Prenatal Sonographic Features of Trisomy 13

REVIEW ARTICLE

Chih-Ping Chen1,2,3*, Shu-Chin Chien4,5

Fetuses with trisomy 13 are characterized by many associated congenital anomalies including defects of the brain, face, heart, and limbs. The complex anomalies usually result in early embryo death or intrauterine fetal death in the late stages. Only 5–10% of live births have a longer survival time after delivery but these patients are often mentally retarded. Prenatal sonography has been reported to detect more than 90% of trisomy 13 fetuses with major structural defects in the second trimester. In recent years, the addition of soft markers to the sonographic screening for fetal trisomy 13 in the first trimester has been significantly beneficial. This article provides an overview of the common sonographic features of fetal trisomy 13 with major structural abnormalities including brain defects, midline facial defects, cardiac anomalies, genitourinary anomalies, limb anomalies and abdominal wall defects, and minor structural abnormalities including increased nuchal translucency thickness, echogenic intracardiac focus, fetal tachycardia, and megacystis. Several diseases may have phenotypic overlaps with trisomy 13 syndrome including Meckel-Gruber syndrome, pseudotrisomy 13 syndrome, Smith-Lemli-Opitz syndrome, Pallister-Hall syndrome, and hydrolethalus syndrome. Due to the seriousness of this congenital anomaly, increased understanding of the different sonographic markers will improve the detection of trisomy 13 and prenatal ultrasound is a valuable tool in detecting a variety of congenital structural malformations of this lethal syndrome throughout gestation.

KEY WORDS — prenatal ultrasound, trisomy 13

■ J Med Ultrasound 2007;15(1):58–66 ■

Introduction resulting from a free copy or translocation. Molecular analysis of the free extra chromosome 13 revealed Chromosomal abnormalities occur in 0.1–0.2% of that in more than 80% of patients, it resulted from live-born infants. The incidence of trisomy 13 live a maternal meiotic nondisjunction [10]. Clinically, births has been reported to range from 1/5,000 to it manifests many associated congenital anomalies 1/30,000 [1–8]. Trisomy 13 was first described by including malformations of the brain, craniofacial Patau et al [9] in 1960 and is the third most common defects, heart defects, limb defects, and severe trisomy following trisomies 21 and 18. Trisomy 13 mental retardation. The complex malformations usu- represents the presence of an extra chromosome 13 ally result in miscarriage or intrauterine fetal death

Departments of 1Obstetrics and Gynecology and 2Medical Research, Mackay Memorial Hospital, Taipei, 3Department of Biotechnology and Bioinformatics, Asia University, and Departments of 4Medical Genetics and 5Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan. *Address correspondence to: Dr. Chih-Ping Chen, Department of Obstetrics and Gynecology, Mackay Memorial Hospital, 92, Section 2, Chung-Shan North Road, Taipei 104, Taiwan. E-mail: [email protected]

