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The Sonographic Detection of Trisomy 13

Introduction

Patau et al identified an additional chromosome 13 in 19601. The incidence of trisomy 13 is approximately 1 per 8,000 births2. The risk increases with maternal age and, because of attrition, decreases with advancing gestational age3. The risk of trisomy 13 for a 20 and a 35 year old at 10 and 40 weeks’ gestation is outlined in Table I. At the beginning of the second trimester, trisomy 21 fetuses outnumber trisomy 13 fetuses by 8 to13.

Table I. Risk of Trisomy 133
 

 Age (yrs) Gestational Age (weeks) Risk of Trisomy 13

20

10

1/6347

 

40

1/42,423

35

10

1/1481

 

40

1/9896

 

A fetus may have a full trisomy 13 or an unbalanced Robertsonian 13/14 translocation; mosaicism of trisomy 13 may also occur.

Twenty-five percent of neonates with trisomy 13 succumb in the first day. In one study, the median survival time for a neonate with trisomy 13 was 8.5 days (range 1 to 412 days)4. The neonatal loss rate of trisomy 13 fetuses is outlined in Table II. With the advent of almost universal prenatal ultrasound examinations, there is likely to be a selective reduction of the trisomy 13 fetuses with the most significant congenital abnormalities. As a result, the median survival of the remaining less severely affected trisomy 13 neonates may lengthen4.

Table II. Neonatal demise of 214 trisomy 13 neonates17
 

 

Demise (%)

1 week

28

1 month

44

4 months

73

1 year+

86

+ survival beyond 3 years is an exception

Kalousek et al5 found that 5% of trisomy 13 fetuses have a mosaic placenta that may permit survival to the neonatal period due to the compensation provided by the diploid cells in the cytotrophoblast.

In order to increase the detection rate of karyotypically abnormal fetuses, a detailed second trimester anatomic survey is required. As the number of detected anomalies increases, so does the likelihood that a fetus is karyotypically abnormal. The likelihood of a karyotypic abnormality increases from approximately 50% with three anomalies to > 90% with eight abnormalities6. Unfortunately, there is not a single congenital anomaly that is pathognomonic for trisomy 13. However, a specific combination of anomalies will increase the likelihood of trisomy 13 over other chromosomal abnormalities.

As the resolution of ultrasound equipment improves, increasingly finer fetal details can be appreciated. Transvaginal sonography has been used to diagnose trisomy 13 in the first trimester.

1st Trimester Diagnosis

Gestational age based upon the crown-rump length is below the 5th percentile in 22% of pregnancies with a trisomy 13 fetus.

The fetal heart rate is > 95th centile for gestational age in 64%7 to 71.3%8 of fetuses with trisomy 13. It has been hypothesized that tachycardia represents an attempt to increase cardiac output in the presence of a left heart obstruction8.

A first trimester thickened nuchal translucency occurs in up to 72% of fetuses with trisomy 137 (Fig. 1). A combination of maternal age and nuchal translucency increases the detection rate of trisomy 13 to 80% with a 5% false positive rate.

figure1

Figure 1: A thickened nuchal translucency (A) of 3.5 mm

To view an enlargement, click on the image.​​​​​​​

An absent nasal bone in the first trimester is present in 31.8% of trisomy 13 fetuses, in contrast to 2.8% - 10.4% in karyotypically normal fetuses. The likelihood ratio for the nasal bone has been found to depend on the ethnic origin of the patient, the crown-rump length, and the nuchal translucency measurement9.

In addition to first trimester screening, a transvaginal examination can be utilized to evaluate fetal anatomy. The major defects identified with trisomy 13 in the first trimester include holoprosencephaly, omphalocele and megacystis (Fig. 2). Approximately 50% of first trimester fetuses with trisomy 13 have been found to have one of these structural malformations7,8.​​​​​​​

figure2

Figure 2: Megacystis (arrow) at 14 weeks’ gestation

To view an enlargement, click on the image.

