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Objective: The purpose of this study was to evaluate the association between the second-trimester fetal biparietal diameter/nasal bone length (BPD/NBL) ratio and trisomy 21., Methods: Thirty-one cases of trisomy 21 for which complete ultrasound images included the nasal bone were identified from the University of Washington prenatal diagnosis database and matched to 136 euploid fetuses based on maternal age, indication for referral, and gestational age., Results: The mean NBL was shorter (mean +/- SD, 2.3+/-1.7 mm versus 3.9+/-1.2 mm; P<.001) and the BPD/NBL ratio was greater (17.7 [range, 6.2-114] versus 11.7 [range, 5.8-80]; P<.001) in the fetuses with trisomy 21. The risk of trisomy 21 increased 2.4-fold (95% confidence interval [CI], 1.7-3.4) with every 1-mm decrease in NBL and increased 1.08-fold (95% CI, 1.03-1.12) with each unit increase in the BPD/NBL ratio (P<.001). A multiple logistic regression model was constructed and included the BPD/NBL ratio, maternal indications (age>or=35 years, positive serum screening results, or both, yielding a risk of <1 per 270 for trisomy 21), and sonographic markers as covariates. The BPD/NBL ratio was found to be an independent predictor of trisomy 21 (odds ratio, 1.08; 95% CI, 1.03-1.11). An analysis of receiver operating characteristic curves revealed an improvement after the BPD/NBL ratio was added to a model containing the current second-trimester screening based on maternal age, serum screening, and sonographic markers (receiver operating characteristic curve area, mean +/-SE, 0.89+/-0.03 for the model with the BPD/NBL ratio versus 0.76+/- 0.06 without the BPD/NBL ratio; P=.009)., Conclusions: The second-trimester BPD/NBL ratio was a significant and independent predictor of trisomy 21. An assessment of the BPD/NBL ratio may improve the diagnosis of trisomy 21 when used with current prenatal screening practices.

Purpose: To determine whether there is a relationship between the presence of an echogenic intracardiac focus in 2nd-trimester fetuses and trisomy 21 (Down syndrome)., Materials and Methods: A complete genetic ultrasonographic (US) scan was obtained in 3,303 consecutive fetuses with an estimated gestational age of 14.0-24.0 weeks (mean +/- SD, 17.1 weeks +/- 1.75). US was performed in a prospective fashion without any knowledge of karyotype and included assessment of any potential echogenic intracardiac focus (ie, calcified papillary muscle). Karyotypes were obtained in all fetuses. Maternal ages ranged from 13.0 to 47.4 years (mean, 35.1 years +/- 5.1). The prevalence of Down syndrome in this population was 1.6% (53 of 3,303 fetuses)., Results: An echogenic intracardiac focus was seen in 147 of the 3,192 karyotypically normal fetuses (4.6%) and 16 of the 53 fetuses with trisomy 21 (30%). The positive predictive value (PPV) of an echogenic intracardiac focus in this high-risk population was 9.8%; sensitivity, 30%; specificity, 95%; likelihood ratio, 6.6; and relative risk (RR), 8.2 (P <.001). For a sonographically isolated echogenic intracardiac focus, the PPV was 3.7%; sensitivity, 19%; specificity, 95%; likelihood ratio, 4.2; and RR, 4.8 (P =.002)., Conclusion: A sonographically isolated echogenic intracardiac focus (no other anomalies or markers noted on a complete genetic sonogram) was associated in our high-risk population with a 4.8-fold (95% CI: 1.8, 12.5) increase in RR for trisomy 21 (P =.002).

Purpose: To compare two ultrasonographic (US) methods for prenatal detection of fetal Down syndrome., Materials and Methods: Genetic amniocentesis was successfully performed in 3,303 consecutive women with high-risk pregnancies (mean gestational age, 17.1 weeks). All patients underwent a complete "genetic US" examination prospectively. Risk was assessed by using (a) various modifications of the index scoring system (ISS) and (b) the age-adjusted US risk assessment (AAURA)., Results: The prevalence of Down syndrome in this population was 1.6% (53 of 3,303). By using a threshold of at least 2 points to detect trisomy 21, the best ISS had a sensitivity of 45.3%, false-positive rate of 4.9%, likelihood ratio of 9.3, and positive predictive value in the high-risk population in this study of 13.3%. Lowering the threshold to 1 point increased the sensitivity to 60.4% but increased the false-positive rate to 15.8%. Adding points for age increased the sensitivity to 67.9% but increased the false-positive rate to 24.3%. Results of using AAURA to detect trisomy 21 were nearly identical, with a sensitivity of 43.4% and false-positive rate of 4.9% at a 1 in 36 risk threshold and a sensitivity of 69.8% and false-positive rate of 26.1% at a 1 in 200 threshold. Trisomies 18 and 13 were detected with sensitivities of 80.0% and 100.0%, respectively, with either system., Conclusion: The modified ISS and AAURA are equivalent in screening for Down syndrome, with detection of approximately half of all trisomy 21 fetuses at a 5% false-positive rate.

