Prenatal presentation in two fetuses with features of Beckwith Wiedemann syndrome-An unexpected diagnosis of androgenetic chimera and its clinical implications.

Beckwith Wiedemann Syndrome (BWS, OMIM 130650) is an imprinting disorder that may present antenatally with a constellation of sonographic features namely polyhydramnios, macrosomia, macroglossia, omphalocele, placental mesenchymal dysplasia, cardiomegaly, nephromegaly, fetal hydrops, and other rare anomalies. Paternal uniparental disomy in chromosome 11p15 imprinting region accounts for 20% of all BWS, and 8% among those were due to genome-wide paternal uniparental disomy (GWpUPD). GWpUPD is a rare condition and usually results in prenatal lethality. The 31 liveborns reported in the literature demonstrate female predominance in surviving GWpUPD. Here, we reported two prenatal cases which initially presented with features suggestive of BWS, which subsequently were confirmed to have GWpUPD. Further trio SNP genotyping analysis using SNP-based chromosomal microarray revealed androgenetic biparental chimera as the underlying cause. Finally, we highlighted the importance of recognizing GWpUPD as a possible cause in a fetus presenting with BWS phenotype, as it carried a different disease prognosis, tumor predisposition, manifestations of other imprinting disorders, and possibility in unmasking autosomal recessive disorders from the paternal alleles.

Predicting Intra-abdominal Adhesions for Repeat Cesarean Delivery with the Ultrasound Sliding Sign.

OBJECTIVE: To evaluate the diagnostic value of the "sliding sign", a sonographic test, in predicting intra-abdominal adhesions for women undergoing repeat cesarean delivery. METHODS: This was a prospective observational study of women undergoing a scheduled repeat cesarean delivery at a regional hospital. The sliding sign is a sonographic observation of sliding movement between the uterus and the abdominal wall during deep breathing. The absence of the sliding sign was considered indicative of a high risk for dense uterine-abdominal adhesions, and this finding was compared with the operative findings. The primary outcome was the accuracy of the sliding sign in predicting adhesions. Secondary outcomes included incision-to-delivery time, operative time, and blood loss. RESULTS: We examined 112 pregnant women. Dense uterine-abdominal adhesions were found in 15 women, 8 of whom had no sliding sign identified on ultrasound. Therefore, the presence of the sliding sign detected 78 out of 97 women without uterine-abdominal adhesions. The sensitivity, specificity, and positive and negative predictive values of the sliding sign were 53.3%, 80.4%, 29.6%, and 91.8%, respectively. The intra- and inter-observer reliability using the kappa coefficient showed moderate consistency at 0.43 and 0.45, respectively. CONCLUSION: The sliding sign was less predictive than desired for clinical use, and it only detected half of the women with dense uterine-abdominal adhesions. Furthermore, a moderately low kappa coefficient indicates a lack of reproducibility, further emphasizing the sign's limited clinical value.

Characteristics of Maternal Mortality Missed by Vital Statistics in Hong Kong, 2000-2019.

Importance: Reducing maternal mortality is a global objective. The maternal mortality ratio (MMR) is low in Hong Kong, China, but there has been no local confidential enquiry into maternal death, and underreporting is likely. Objective: To determine the causes and timing of maternal death in Hong Kong and identify deaths and their causes that were missed by the Hong Kong vital statistics database. Design, Setting, and Participants: This cross-sectional study was conducted among all 8 public maternity hospitals in Hong Kong. Maternal deaths were identified using prespecified search criteria, including a registered delivery episode between 2000 to 2019 and a registered death episode within 365 days after delivery. Cases as reported by the vital statistics were then compared with the deaths found in the hospital-based cohort. Data were analyzed from June to July 2022. Main Outcomes and Measures: The outcomes of interest were maternal mortality, defined as death during pregnancy or within 42 days after ending the pregnancy, and late maternal death, defined as death more than 42 days but less than 1 year after end of the pregnancy. Results: A total of 173 maternal deaths (median [IQR] age at childbirth, 33 [29-36] years) were found, including 74 maternal mortality events (45 direct deaths and 29 indirect deaths) and 99 late maternal deaths. Of 173 maternal deaths, 66 women (38.2%) of individuals had preexisting medical conditions. For maternal mortality, the MMR ranged from 1.63 to 16.78 deaths per 100 000 live births. Suicide was the leading cause of direct death (15 of 45 deaths [33.3%]). Stroke and cancer deaths were the most common causes of indirect death (8 of 29 deaths [27.6%] each). A total of 63 individuals (85.1%) died during the postpartum period. In the theme-based approach analysis, the leading causes of death were suicide (15 of 74 deaths [20.3%]) and hypertensive disorders (10 of 74 deaths [13.5%]). The vital statistics in Hong Kong missed 67 maternal mortality events (90.5%). All suicides and amniotic fluid embolisms, 90.0% of hypertensive disorders, 50.0% of obstetric hemorrhages, and 96.6% of indirect deaths were missed by the vital statistics. The late maternal death ratio ranged from 0 to 16.36 deaths per 100 000 live births. The leading causes of late maternal death were cancer (40 of 99 deaths [40.4%]) and suicide (22 of 99 deaths [22.2%]). Conclusions and Relevance: In this cross-sectional study of maternal mortality in Hong Kong, suicide and hypertensive disorder were the dominant causes of death. The current vital statistics methods were unable to capture most of the maternal mortality events found in this hospital-based cohort. Adding a pregnancy checkbox to death certificates and setting up a confidential enquiry into maternal death could be possible solutions to reveal the hidden deaths.

