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(Radiology. 2000;214:533-538.)
© RSNA, 2000

Obstetric Imaging

Cerebellar and Frontal Lobe Hypoplasia in Fetuses with Trisomy 21: Usefulness as Combined US Markers1

Thomas C. Winter, MD, Aaron A. Ostrovsky, BA, Cathy A. Komarniski, RDMS and Stefanie B. Uhrich, MS, CGC

1 From the Department of Radiology, Division of Ultrasound (T.C.W., A.A.O., C.A.K.), and the Department of Obstetrics and Gynecology, Division of Perinatal Medicine (S.B.U.), University of Washington Medical Center, Seattle. Received January 11, 1999; revision requested March 22; revision received May 7; accepted May 12. Address reprint requests to T.C.W., University of Wisconsin Medical Center, E3/311 CSC, 600 Highland Ave, Madison, WI 53792-3252 (e-mail: tcwinter@facstaff.wisc.edu).


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To confirm that cerebellar hypoplasia is ultrasonographically recognizable in second-trimester fetuses with Down syndrome and determine whether the combination of frontal lobe shortening and cerebellar hypoplasia is superior to either measurement alone as a marker of this abnormality.

MATERIALS AND METHODS: The frontothalamic distance (FTD) and transcerebellar diameter (TCD) were measured in 52 middle-trimester fetuses with euploid karyotypes and in 52 fetuses with Down syndrome. Receiver operating characteristic (ROC) curves were constructed with various thresholds for observed-to-expected ratios (O/Es) of the FTD, TCD, and average of these two parameters.

RESULTS: The area under the average ROC curve, 0.80, was greater than that for either the FTD alone (0.75) or the TCD alone (0.76). At a 6% false-positive rate, the sensitivity for the detection of Down syndrome obtained with the average parameter was 34% better than that obtained with only the FTD and 12% better than that obtained with only the TCD. With an O/E threshold of 0.92 for the average parameter, an odds ratio of 16.3 and positive predictive value of 12.7% in the high-risk population were achieved.

CONCLUSION: Although both measurements are individually statistically significant, the combination of TCD and FTD measurements may be superior to the use of either parameter alone as a marker of trisomy 21.

Index terms: Chromosomes, abnormalities, 856.1841 • Down syndrome, 10.184, 856.1841, 856.874 • Fetus, abnormalities, 10.184, 856.1841, 856.874, • Fetus, US, 856.1298


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Trisomy 21, or Down syndrome, is the most common karyotype abnormality in live born infants (one per 800 live births) (1) and one of the leading causes of mental retardation. In the past, diagnostic amniocentesis was offered to women of advanced (>35 years) maternal age. However, only 20% of fetuses with Down syndrome are born to women older than 35 years (2); these findings have prompted searches for better methods of prenatal diagnosis. One approach is the analysis of serologic markers (ie, {alpha}-fetoprotein, human chorionic gonadotropin, and estriol) in the maternal serum. The analysis of all three biochemical markers together with maternal age can help to detect approximately 60% of fetuses with Down syndrome (3).

Another avenue for prenatal diagnosis is the ultrasonographic (US) evaluation of the fetus. Benacerraf et al (4) provided an excellent review of the use of US markers in determining the risk of trisomy 21 in second-trimester fetuses. These markers include a thickened nuchal fold (5), rhizomelic limb shortening (6), mild fetal pelvicaliectasis (7), echogenic bowel (8), a flared iliac crest (9), and an echogenic intracardiac focus (10). Two cranial markers are the subject of this article.

