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Trisomy 18 (Edward's Syndrome)

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DESCRIPTION

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).

ETIOLOGY

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).

PREVALENCE

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).

REFERENCES

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  • Baty BJ, Blackburn BL, Carey JC. Natural history of trisomy 18 and trisomy 13. I. Growth, physical assessment, medical histories, survival, and recurrence risk. Am J Med Genet 1994;49:175-188.
  • Berkowitz GS, Obel J, Deych E, Lapinski R, Godbold J, Liu Z, Landrigan PJ, Wolff MS. Exposure to indoor pesticides during pregnancy in a multiethnic urban cohort. Environmental Health Perspectives 2003;111:1:79-84.
  • Botto LD, Mulinare J, Yang Q, Liu Y, Erickson JD. Autosomal trisomy and maternal use of multivitamin supplements. American Journal of Medical Genetics 2004:125A:113-116.
  • Buyse ML, editor-in-chief. Birth Defect Encyclopedia. Cambridge, Massachusetts: Blackwell Scientific Publications, 1990.
  • Canfield MA, Honein MA, Yuskiv N, Xing J, Mai CT, Collins JS, Devine O, Petrini J, Ramadhani TA, Hobbs CA, Kirby RS.  National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999-2001. Birth Defects Res A Clin Mol Teratol. 2006 Nov;76(11):747-56.
  • Canick JA, Saller DN. Maternal serum screening for aneuploidy and open fetal defects. Obstet Gynecol Clin North Am 1993;20:443-454.
  • Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. The Lancet Oncology 2004;5:283-291.
  • Carothers AD, Boyd E, Lowther G, Ellis PM, Couzin DA, Faed MJ, Robb A. Trends in prenatal diagnosis of Down syndrome and other autosomal trisomies in Scotland 1990 and 1994, with associated cytogenetic and epidemiological findings. Genet Epidemiol 1999;16:179-190.
  • Cedergren MI, Selbing AJ, Lofman O, Kallen BAJ. Chlorination byproducts and nitrate in drinking water and risk for congenital cardiac defects. Environmental Research Section A 2002;89:124-130.
  • Chen M, Yeh GP, Shih JC, Wang BT. Trisomy 13 mosiacism: study of serial cytogentic changes in a case from early pregnancy to infancy. Prenatal Diagnosis 2004;24:137-143.
  • Cordier S, Chevrier C, Robert-Gnansia E, Lorente C, Brula P, Hours M. Risk of congenital anomalies in the vicinity of municipal solid waste incinerators. Occup Environ Med 2004;61:8-15.
  • Doran TA, Cadesky K, Wong PY, Mastrogiacomo C, Capella T. Maternal serum alpha-fetoprotein and fetal autosomal trisomies. Am J Obstet Gynecol 1986;154:277-281.
  • Forrester MB, Merz RD. Trisomies 13 and 18: Prenatal diagnosis and epidemiologic studies in Hawaii, 1986-1997. Genet Test 1999;3:335-340.
  • Forrester MB , Merz RD, Yoon PW. Impact of prenatal diagnosis and elective termination on the prevalence of selected birth defects in Hawaii. Am J Epidemiol 1998;148:1206-1211.
  • Fried PA. The consequences of marijuana use during pregnancy: a review of the human literature, in Women and Cannabis: Medicine, Science, and Sociology, The Haworth Integrative Healing Press, 2002.
  • Gessner BD. Reasons for trisomy 13 and 18 births despite the availability of prenatal diagnosis and pregnancy termination. Early Human Development 2003; 73:53-60.
  • Goldstein H, Nielsen KG. Rates and survival of individuals with trisomy 13 and 18. Clin Genet 1988;34:366-372.
  • Greenberg F, Schmidt D, Darnule AT, Weyland BR, Rose Esmie, Alpert E. Maternal serum alpha-fetoprotein, beta-human chorionic gonadotropin, and unconjugated estriol levels in midtrimester trisomy 18 pregnancies. Am J Obstet Gynecol 1992;166:1388-1392.
  • Harrison RM. Hazardous waste landfill sites and congenital anomalies. Occup Environ Med 2003; 60:79-80.
  • Hassold TJ, Burrage LC, Chan ER, Judis LM, Schwartz S, James SJ, Jacobs PA, Thomas NS. Maternal folate polymorphisms and the etiology of human nondisjuntion. American Journal of Human Genetics; 2001:69:434-439.
  • Hook EB, Topol BB, Cross PK. The natural history of cytogenetically abnormal fetuses detected at midtrimester amniocentesis that are not terminated electively: New data and estimates of the excess and relative risk of late fetal death associated with 47,+21 and other abnormal karyotypes. Am J Hum Genet 1989;45:855-861.
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  • Nothen MM, Eggermann T, Erdmann J, Eiben B, Hofmann D, Propping P, Schwanitz G. Retrospective study of the parental origin of the extra chromosome in trisomy 18 (Edwards syndrome). Hum Genet 1993;92:347-349.
  • Palermo GD, Neri QV, Hariprashad JJ, Davis OK, Veeck LL, Rosenwaks Z. ICSI and its outcome. Seminars in Reproductive Medicine 2000; 18:2: 161-169.
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  • Pradat P. Is trisomy 18 increasing in Sweden? An analysis of the syndrome during a ten-year period and a comparison with a French registry. Hereditas 1991;114:97-102.
  • Ramesh KH, Verma RS. Parental origin of the extra chromosome 18 in Edwards syndrome. Ann Genet 1996;39:110-112.
  • Rasmussen SA, Wong LYC, Yang Q, May KM, Friedman JM. Population based analysis of mortality in trisomy 13 and trisomy 18. Pediatrics 2003;111:777-784.
  • Schreinemachers DM, Cross PK, Hook EB. Rates of 47,+21, 47,+18, 47,+13 and other chromosome abnormalities in about 20,000 prenatal studies compared with estimated rates in live births. Hum Genet 1982;61:318-324.
  • Sorensen HT, Czeizel AE, Rockenbauer M, Steffensen FH, Olsen J. The risk of limb deficiencies and other congenital abnormalities in children exposed to calcium channel blockers. Acta Obst Gynecol Scand 2001;80:397-401.
  • Vintzileos AM, Campbell WA, Nochimson DJ, Weinbaum PJ. Antenatal evaluation and management of ultrasonically detected fetal anomalies. Obstet Gynecol 1987;69:640-660.
  • Wennborg H, Magnusson LL, Bonde JP, Olsen J. Congenital malformations related to maternal exposure to specific agents in biomedical research laboratories. JOEM 2005; 47:1:11-19.
  • Vrijheid M, Dolk H, Stone D, Abramsky L, Alberman E, Scott JES. Socioeconomic inequalities in the risk of congenital anomaly. Arch Dis Child 2000; 82:349-352.
  • Ya-gang X, Robinson WP, Spiegel R, Binkert F, Ruefenacht U, Schinzel AA. Parental origin of the supernumerary chromosome in trisomy 18. Clin Genet 1993;44:57-61.

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.

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Birth Defects Epidemiology and Surveillance
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512-776-7232 Fax 512-776-7330

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Last updated February 10, 2012