Renal and extra-renal phenotypes in a fetus with a de novo pathogenic variant in the HNF1B gene.

We report a fetus with prenatal ultrasound at 21 gestational weeks showing left cystic renal dysplasia with subcapsular cysts and echogenic parenchyma, right echogenic kidney with absent corticomedullary differentiation, and left congenital diaphragmatic hernia (CDH) with bowel herniation, with intestinal atresia (IA) found on postmortem examination. Whole genome sequencing of fetal blood DNA revealed a heterozygous pathogenic variant c.344 + 2 T>G in the HNF1B gene (NM_000458). Sanger sequencing of the parental samples suggested that it arose de novo in the fetus. HNF1B-associated disorders affect multiple organs with significant phenotypic heterogeneity. In pediatric and adult patients, renal cystic disease and cystic dysplasia are the dominant phenotypes. In prenatal settings, renal anomaly is also the most common presentation, typically with bilateral hyperechogenic kidneys. Our case presented with two uncommon extra-renal phenotypes of CDH and IA besides the typical bilateral cystic renal dysplasia. This association has been reported in fetuses with 17q12 microdeletion but not with HNF1B point mutation. Our case is the first prenatal report of such an association and highlights the possible causal relationship of HNF1B defects with CDH and IA in addition to the typical renal anomalies.

Genome-Wide Cell-Free DNA Test for Fetal Chromosomal Abnormalities and Variants: Unrestricted Versus Restricted Reporting.

This study aimed to compare the screening performance of genome-wide cfDNA testing for chromosomal abnormalities between two periods where additional findings were reported and not reported. Data were obtained from consecutive pregnant women with a singleton pregnancy at ≥10 weeks who requested cfDNA testing during 2015-2019. The performance of screening of the cfDNA test was determined by calculating the concordance rate, detection rate, and false-positive rate. Data from 3981 women were included. The no-result rates were similar between the two reporting periods (2.04% vs. 2.08%). Concordance rates for trisomy 21 and 18 were 100% and 100%, respectively. There were two cases tested high risk for trisomy 13, with a concordance rate of 0%. In total, 12 cases were high risk for any sex chromosome aneuploidy with an overall concordance of 75%, and 15 cases tested high risk for any rare autosomal trisomy, with a 13.3% concordance rate. The detection rates for trisomy 21 and 18 were 100% and 100%, respectively. For any SCA, the detection rate was 90%. For the two reporting periods, the combined false-positive rates were 0.93% and 0.17%, which were significantly different (p = 0.002). Restricting the reporting of additional findings from genome-wide cfDNA analysis has reduced the false-positive rate but without a reduction in the no-result rate.

Impact of replacing or adding placental growth factor on Down syndrome screening: A prospective cohort study.

OBJECTIVES: To assess whether adding placental growth factor (PlGF) or replacing pregnancy-associated plasma protein-A (PAPP-A) improves the first trimester combined test performance for trisomy 21. METHODS: A total of 11,518 women with a singleton pregnancy who underwent the first trimester combined test between December 2016 and December 2019 were included. PlGF was measured and estimated term risk for trisomy 21 was calculated by (1) adding PlGF to the combined test and (2) replacing PAPP-A with PlGF. RESULTS: Twenty-nine pregnancies had trisomy 21. The combined tests detection rate (DR), false positive rate (FPR) and screen positive rate (SPR) were 89.7%, 5.7% and 6% respectively. DR when adding PlGF to the combined test or replacing PAPP-A remained unchanged. Replacing PAPP-A by PlGF increased FPR and SPR to 6.2% and 6.4% respectively. Adding PlGF to the combined test gave FPR and SPR rates of 5.5% and 5.7% respectively. Change in FPR and SPR was not significant (p > 0.1 for all). CONCLUSION: Adding PlGF to the combined test or replacing PAPP-A with PlGF did not improve trisomy 21 DR and resulted in a non-significant marginal change in FPR and SPR.

