Expansion of the prenatal phenotype of Baraitser-Winter syndrome: Presentation of two cases of multiple congenital anomaly syndrome.

Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) is a variable multiple congenital anomaly condition, typically presenting postnatally with neurocognitive delays, distinctive facial features, cortical brain malformations, and in some, a variety of additional congenital malformations. However, only a few cases have reported the prenatal presentation of this syndrome. Here, we report two cases of BWCFF and their associated prenatal findings. One case presented with non-immune hydrops fetalis and a horseshoe kidney and was found to have a de novo heterozygous variant in ACTB (c.158A>G). The second case presented with gastroschisis, bilateral cleft lip and palate, and oligohydramnios, and was found to harbor a different de novo variant in ACTB (c.826G>A). Limited reports exist describing prenatally identified anomalies that include fetal growth restriction, increased nuchal fold, bilateral hydronephrosis, rocker bottom foot, talipes, cystic hygroma, omphalocele, and hydrops fetalis. In addition, only three of these cases have included detailed prenatal imaging findings. The two prenatal cases presented here demonstrate an expansion of the prenatal phenotype of BWCFF to include gastroschisis, lymphatic involvement, and oligohydramnios, which should each warrant consideration of this diagnosis in the setting of additional anomalies.

Is there an increased risk of genetic abnormalities in fetuses with congenital heart disease in the setting of growth restriction?

OBJECTIVE: To determine if the presence of fetal growth restriction (FGR) is associated with an increased risk of genetic abnormalities in the setting of congenital heart disease (CHD). METHODS: This was a retrospective cohort study involving pregnancies that met the following criteria: (i) prenatal diagnosis of CHD, (ii) singleton live-birth, and (iii) genetic testing was performed either pre- or postnatally. Genetic results were reviewed by a clinical geneticist for updated variant classification. Fetal growth was stratified as appropriate for gestational age (AGA) or FGR. RESULTS: Of the total of 445 fetuses that met the study criteria, 325 (73.0%) were AGA and 120 (27.0%) were FGR. Genetic abnormalities were detected in 131 (29.4%) pregnancies. There was a higher rate of genetic abnormalities (36.7% vs. 26.8%, p = 0.04), which was driven by aneuploidies (20.8% vs. 8.9%, p = 0.0006) in the FGR population. Early onset growth restriction was associated with a higher rate of genetic abnormalities (44.5% vs. 25.9%, p = 0.03). The rate of genetic abnormalities was significantly higher in the shunt category as compared to remainder of the cardiac anomalies (62.5% in shunt lesions vs. 24.7%, p < 0.00001). The rates of FGR (40.9% vs. 21.4%, p < 0.0001) and genetic abnormalities (52% vs. 20.4%, p < 0.0001) were significantly higher in the presence of extra-cardiac anomalies (ECA). CONCLUSION: The presence of FGR in fetal CHD population was associated with underlying genetic abnormalities, specifically aneuploidies. Patients should be appropriately counseled regarding the higher likelihood of a genetic condition in the presence of FGR, early onset FGR, shunt lesions and ECA.

Fetus with multiple congenital anomaly syndrome caused by novel variant in ATP1A2.

We report a 32-year-old G3P1 at 35 weeks 3 days with a dichorionic, diamniotic twin gestation who presented for evaluation secondary to ventriculomegaly (VM) in one twin. Fetal ultrasound and MRI demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture, indicative of a prior insult in the affected twin. The co-twin was grossly normal. The family pursued a palliative care pathway for the affected twin and was delivered at 37 weeks and 6 days. The affected twin passed away within the first hour of life due to respiratory compromise. Postmortem trio exome sequencing identified a homozygous likely pathogenic variant in ATP1A2 (c.2439+1G>A). Although this variant is novel, it is predicted to affect the donor split site in intron 17, resulting in a frameshift and complete loss-of-function of the gene. Biallelic loss of function variants in this gene have been reported in seven individuals with multiple anomalies similar to those in the affected twin. However, only one other individual with a possible CDH has been previously reported. Our case suggests that CDH be included in the phenotypic spectrum of this disorder and reports the first frameshift mutation causing this autosomal recessive multiple congenital anomaly syndrome.

Case report of fetus with Lowe syndrome: Expanding the prenatal phenotype.

