Prenatal nasal bone evaluation with ultrasound is proving to be an exceptionally powerful marker for Down syndrome (DS). This is not surprising given the fact that the DS phenotype has been known to be associated with nasal bridge abnormalities ever since its original description by Langdon Down in 18661. However, the striking abnormalities of the nasal bone appearance as seen by prenatal sonography were not recognized until early 2001. Three DS fetuses were evaluated in the second trimester. Two of them had no identifiable nasal bones and one had a hypoplastic nasal bone2. A review of the videotape recording of the first-trimester examination of one of the fetuses at the time of the nuchal translucency (NT) evaluation revealed that the nasal bone could not be identified at that point in pregnancy. Armed with this information, observational studies were undertaken to evaluate the utility of nasal bone evaluation in screening for DS. The first of these studies was published in 20013. In this study, a remarkable difference in the incidence of nasal bone absence in fetuses with DS and in euploid fetuses was found during the 11–14-week scan. The incidence of nasal bone absence in DS fetuses was 73% whereas only 0.5% fetuses with normal chromosomes were noted to have an absent nasal bone. The presence or absence of the nasal bone was found to be independent of other fetal and maternal variables. Therefore, nasal bone evaluation can be added to the armamentarium of ultrasound markers for DS. This large difference in the incidence of nasal bone absence not only increased the sensitivity of the early (11–14 weeks) pregnancy-screening test but also decreased the false-positive rate. In this way, the addition of nasal bone evaluation increases the correct identification of DS fetuses whilst decreasing the exposure of euploid fetuses to the risk of invasive procedures. A comparison of the actual measurements of nasal bone length (NBL) in DS and in euploid fetuses during the 11–14-week scan was evaluated in another study4. In this study, the difference in NBLs was not found to be sufficiently great to be of clinical use. Otano et al.5 published a study on ultrasonographic nasal bone evaluation in 2002. These investigators also showed an increased incidence of nasal bone absence in DS fetuses (3/5 or 60%) in comparison with euploid fetuses (1/175 or 0.6%). The NBLs were not reported in this study. The benefit of nasal bone evaluation in screening for DS in the early- and mid-second trimester has now been confirmed in larger trials. The absence vs. presence of the nasal bone continues to be very important. In a publication by Bromley et al.6, nasal bone absence in DS fetuses between 15 and 20 weeks' gestation was noted to be 43%. Among the fetuses with a normal chromosomal complement, the incidence of nasal bone absence was again noted to be very low (0.5%). The absence of a fetal nose during the 15–20-week scan was noted to increase the risk of DS 83 times. The actual NBL has been found to play an important role as well. These investigators looked at the utility of biparietal diameter (BPD)/NBL ratios. This ratio increases as the nasal bone becomes shorter. They found that a discriminatory BPD/NBL ratio of ≤ 10 would give this test a sensitivity of 81% with a false-positive rate of 11%. Bromley et al.6 also confirmed that NBL increases linearly with gestational age in euploid fetuses. However, the NBLs in DS fetuses were found to be remarkably uniform (3.5 ± 0.47 mm) over the gestational period investigated. Another study looking at the utility of nasal bone evaluation in the second trimester (15–22 weeks' gestation) was published earlier this year7. A total of 62% of DS fetuses were noted to have absent or hypoplastic nasal bones (< 2.5 mm) during this gestational period. The incidence of nasal bone hypoplasia in trisomy 18 fetuses was 7%. Euploid fetuses were found to have an incidence of nasal bone hypoplasia of 1.2% during the same time period. A difference between Caucasian and Afro-Caribbean populations in the incidence of nasal bone hypoplasia was noted, suggesting that racial adjustments need to be made when using the nasal bone for screening. Bunduki et al.8 looked at the utility of nasal bone measurement in the second trimester (16–24 weeks' gestation) in 1631 patients. The association between a relative nasal bone hypoplasia and DS was demonstrated. Using the 5th percentile of the normal curves generated by these investigators as a cut-off for screening for DS, a sensitivity of 59% was achieved. Interestingly, none of the DS fetuses was reported to have an absent nasal bone. Three-dimensional ultrasound was used to evaluate the nasal bone of 20 fetuses with DS and 20 fetuses with a normal karyotype between 16 and 30 weeks' gestation by Lee et al.9. Two examiners independently evaluated the same images. The incidence of nasal bone absence in the fetuses with DS was 8/12 (40%) and 9/11 (45%) by Examiners 1 and 2, respectively, which is similar to the observations made using two-dimensional (2D) sonography. However, the incidence of nasal bone absence in the normal population was 4/16 (20%) and 2/18 (10%) by Examiners 1 and 2, respectively. This