Trisomy 18 (Edwards syndrome) is the most common autosomal abnormality among live births after Down syndrome (trisomy 21). Most trisomy 18 cases result from true trisomy 18, which results from nondisjunction during meiosis. A small proportion results from mosaicism (a condition in which tissues of genetically different types occur in the same person), caused by postzygotic nondisjunction or anaphase lag, and translocation (Chen 2004, Forrester 1999, Carothers 1999, Huether 1996, Pradat 1991, Buyse, 1990). The origin of the extra chromosome has most often been traced to the mother (Ramesh 1996, Nothen 1993, Ya-gang 1993, Kupke 1989). Most trisomy 18 fetuses detected in mid-second trimester do not survive to term (Hook 1989).
Clinical features associated with trisomy 18 include but are not limited to the following: central nervous system disorders (holoprosencephaly, meningomyelocele), eye malformations (hypo/hypertolerism, monophthalmia), nose malformations (cebocephaly), cleft lip and/or palate, abnormal ears, malformed extremities (polydactyly, rocker-bottom feet), and defects of the heart, genitals, and midline.
The prognosis for this disorder is generally not positive. Most infants who survive to term have a median survival time of 2 to 10 days (Parker 2003). However, there are some infants who do survive for a year or more (Rasmussen 2003). Infants who do survive often experience both physical and mental developmental delays (Parter 2003).
Trisomy 18 involving total trisomy 18 results from nondisjunction, usually in formation of the eggs or sperm, where one gamete ends up with an extra chromosome 18. Nondisjunction may occur in the first meiotic stage (MI) or the second meiotic stage (MII).
The extra chromosome 18 is of maternal origin in 90-97% of the cases and of paternal origin in 3-10 percent of the cases. Among trisomy 18 cases of maternal origin, 31-39% result from nondisjunction in MI and 61-69% result from nondisjunction in MII (Bugge et al., 1998; Nicolaidis and Petersen, 1998; Eggermann et al., 1996; Ramesh and Verma, 1996; Fisher et al., 1995; Jacobs and Hassold, 1995; Fisher et al., 1993; Ya-gang et al., 1993).
DEMOGRAPHIC AND REPRODUCTIVE
Risk of trisomy 18 is well known to increase with increasing maternal age (Munne 2004, Naguib 1999, Baty 1994, Buyse 1990, Goldstein 1988, Schreinemachers 1982). Trisomy 18 risk has been associated with increasing paternal age; however, once maternal age is taken into consideration the association with paternal age disappears (Naguib 1999, Baty 1994).
Race/ethnicity has not been reported to influence trisomy 18 risk (Buyse 1990). One study found that, of the four racial/ethnic groups examined (white, Far East Asian, Pacific Islander, Filipino), trisomy 18 risk was highest for Far East Asians and lowest for Pacific Islanders (Forrester 1999). However, the differences in risk appeared to be due to differences in maternal age distribution among the racial/ethnic groups.
Geographic area may influence trisomy 18 risk. One study reported higher trisomy 18 rates among urban residents (Forrester 1999). This increased risk remained after controlling for maternal age. Several studies have suggested that trisomy 18 prevalence can show seasonal variation (Naguib 1999).
Several studies have reported a secular trend for trisomy 18, with the prevalence of the aneuploidy increasing over time. However, in one study this trend was believed to reflect improvements in ascertainment of the aneuploidy (Pradat 1991). In the other study the increase in trisomy 18 prevalence over time was considered due to increasing numbers of births to older women and increasing prenatal diagnosis of affected pregnancies (Gessner 2003, Forrester 1999).
Over the past several decades, women carrying a fetus with trisomy 18 have been found to have a prenatal marker screen with low maternal serum levels of alpha-fetoprotein, human chorionic gonadotropin, and estriol (Canick 1993, Greenberg 1992, Doran 1986). Moreover, prenatal ultrasonography can detect a variety of structural anomalies frequently associated with trisomy 18 (Abramsky 1993, Vintzileos 1987). Prenatal marker screening, ultrasonography, and definitive diagnosis by karyotyping through such procedures as amniocentesis and chorionic villus sampling, have allowed trisomy 18 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 trisomy 18 (Forrester 1999, Carothers 1999, Forrester 1998, Abramsky 1993, Pradat 1991).
Infant sex influences the risk for trisomy 18. Females are more likely than males to have the aneuploidy (Forrester 1999, Naguib 1999, Carothers 1999, Huether 1996, Pradat 1991, Buyse 1990, Goldstein 1988). One study found that sex ratio varied with race/ethnicity; however, this observation was attributed to small sample size (Huether 1996).
The recurrence risk for trisomy 18 has been reported to be approximately 1 percent (Baty 1994, Buyse 1990). A more recent study indicates that the risk of a trisomy increases for women who have had previous trisomy pregnancies, regardless of whether that pregnancy was viable. That is, even if the pregnancy was spontaneously aborted, the risk remains elevated (Munne 2004). There is also an increased risk for trisomic pregnancy in women who have decreased numbers of oocytes (Kline 2000). This condition is due to the onset of menopause.
FACTORS IN LIFESTYLE OR ENVIRONMENT
No lifestyle or environmental factors have been definitively reported to affect trisomy 18 risk. However, the differences in trisomy 18 prevalence between populations (Forrester 1999, Naguib 1999) suggest that environmental factors may influence risk for chromosomal errors. This defect has not been associated with living near solid waste incinerators or landfills (Cordier 2004, Harrison 2003). Exposure to cholorination byproducts and nitrate in drinking water (Cedergren 2002) or pesticides (Berkowitz 2003) does not increase the risk of this defect. Maternal exposure to chemical solvents does not increase the risk of trisomy 18 (Wennborg 2005).
The rate of chromosomal errors present due to Assisted Reproductive Technology (ART) is unclear, as is whether there are more chromosomal errors due to the laboratory techniques associated with these procedures, or if there are underlying genetic issues with the parental contribution(s) to the process. That is, couples that are not able to conceive naturally may be predisposed to genetic errors (Palermo 2000). One study has indicated that polymorphisms in the folate pathway are not responsible for human meiotic nondisjunctions of any kind (Hassold 2001). The use of multivitamins is not associated with a decreased risk of trisomy 18 (Botto 2004).
Trisomy 18 birth prevalence in Texas among 1999-2003 deliveries was 2.21 cases per 10,000 live births (Texas Department of State Health Services 2006). Birth prevalence in the United States is 2.29 per 10,000 live births (Canfield 2006).
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