58 J Med Ultrasound 2007 • Vol 15 • No 1 ©Elsevier & CTSUM. All rights reserved. Prenatal Sonography of Trisomy 13 throughout the gestation [11]. Even after birth, the the limbs, and abdominal wall defects in the second majority of affected fetuses die shortly thereafter. trimester. Above 14 weeks of gestation, Picklesimer Only 5–10% of live births have a longer survival time et al [14] found that all the major structural anom- and the survivors often have mental retardation [1]. alies of trisomy 13 could be prenatally detected. In obstetric practice, ultrasound is a valuable tool With the advent of high-quality ultrasound equip- in the detection of fetal structural anomalies, and it ment, many structural abnormalities of fetal trisomy has been reported to detect more than 90% of 13 can be detected before the second trimester. In a fetuses with trisomy 13 [12,13]. Here, we review the first trimester scanning between 11 and 13+6 weeks associated prenatal sonographic features in the detec- of gestation, sonographic findings of holopros- tion of fetal trisomy 13. The common major sonogra- encephaly (HPE), exomphalos, and/or megacystis phic abnormalities of fetal trisomy 13 include brain can be seen in approximately 50% of trisomy 13 defects, midline facial defects, cardiac anomalies, fetuses [15]. Clinically, most pregnant women pre- genitourinary anomalies, limb anomalies, and abdo- fer early identification of the major fetal structural minal wall defects, and minor sonographic abnor- defects and this service can significantly promote malities include increased nuchal translucency their autonomy. thickness (NT), echogenic intracardiac focus (EIF), fetal tachycardia, and megacystis. Early prenatal Brain anomalies diagnosis is significantly beneficial to determina- The brain anomalies in trisomy 13 patients include tion of the course of pregnancy. In addition, differen- HPE, agenesis of the corpus callosum, cerebellar tial diagnoses including Meckel-Gruber syndrome, anomalies, hydrocephalus, ventriculomegaly, enlar- pseudotrisomy 13 syndrome, Smith-Lemli-Opitz ged cisterna magna, and microcephaly [13]. HPE is syndrome, Pallister-Hall syndrome, and hydroletha- a severe malformation in the brain and is caused lus syndrome are discussed. Both the prenatal sono- by impaired midline cleavage of the embryonic pro- graphic features and differential diagnoses of trisomy sencephalon resulting in different degrees of fusion 13 are summarized in Table 1. of the lateral ventricles [16]. The variable phenotypes of HPE can be classified as alobar type, semilobar type, lobar type, and a middle interhemispheric Prenatal Sonographic Features fusion variant. Alobar HPE is characterized by total absence of interhemispheric fissure, the third ven- Prenatal ultrasound has been extensively applied in tricle, falx cerebri, neurohypophysis, and olfactory the assessment of fetal chromosomal aneuploidy for bulbs. Semilobar HPE is characterized by partial a long time. Clinically, two types of sonographic mar- separation of posterior cerebral hemispheres with kers suggestive of aneuploidy are used. Type I mark- presence of occipital lobe and usually the absence ers represent major fetal structural abnormalities of olfactory bulbs and corpus callosum. Lobar HPE is and type II markers, also called soft markers, are characterized by complete division of cerebral characterized by nonspecific and often transient hemispheres with a variable degree of fusion at the fetal abnormalities. cingulated gyrus [17]. Genetic and nongenetic factors can both result in the development of fetal HPE. In cases with HPE of an abnormal karyotype, Type I Markers — Major Structural trisomy 13 is the most frequent, and approxi- Abnormalities mately 70% of fetuses with trisomy 13 can manifest HPE [7,18]. Prenatal diagnosis of HPE was first Currently, type I sonographic markers in the majority described by Kurtz et al in 1980 [19]. The most of fetuses with trisomy 13 include the anomalies of specific sonographic findings in trisomy 13 with the brain, the face, the heart, the genitourinary tract, alobar HPE are single fused lateral ventricle, fusion

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Table 1. Prenatal sonographic features of trisomy 13 and differential diagnoses Prenatal sonographic features

● Type I markers — major structural anomalies Brain anomalies: holoprosencephaly, agenesis of the corpus callosum, cerebellar anomalies, hydrocephalus, ventriculomegaly, enlarged cisterna magna, and microcephaly. Facial anomalies: cyclopia, ethmocephaly, cebocephaly, median cleft lips, a single incisor, and absent or hypoplastic nasal bone. Cardiac anomalies: ventricular septal defects, atrial septal defects, patent ductus arteriosus, double-outlet right ventricle, hypoplastic left ventricle, mitral or aortic atresia, pulmonary stenosis, and anomalous venous return. Genitourinary anomalies: pyelectasis, renal cystic dysplasia, multicystic kidneys, enlarged and echogenic kidneys, hydronephrosis, ureteral obstruction, and duplication. Limb anomalies: postaxial polydactyly of the hands and feet, clenched or overlapping digits, prominent calcaneus, and rocker bottom or club feet. Abdominal wall defects: omphalocele, bladder exstrophy.

● Type II markers — soft markers Increased nuchal translucency thickness Echogenic intracardiac focus Fetal tachycardia Megacystis Differential diagnoses Meckel-Gruber syndrome Pseudotrisomy 13 syndrome Smith-Lemli-Opitz syndrome Pallister-Hall syndrome Hydrolethalus syndrome