The serum concentration of PAPP-A is approximately one-third of normal in fetuses with trisomy 13. This finding is consistent with 39% of trisomy 13 fetuses having a first trimester placental volume below the 5th percentile10.

By combining the measurement of first trimester nuchal translucency and fetal heart rate with a fetal survey for holoprosencephaly, omphalocele and megacystis over 90% of trisomy 13 fetuses can be detected8 (Table III).

 Author  Year  Ref  Years of Study  N Gestational age (weeks) Detection Trisomy 13 (%)

Benacerraf

1988

18

1984-1987

9

15 – 40

100

Lehman

1995

11

1987-1993

33

13.6 – 32.7

91

DeVigan

2001

19

1996-1998

86

10 – 30

< 14 – 19.0
< 24 – 54.8
all ages  68.2

Tongsong

2002

20

1989-2001

15

16 – 22

100

Picklesmier

2005

21

2001-2004

15

14 1/7 – 36 4/7

100

Papageorghiou

2006

8

1994-2004

181

11 – 13 6/7

Major anomaly
Thick NT
Fhr > 95th centile
​​​​​​​

}

95

 

NT – nuchal translucency, Fhr – fetal heart rate

2nd and 3rd Trimester

Approximately 50% of fetuses with trisomy 13 will have sonographic evidence of intrauterine growth restriction; the likelihood of detecting growth restriction increases with gestational age11. Polyhydramnios is also a third trimester manifestation of trisomy 13, occurring in 15% of cases. The combination of intrauterine growth restriction and polyhydramnios is distinctly unusual and should raise a concern about a possible chromosomal abnormality11.

A single umbilical artery is present in 25% of trisomy 13 fetuses (Fig. 3).

figure3

Figure 3: Two-vessel umbilical cord (arrow)

To view an enlargement, click on the image.

One or more congenital anomalies are detected in ≥ 70% of fetuses with trisomy 13 (Table IV). However, the number and severity of congenital anomalies are highly variable from one case to the next.

Table IV.  Congenital anomalies associated with trisomy 1311,13,14,15,18,19,22,23,24
 

Central Nervous System
   Holoprosencephaly
   Cerebellar hypoplasia
   Microcephaly
   Ventriculomegaly
   Choroid plexus cyst
   Neural tube defect
Face
  Cleft lip/palate
   Hypotelorism
   Cyclopia
   Cystic hygroma
   Nuchal edema
Gastrointestinal
  Omphalocele
   Echogenic small bowel Genitourinay
   Enlarged echogenic kidneys
   Pyelocaliectasis
 
Extremities
   Polydactyly
   Clenched hands
   Chort femur/humerus in 2nd trimester
   Clubbed feet
2-Vessel Umbilical Cord
Cardiac
  Atrial septal defect
   Ventricular septal defect
   Hypoplastic left heart
   Echogenic intracardiac focus
   Tetralogy of Fallot
   Pulmonary atresia
   Valvular dysplasia with or without
            regurgitation and stenosis
   Abnormal heart axis/dextrocardia
   Double outlet right ventricle
Hydrops

 

 

Monozygotic trisomy 13 fetuses with discordant major congenital anomalies have been reported12.

Central nervous system (58%) and facial anomalies (48%) are quite common with trisomy 13. Holoprosencephaly (Fig. 4) is the central nervous system anomaly commonly associated with trisomy 13, occurring in approximately 29% - 39% of cases11. Other central nervous system anomalies include mild ventricular dilatation (Fig. 5) and enlargement of the cisterna magna. The overall incidence of CNS abnormalities with trisomy 13 has been reported to be between 65% and 83%11.

figure4

Figure 4: A single median cerebral ventricle (arrow) associated with holoprosencephaly

To view an enlargement, click on the image.

figure5

Figure 5: The lateral ventricular measurement of 1.31 cm (A) indicates mild ventriculomegaly

To view an enlargement, click on the image.