incidence is much higher than the incidence reported elsewhere with 2D ultrasound for this gestational period (< 1.3%). This finding illustrates the need for a separate standardization of nasal bone evaluation when using these two modalities. A reference range for NBLs during gestation (14–34 weeks' gestation) was initially published by Guis et al.10 in 1995. This study suffered from a relatively small sample size (376 patients). A new reference range (11–40 weeks' gestation) was published earlier this year based on a total of 3547 patients11. The NBL ranges established for the early to mid-trimester confirm that the discriminatory NBL measurements of 2.5–4 mm or less may be appropriate in screening for DS. This issue of the journal contains several articles that look further at the utility of nasal bone evaluation with ultrasound in screening for aneuploidy, standardization of the ultrasound view for the evaluation of the nasal bone, and the comparison of ultrasound, radiological and histological findings in fetuses with DS. Nasal bone abnormalities observed postnatally on radiography in DS individuals have been recognized for decades. The feasibility of evaluating the nasal bone using X-ray in aborted fetuses was demonstrated in 1994 by Sandikcioglu12. This investigation of the appearance of the nasal bone using radiography in aborted DS fetuses showed a 60% incidence of nasal bone abnormalities (nasal bone absence (26%) or nasal bone hypoplasia (34%)). Stempfle et al.13 found a 23% incidence of radiologically absent nasal bones in DS fetuses. An observation here was also made that, when present, the nasal bones in the DS fetuses were short. In this issue of the journal, Tuxen et al.14 present 33 fetuses between 14 and 25 weeks' gestation that were terminated after the diagnosis of DS was made. All of the fetuses had a radiological evaluation performed. Eight were noted to have complete absence of the nasal bones, two were noted to have unilateral absence of the nasal bone, and the nasal bones were noted to be radiographically present bilaterally in 23 fetuses. The histological evaluation confirmed a complete nasal bone absence in 7/10 fetuses. Histological evaluation was not performed in the remaining three, including the two fetuses that had unilateral absence of the nasal bone. Histological presence of nasal bone was confirmed in all the 23 fetuses that had radiological evidence of nasal bone formation. The 30% nasal bone absence is close to the previously published rates on X-ray in the second trimester (26% and 23%). The observation of unilateral absence of the nasal bone may have a bearing on DS screening in the future. However, this cannot be done until data on the incidence of this finding in the normal population become available. Nonetheless, the report of the existence of this entity is an important contribution and should be borne in mind when evaluating the fetal nasal bone with ultrasound. Minderer and colleagues15 compared nasal bone ultrasound findings and those on a histomorphological evaluation in 17 DS fetuses between 11 and 14 weeks' gestation. In their study, the incidence of nasal bone absence on ultrasound was 6/17 (35%) cases. One fetus could not have its nasal bone evaluated due to position and the nasal bone was present in the remaining 10 fetuses. The authors comment that all of these 10 fetuses had severely hypoplastic nasal bones though the definition of this is not made completely clear in the study. In contrast, the histomorphological evaluation of the nasal bone area showed evidence of nasal bone formation in 16/17 cases. The investigators reviewed the ultrasound images of the fetuses originally classified as having absent nasal bone. They claim that they were able to now detect evidence of a nasal bone albeit ‘smaller, less distinct, and less echogenic’. The significance of this finding must be confirmed by a prospective study since the authors were armed with the knowledge of the results of the histomorphological evaluation when reviewing the ultrasound images. The authors argue that based on their findings, the term ‘nasal bone absence’ should be replaced by ‘nasal bone hypoplasia’. The difference in the incidence of nasal bone absence on histomorphology of 23%14 vs. 0%15 is especially surprising since Minderer et al.'s study15 was performed in fetuses of a much earlier gestational age than those in the study by Tuxen et al.14. As such one would expect the incidence of nasal bone absence to be, if anything, higher. It must be noted that the methods of histological preparation and the staining techniques used in the two studies were different. The study by Larose et al.16 compares ultrasound findings with subsequent radiological evaluation of 21 DS fetuses. The ultrasonographic evaluations were performed between 11.3 and 13.7 weeks' gestation. The subsequent radiological studies on the aborted fetuses were performed between 13 and 29 weeks' gestation. Interestingly, the incidence of nasal bone absence on ultrasound (52.4%) was very similar to the one noted on X-ray (47.6%). However, the ultrasound and X-ray findings were discordant in 9/21 cases (43%)! Four of the cases where the nasal bone was present on