Following pathologic observations that children aged birth to 5 years with Down syndrome have frontal lobe shortening (11), the question of whether differences in various cranial biometric parameters can be demonstrated in second-trimester fetuses with trisomy 21 was examined in several studies (12–16). In studies by Bahado-Singh et al (19 fetuses) (13) and Winter et al (43 fetuses) (17), it was found that measuring the frontothalamic distance (FTD) yielded sensitivities of 16%–21% and specificities of 95%–97% for the detection of Down syndrome in the second-trimester fetus. Similarly, the results of pathologic (18,19), computed tomographic (CT) (20), and magnetic resonance (MR) imaging (21) studies involving infants, children, and adults with trisomy 21 have shown a smaller cerebellum in these individuals. Hill et al (22) found a normal cerebellar diameter in 23 fetuses with Down syndrome, but Rotmensch et al (23), in a study involving 42 second-trimester fetuses with trisomy 21, concluded that cerebellar hypoplasia is ultrasonographically recognizable. The purpose of our study was to confirm the US-detectable second-trimester shortening of the cerebellum and determine whether combining US measurements of the frontal lobe and cerebellum leads to an improved ability to detect Down syndrome in the second-trimester fetus.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Patients
Fifty-two fetuses with karyotypically proved trisomy 21 and an estimated gestational age of 14.7–20.4 weeks (mean ± 1 SD, 17.5 weeks ± 1.5) were identified from the results of genetic amniocentesis procedures performed between December 24, 1990, and April 6, 1998. The patients who were pregnant with these fetuses were referred for amniocentesis on the basis of advanced maternal age, abnormal triple-screen results, or a family history of fetal anomaly. None of the fetuses had intracranial anomalies at US. The gestational age was based on menstrual history; results of prior US examinations, when available; and previously published regression equations based on biometric analysis of the biparietal diameter, head circumference, abdominal circumference, and femoral length (24). Fifty-two fetuses with an estimated gestational age of 15–21 weeks (mean, 17.2 weeks ± 1.4), euploid karyotypes, and normal findings at second-trimester US served as a control group. These fetuses were from the same high-risk population as those with trisomy 21. All of the studies of the euploid group were performed between March 4, 1996, and November 20, 1997.

Criteria for inclusion in the study were a proved fetal karyotype of either trisomy 21 or euploidy and the ability to obtain clear images of the fetal head, from which the FTD, transcerebellar diameter (TCD), and biparietal diameter could be measured accurately. Twin (or higher) fetuses were excluded from both the euploid and Down syndrome study populations.

Our study involved a high-risk population: The prevalence of Down syndrome was 1.65%—that is, 30 fetuses with trisomy 21 identified from 1,814 consecutive second-trimester genetic amniocenteses performed between February 14, 1996, and August 17, 1998. The mean age (± SD) of the mothers of the 52 fetuses with Down syndrome was 36.5 years ± 5.9 (range, 18.2–47.0 years), whereas that of the mothers of the fetuses with euploid karyotypes was 35.5 years ± 5.1 (range, 18.4–47.4 years).

Measurements Performed
The length of the fetal frontal lobe was estimated by means of the FTD (13,17). The FTD was measured from the inner table of the frontal bone to the posterior thalamus (Fig 1a), in the same transverse plane in which the biparietal diameter was obtained. The TCD was measured as the maximum diameter of the cerebellum, from lateral hemisphere to lateral hemisphere, in a slightly oblique transverse plane that was oriented in a suboccipital-bregmatic manner (Fig 1b). All measurements were made retrospectively on the optimal representative image by one of two of the authors (A.O., T.W.) with mechanical calipers. The results of a previously published study (17) showed no significant difference between measurements of both the FTD and the occipitofrontal distance obtained with prospective electronic calipers and those obtained with retrospective mechanical calipers.



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  		Figure 1a. (a) Transverse sonogram of the fetal head at the level of the thalami demonstrates measurement of the FTD (between arrows). The FTD is measured from the inner table of the frontal bone to the posterior thalamus. (b) Slightly oblique transverse sonogram of the fetal head that is oriented in a suboccipital-bregmatic manner demonstrates measurement of the TCD (between arrows). The TCD is measured as the maximal diameter of the cerebellum from lateral hemisphere to lateral hemisphere.

 


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  		Figure 1b. (a) Transverse sonogram of the fetal head at the level of the thalami demonstrates measurement of the FTD (between arrows). The FTD is measured from the inner table of the frontal bone to the posterior thalamus. (b) Slightly oblique transverse sonogram of the fetal head that is oriented in a suboccipital-bregmatic manner demonstrates measurement of the TCD (between arrows). The TCD is measured as the maximal diameter of the cerebellum from lateral hemisphere to lateral hemisphere.

 
Statistical Evaluation
The expected values of the FTD were calculated according to a formula from a previously published report (17), which was based on 160 normal singleton pregnancies: FTDE = 0.6837 x BPD + 0.5525, where BPD is the biparietal diameter and FTDE is the expected FTD based on this formula. The expected values of the TCD also were calculated according to a formula from a previously published report (25), which was based on 1,040 normal singleton pregnancies:

where EGA is the estimated gestational age and TCDE is the expected TCD based on this formula. Data from the report by Snijders and Nicolaides (25) rather than those from the series of Rotmensch et al (23) were used to estimate the expected TCD, because the former series had 1,040 singleton pregnancies whereas the latter had 387. The O/Es for the FTD and the TCD were then calculated, and the combined parameter, defined as O/EAVG = (O/EFTD + O/ETCD)/2, was calculated for each fetus in the Down syndrome and control populations, where O/EFTD is the observed-to-expected FTD ratio; O/ETCD, the observed-to-expected TCD ratio; and O/EAVG, the average of the FTD and TCD O/Es.

