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Down Syndrome (Trisomy 21)

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DEFINITION

Down syndrome is the most common autosomal abnormality among live births. Most Down syndrome cases result from true trisomy 21, with trisomy 21 mosaicism and translocations involving chromosome 21 each accounting for less than 5 percent of the diagnoses (Bishop 1997, Iselius 1986, Leisti 1985, Baird 1988, Stoll 1998, Owens 1983). The prenatal prevalence of Down syndrome is much higher than among live births, with only approximately 70 percent of fetuses with Down syndrome identified in mid-second trimester surviving to term (Hook 1983).

DEMOGRAPHIC AND REPRODUCTIVE FACTORS

The only well established risk factor for Down syndrome is advanced maternal age (Hook 1992, Mikkelsen 1985). Age-specific rates have been well documented (Hecht 1996). However, if the child has the syndrome as a result of a translocation in chromosome 21 and either or both parents are translocation carriers, there is an increased risk for additional children to also have the syndrome. It should be noted that this is a very rare condition (Jones 1997).

In a few studies, advanced paternal age (>49) has been associated with increased risk of Down syndrome births (Stene 1979, Erickson 1981, Murdock 1984). The risk associated with advanced paternal age has not been large, and is considerably diminished with the appropriate adjustment for maternal age. A large number of studies have failed to find evidence of this effect (Janerich 1986).

An association has been found between risk of Down syndrome and age of the maternal grandmother at the mother’s birth (Aagesen 1984. Mikkelsen 1985). Female meiosis starts in fetal life, and nondisjunction in the first meiotic division of a female might be induced during the fetal period, especially if her mother is older.

Several studies have reported secular trends in Down syndrome prevalence; however, these trends have not been consistent, with some studies reporting an increase while others a decline (Hahn 1993, CDC 1994, O’Leary 1996, Adams 1981, Iselius 1986, Leisti 1985, Baird 1988, Harlap 1974, Hook 1981, Owens 1983, Evers-Kiebooms 1989). A study of Down syndrome births between 1989 and 2001 indicated a decline in live births; however, the authors of this study indicated that this decrease might be due to an increase in pregnancy terminations (Egan 2004).

Over the last several decades, women carrying a fetus with Down syndrome have been found to have low maternal serum levels of alpha-fetoprotein and estriol and elevated levels of human chorionic gonadotropin (Canick 1993). Prenatal screening for these substances along with chorionic villus sampling and amniocentesis has allowed Down syndrome to be identified in utero. Studies from various birth defects surveillance systems have found that, in regions where elective termination is allowed, prenatal diagnosis and elective termination reduce the birth prevalence of Down syndrome (Olsen 2003, Forrester 1999, Mansfield 1999).

Down syndrome prevalence is known to vary by race/ethnicity. Hispanic infants were found to exhibit higher rates of Down syndrome than other infants, even after differences in maternal age were considered (CDC 1994). Rates for Hispanic, white, and African American infants were respectively 11.8, 9.2 and 7.3 per 10,000 live births (CDC 1994). This may be due partly to differential use of prenatal diagnosis services. Racial composition of women who use prenatal screening services varied from the racial composition of the U.S. population (Meaney 1993), though racial difference in usage was not found in another study (Naber 1987). Also, use of prenatal diagnosis services and abortion significantly reduced the birth prevalence of Down syndrome among white women but not among women of other races in Atlanta (Krivchenia 1993). That was not supported in a Los Angeles study ( Wilson 1992). Racial differences may also reflect differential under-diagnosis of the defect at birth.

Down syndrome prevalence varies by sex. Among live births, males have higher Down syndrome rates than females, although the discrepancy is less severe among fetuses, suggesting differential in utero survival between the sexes (Bishop 1997, Huether 1996, Bell 1989, Iselius 1986, Leisti 1985, Mikkelsen 1992). It should also be noted Down syndrome is selected against, as all reported males and most females are infertile (Olsen 2003).

An association of Down syndrome with multiparity (Schimmel 1994) tends to disappear when maternal age is taken into account (Chan 1998, Haddow 1994, Castilla 1994). A second study found that higher parity (four or more live births) led to an increased risk for Down syndrome even when the results were controlled for maternal age (Doria-Rose 2003). First-born infants may be at higher risk of Down syndrome than are those later born, independent of maternal age (Hay 1972). However, this is a very small effect if it exists (Janerich 1986).

The cluster investigation by Brender (1986) implicated short interval between pregnancies as a risk factor. Jongbloet (1982, 1985) had noted that periods of anovulatory activity followed by conception appear to correlate with increased occurrence of Down syndrome. It is possible that conceptions occurring during the transitional period between anovulation and the establishment of regular ovulation after childbirth might be more vulnerable to maternal meiotic nondisjunction. Therefore, a short interval between pregnancies might increase a woman’s risk of subsequently bearing a child with Down syndrome.

That theory has also been posed as an explanation for the observation that risk of Down syndrome is associated with season of child’s conception and season of mother’s conception (Jongbloet 1982, 1994).

