Cytogenetic Findings and Pregnancy Outcomes in Fetuses With Apparently Isolated Increased Nuchal Translucency or Cystic Hygroma

Background: To evaluate cytogenetic findings and pregnancy outcomes in fetuses with apparently isolated increased nuchal translucency (NT) or cystic hygroma and to characterize molecular testing results, primarily based on whole-exome sequencing (WES) or clinical exome sequencing (CES), in clinically selected cases. Methods: This retrospective cohort study included 81 fetuses diagnosed with apparently isolated increased NT or cystic hygroma between January 2016 and October 2024. All cases underwent invasive prenatal testing with conventional karyotyping. Pregnancy outcomes were subsequently analyzed among fetuses with a normal karyotype. Molecular testing, primarily based on WES or CES, was performed solely in clinically selected cases during prenatal or postnatal evaluation when persistent, evolving, or newly recognized postnatal clinical concerns were present. These findings were analyzed descriptively and were not used to estimate the cohort-level diagnostic yield. Results: Among the 81 fetuses, 60 (74.1%) presented with apparently isolated increased NT, whereas 21 (25.9%) presented with apparently isolated cystic hygroma. Chromosomal abnormalities were identified in 35 cases (43.2%). Trisomy 21 was the most frequent abnormality (24.7%), followed by trisomy 18 (9.9%) and monosomy X (6.2%). Chromosomal abnormalities were more frequently identified in fetuses with apparently isolated cystic hygroma than in those with apparently isolated increased NT; however, this difference was not statistically significant (52.4% vs. 40.0%; p = 0.443). Within the increased NT group, the median NT thickness was significantly greater in fetuses with chromosomal abnormalities than in those with a normal karyotype (4.50 vs. 3.50 mm; p = 0.005). Among fetuses with a normal karyotype, live birth occurred in 94.4% of those with apparently isolated increased NT and in 70.0% of those with apparently isolated cystic hygroma. Molecular evaluation, predominantly based on WES or CES, was performed in 11 clinically selected cases. 2 cases yielded potentially relevant but unconfirmed findings, 4 demonstrated non-diagnostic findings of uncertain relevance or possible carrier/incidental significance, 1 fetus with aneuploidy had an additional non-diagnostic molecular finding, and 4 evaluations were negative or otherwise non-diagnostic. None of the molecular findings could be considered a confirmed explanation for the initial increased NT or cystic hygroma phenotype. Among the 41 live-born children with a normal karyotype, clinically relevant postnatal abnormalities or diagnoses were documented in 8 (19.5%). As molecular testing and postnatal follow-up were selective and heterogeneous, the findings were interpreted descriptively, and neither a cohort-level molecular diagnostic yield nor a median duration of postnatal follow-up could be calculated. Conclusions: Chromosomal abnormalities were identified in a substantial proportion of fetuses with apparently isolated increased NT or cystic hygroma. Among fetuses with a normal karyotype, live birth rates were high, particularly in the increased NT group. However, these outcomes reflect the apparently isolated phenotype documented at the initial first-trimester assessment and should be interpreted together with the available postnatal clinical findings. Molecular testing, predominantly based on WES or CES, yielded heterogeneous case-level findings, none of which could be established as a confirmed explanation for the initial prenatal phenotype on the basis of the available records. Because molecular testing was selectively performed, these findings should not be interpreted as an estimate of the cohort-level diagnostic yield.