The positive predictive value depends heavily on the disease prevalence. The middle-trimester incidence of trisomy 21 in low-risk populations is estimated to be one in 600 pregnancies (1,26–29). Algebraic and receiver operating characteristic calculations (30) were performed by using MATHCAD PLUS 6 software (MathSoft, Cambridge, Mass). Statistical calculations were performed with SPSS software (SPSS, version 6.1.1 for Macintosh; Statistical Product for Service Solutions, Chicago, Ill).

Relative risk is defined as the probability of disease in the test-positive group divided by the probability of disease in the test-negative group. Although the relative risk may be used in prospective or cross-sectional studies, it is entirely meaningless in retrospective studies like this (Instat for Macintosh instruction manual, Graph Pad Software, San Diego, Calif). Instead, the odds ratio is most useful in retrospective studies. When the prevalence of the condition being studied is quite low, the odds ratio can be interpreted as a relative risk.


   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The difference in mean estimated gestational age between the 52 karyotypically normal fetuses (17.16 weeks) and the 52 fetuses with trisomy 21 (17.49 weeks), 0.3310 weeks, was not statistically significant according to two-tailed t test analysis for independent samples (P = .248). The difference in mean maternal age between the 52 karyotypically normal fetuses (35.49 years) and the 52 fetuses with trisomy 21 (36.52 years), 1.0285, also was not statistically significant (P = .344).

There was no statistically significant difference between the TCD measured in the 52 fetuses with euploid karyotypes and the predicted TCD as a function of either the formula used by Rotmensch et al (23) (mean paired difference, -.1606 mm; P = .489, t test for paired samples) or the formula used by Snijders and Nicolaides (25) (mean paired difference, -.2399 mm; P = .298, t test for paired samples).

The mean (± 1 SD) O/E for the FTD was 1.02 ± .081 in the 52 fetuses with euploid karyotypes and 0.934 ± .090 in the 52 fetuses with Down syndrome (Fig 2). This 8.3% (.0841/1.0184) difference of .0841 was statistically significant (P < .001, two-tailed Student t test). The mean (± 1 SD) O/E for the TCD was .986 ± .099 in the 52 fetuses with euploid karyotypes and 0.881 ± .108 in the 52 fetuses with Down syndrome (Fig 3). This 10.6% difference of .1048 was statistically significant (P < .001, two-tailed Student t test). The mean (± 1 SD) value for the observed-to-expected combined parameter—that is, the average of the FTD and TCD O/E measurements (O/EAVG)—was 1.00 ± .068 in the 52 fetuses with euploid karyotypes and 0.908 ± .081 in the 52 fetuses with Down syndrome (Fig 4). This 9.4% difference of .0944 was statistically significant (P < .001, Student two-tailed t test).



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  		Figure 2. Graph illustrates O/Es for the FTD plotted against the estimated gestational age. The O/Es were calculated from the biparietal diameter by using a formula from a previous study (17). = fetuses with euploid karyotypes, {odot} = fetuses with trisomy 21. The thick line represents the mean O/E for the 52 fetuses in the euploid population, 1.02. Note that the O/Es for the fetuses with trisomy 21 cluster significantly lower than the average for the fetuses with euploid karyotypes.

 


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  		Figure 3. Graph illustrates O/Es for the TCD plotted against the estimated gestational age. The O/Es were calculated from the estimated gestational age by using a formula from a previous study (25). = fetuses with euploid karyotypes, {odot} = fetuses with trisomy 21. The thick line represents the mean O/E for the 52 fetuses in the euploid population, 0.99. Note that the O/Es for the fetuses with trisomy 21 cluster significantly lower than the average for the fetuses with euploid karyotypes.

 


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  		Figure 4. Graph illustrates the O/Es for the average of the two parameters, expressed as (O/EFTD + O/ETCD)/2, plotted against the estimated gestational age. = fetuses with euploid karyotypes, {odot} = fetuses with trisomy 21. The thick line represents the mean O/E for the 52 fetuses in the euploid population, 1.00. Note that the O/Es for the fetuses with trisomy 21 cluster significantly lower than the average for the fetuses with euploid karyotypes.