Facial clefts (Fig. 6a & b) occur in half of the fetuses with trisomy 13. A median cleft is particularly characteristic of fetuses with this chromosomal abnormality. Facial anomalies of some variant are characteristic among the majority of fetuses with holoprosencephaly (Fig. 7). Fetuses with trisomy 13 generally have more severe central nervous system and craniofacial defects than fetuses with trisomy 21 or trisomy 18.

figure6a

Figure 6a: normal upper lip

figure6b

 Figure 6b: bilateral cleft lip (arrows)

figure7

 Figure 7: Severe hypotelorism

To view an enlargement, click on the image.

While facial and CNS anomalies are quite common with trisomy 13, it must be emphasized that these fetuses may also have an isolated anomaly. As a result, an extended fetal anatomic survey, that includes a detailed evaluation of the heart, is required. For example, Papp et al13 reported 5/28 (17.9%) cases of trisomy 13 had only an isolated cardiac abnormality (Fig. 8). Because of fetal wastage, the spectrum and severity of cardiac malformations detected in the second trimester11,13 may be different from the lesions detected during neonatal echocardiography14,15.

figure8

Figure 8: Endocardial cushion defect

To view an enlargement, click on the image.

 

Many of the abnormalities outlined above are also present with trisomy 18. Hence, a definitive diagnosis prior to karyotyping is frequently in doubt.

In addition to major anomalies, there are a number of soft sonographic markers that have been associated with karyotypic abnormalities16. Some of the soft sonographic markers outlined in Table II are nuchal thickening ≥ 5 mm (Fig. 9), echogenic small bowel, echogenic intracardiac focus, renal pelvic diameter ≥ 4 mm, choroid plexus cysts, and shortened humerus and femur length. Fetuses with trisomy 13 may only manifest one or two of these soft sonographic signs and no major malformations13. When stratified by gestational age major anomalies are detected throughout gestational age categories, while soft markers are characteristically found between 18 and 24 weeks' gestation.

figure9

​​​​​​​

Figure 9: Thickened nuchal fold (arrow)

To view an enlargement, click on the image.

Conclusion

Pregnancy carries with it an inherent risk of having a karyotypically abnormal fetus. This risk increases with maternal age and decreases with advancing gestation. The association between major structural malformations and karyotypic abnormalities is well known. As the resolution of sonographic equipment continues to improve, subtle sonographic markers, in addition to major malformations, have been utilized to detect the majority of trisomy 13 fetuses in the first trimester.