of the thalami, and no visible midline structures in Facial anomalies the midtrimester. The associated findings often in- Normally developed facial features depend on the clude the presence of a dorsal sac and midline facial normal development of the underlying brain struc- anomalies such as cyclopia, hypotelorism, anoph- tures. Because of the common brain anomalies in thalmia, arhinia, proboscis, and midline facial clefts fetuses with trisomy 13, midline facial defects are [20,21]. In a sonographic scanning of 28 trisomy also frequently seen. The facial anomalies associated 13 fetuses between 13 and 25 weeks of gestation, with alobar HPE are invariably characterized by a brain anomalies were detected in 18 fetuses (18/28, wide range of midline facial defects ranging from a 64.3%), of which ventriculomegaly and HPE were single incisor to cyclopia and clinically these features the most common [22]. Recently, first-trimester can be classified as cyclopia, ethmocephaly, cebo- sonographic screening for fetal trisomy 13 has re- cephaly, and median cleft lips [17,25,26]. The main ported that HPE can be detected as early as 9+2 facial features in cyclopia include median mono- weeks’ gestation with improved ultrasound equip- phthalmia, synophthalmia or anophthalmia, and ment [23]. Sepulveda et al proposed that failure to absent or single proboscis. Ethmocephaly manifests identify the “butterfly” sign which describes visual- extreme hypotelorism and a proboscis above the ization of the choroid plexus in both lateral ventri- orbits. Cebocephaly is characterized by ocular hypo- cles is a warning sign of HPE in the first trimester [24]. telorism and single nostril nose. Features in the case

60 J Med Ultrasound 2007 • Vol 15 • No 1 Prenatal Sonography of Trisomy 13 of median cleft lips also include ocular hypotelorism Limb anomalies and flat nose. The variable and less severe facial The limb defects described in trisomy 13 include malformations associated with semilobar or lobar postaxial polydactyly of the hands and feet, clen- HPE include hypotelorism, coloboma of the iris, ched or overlapping digits, prominent calcaneus, unilateral or bilateral cleft lip and/or palate, micro- and rocker bottom or club feet, of which postaxial phthalmia, flat nose, and other anomalies [17,25, polydactyly was the most frequent in Lehman et al’s 26]. In a prenatal detection of 28 trisomy 13 fetuses, report [13]. An epidemiologic analysis revealed midline facial defects were the most common 155 cases with the suspected or proved trisomy 13 (12/28, 42.9%) and usually associated with the cases having postaxial polydactyly and only 15 cases underlying brain defects (11/12, 92%) [22]. Absent having preaxial polydactyly [34]. However, in a or hypoplastic nasal bone has been suggested as a recent study of 28 trisomy 13 fetuses, prenatal marker for identification of fetal aneuploidy in the detection of a limb defect with postaxial polydactyly first and second trimesters [27–29]. It can be was only documented in two cases (2/28, 7.1%) detected in approximately 34–55% of fetuses with [22]. The difficulty in prenatal sonographic detection trisomy 13 [30,31]. Because of lack of relationship of limb anomalies may be strongly associated with between absent nasal bone and first trimester bio- maternal obesity, unfavorable fetal postures, earlier chemical markers in trisomy 13 fetuses, it could be sonographic scanning, and suboptimal visualization expected to increase the detection of this aneu- of fetuses. ploidy after incorporating the study of the characteristics of the absent nasal bone into the existing Abdominal wall defects first trimester screening program [32]. Abdominal wall defects in fetuses with trisomy 13 may have omphalocele and bladder exstrophy [13]. Cardiac anomalies Omphalocele may be the manifestation of a chro- Congenital heart defects are common in fetuses with mosomal abnormality. In a study of 40 fetuses with trisomy 13, including ventricular septal defects, central type of omphalocele, trisomy 13 was the sec- atrial septal defects, patent ductus arteriosus, double- ond most frequent chromosomal abnormality (5/40, outlet right ventricle, hypoplastic left ventricle, mitral 12.5%) after trisomy 18 (29/40, 72.5%) [35]. In a or aortic atresia, pulmonary stenosis, and anom- large ultrasound screening at 11–14 weeks of ges- alous venous return [13,33]. Cardiovascular anom- tation, the frequency of fetal omphaloceles with alies were prenatally detected in 15 (53.6%) out of trisomy 13 was 9.1% [36]. Although the early 28 trisomy 13 fetuses, of which ventricular septal diagnosis of omphalocele is often easy by prenatal defects were the most common (4/15, 26.7%) [22]. ultrasound, we should caution about the diagnosis before the completion of the physiologic hernia- Genitourinary anomalies tion in the first trimester. The frequently associated genitourinary anomalies in trisomy 13 fetuses, occurring unilaterally or bila- terally, include multicystic kidneys, enlarged and Type II Markers — Soft Markers echogenic kidneys, renal cystic dysplasia, hydronephrosis, ureteral obstruction, and duplication [13]. The most common soft markers in trisomic fetuses These abnormalities may be seen in approximately include a thickened nuchal fold, EIF, fetal tachy- one third of trisomy 13 fetuses [13]. In another study cardia, megacystis, intrauterine growth restriction, of 28 trisomy 13 fetuses, renal anomalies were pre- echogenic bowel, single umbilical artery, shortened natally detected in 42.9% (12/28), of which the two femurs or humerus, renal pelvic dilation, and choroid common findings were pyelectasis (8/12, 66.6%) plexus cysts. Although these findings are seen and renal cystic dysplasia (4/12, 33.3%) [22]. in normal fetuses, they can be found in a higher