The Use of Somatex Shunt for Fetal Pleural Effusion: A Cohort of 8 Procedures.

INTRODUCTION: Fetal pleural effusion may require in utero shunting which is associated with procedure-related complications. OBJECTIVE: To evaluate the efficacy and complications of the newly designed Somatex shunt in treating fetal pleural effusion. METHODS: Consecutive cases with primary fetal pleural effusion who were treated with the Somatex shunt between 2018 and 2019 were evaluated. Perinatal outcomes and complications were retrospectively analyzed. RESULTS: There were 6 cases of unilateral and 1 case of bilateral pleural effusion, and hence a total of 8 pleuroamniotic shunting procedures were performed. The median gestational age at diagnosis and shunting was 20.7 and 22.6 weeks, respectively. All 8 procedures were successful, achieving complete in utero drainage. All but one were live births (85.7%) with a median gestational age of 38 weeks. The single case of in utero death occurred 4.7 weeks after successful shunting, and no cause could be identified after autopsy. The rates of preterm birth and premature rupture of membranes were 33.3% (2/6) and 16.7% (1/6), respectively. Four of the 8 procedures (50%) had minor shunt-related complications such as dislodgement and entrapment, occurring at a median of 7.7 weeks after shunting. None of the shunts became blocked. CONCLUSIONS: The Somatex shunt is effective in relieving fetal pleural effusions with good survival rate. Overall, it was a safe instrument, though minor shunt complications occurred.

Hypoechoic liver in fetuses with trisomy 21.

The association between hypoechoic hepatomegaly in the third trimester and transient abnormal myelopoiesis (TAM) was reported previously in six fetuses with trisomy 21 (T21). We report a series of three cases of T21 in which hypoechoic liver (HL) was found in the second trimester but without evidence of TAM on both hematological and histological examination. We postulate that the hypo-echogenicity may be due to liver congestion secondary to hemodynamic disturbances seen in T21 fetuses. All three cases had negative first trimester Down syndrome screening and one case was detected solely because of the isolated finding of HL. HL per se may be associated with T21 and more positive cases are required to support this association.

Pitfalls in assessing chorioamnionicity: novel observations and literature review.

Accurate diagnosis of chorioamnionicity in multiple pregnancies is the key to appropriate clinical management of multiple gestation. Although prenatal ultrasound assessment of chorioamnionicity is well established and highly accurate if performed in early pregnancy, exceptions and artifacts arise from anatomic variations in multiple pregnancies and unusual sonographic features do exist. We have summarized our own experiences and reports from the literature on these pitfalls as follows: (1) discordant fetal sex in monochorionic pregnancies due to sex chromosome abnormalities, genital malformation in 1 fetus, or dizygotic twins forming a monochorionic placenta; (2) separate placental masses in monochorionic pregnancies due to bipartite placenta; (3) false-negative and false-positive λ sign can arise for various reasons, and in partial monochorionic/dichorionic placentas both T and λ sign may co-exist; (4) intrauterine synechia appearing as a thick and echogenic intrauterine septum may lead to erroneous diagnosis of dichorionic twins; and (5) errors in ascertaining amnionicity by the visualization of thin intertwin amniotic membranes and the number of yolk sacs. The ultrasound techniques to reduce inaccuracy in prenatal determination of chorioamnionicity and the use of single nucleotide polymorphisms based on noninvasive prenatal test to determine zygosity are also reviewed.

Prenatal Diagnosis of a Retroesophageal Left Brachiocephalic Vein: Two Case Reports.

A retroesophageal left brachiocephalic vein is an extremely rare anomaly and has only been reported in 6 postnatal cases. Two prenatally diagnosed cases are reported. On the 3-vessel view, the vein appears as an aberrant vessel transversely coursing behind the aorta and trachea, which subsequently drains into the superior vena cava, giving rise to a U-shaped configuration. On color Doppler sonography, the U sign is bicolored. This anomaly should prompt the sonographer to carefully assess for other congenital heart defects, suggest consideration for genetic testing, and alert the cardiologist because it could affect central line procedures and cardiac interventions after delivery.

