Sonographic Markers of Fetal Trisomies

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  • Sonographic Markersof Fetal TrisomiesSecond Trimester

    David A. Nyberg, MD, Vivienne L. Souter, MD, MRCOG

    Objective. Second-trimester sonographic findings of fetal trisomy may include structural abnormali-ties or sonographic markers of fetal aneuploidy. Unlike structural anomalies, sonographic markers offetal aneuploidy are insignificant by themselves with regard to outcome, are nonspecificmost fre-quently seen in normal fetuses, and are often transient. Our objective was to review the second-trimester sonographic findings of the major trisomic conditions, trisomies 13, 18, and 21. Methods.We reviewed a number of the most commonly accepted markers, including nuchal thickening, hyper-echoic bowel, echogenic intracardiac focus, renal pyelectasis, shortened extremities, mild cerebral ven-tricular dilatation, and choroid plexus cysts. Markers associated with trisomy 21 were emphasized.Results. The sensitivity of sonography for detection of fetal trisomic conditions varies with the type ofchromosome abnormality, gestational age at the time of sonography, reasons for referral, criteria forpositive sonographic findings, and the quality of the sonography. As an estimate, 1 or more sono-graphic findings can be identified in approximately 90% of fetuses with trisomy 13, 80% of fetuseswith trisomy 18, and 50% to 70% of fetuses with trisomy 21 (Down syndrome). Conclusions. Thepresence or absence of sonographic markers can substantially modify the risk of fetal Down syndromeand is the basis of the so-called genetic sonogram. Because maternal biochemical and sonographicmarkers are largely independent, combined risk estimates will result in even higher detection ratesthan either alone. Key words: trisomy 21; trisomy 18; trisomy 13; Down syndrome; prenatal sonog-raphy; nuchal thickening; hyperechoic bowel; echogenic intracardiac foci; pyelectasis; choroid plexuscyst; ventricular dilatation.

    Received February 14, 2001, from the Center forPerinatal Studies, Seattle Medical Center (D.A.N.),and Departments of Radiology (D.A.N.), Obstetricsand Gynecology (D.A.N.), and Genetics (V.L.S.),University of Washington Medical Center, Seattle,Washington. Revision requested February 20, 2001.Revised manuscript accepted for publicationFebruary 20, 2001.

    Address correspondence to David A Nyberg,MD, 1229 Madison St, 1150, Seattle, WA 98104.

    AbbreviationsAAURA, age-adjusted ultrasound risk assessment; EIF,echogenic intracardiac foci; hCG, human chorionicgonadotropin; IUGR, intrauterine growth restriction;SMFA, sonographic markers of fetal aneuploidy

    onography can show abnormalities in many fetus-es with chromosomal aberrations.1,2 These mayinclude both major or structural defects and non-structural findings, also known as sonographic

    markers. Unlike structural anomalies, sonographic mark-ers of fetal aneuploidy (SMFA) are insignificant by them-selves with regard to outcome, are nonspecificmostfrequently seen in normal fetuses, and are often tran-sient. The most common SMFA in the second trimesterare nuchal thickening, hyperechoic bowel, shortenedextremities, renal pyelectasis, echogenic intracardiac foci(EIF), and choroid plexus cysts.

    Table 1 summarizes the common structural anomaliesand sonographic markers associated with the 3 commontrisomic conditions (trisomies 13, 18, and 21). Althougheach trisomic condition has a typical phenotype, there iswide variation in phenotypic expression. The sensitivity ofsonography for detecting these abnormalities varies witha number of factors, including the type of chromosomeabnormality, gestational age at the time of sonography,

    2001 by the American Institute of Ultrasound in Medicine J Ultrasound Med 20:655674, 2001 0278-4297/01/$3.50

    S

    Review Article

  • reasons for referral, criteria for positive sonograph-ic findings, and the quality of the sonography.

    As an estimate, major or structural abnormali-ties are seen in 20% of fetuses with trisomy 21(Down syndrome) during the second trimester,whereas they are seen in most fetuses with tri-somies 18 and 13.37 Combined with SMFA,sonographic findings are identified in approxi-mately 50% to 70% of fetuses with Down syn-drome, 80% of fetuses with trisomy 18, and 90%of fetuses with trisomy 13. This emphasizes thepotential importance of nonstructural markersin detection of fetal trisomy.

    In the following sections, we review the second-trimester sonographic findings of themajor trisomic conditions, trisomies 13, 18,and 21. We emphasize fetal Down syndromebecause it is the most common trisomic con-dition, the most likely to result in a survivingneonate, and the most likely to show SMFAwithout structural anomalies.

    Trisomy 13

    In trisomy 13, malformations of the central ner-vous system are common. These may includeholoprosencephaly, agenesis of the corpus callo-sum, Dandy-Walker malformation, vermianagenesis, and neural tube defects. Other com-

    mon malformations detected are facial abnor-malities, including cyclopia, hypotelorism, andcleft lip and palate (Fig. 1A), renal cystic dysplasiaor hydronephrosis, cardiovascular malforma-tions, cystic hygroma, polydactyly, and club orrocker-bottom feet.

