The fetal brain neurosonography in trisomy 21: the seagull sign and thinned subplate.

Abstract

Down syndrome, first systematically characterized by John Langdon Down in 1866 and later identified as trisomy 21 by Jérôme Lejeune in 1959, has seen dramatic improvements in life expectancy due to advances in medical care and social support. Despite this progress and the National Institutes of Health's INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE project's focus on Down syndrome research, prenatal diagnosis remains largely binary-positive or negative for trisomy 21-without capturing the wide phenotypic variability that characterizes this condition. Advanced neuroimaging techniques may provide insights into the neuroanatomical basis of this variability. To establish objective, quantifiable metrics for 2 previously unreported morphological features observed in our clinical practice in fetal brains with Down syndrome (the "seagull sign" [cerebral hemispheres forming a seagull-like shape on coronal view] and "thinned subplate") and to characterize their developmental trajectory between 17 and 30 weeks' gestation. This multicenter retrospective case-control study analyzed stored 3-dimensional transvaginal neurosonography archives of fetal brains from 76 cases with trisomy 21 and 772 controls between 17 and 30 weeks' gestation. We developed standardized measurements for the cerebral hemisphere configuration ("seagull ratio") and subplate thickness to scientifically validate these features that were consistently observed and increasingly recognized during our 2 decades of clinical experience. Statistical comparisons were performed using Mann-Whitney U tests with significance set at P<.01. The seagull ratio was significantly higher in trisomy 21 cases (P<.0001), particularly before 22 weeks, while subplate thickness was consistently reduced throughout the observed gestation (P<.0001). Both measurements demonstrated excellent reliability with intraobserver (intraclass correlation coefficient=0.997; 95% confidence interval, 0.995-0.998 for seagull ratio and intraclass correlation coefficient=0.989, 95% confidence interval, 0.973-0.996 for subplate thickness) and interobserver reliability (intraclass correlation coefficient=0.958; 95% confidence interval, 0.930-0.975 and intraclass correlation coefficient=0.983; 95% confidence interval, 0.957-0.993, respectively). Longitudinal analysis in 9 cases revealed that the seagull ratio approached normal ranges after 22 weeks, while thinned subplate persisted. Notably, in the 3 trisomy 21 mosaicism cases (3.9%), we observed variable patterns that suggest a possible relationship between neuroanatomical features and the percentage of trisomic cells, although the small sample size limits this observation. This study scientifically validates 2 new neuroanatomical features in fetal Down syndrome brains that transform our understanding from a binary diagnosis to a spectrum of neurodevelopmental variations. These visually recognizable features may enhance prenatal counseling by acknowledging the observable differences that exist among fetuses with the same genetic diagnosis. While their relationship to developmental outcomes requires further study, the seagull sign and thinned subplate may eventually serve as objective parameters for individualized assessment and as potential endpoints for future therapeutic interventions, contributing to the emerging field of personalized fetal medicine.