OTHER FACTORS

Risk of bearing a child with Down syndrome increases with trisomy in the mother, translocation carrier in the parents, or previous affected pregnancy in the same sibship (Uchida 1970). Parental mosaicism has been found to be an etiologic factor in recurrent trisomy 21 (Panalos 1992). Increased rates in consanguineous marriages suggest that an autosomal recessive gene may predispose toward nondisjunction (Alfi 1980).

Some evidence suggests that thyroid disorders in the mother may increase risk of bearing a Down syndrome child (Fialkow 1971, Hook 1984).

Families with histories of Alzheimer’s disease are more likely to have Down syndrome offspring (NIH 1985). Of thirteen studies of the association between the two conditions, only four reported a significant relation, but statistical power may have been lacking in most of them (Schupf 1994).

Mothers of Down syndrome children had more significant illnesses before conception, particularly psychological illness, and more medication ingestion in the year before conception (Murdoch 1984). These remained statistically significant when adjusted for each other and for maternal age. Unfortunately, specific medications were not identified in this study.

Women who suffered from gestational diabetes were twice as likely to have offspring with chromosomal abnormalities, including Down syndrome, as women who do not have gestational diabetes (Moore 2002).

One study indicated that the rate of Down syndrome for mothers under 35 who conceived while taking oral contraceptives was the same as that for mothers over 35 (Martinez-Frias 2003).

FACTORS IN LIFESTYLE OR ENVIRONMENT

Ionizing radiation is the only known lifestyle/environmental agent to induce nondisjunction in experimental animals (Hook 1984). Epidemiologic evidence is less conclusive. Reports of increased occurrence of chromosomal anomalies from Hiroshima and Nagasaki (Awa 1975, 1987) are not consistent. A similar report from Kerala, India (Kochupillai 1976) has met with criticism (Hook 1977). Low-dose ionizing radiation from atomic weapon testing correlated with increased occurrence of Down syndrome in a time-series study in England (Bound 1995). The Chernobyl reactor accident was presented as an explanation for a cluster of trisomy 21 cases in Berlin (Sperling 1994), though significant clustering at that time was not reported from other European birth defect registries (de Wals 1988, Harjulehto-Mervaala 1992).

One explanation presented for the increased risk with maternal age is irradiation, such as from x-rays, accumulating over a lifetime (Alberman 1972). However, published data do not confirm x-rays as a risk factor (Evans 1986).

A statistically significant association was identified with fathers working in restaurants at the time of conception (Brender 1986). Though sanitation violations were observed, no unusual pesticides, cleaning compounds, or use practices were noted.

One study failed to find any link between parental occupational exposure to lead and Down syndrome risk. However, the number of cases in the study was small, and the measure of lead exposure was based on census records (Irgens 1998). Maternal use of contraceptive spermicides was not found to affect Down syndrome risk (Louik 1987).

One study has reported that women who had children with Down syndrome were more likely to have abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (James 1999). This suggests that periconceptional folic acid supplementation or fortification may reduce Down syndrome risk.

Trisomy 21 birth prevalence in Texas among 1999-2003 deliveries was 12.54 cases per 10,000 live births (Texas Department of State Health Services 2006). Birth prevalence in the United States is 12.94 per 10,000 live births (Canfield 2006).

REFERENCES

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  • James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, Gibson JB, Yi P, Tafoya DL, Swenson DH, Wilson VL, Gaylor DW. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am J Clin Nutr 1999;70:495-501.
  • Janerich DT, Bracken MB. Epidemiology of trisomy 21: a review and theoretical analysis. J Chronic Dis 1986;39:1079-1093.
  • Jongbloet PH, Mulder A, Hamers AJ. Seasonality of pre-ovulatory non-disjunction and the aetiology of Down syndrome. A European collaborative study. Hum Genet 1982;62:134-138.
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  • Pangalos CG, Talbot CC Jr, Lewis JG, Adelsberger PA, Petersen MB, Serre JL, Rethore MO, de Blois MC, Parent P, Schinzel AA, Binkert F, Boue J, Corbin E, Croquette MF, Gilgenkrantz S, de Grouchyy J, Bertheas MF, Prieur M, Raoul O, Serville F, Siffroi JP, Thepot F, Lejeune J, Antonarakis SE. DNA polymorphism analysis in families with recurrence of free trisomy 21. Am J Hum Genet 1992;51:1015-1027.
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  • Texas Department of State Health Services. Texas birth defects registry report of birth defects among 1999-2003 deliveries. 2006.
  • Uchida IA , Epidemiology of mongolism in the Manatoba study. Proc Natl Acad Sci 1970;171:361-369.
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Please Note: The primary purpose of this report is to provide background necessary for conducting cluster investigations. It summarizes literature about risk factors associated with this defect. The strengths and limitations of each reference were not critically examined prior to inclusion in this report. Consumers and professionals using this information are advised to consult the references given for more in-depth information. 

This report is for information purposes only and is not intended to diagnose, cure, mitigate, treat, or prevent disease or other conditions and is not intended to provide a determination or assessment of the state of health. Individuals affected by this condition should consult their physician and when appropriate, seek genetic counseling.

For more information:

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Document E58-10957D                    Revised March 2007

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Last updated June 17, 2014