    MarkersNonspecific markers of trisomy 13 may includemild dilatation of the lateral cerebral ventricles,hyperechoic bowel, and EIF. Lehman et al6 report-ed EIF in 39% of fetuses with trisomy 13 before 20weeks. Multiple EIF probably increase the risk ofaneuploidy, including trisomy 13 (Fig. 1B). Thecombination of EIF and a hypoplastic-appearingleft side of the heart is a characteristic pattern oftrisomy 13 (Fig. 2).6 We have encountered 1 caseof trisomy 13 in which multiple EIF was the onlysonographic finding and several other cases inwhich EIF was the initial finding that led todetection of other subtle anomalies. Because ofits association with trisomy 21, EIF is discussedfurther below (see Trisomy 21).

    Trisomy 18

    A wide diversity of sonographic and pathologicabnormalities have been associated with trisomy18 during the second trimester, including cystic

    656 J Ultrasound Med 20:655674, 2001

    Sonographic Markers of Fetal Trisomies: Second Trimester

    Table 1. Common Structural Anomalies and Sonographic Markers Associated With the 3 Common Trisomic Conditions

    Trisomy 21 Trisomy 18 Trisomy 13

    Major anomalies Cardiac defects Cardiac defects Cardiac defects Duodenal atresia Spina bifida Central nervous system abnormalitiesCystic hygroma Cerebellar dysgenesis Facial anomalies

    Micrognathia Cleft lip/palateOmphalocele Urogenital anomaliesClenched hands/wrists Echogenic kidneysRadial aplasia OmphaloceleClub feet PolydactylyCystic hygroma Rocker-bottom feet

    Cystic hygromaMarkers Nuchal thickening* Choroid plexus cysts* EIF*

    Hyperechoic bowel* Brachycephaly IUGREIF* Shortened limbs PyelectasisShortened limbs* IUGR Single umbilical arteryPyelectasis* Single umbilical arteryMild ventriculomegaly*ClinodactylySandal gapWidened pelvic anglePericardial effusionRight-left heart disproportion

    *Discussed in greater detail in text.

  • hygroma, nonimmune hydrops, hydrocephalus,spina bifida, diaphragmatic hernia, tracheo-esophageal fistula, genitourinary anomalies,cardiovascular malformations, and omphalo-cele. Subtle abnormalities may include ver-mian agenesis and8,9 small-bowelcontainingomphalocele (Fig. 3),10,11 Skeletal abnormalitiesare common and include clenched hands (Fig.4),12,13 club feet, and radial aplasia or limb short-ening. In the third trimester, some fetuses withtrisomy 18 may primarily have intrauterinegrowth restriction (IUGR), which is often associ-ated with polyhydramnios.

    MarkersSubtle or nonstructural findings of trisomy 18may include choroid plexus cysts, brachy-cephaly or strawberry-shaped head,14 and sin-gle umbilical artery.15 Of these, choroid plexuscysts (Fig. 5) have been the most controversialand the subject of considerable interest.1621 Likeother SMFA, choroid plexus cysts are a relativelycommon variant during the second trimester,are transient, and have no known effect on fetal

    development. Unlike some of the other potentialmarkers (e.g., nuchal thickening and hyper-echoic bowel), choroid plexus cysts have noknown association with other adverse outcomeswhen the karyotype is normal.

    Variables that may influence detection ofchoroid plexus cysts include gestational age, thethoroughness of the sonography, the thresholdfor calling a finding a choroid plexus cyst, under-lying risk factors, and reasons for referral. Itshould be noted that studies that restrictpatients to those with known karyotypes may bebiased, because sonographic findings influencepatients decisions about invasive testing. High-risk patients with SMFA are more likely to under-go invasive testing than low-risk patients withthe same findings. For this reason, a higher riskwill be found among patients who choose inva-sive testing compared with patients who do not.Snijders et al22 reported that among 107 fetuseswith isolated choroid plexus cysts who had kary-otyping, 2 had chromosome defects (1 each oftrisomy 18 and 21), whereas no chromosomeabnormality was found among the 174 fetuses

    J Ultrasound Med 20:655674, 2001 657

    Nyberg and Souter

    Figure 1. Trisomy 13. A, Bilateral cleft lip and plate. Coronal view of the face shows features of bilateral cleft lip and palate, seen as premaxillary pro-trusion (arrows). O indicates orbits. B, Bilateral EIF. Transverse view of the heart with the apex away from the transducer shows prominent bilateral EIF(arrows). No other abnormalities were identified in this fetus. LV indicates left ventricle; RV, right ventricle; and Sp, spine.

    A B

  • with choroid plexus cysts who did not haveamniocentesis. Similar results can be found withother SMFA.

    The prevalence of choroid plexus cysts in thegeneral population has been reported a