Epidemiology and Etiology

The presence of the additional number 21 chromosome in all cells of the individual with Down syndrome is usually the result of an error in cell division called nondisjunction. In normal cell division, the two members of each of the 23 chromosome pairs separate and move into one of the two resulting cells, whereas in nondisjunction, both members of the chromosome pair end up in a single cell. In Down syndrome, the nondisjunction has usually occurred during meiosis (sex cell division) usually of the female sex cell (the ovum). Thus, when an ovum with two number 21 chromosomes is fertilized, three number 21 chromosomes (two from the mother and one from the father) will be passed on to all the cells in the developing fetus. The occurrence of Down syndrome is most consistently associated with advanced maternal age, with incidence rising from 0.45 per 1,000 live births in women 20 to 24 years of age (8 studies) to 9.4 per 1,000 live births for women 40 to 44 years (7 studies). The largest risk increase occurs between the age groups 30 to 34 and 34 to 39 years (Lilienfeld 1969).

Four potential reasons for the maternal age association have been suggested:

1. Whereas the prenatal incidence of Down syndrome is constant across all ages, the older uterus is less selective in rejecting the Down syndrome conceptus.

2. Longer delays between intercourse result in a relatively "aged ovum," more likely to experience nondisjunction.

3. In older women, the ova themselves have aged longer and have an increased rate of nondisjunction.

4. Long-term exposure to environmental agents has resulted in damage to the spindle mechanism that in turn produces meiotic nondisjunction.

Because the additional chromosome can be traced to the father in 20 percent of the cases of Down syndrome, studies have also evaluated a paternal age effect on incidence. However, such an effect cannot be conclusively demonstrated (Janerich and Bracken 1986).

About 30 to 60 percent of all Down syndrome births, however, are not age dependent, meaning that they occur in mothers of ages under 30 years. Indeed, a high incidence of infants with Down syndrome has recently been reported in women less than 15 years of age. In both younger and older sibs of index patients, the risk of having offspring with Down syndrome is increased 2- to 10-fold. Younger mothers are more likely to have a second offspring with Down syndrome than are older mothers. The recurrence risk is 1 in 3 for mothers who are translocation carriers.

A number of environmental and metabolic mechanisms for Down syndrome have been evaluated, among them maternal drug, tobacco, alcohol, and caffeine use; use of hormonal and nonhormonal contraceptives; fluoridated water; and radiation exposure. However, findings from these studies have been inconsistent. Some investigators have suggested that a possible recessive gene producing nondisjunction might explain up to 10 percent of the cases. However, studies in consanguineous marriages do not support this suggestion. Dwight Janerich and Michael Bracken (1986) indicate that the association with elevated maternal age is undoubtedly a surrogate variable for other underlying associated factors, the most important of which are probably endocrine changes associated with aging.

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