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.

Purpose: To determine whether the frontal lobe is disproportionately smaller than normal in second-trimester fetuses with Down syndrome by using prenatal ultrasonographic (US) measurements of the frontothalamic distance (FTD)., Materials and Methods: The FTD, measured from the inner table of the frontal bone to the posterior margin of the thalamus, was measured in 43 fetuses (mean gestational age, 17.2 weeks +/- 1.3 [standard deviation]; range, 15.0-20.4 weeks) with chromosomally proved trisomy 21 and in 160 chromosomally normal fetuses (mean gestational age, 17.1 weeks +/- 1.5; range, 14.5-22.5 weeks). Other cranial biometric ratios also were calculated., Results: The FTD was best predicted from the estimated gestational age (EGA) in the euploid population with the quadratic equation FTD = -0.0120 x EGA2 + 0.6917 x EGA - 5.2349 (R2 = .731) or from the biparietal diameter (BPD) with the linear equation FTD = 0.6837 x BPD + 0.5525 (R2 = .731). If an observed-to-expected ratio of 0.84 is used as a cutoff sign to screen for trisomy 21, a sensitivity of 16%, specificity of 97%, odds ratio of 6.03 (95% confidence interval, 1.81, 20.1), and relative risk of 5.98 are achieved., Conclusion: The frontal lobe is statistically significantly smaller in fetuses with trisomy 21. US measurement of the FTD may prove to be a useful adjunctive screening tool if used with other markers for Down syndrome.

The purpose of this retrospective study was to evaluate the utility of routine measurement of amniotic fluid alpha-fetoprotein levels at the time of second trimester genetic amniocentesis (mean gestational age, 17.3 weeks +/- 2.5 weeks standard deviation; median, 16.8 weeks; range, 15 to 22 weeks). During the study period 7174 patients underwent second trimester genetic amniocentesis. Outcome data were available in all cases. In 79 (1.1%) cases the amniotic fluid alpha-fetoprotein level was > or = 2.0 multiples of the median. Thirty-three of the 79 (42%) patients had normal ultrasonograms, and in 31 of 33 (94%) the amniotic fluid alpha-fetoprotein level was between 2.0 and 3.0 multiples of the median. Forty-six of the 79 (58%) patients had abnormal ultrasonographic findings, and of these, 82% were neural tube defects, abdominal wall defects, or cystic hygromas. Acetylcholinesterase was positive in 37 cases, all of which had abnormal ultrasonographic findings. None of the fetuses with negative findings on sonographic screening had detectable abnormalities at birth. In this study, with over 7000 patients, amniotic fluid alpha-fetoprotein and acetylcholinesterase levels did not increase the detection of fetal abnormalities. On the basis of these results, routine measurement of amniotic fluid alpha-fetoprotein level at the time of routine genetic amniocentesis (15 to 22 weeks) does not appear justified.

The purpose of this study was to evaluate the risk of fetal aneuploidy in the presence of isolated choroid plexus cysts and to evaluate the results obtained from our institution and those reported previously in the English literature. All patients with fetal choroid plexus cysts on prenatal ultrasonography were offered genetic counseling and amniocentesis for fetal karyotyping. Seven of 274 fetuses, 2.6% (95% confidence interval = 1.0 to 5.2%), with isolated choroid plexus cysts were aneuploid. Literature analysis located 23 other reports of 1537 fetuses with isolated choroid plexus cysts; 26 were karyotypically abnormal, 1.7% (95% confidence interval = 1.0 to 2.4%). When evaluating only those patients whose indication for amniocentesis was choroid plexus cysts (i.e., eliminating those patients with advanced maternal age or abnormal serum screening) the risk of having a fetus with trisomy 18 changed little, 1.9% (95% confidence interval = 0.4 to 5.5%). Our data, combined with those of the literature, suggest that the risk of finding an abnormal fetal karyotype in the presence of isolated choroid plexus cysts is at least 1% and may be as high as 2.4%. On the basis of these results, genetic counseling and prenatal diagnosis should be offered to these patients.