ultrasound showed no evidence of a nasal bone on X-ray and five of the cases where the nasal bone was noted to be absent on ultrasound subsequently showed evidence of a nasal bone on X-ray. The issue of how the ultrasound appearance of the nasal bone translates into what is seen on X-ray and on histomorphological evaluation remains to be fully elucidated. However, given the fact that neither X-ray nor histomorphology can be used for prenatal screening, the appearance of the nasal bone on ultrasound, assuming that the examination is done in a reproducible and standardized manner, remains the gold standard for prenatal screening. The final two studies17, 18 both deal with the continued evaluation of the nasal bone in the 11–14-week range. Both studies support the initial impression that the evaluation of the nasal bone at this gestation will become an important part of prenatal screening for DS. The paper that summarizes a multicenter study headed by Orlandi17 validates the studies published to date. A total of 1089 patients were investigated in three separate centers, two in Italy and one in the Netherlands. A successful nasal bone evaluation was achieved in 94% of the patients. Nasal bone absence was noted in 10/15 (67%) of the fetuses with DS and only 1% of the normal fetuses. The researchers also noted that in all of the fetuses with DS that did have an identifiable nasal bone, the NBL was below the 50th percentile according to the reference ranges generated in the euploid population in this study. However, they also noted that normal ranges varied significantly among the three study centers. This underscores the need for a standardized approach to nasal bone evaluation and measurement. It is conceivable that nasal bone measurements above a certain percentile may come close to being able to rule out the presence of DS completely. This study proves that the presence or absence of the nasal bone during the 11–14-week scan can be successfully used as a marker for DS in a multicenter study setting. Cicero et al.18 present updated data on nasal bone evaluation during the 11–14-week scan. The number of patients now totals 3788. The ability to evaluate the nose at this point in gestation remains very high (98.9%). The incidence of nasal bone absence in association with trisomy 21 has not changed significantly from the original paper published in 2001 (67% vs. 73%). However, the incidence of nasal bone absence with normal karyotype is larger than noted previously (2.8% vs. 0.5%). In the most recent analysis, stratification according to race, NT measurement, and gestational age (crown–rump length (CRL) measurement) was done. It was noted that the incidence of nasal bone absence is higher in the normal Afro-Caribbean and Asian fetuses, which reduces the contribution of this finding to assessing the risk of DS in these populations. Similarly, it was noted that when the CRL measurement was in the range 45–64 mm, the incidence of nasal bone absence in the euploid population is 3.9–4.6%, whereas later in gestation (CRL 65–84 mm) the incidence of nasal bone absence is 1.0–1.5%. At the same time, however, the incidence of nasal bone absence in the DS population remains relatively constant for CRL values in the range 45–74 mm (66–79%) but drops to 44% at 75–84 mm (13–14 weeks' gestation) which more closely approximates the incidences reported in the second trimester overall. The likelihood ratios associated with nasal bone absence remain remarkably high. Between 45 and 64 mm, if the nasal bone is absent, the risk of DS is increased 17 times. In the 65–84 mm CRL range, the likelihood ratio is 44–48 times. It was also noted that as the NT measurement increases, the incidence of nasal bone absence also increases. Similarly, the likelihood ratios for DS decrease as the NT measurement increases. However, since these two parameters move in the opposite direction, the effectiveness of the test may not suffer significantly. The authors developed equations that take into account the ethnic origin, CRL and the NT measurement to arrive at the odds ratio for each specific patient. Among the aneuploidies other than DS, trisomy 18 continues to have the highest incidence of absent nasal bone (57%), followed by trisomy 13 (32%) and Turner syndrome (9%). It is clear that evaluation of the fetal nasal bone is becoming a powerful tool in prenatal screening for DS. It will be argued for some time to come as to what the findings equivalent to nasal bone absence or hypoplasia are in either radiological or histomorphological studies. During the 11–14-week scan, the most powerful predictor of DS is the virtual absence of the nasal bone (severe hypoplasia) as viewed on ultrasound. The idea of using NBLs in screening at this point in gestation needs to be investigated further. The optimal time for nasal bone evaluation during this time period appears to be when the fetal CRL is in the range 65–74 mm. The incidence of nasal bone absence in the euploid population appears to be the lowest (approximately 1.5%) and the incidence of nasal bone absence is still very high (approximately 73%) in fetuses with DS, with the resultant likelihood ratio being approximately 4818. To arrive at the