162: Down Syndrome

Key Points

  • Disease summary:

    • Down syndrome (DS) is a chromosomal aneuploidy of chromosome 21 and represents the most frequently identified cause of intellectual disability, with a wide range of severity.

    • In addition to typical facial features, the phenotype includes skeletal, neurologic, gastrointestinal, endocrine, and hematologic components or risks. Anticipatory guidance is the key to the prevention and treatment of these complications.

    • DS is associated with increased mortality in childhood (usually due to congenital heart disease) and in adulthood (due to Alzheimer disease and premature aging, among other factors).

    • Prenatal screening for DS is widely practiced and has evolved from ultrasound-based approach to combined ultrasound and biochemical marker-based approach to DNA-based approach.

  • Hereditary basis:

    • DS is usually caused by the sporadic de novo occurrence of a meiotic error involving chromosome 21 in the parent (usually the mother especially in the older age group), which is associated with a low recurrence risk.

    • A much higher recurrence risk is observed when the meiotic error is the result of a constitutional parental translocation (<5% of DS cases) or parental mosaicism (frequency unknown).

  • Differential diagnosis:

    • Single palmar (Simian) crease, sandal gap, upslanting palpebral fissures, epicanthic folds, protruding tongue, and hypotonia are seen in the majority of DS but can also be seen in normal individuals and this explains why clinical diagnosis is only accurate in two-thirds of the cases in the neonatal period. Hypothyroidism may present with similar features. Other rare disorders, such as peroxisomal disorders and Menkes syndrome are possible alternatives in infants. Short stature and mental retardation occur in a number of disorders.

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria for Down Syndrome

  • Common features

  • Epicanthic folds

  • Upslanting palpebral fissures

  • Protruding tongue

  • Single palmar creases

  • Hypotonia

  • Sandal gap (abnormally wide gap between the first and second toes)

In one study, the above six features were identified in 100% of trisomy DS and 90% of translocation DS but in 38% of those with mosaic DS. Any of these features in isolation can be seen in normal individuals and the presence of these features combined strongly predict DS but karyotypic testing is a must to both confirm the clinical suspicion and to determine the recurrence risk (see Counseling).

Clinical Characteristics

The conspicuous profile of DS makes it highly unlikely that the diagnosis is first made in adulthood. A summary of the clinical features seen in adults with DS is summarized in Table 162-1. Individuals with mosaicism have variable expression of the clinical characteristics that is dependent on the proportion of trisomic cells.

Table 162-1   Clinical Characteristics of Adult Patients With DS (based on 36 adults, adapted from van Allen et al. 1999) 

Screening and Counseling


Screening for DS is usually done prenatally. In 2006, the American College of Obstetrics and Gynecology issued recommendations that all women regardless of their age should be offered noninvasive screening and the option for chorionic villous sampling (CVS) or amniocentesis. According to the new recommendations, “first-trimester screening using both nuchal translucency (NT) and a blood test is an effective screening test in the general population, and that women found to be at increased risk of having a baby with DS with first-trimester screening should be offered genetic counseling and the option of CVS or mid-trimester amniocentesis.” Recently, isolation of circulating cell-free fetal DNA followed by next-generation sequencing has shown a remarkable degree of sensitivity and specificity and is currently offered clinically.

It is highly unusual that a DS patient will reach adulthood without being diagnosed but one should consider making the diagnosis in an adult patient with intellectual disability and typical facial features. More relevant to the issue of screening in adult DS patients is the screening for certain health conditions that occur at a higher frequency compared to the general population and these are detailed in Table 162-2 in which a guideline for anticipatory guidance is recommended. Several health issues deserve a special mention. Normal eyes are considered to be the exception in adults with DS so regular assessment for the development of cataract, keratoconus, and other visual problems is important. Just like in children, DS adults are more likely than others to have undiagnosed otitis media and failure to recognize and treat these infections can lead to a more severe mastoiditis so regular ENT assessment is recommended. Obesity, which is very common in DS adults, can result in hypoventilation and sleep apnea, so this needs to be considered in the regular assessment of these patients. Although Alzheimer disease is much more common in DS adults compared to the general population, a decrease in cognitive function should be investigated considering other possibilities including hypothyroidism which is very common in this patient population and should be screened for on an annual basis.

Table 162-2   Healthcare Screening of Adults With Down Syndrome