 
The receiver operating characteristic curves for various O/E thresholds (ie, findings interpreted as positive when the O/E was less than the threshold value) are illustrated in Figure 5. An area under the curve Az of 1.0 is indicative of a perfect test (ie, with 100% sensitivity and 100% specificity) (31), whereas a curve that follows the identity line (Az, 0.5) indicates no better than random chance. The sensitivity, specificity, odds ratio, and positive predictive values in our high-risk study population, in which the prevalence of trisomy 21 was one in 60 pregnancies, and in low-risk populations in general, in which the incidence of trisomy 21 is estimated to be one in 600 pregnancies, for a select subset of cranial biometric measurements are listed in the Table, which provides a range of O/E thresholds. For example, with an O/E threshold for the FTD of 0.90, a sensitivity of 33%, specificity of 94%, odds ratio of 7.9 (95% CI: 2.16, 29.2), and positive predictive values in high- and low-risk populations of 8.7% and 0.9%, respectively, can be achieved. By using an O/E threshold for the TCD measurement of 0.87, a sensitivity of 44%, specificity of 94%, odds ratio of 13.0 (95% CI: 3.57, 47.0), and positive predictive values in high- and low-risk populations of 11.4% and 1.3%, respectively, can be achieved. By using an O/E threshold for the average measurement of 0.92, a sensitivity of 50%, specificity of 94%, odds ratio of 16.3 (95% CI: 4.51, 59.1), and positive predictive values in high- and low-risk populations of 12.7% and 1.4%, respectively, can be achieved.



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  		Figure 5. Graph illustrating receiver operating characteristic curves. An Az value of 1.0 indicates a perfect test; values of the sensitivity versus false-positive rate are shown. Each data point is 0.01 O/E units away from its adjacent neighbor. Knowing this and reference to the Table enables relevant statistics to be inferred for any chosen threshold. {square} = FTD (Az, 0.747), x = TCD (Az, 0.762), • = average of FTD and TCD values (Az, 0.797).

 

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  		Select Cranial Biometrics and Trisomy 21
 
The above sensitivities should be interpreted with caution and full knowledge of the underlying data (Table) (Fig 5). Because of overlap in the raw data, at a 6% false-positive rate, the sensitivity for the FTD was between 29% and 33%, and that for the TCD was between 17% and 44%, whereas there was only one data point for the average measurement, 50%. Even by using the conservative end of the range, however, the average parameter as a marker of trisomy 21 was at least 34% better than the FTD measurement alone (1 - 33%/50%) and 12% better than the TCD measurement alone (1 - 44%/50%).


   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Schmidt-Sidor et al (11) examined 101 children aged birth to 5 years with Down syndrome and 80 with normal karyotypes and found substantial frontal lobe shortening in the children with trisomy 21. This difference was demonstrated ultrasonographically in second-trimester fetuses with Down syndrome in two prior studies (13,17). Similarly, the results of pathologic (18,19), CT (20), and MR imaging (21) studies of infants, children, and adults with trisomy 21 have shown these patients to have a smaller cerebellum. Hill et al (22) found no reduction in the US-measured in utero TCD, but they did not compare gestational age–stratified measurements (32). Rotmensch et al (23) demonstrated that cerebellar hypoplasia was ultrasonographically recognizable in 42 second-trimester fetuses with trisomy 21 but concluded that the shortening was too minimal to be clinically useful.

This study builds slightly upon an earlier study of the FTD (17), and the present study results indicate that the mean O/E for the FTD was 8.3% smaller in the trisomy 21 group and that this difference was statistically significant (P < .001). The first real objective of this study was to confirm the work of Rotmensch et al (23) regarding second-trimester US of the hypoplastic cerebellum in fetuses with Down syndrome. We confirmed the observations of Rotmensch et al in a larger series (n = 52) of second-trimester fetuses with trisomy 21. Specifically, the mean O/E for the TCD was 10.6% smaller in the Down syndrome group, and this difference also was statistically significant (P < .001).