Oculocerebrorenal syndrome (Lowe syndrome) is a rare X-linked disorder affecting 1/500,000 males that most frequently affects the eyes, central nervous system, and kidneys. Phenotypic presentation includes congenital cataracts, developmental delay, intellectual disability, and Fanconi-type renal dysfunction. Lowe Syndrome is caused by hemizygous loss of function variants in the OCRL gene. While individuals may live into the third and fourth decade of life, some will die in the first few years of either renal failure or infection. While early diagnosis is important, few cases have documented the prenatal phenotype of this condition, which has included bilateral cataracts and variable neurological abnormalities. We report a case of a family with an extensive history of congenital cataracts, immune compromise, and neonatal death in male members. The fetus was found to have a unilateral cataract, mild ventriculomegaly, vertebral anomalies, and an underlying diagnosis of Lowe Syndrome with a mutation in OCRL at c.2582-1G>C (IVS23-1G>C).

The Reliability of Ultrasound Markers in Identifying Fetuses With a Life-Limiting Skeletal Dysplasia.

OBJECTIVE: To determine the diagnostic performance of ultrasound markers associated with life-limiting fetal skeletal dysplasia in a fortified cohort. METHODS: Retrospective review from 2013 to 2023 of pregnancies with suspected fetal skeletal dysplasia. Ultrasound evaluation included measurements predictive of a life-limiting dysplasia: thoracic circumference/abdominal circumference (TC/AC) < 0.6, femur length/abdominal circumference (FL/AC) < 0.16, and thoracic circumference (TC) < 2.5th percentile. Demographics, ultrasound findings, genetic testing, and fetal/neonatal outcome were reviewed. RESULTS: Of 96 fetuses with complete outcome data, 47 (49%) had a non-life-limiting dysplasia and 49 (51%) had a life-limiting dysplasia. 22 (23%) had no life-limiting markers, 42 (44%) had one, 27 (28%) had two, and 5 (5%) had three. FL/AC < 0.16 and TC < 2.5th percentile were associated with life-limiting dysplasia (p < 0.001; p < 0.001), while TC/AC < 0.6 was rare and did not reach statistical significance (p = 0.056). The positive predictive value (PPV) for predicting life-limiting dysplasia increased from 50% to 78% to 100% with one, two, or three markers. The PPV of the two life-limiting markers was significantly higher in those diagnosed at < versus ≥ 28 weeks (90% vs. 43%, p = 0.02) but the analysis was limited by small numbers in the ≥ 28 weeks cohort. The negative predictive value of no life-limiting markers was 91%. CONCLUSIONS: In our cohort, the presence of two life-limiting ultrasound markers prior to 28 weeks was highly suggestive of a life-limiting dysplasia, whereas the absence of life-limiting markers was strongly associated with a non-life-limiting dysplasia throughout gestation. Nonetheless, individual markers had a poor predictive value of lethality, and a life-limiting diagnosis ≥ 28 weeks is challenging based on ultrasound markers alone. This highlights the importance of integrating thorough sonography, genetic testing, and balanced parental counseling.

Prenatal cardiac findings and 22q11.2 deletion syndrome: Fetal detection and evaluation.

Clinical features of 22q11.2 microdeletion syndrome (22q11.2DS) are highly variable between affected individuals and frequently include a subset of conotruncal and aortic arch anomalies. Many are diagnosed with 22q11.2DS when they present as a fetus, newborn or infant with characteristic cardiac findings and subsequently undergo genetic testing. The presence of an aortic arch anomaly with characteristic intracardiac anomalies increases the likelihood that the patient has 22q11.2 DS, but those with an aortic arch anomaly and normal intracardiac anatomy are also at risk. It is particularly important to identify the fetus at risk for 22q11.2DS in order to prepare the expectant parents and plan postnatal care for optimal outcomes. Fetal anatomy scans now readily identify aortic arch anomalies (aberrant right subclavian artery, right sided aortic arch or double aortic arch) in the three-vessel tracheal view. Given the association of 22q11.2DS with aortic arch anomalies with and without intracardiac defects, this review highlights the importance of recognizing the fetus at risk for 22q11.2 deletion syndrome with an aortic arch anomaly and details current methods for genetic testing. To assist in the prenatal diagnosis of 22q11.2DS, this review summarizes the seminal features of 22q11.2DS, its prenatal presentation and current methods for genetic testing.

Enlarged cavum septum pellucidum and small thymus as markers for 22q11.2 deletion syndrome.