Reference List

  1. Patau K, Smith DW, Therman E, Inhorn SL, Wagner SP.  Multiple congenital anomaly caused by an extra chromosome.  Lancet 1960;1:790-793.
  2. Moerman P, Fryns J-P, VanderSteen K, Kleczkowski A, Lauweryns J.  The pathology of trisomy 13 syndrome.  A study of 12 cases.  Hum Genet 1988;80:349-356.
  3. Snijders RJM, Sebire NJ, Nicolaides KH.  Maternal age and gestational age-specific risk for chromosomal defects.  Fetal Diagn Ther 1995;10:356-367.
  4. Brewer CM, Holloway SH, Stove DH, Carothers AD, Fitzpatrick DR.  Survival in trisomy 13 and trisomy 18 cases ascertained from population based registers.  J Med Genet 2002;39:e54.
  5. Kalousek DK, Barrett IJ, McGillivray BC.  Placental mosaicism and intrauterine survival of trisomies 13 and 18.  Am J Hum Genet 1989;44:338-343.
  6. Nicolaides K, Shawwa L, Brizot M, Snijders R.  Ultrasonographically detectable markers of fetal chromosomal defects.  Ultrasound Obstet Gynecol 1993;3:56-69.
  7. Snijders RJM, Sebire NJ, Nagar R, Souka A, Nicolaides KH. Increased nuchal translucency in trisomy 13 fetuses at 10-14 weeks of gestation.  Am J Med Genet 1999;86:205-207.
  8. Papageorghiou AT, Avgidou K, Spencer K, Nix B, Nicolaides KH.  Sonographic screening for trisomy 13 at 11 to 13+6 weeks of gestation.  Am J Obstet Gynecol 2006;194:397-401.
  9. Cicero S, Longo D, Rembouskos G, Sacchini C, Nicolaides KH.  Absent nasal bone at 11-14 weeks of gestation and chromosomal defects.  Ultrasound Obstet Gynecol 2003;22:31-35.
  10. Wegrzyn P, Faro C, Falcon O, Peralta FA, Nicolaides KH.  Placental volume measured by three-dimensional ultrasound at 11 to 13+ 6 weeks of gestation:  relation to chromosomal defects.  Ultrasound Obstet Gynecol 2005;26:28-32.
  11. Lehman CD, Nyberg DA, Winter III TC, Kapur RP, Resta RG et al.  Trisomy 13 syndrome: Prenatal US findings in a review of 33 cases.  Radiology 1995;194:217-222.
  12. Jones KL.  Smith’s Recognizable Patterns of Human Malformations.  4th ed. Phil:WB Saunders Co, 1988:16-25.
  13. Papp C, Beke A, Ban Z, Szigeti Z, Toth-Pal E et al.  Prenatal diagnosis of trisomy 13.  Analysis of 28 cases.  J Ultrasound Med 2006;25:429-435.
  14. Musewe NN, Alexander DJ, Teshima I, Smallhorn JF, Freedom RM.  Echocardiographic evaluation of the spectrum of cardiac anomalies associated with trisomy 13 and trisomy 18.  J Am Coll Cardiol 1990;15:673-677.
  15. Wladimiroff JW, Stewart PA, Reuss A, Sachs ES.  Cardiac and extra-cardiac anomalies as indicators for trisomies 13 and 18:  A prenatal ultrasound study.  Prenat Diagn 1989;9:515-520.
  16. Nyberg DA, Luthy DA, Resta RG, Nyberg BC, Williams MA.  Age-adjusted ultrasound risk assessment for fetal Down’s syndrome during the second trimester:  description of the method and analysis of 142 cases.  Ultrasound Obstet Gynecol 1998;12:8-14.
  17. Magenis RE, Hecht F, Milham S Jr.  Trisomy 13 (D) syndrome: studies on parental age, sex ratio, and survival.  J Pediatr 1968;73:222-228.
  18. Benacerraf BR, Miller WA, Frigoletto FD.  Sonographic detection of fetuses with trisomy 13 and 18:  Accuracy and limitations.  Am J Obstet Gynecol 1988;158:404-409.
  19. DeVigan C, Baena N, Cariati E, Clementi M, Stoll C et al.  Contribution of ultrasonographic examination to the prenatal detection of chromosomal abnormalities in 19 centres across Europe.  Annales Genet 2001;44:209-217.
  20. Tongsong T, Sirichotiyakul S, Wanapirak C, Chanprapaph P.  Sonographic features of trisomy 13 at midpregnancy.  Int J Gynecol Obstet 2002;76:143-148.
  21. Picklesimer AH, Moise KJ, Wolfe HM.  The impact of gestational age on the sonographic detection of aneuploidy.  Am J Obstet Gynecol 2005;193:1243-1247.
  22. Benacerraf BR, Frigoletto Jr FD, Green MF.  Abnormal facial features and extremities in human trisomy syndromes:  prenatal US appearance.  Radiology 1986;159:243-246.
  23. Hodes ME, Cole J, Palmer CG, Reed T.  Clinical experience with trisomies 18 and 13.  J Med Genet 1978;15:48-60.
  24. Inagaki M, Ando Y, Mito T, Ieshima A, Ohtari K et al.  Comparison of brain imaging and neuropathology in cases of trisomy 18 and trisomy 13.  Neuroradiol 1987;29:474-479.

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