The second objective of our study was to determine whether combining measurements of the FTD and the TCD would lead to better predictability of Down syndrome. This is not necessarily true, because one could argue that the same degree of shortening in both parameters would always be present in fetuses with trisomy 21—that is, the two factors are not independent. The mean O/E for the combined parameter (O/EAVG) was 9.4% smaller in the Down syndrome group, and this difference was statistically significant (P < .001). In addition, the Az for this parameter, 0.80, was slightly higher than the Az for either the O/E for the FTD alone (0.75) or the O/E for the TCD alone (0.76). Much of the literature on obstetric screening for aneuploidy is based on 5% false-positive rates. With a 6% false-positive rate (to enable easy comparison between the three tests, because exact 5% false-positive rates are not present in the Table), the sensitivity for the detection of Down syndrome increased from 33% by using the FTD to 44% by using the TCD, and then to 50% by using the average of both parameters. Therefore, using both frontothalamic and transcerebellar cranial biometric parameters together may lead to an improved rate of Down syndrome detection.

The theoretical advantage of using the FTD and TCD rather than several of the other proposed markers for trisomy 21 (eg, clinodactyly, echogenic bowel, sandal gap toe, echogenic intracardiac focus, iliac angle) is that these measurements should be easier to obtain with decreased interobserver variability; they are less subjective in assessment. The major disadvantage of these measurements, which is true of all of the proposed markers, lies in the distinction between statistically significant and clinically useful results. As seen graphically in Figures 2–4, despite the statistically significant differences, there is a large degree of overlap between the two studied karyotype populations; therefore, it is unlikely that any of these cranial markers in isolation could be used to accurately determine fetal Down syndrome.

Another weakness of this study was owing to the use of predominantly retrospective measurements of FTD and TCD biometric measurements in the trisomy 21 population. However, no statistically significant difference between prospective electronic caliper and retrospective mechanical measurements of several cranial biometric parameters was shown in a study (17) that specifically addressed this issue. In addition, in the current study, we found no statistically significant difference between the retrospective TCD measurements in 52 fetuses with euploidy and the expected TCD measurements that were mathematically predicted on the basis of published normative data based on the estimated gestational age in either of two prior studies—that is, that of Rotmensch et al (23) with 387 normal fetuses (P = .489) or that of Snijders and Nicolaides (25) with 1,040 normal fetuses (P = .298). A prospective study to more accurately determine the usefulness of combining cranial biometric parameters in the diagnosis of trisomy 21 is under way at our institution.

Perhaps the most fruitful area of future study would be the incorporation of the combined FTD-TCD parameter into a probabilistic risk assignment scheme, as exemplified in the age-adjusted US risk assessment proposed by Nyberg et al (33,34). In this algorithm, individual probabilities are assigned to each of the different US markers on the basis of their ratios of likelihood to be associated with trisomy 21. The theoretical advantage of the age-adjusted US risk assessment lies in the fact that the parents can be assigned a numeric probability of Down syndrome—rather than a list of US findings and markers that do not readily translate into conceptually useful information—to assist them in making an informed choice.

In conclusion, our study results confirm that statistically significant hypoplasia of the cerebellum in fetuses with trisomy 21 can be detected by using US performed in the second trimester. This observation may be combined with measurements of the frontal lobe to yield an improved parameter—that is, one that may have a higher sensitivity than either frontal lobe measurement alone or cerebellum measurement alone for the detection of Down syndrome. It is hoped that this US marker can be combined with other US markers, maternal age, and, potentially, serum biochemical analysis to develop an improved screening system for the detection of trisomy 21 and thereby allow the patient to make a more informed choice.


   Acknowledgments
 
We thank the sonographers and laboratory personnel for their assistance with data collection and are particularly grateful to Amy Anderson for help in compiling the database and to Maureen Michaud for help in manuscript preparation.


   Footnotes
 
Abbreviations: FTD = frontothalamic distance O/E = observed-to-expected ratio TCD = transcerebellar diameter

Author contributions: Guarantor of integrity of entire study, T.C.W.; study concepts and design, T.C.W.; definition of intellectual content, T.C.W.; literature research, T.C.W.; clinical studies, all authors; data acquisition, T.C.W., A.A.O., S.B.U.; data analysis, T.C.W.; statistical analysis, T.C.W.; manuscript preparation, editing, and review, T.C.W.


   References
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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T. C. Winter, S. B. Uhrich, V. L. Souter, and D. A. Nyberg
The "Genetic Sonogram": Comparison of the Index Scoring System with the Age-adjusted US Risk Assessment
Radiology, June 1, 2000; 215(3): 775 - 782.
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