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percentage of fetal aneuploidy, and their presence and its detection depends on a variety of factors has become an important element of risk adjustment including resolution of the sonographic equip- in early pregnancy. Similar to other trisomies, soft ment, the operator’s experience and the fetal pos- markers on prenatal ultrasound have been increas- ture. Approximately 3–4% of normal fetuses can be ingly applied in screening of fetal trisomy 13. The detected with EIFs in the second trimester [41,42]. more commonly studied soft markers for trisomy Shipp et al [43] found three times more detections 13 include an increased fetal NT, an EIF, fetal among Asian patients with EIFs compared with tachycardia, and megacystis. white patients. In a pathologic study, Roberts and Genest first suggested an association between aneu- Increased NT ploidy and mineralization of the papillary muscle, In the first trimester, the term “fetal NT” refers to which was observed in 2% of normal fetuses com- the sonographic finding of a subcutaneous collec- pared with 39% of those with trisomy 13 [44]. tion of fluid behind the fetal neck. Previous studies Clinically, most trisomy 13 fetuses with EIFs also provide evidence that increased fetal NT is signi- had detection of other structural anomalies, except ficantly associated with chromosomal abnormali- for one trisomy 13 fetus who had multiple EIFs as the ties [37]. Currently, the Fetal Medicine Foundation, a only abnormal finding on prenatal ultrasound [45]. registered charity in the United Kingdom, proposed that the optimal gestational age for the measure- Fetal tachycardia ment of fetal NT is from 11 to 13+6 weeks of gesta- In first trimester studies, fetal tachycardia was tion. The corresponding fetal crown–rump length reported to be associated with trisomy 13 [46,47]. (CRL) is between 45 mm and 84 mm. Increased NT Fetal heart rate in normal pregnancy is observed to is defined by the vertical thickness equal to or above increase from about 110 beats per minute (bpm) the 95th centile of a reference range. The 95th centile at 5 weeks of gestation to 170 bpm at 9 weeks due of NT increased linearly with fetal CRL from 2.1 mm to cardiac structural development and then gradu- at a CRL of 45 mm to 2.7 mm for a CRL of 84 mm, ally to decrease to 150 bpm by 14 weeks, suggestive whereas the 99th centile did not change with CRL, of functional maturation of the parasympathetic and it was approximately 3.5 mm [38]. Kagan et al system [48,49]. Fetal heart rate was reported to be [39] reported that NT thickness was 4.5 mm or above the 95th centile of the normal range in 67% more in approximately 60% of trisomy 13 fetuses. of trisomy 13 fetuses and the possible explanation In addition, maternal serum proteins including free of first-trimester fetal tachycardia of trisomy 13 is β-human chorionic gonadotropin (β-hCG) and associated with congenital cardiac defects such as pregnancy associated plasma protein-A (PAPP-A) septal and/or valvular abnormalities [46]. are decreased in trisomy 13 fetuses [40]. Nicolaides reported that first trimester screening by a combi- Megacystis nation of fetal NT and PAPP-A and free β-hCG can By definition, fetal megacystis is defined by a longi- identify approximately 90% of chromosomal aneu- tudinal bladder diameter of 7 mm or more at 10–14 ploidies including trisomy 13, which represents a weeks of gestation and the incidence is about 1 in screen positive rate of 1% [31]. After the second 1,500 pregnancies [50]. If a longitudinal diameter trimester, nuchal cystic hygroma or nuchal edema of the fetal bladder is measured as 7–15 mm during can be seen in approximately 20% of fetuses with 10–14 weeks of gestation, there is a risk of approx- trisomy 13 [13]. imately 25% that the fetus will have a chromosomal defect, mainly trisomies 13 or 18 [51]. Approximately EIF 90% of fetuses with megacystis of a normal kary- An EIF is a subjective sonographic finding of an otype will spontaneously resolve without any adverse echogenic spot over the cardiac papillary muscle consequence of the urinary system.

