other fingers, most commonly the fifth finger toward the other four fingers; Figure 221-4).

  
  
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  Simian crease (Figure 221-2).

  
  
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  Craniofacial abnormalities such as brachycephaly.

  
  
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  Small and low-set ears (Figure 221-5).

  
  
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  Epicanthal folds, upward-slanting palpebral fissures (Figures 221-6 and 221-7).

  
  
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  Flat nasal bridge (Figures 221-6 and 221-7).

  
  
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  Brushfield spots (speckled white spots on the iris; Figure 221-8).