The construction of an accurate family pedigree is a fundamental component of a clinical genetic evaluation and of human genetic research. Previous surveys of genetic counselors and human genetic publications have demonstrated significant inconsistencies in the usage of common pedigree symbols representing situations such as pregnancy, termination of pregnancy, miscarriage, and adoption, as well as less common scenarios such as pregnancies conceived through assisted reproductive technologies. The Pedigree Standardization Task Force (PSTF) was organized through the Professional Issues Committee of the National Society of Genetic Counselors, to establish recommendations for universal standards in human pedigree nomenclature. Nomenclature was chosen based on current usage, consistency among symbols, computer compatibility, and the adaptability of symbols to reflect the rapid technical advances in human genetics. Preliminary recommendations were presented for review at three national meetings of human genetic professionals and sent to >100 human genetic professionals for review. On the basis of this review process, the recommendations of the PSTF for standardized human pedigree nomenclature are presented here. By incorporating these recommendations into medical genetics professional training programs, board examinations, genetic publications, and pedigree software, the adoption of uniform pedigree nomenclature can begin. Usage of standardized pedigree nomenclature will reduce the chances for incorrect interpretation of patient and family medical and genetic information. It may also improve the quality of patient care provided by genetic professionals and facilitate communication between researchers involved with genetic family studies.

To determine consistency in usage of pedigree symbols by genetics professionals, we reviewed pedigrees printed in 10 human genetic and medical journals and 24 medical genetics textbooks. We found no consistent symbolization for common situations such as pregnancy, spontaneous abortion, death, or test results. Inconsistency in pedigree design can create difficulties in the interpretation of family studies and detract from the pedigree's basic strength of simple and accurate communication of medical information. We recommend the development of standard pedigree symbols, and their incorporation into genetic publications, professional genetics training programs, pedigree software programs, and genetic board examinations.

The construction of an accurate family pedigree is a fundamental component of a clinical genetic evaluation and of human genetic research. Previous surveys of genetic counselors and human genetic publications have demonstrated significant inconsistencies in the usage of common pedigree symbols representing situations such as pregnancy, termination of pregnancy, miscarriage, and adoption, as well as less common scenarios such as pregnancies conceived through assisted reproductive technologies. The Pedigree Standardization Task Force (PSTF) was organized through the Professional Issues Committee of the National Society of Genetic Counselors, to establish recommendations for universal standards in human pedigree nomenclature. Nomenclature was chosen based on current usage, consistency among symbols, computer compatibility, and the adaptability of symbols to reflect the rapid technical advances in human genetics. Preliminary recommendations were presented for review at three national meetings of human genetic professionals and sent to > 100 human genetic professionals for review. On the basis of this review process, the recommendations of the PSTF for standardized human pedigree nomenclature are presented here. By incorporating these recommendations into medical genetics professional training programs, board examinations, genetic publications, and pedigree software, the adoption of uniform pedigree nomenclature can begin. Usage of standardized pedigree nomenclature will reduce the chances for incorrect interpretation of patient and family medical and genetic information. It may also improve the quality of patient care provided by genetic professionals and facilitate communication between researchers involved with genetic family studies.

To assess the variation in usage of symbols used in recording a genetic family history, full members of the National Society of Genetic Counselors were surveyed by questionnaire. The questionnaire return rate was 55.3% and genetic counselors from a broad range of clinical experience, genetic counseling training programs and geographic regions responded. There was striking variation in symbols used for recording routine medical information in a genetic family history (i.e., pregnancy, spontaneous abortion, termination of pregnancy). There was even less consensus in recording situations representing new reproductive technologies (i.e., artificial insemination by donor semen, donor ovum, surrogate motherhood). The results of this survey document the need for developing standardized nomenclature in recording genetic family histories as a quality assurance measure in the delivery of genetic services. Such standardization will reduce the chance of incorrect interpretation of patient and family medical and genetic information.