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Differential Diagnosis Several cases provide evidence that pseudotrisomy 13 syndrome is an autosomal recessive inheritance The definite diagnosis of fetal trisomy 13 depends and carries a 25% risk of recurrence [62–65]. The on cytogenetic analysis. Owing to these common phenotypes of trisomy 13 have a considerable over- structural abnormalities in fetal trisomy 13, differ- lap with pseudotrisomy 13 and the most powerful ential diagnoses should include Meckel-Gruber diagnosis in distinguishing trisomy 13 from pseu- syndrome, pseudotrisomy 13 syndrome, Smith- dotrisomy 13 relies on fetal karyotyping. Lemli-Opitz syndrome, Pallister-Hall syndrome, and hydrolethalus syndrome. Smith-Lemli-Opitz syndrome (SLOS, OMIM 270400) Meckel-Gruber syndrome or Meckel syndrome SLOS is a metabolic syndrome of multiple congenital (MKS, OMIM 249000) malformations characterized by psychomotor retar- MKS was described initially in 1822 by Meckel [52] dation, growth restriction, cleft palate, postaxial and redefined in 1934 by Gruber [53]. MKS is clas- polydactyly, and rare craniofacial abnormalities sified into three subtypes and the genetic loci have including microcephaly, micrognathia, and HPE. been mapped including MKS1 (OMIM 609883) The causative factor is deficiency of 7-dehydrocho- on 17q21-q24 [54], MKS2 (OMIM 603194) on lesterol reductase (DHCR7) resulting from muta- 11q13 [55], and MKS3 (OMIM 607361) on 8q21- tions in the DHCR7 gene mapping to 11q12-q13 q22 [56]. MKS is an autosomal recessive disorder [66]. The reductase is the final enzyme of the cho- manifesting a combination of polycystic kidneys, lesterol biosynthetic pathway. Prenatal diagnosis anomalies of the central nervous system (typically of SLOS can be done by biochemical analysis of occipital encephalocele), hepatic ductal dysplasia 7-dehydrocholesterol levels in amniotic fluid or and cysts, and postaxial polydactyly [57]. Clinical chorionic villi and mutation analysis of the DHCR7 spectrums of MKS showed that cystic kidney dys- gene [67,68]. Since recently, steroid measurements plasia is the most common defect, whereas occipi- in maternal urine are supposed to be a reliable basis tal encephalocele and polydactyly are found in for prenatal diagnosis [69]. only 50% [58]. Compared with trisomy 13, occipital encephalocele but not HPE is the major brain Pallister-Hall syndrome (PHS, OMIM 146510) anomaly in MKS. In addition, oligohydramnios PHS is defined by postaxial polydactyly, hypotha- is often seen in MKS fetuses due to severe renal lamic hamartoma, abnormal lung lobations, renal dysfunction. agenesis or dysplasia, epiglottic or laryngeal clefts, congenital heart defects, and intrauterine growth Pseudotrisomy 13 syndrome restriction. The syndrome is caused by frameshift, (holoprosencephaly-polydactyly nonsense, and splicing mutations in the zinc finger syndrome, OMIM 264480) transcription factor gene, GLI3, mapping to 7p13 Patients with pseudotrisomy 13 syndrome manifest [70]. The specific finding of hypothalamic hamar- HPE, severe facial anomalies, postaxial polydactyly, toma in PHS is different from HPE in trisomy 13 and and a normal karyotype [59]. Other congenital magnetic resonance imaging is the most valuable defects may include cerebellar hypoplasia, ence- diagnostic tool [71]. phalocele, microphthalmia, cleft lip and palate, cardiac defects, ambiguous genitalia, malformations of Hydrolethalus syndrome (HYLS, OMIM the urinary and digestive system, malsegmentation 236680) of the lungs, and adrenal hypoplasia [60]. Neither Hydrolethalus syndrome, discovered in Finland, HPE nor polydactyly is obligatory because affected was characterized by midbrain anomalies with sibs did not always show these malformations [61]. severe hydrocephalus, micropolygyria, facial clefts,

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