Pseudoamniotic Band Syndrome after In Utero Intervention for Twin-to-Twin Transfusion Syndrome: Case Reports and Literature Review.

Pseudoamniotic band syndrome (PABS) is a rare iatrogenic complication that arises after invasive procedures in monochorionic twins. We report 3 cases of PABS, 2 after fetoscopic laser photocoagulation and 1 after bipolar cord coagulation. Two cases were detected antenatally by ultrasound; out of the two, one underwent successful fetoscopic release of amniotic band, which is the first report in twin pregnancy to our knowledge. In our centre, the incidence of PABS was found to be 2%. There were 25 cases of PABS reported previously, of which 12 cases with clinical details were reviewed together with our 3 cases. The fetal limbs were involved in all 15 cases, leading to constriction or amputation. The umbilical cord was involved in 2 cases, resulting in fetal death in one and pregnancy termination in the other. Antenatal detection of PABS is rare (27%; 4/15) as this requires a high index of suspicion. Serial postoperative targeted ultrasound surveillance of the fetal limbs and umbilical cord is necessary, particularly when features of septostomy or chorioamniotic membrane separation are found. Colour Doppler examination for the perfusion of the affected limb should be performed when PABS is detected. Fetoscopic release of amniotic band could salvage the fetal limb from amputation when impaired blood flow is detected.

Prenatal diagnosis of maternally inherited X-linked Opitz G/BBB syndrome by chromosomal microarray in a fetus with complex congenital heart disease.

BACKGROUND: Prenatal sonographic diagnosis of Optiz G/BBB syndrome is difficult because the common clinical features, such as hypertelorism, hypospadias and abnormalities of midline structures, including laryngotracheoesophageal defects, are subtle. METHOD: Chromosomal microarray (CMA) analysis using a target enriched Fetal DNA Chip design was performed on the DNA of a fetus with congenital cardiac abnormalities. RESULTS: Fetal DNA chip revealed a 48Kb single copy number loss within chromosome region Xp22.2 (arr[hg18]Xp22.2(10,627,354-10,675,946)x0 mat). This deletion included the 3' UTR region of the MID1 gene predicted to cause the X-linked Opitz G/BBB syndrome. CONCLUSIONS: This case supports the use of CMA in prenatal diagnosis of fetuses with congenital heart disease. CMA allows prenatal diagnosis of genomic aberrations at a much higher resolution compared with conventional karyotyping, and such findings enable proper genetic counseling and decision making in the pregnancy.

Radiofrequency ablation for selective reduction in complicated monochorionic multiple pregnancies.

OBJECTIVE: To evaluate the perinatal outcome of monochorionic (MC) multiple pregnancies after selective reduction by radiofrequency ablation (RFA). METHODS: A case series of all MC multiple pregnancies with selective reduction by RFA in one single institution was reviewed. RESULTS: Ten consecutive patients with an MC pregnancy (9 pairs of twins and 1 set of triplets) underwent RFA. The median gestational age at the time of the procedure was 15.6 weeks (range, 12.3-19.6). The indications for selective reduction included discordance for fetal anomalies (4 cases), twin reversed arterial perfusion sequence (3 cases), selective intrauterine growth restriction (2 cases) and severe twin-twin transfusion syndrome (1 case). All procedures were technically successful in achieving selective reduction. The overall survival rate of the co-twin was 81.8% (9/11), and the median gestational age at delivery was 35.9 weeks (range, 32.4-38.6). There was one preterm delivery before 34 weeks of gestation (11.1%). Preterm premature rupture of the membranes occurred in 2 patients (20%); however, this was not observed within 4 weeks postoperatively, nor did they deliver before 32 weeks. CONCLUSIONS: RFA is a promising technique for selective reduction in complicated MC multiple pregnancies with a high survival rate and low complication rate.