appropriate risk assessment, several factors including the patient's race, the NT measurement and the CRL measurement must be taken into consideration. However, even in the Afro-Caribbean population where the incidence of nasal bone absence in euploid fetuses appears to be the highest, the likelihood ratio remains significant (approximately 7.2). The fact that the nasal bone presence decreases the risk of DS by approximately three-fold inevitably results in a decreased false-positive rate. Nasal bone evaluation in the second trimester makes use of both the phenomenon of nasal bone absence and the fact that the NBL in DS fetuses with an identifiable nasal bone is shorter than in euploid fetuses. The finding of an absent nasal bone on the 15–22-week scan increases the risk of DS 83 times6. In the case where the nasal bone is present, if the measurement is short, either with the absolute measurement being 2.5 mm or less or if the BPD/NBL ratio is ≥ 10, the sensitivity of the test approaches 81% with a false-positive rate of 11%. The importance of a standardized view of the nasal bone cannot be overstated. The fetus must be imaged facing the transducer. The fetal face is viewed longitudinally and strictly in the midline. In this view, a normal nasal bone is identified as a thin echogenic line within the bridge of the nose. The skin over the nasal bridge can be as echogenic as the nasal bone itself. This is especially true during the 11–14-week scan. Therefore, the nasal bone must be clearly identified as a second echogenic line beneath the skin. A second surface echogenic line in front of the nasal bridge is usually seen. This represents the skin over the tip of the nose. An echogenic line or lines can also often be seen within the tip of the nose. These lines probably represent the cartilage and/or parts of the vomeral bones. This view was proposed and described by The Fetal Medicine Foundation3. One source of some confusion is the angle of insonation with which the nasal bone should be imaged. For example, the method proposed by The Fetal Medicine Foundation uses an angle of insonation of 45° with respect to a reference line, which connects the fetal forehead and the chin. The angle of insonation described in the paper by Minderer et al.15 is also 45° but the reference line here connects the forehead and the tip of the fetal nose. In practice, the actual angle of insonation only roughly approximates to the 45° proposed in these two descriptions. A much simpler way to describe the angle of insonation is to use the longitudinal axis of the nasal bone as the reference line, i.e. the nose should be viewed with the longitudinal axis of the nasal bone being at 90° to the insonating beam2, 19 (Figure 1). Absence of the nasal bone is best demonstrated in the same view with the angle of insonation being perpendicular to the echogenic skin over the nasal bridge. A diagrammatic representation of the fetal skull. Angles of insonation with respect to the longitudinal axis of the nasal bone are shown. Figure reproduced and modified, with permission, from O'Brien W, Cefalo R, Labor and delivery, in Obstetrics: Normal and Problem Pregnancies (3rd edn), Niebyl JR, Simpson JL (eds), Churchill Livingstone: New York, NY, 1996; 393. Copyright © Elsevier. The nasal bone length is obtained by simply measuring the nasal bone from one end to the other. The optimal way to measure the length is with accuracy to within 0.1 mm. This is especially important during the 11–14-week scan where the nasal bone size is small4, 5, 11, 17; therefore, each 0.1 mm represents a large percentage of the actual measurement. A 90° angle of insonation allows for the best visualization of the nasal bone. However, the scatter of the ultrasound beam at both ends of the nasal bone in this view can artificially increase the nasal bone length. One way to reduce this scatter is to change the angle of insonation so that it is closer to either 45° or 135° (Figure 1). In addition to the lateral scatter of the ultrasound beam, the nasal bone during the 11–14-week scan often has short ‘extensions’, which are less echogenic than the nasal bone itself. These probably represent areas of early ossification or slightly hyperechoic cartilage. A method of measuring the nasal bone, which was proposed by Cicero et al.4, excludes these ‘extensions’ from the measurement of the more echogenic nasal bone proper. Care must be taken to avoid imaging the nasal bone with the angle of insonation approaching either 0° or 180° (Figure 1). Since the nasal bone is very thin, when it is viewed ‘on end’ the lateral resolution of the ultrasound equipment is often not sufficient to image the nasal bone and the diagnosis of nasal bone absence can be made in error. Finally, in common with the evaluation of NT and other ultrasound markers whose effectiveness depends on a consistent and standard approach, care must be taken to implement nasal bone evaluation in clinical practice only when there is the expertise and equipment to do so. Optimally, formal training and ongoing quality assurance audit should be a part of implementing such a program.
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Jiri Sonek (2003) studied this question.