Objectives: To compare the frequency of abnormal genetic diagnoses spanning a period before and after the availability of chromosomal microarray analysis (CMA).We hypothesised that microarray would provide additional clinically relevant information in cases of isolated hypoplastic nasal bone.Method: Fetuses with ultrasound-detected hypoplastic nasal bone (absent or <2.5th percentile in length) between 16 and 37 weeks' gestation over a 10-year period were analysed retrospectively.Results: A total of 118 cases of hypoplastic nasal bone met the inclusion criteria. A pathogenic or potentially pathogenic karyotype was detected more frequently in the era where CMA was available (31/60, 52% vs 19/58, 33%). Of these, 25 cases (42%) had common aneuploidies, and six cases (10%) had clinically relevant copy number variants (CNVs). A clinically relevant CNV was detected in two fetuses that presented with isolated hypoplastic nasal bone on initial ultrasound.Conclusion: In addition to its known association with trisomy 21, a hypoplastic nasal bone may be an objective marker of facial dysmorphism associated with clinically relevant CNVs. Our results support consideration of invasive testing with microarray for pregnancies in which a hypoplastic nasal bone has been diagnosed on ultrasound irrespective of a low-risk screening result for common chromosomal abnormalities.

We read with interest the Letter to the Editor by Lostchuck and Hui 1 reporting on a population-based series of prenatal diagnostic procedures performed from 18 weeks' gestation following the diagnosis of hypoplastic nasal bone (NB) on ultrasound. Of the 127 amniocenteses performed for an indication including hypoplastic NB, 80 were performed for isolated hypoplastic NB. There were no cases of pathogenic copy-number variant (CNV) in the 47/80 cases that were analyzed by chromosomal microarray (0%; 95% CI, 0-7.1%). We note that the upper limit of this CI for the yield of chromosomal microarray analysis (CMA) is similar to the overall CMA yield for a fetus with any ultrasound abnormality 2 .We reported recently our tertiary-center experience with isolated hypoplastic NB, including newborn followup and postnatal microarray results 3 . We found a nontrisomy-21 abnormality in two of the 39 fetuses, resulting in a frequency of pathogenic CNV in isolated hypoplastic NB of 5.1%. The first fetus had Wolf-Hirschhorn syndrome presenting as isolated hypoplastic NB on ultrasound at 19 weeks; amniocentesis was performed at 24 weeks due to subsequent early-onset fetal growth restriction. The second case underwent chorionic villus sampling for advanced maternal age which detected de-novo microdeletions (1p31.3 (1.2 Mb) and 6p21q22.1 (2.2 Mb)); however, fetal anatomy was normal on first-trimester ultrasound. Subsequent ultrasound examinations showed isolated hypoplastic NB at 20 weeks and then mild ventriculomegaly and fetal growth restriction in the third trimester; the newborn had minor dysmorphisms, a hypoplastic corpus callosum and paraventricular cysts on postnatal magnetic resonance imaging 3 .Our findings are not dissimilar to those of Lostchuck and Hui, with the frequency of pathogenic results in our cohort being within their reported CI. However, our results highlight the limitations of conclusions based only on a cross-sectional prenatal dataset. It is important to keep in mind that the timing of invasive testing may not necessarily align with the exact time of the initial detection of hypoplastic NB. Invasive testing could be undertaken after additional ultrasound findings arise. The data captured by Lostchuck and Hui included only amniocenteses from 18 weeks and would not have included those cases returning at 16 weeks for review of uncertain findings, such as a NB that could not be confidently assessed at 12-13 weeks.Until larger population-based series, providing prenatal and postnatal data, are available, we caution against considering hypoplastic NB as a marker for trisomy 21 only. Fetuses with isolated hypoplastic NB and a low-risk cell-free DNA result should undergo detailed tertiary-level follow-up ultrasound and genetic counseling, including consideration of the risks of atypical chromosomal abnormalities detectable by CMA. References 1. Lostchuck E, Hui L. Should second-trimester hypoplastic nasal bone be sole indication for diagnostic testing with chromosomal microarray analysis? Ultrasound Obstet Gynecol 20...