Implementation of Public Funded Genome Sequencing in Evaluation of Fetal Structural Anomalies.

With the advancements in prenatal diagnostics, genome sequencing is now incorporated into clinical use to maximize the diagnostic yield following uninformative conventional tests (karyotype and chromosomal microarray analysis). Hong Kong started publicly funded prenatal genomic sequencing as a sequential test in the investigation of fetal structural anomalies in April 2021. The objective of the study was to evaluate the clinical performance and usefulness of this new service over one year. We established a web-based multidisciplinary team to facilitate case selection among the expert members. We retrospectively analyzed the fetal phenotypes, test results, turnaround time and clinical impact in the first 15 whole exome sequencing and 14 whole genome sequencing. Overall, the molecular diagnostic rate was 37.9% (11/29). De novo autosomal dominant disorders accounted for 72.7% (8/11), inherited autosomal recessive disorders for 18.2% (2/11), and inherited X-linked disorders for 9.1% (1/11). The median turnaround time for ongoing pregnancy was 19.5 days (range, 13-31 days). Our study showed an overall clinical impact of 55.2% (16/29), which influenced reproductive decision-making in four cases, guided perinatal management in two cases and helped future family planning in ten cases. In conclusion, our findings support the important role of genome sequencing services in the prenatal diagnosis of fetal structural anomalies in a population setting. It is important to adopt a multidisciplinary team approach to support the comprehensive genetic service.

Application of Prenatal Whole Exome Sequencing for Structural Congenital Anomalies-Experience from a Local Prenatal Diagnostic Laboratory.

Fetal structural congenital abnormalities (SCAs) complicate 2-3% of all pregnancies. Whole-exome sequencing (WES) has been increasingly adopted prenatally when karyotyping and chromosomal microarray do not yield a diagnosis. This is a retrospective cohort study of 104 fetuses with SCAs identified on antenatal ultrasound in Hong Kong, where whole exome sequencing is performed. Molecular diagnosis was obtained in 25 of the 104 fetuses (24%). The highest diagnostic rate was found in fetuses with multiple SCAs (29.2%), particularly those with involvement of the cardiac and musculoskeletal systems. Variants of uncertain significance were detected in 8 out of the 104 fetuses (7.7%). Our study shows the utility of WES in the prenatal setting, and the extended use of the technology would be recommended in addition to conventional genetic workup.

First Case Report of Maternal Mosaic Tetrasomy 9p Incidentally Detected on Non-Invasive Prenatal Testing.

Tetrasomy 9p (ORPHA:3390) is a rare syndrome, hallmarked by growth retardation; psychomotor delay; mild to moderate intellectual disability; and a spectrum of skeletal, cardiac, renal and urogenital defects. Here we present a Chinese female with good past health who conceived her pregnancy naturally. Non-invasive prenatal testing (NIPT) showed multiple chromosomal aberrations were consistently detected in two sampling times, which included elevation in DNA from chromosome 9p. Amniocentesis was performed and sent for chromosomal microarray, which was normal. Maternal karyotype revealed that mos 47,XX,+dic(9;9)(q21.1;q21.1)(24)/46,XX(9) presents mosaic tetrasomy for the short arm of chromosome 9p and is related to the NIPT results showing elevation in DNA from chromosome 9p. The pregnancy was uneventful, and the patient was delivered at term. Maternal samples were obtained at two different time points after delivery showed the same multiple chromosomal aberrations detected during pregnancy. This is a first report on an unusual case of mosaic isodicentric tetrasomy 9p in a healthy adult with normal intellect. With widespread adoption of NIPT for screening fetal aneuploidy and genome-wide copy number changes, a rise in incidental detection of maternal rare genetic syndrome will bring challenges in our current approach to genetic counselling and prenatal diagnosis.