BACKGROUND: Enlarged cavum septum pellucidum (CSP) and hypoplastic thymus are proposed extra-cardiac fetal markers for 22q11.2 deletion syndrome. We sought to determine if they were part of the fetal phenotype of our cohort of fetuses with 22q11.2 deletion syndrome. METHODS: Case-control study of fetuses evaluated from 2016 to 2022. The study group included fetuses with laboratory confirmation of 22q11.2 deletion syndrome. The control group included pregnancies with conotruncal cardiac anomalies with normal microarray as well as structurally normal fetuses with normal microarray. The CSP and thymus were routinely measured during anatomical ultrasound in all patients at their initial visit at 27.1 ± 4.7 weeks. The CSP and thymus measurements were classified as abnormal if they were >95% or <5% for gestational age, respectively. The groups were compared using analysis of variance or Kruskal-Wallis for continuous variables and Fisher's exact test for categorical variables. Logistic regression was performed, and a Receiver Operating Characteristic (ROC) curve was constructed. RESULTS: We identified 47 fetuses with 22q11.2 deletion syndrome and compared them to 47 fetuses with conotruncal anomalies and normal microarray and 47 structurally normal fetuses with normal microarray. 51% (24/47) of fetuses with 22q11.2 deletion syndrome had an enlarged CSP compared to 6% (3/47) of fetuses with a conotruncal anomaly and normal microarray and none of the structurally normal fetuses (p < 0.001). Of the fetuses with 22q11.2 deletion syndrome, 83% (39/47) had a hypoplastic or absent thymus compared to 9% (4/47) of the fetuses with a conotruncal anomaly and normal microarray and none of the structurally normal fetuses (p < 0.001). 87% (41/47) of the fetuses with 22q11.2 deletion syndrome had conotruncal cardiac anomalies. Logistic regression revealed that both enlarged CSP and hypoplastic/absent thymus were associated with 22q11.2 deletion syndrome. The area under the ROC curve for the two markers was 0.94. CONCLUSION: An enlarged CSP and hypoplastic/absent thymus appear to be part of the fetal phenotype of 22q11.2 deletion syndrome. These markers are associated with conotruncal anomalies in the setting of 22q11.2 deletion syndrome but not in normal controls or fetuses with conotruncal defects and normal microarrays.

Predictors of Poor Outcomes in Monochorionic Diamniotic Twin Pregnancies Complicated by Selective Fetal Growth Restriction.

INTRODUCTION: The aim of the study was to identify predictors of poor outcomes in monochorionic diamniotic twin (MCDA) pregnancies with selective fetal growth restriction (sFGR), irrespective of the umbilical artery (UA) Doppler abnormalities. METHODS: Single-center retrospective analysis of MCDA twins diagnosed with sFGR that opted for expectant management between 2010 and 2021. The presence of any of the following variables in the growth-restricted fetus: low amniotic fluid volume (DVP ≤2 cm), lack of a cycling bladder, absent or reversed flow in the ductus venosus (DV) with atrial contraction, and elevated middle cerebral artery peak systolic velocity (MCA-PSV) defined as ≥1.50 multiples of the median was categorized as complicated. sFGR cases were classified as simple in the absence of the above-mentioned variables. RESULTS: Overall, 63.3% of cases qualified as simple, and 36.7% were complicated. Intertwin EFW discordance was higher in the complicated category (26 vs. 33%, p = 0.0002). The median gestational age at delivery was earlier (33 weeks vs. 30.5 weeks, p = 0.002), and the likelihood of survival was lower in the complicated category (p < 0.0001). The likelihood of two survivors to discharge was lower in type I complicated cases (70% in complicated type I vs. 97.1% in simple type I, p = 0.0003). On logistic regression analysis, an increase in the "complicated" score negatively correlated with two survivors to discharge (p < 0.0001). An ROC curve was created, and the AUC was 0.79. Increasing intertwin EFW discordance also decreased the probability of two survivors to discharge. CONCLUSION: The presence of oligohydramnios, lack of a cycling bladder, abnormal DV Doppler, and elevated MCA-PSV in the growth restricted fetus is associated with poor perinatal outcomes and a lower likelihood of having two survivors to discharge. The addition of intertwin EFW discordance to these variables helped improve the survival predictability.

The Delivery Room Resuscitation of Infants with Congenital Diaphragmatic Hernia Treated with Fetoscopic Endoluminal Tracheal Occlusion: Beyond the Balloon.

INTRODUCTION: Randomized controlled trials found that fetoscopic endoluminal tracheal occlusion (FETO) resulted in increased fetal lung volume and improved survival for infants with isolated, severe left-sided congenital diaphragmatic hernia (CDH). The delivery room resuscitation of these infants is particularly unique, and the specific delivery room events are largely unknown. The objective of this study was to compare the delivery room resuscitation of infants treated with FETO to standard of care (SOC) and describe lessons learned. METHODS: Retrospective single-center cohort study of infants treated with FETO compared to infants who met FETO criteria during the same period but who received SOC. RESULTS: FETO infants were more likely to be born prematurely with 8/12 infants born <35 weeks gestational age compared to 3/35 SOC infants. There were 5 infants who required emergent balloon removal (2 ex utero intrapartum treatment and 3 tracheoscopic removal on placental bypass with delayed cord clamping) and 7 with prenatal balloon removal. Surfactant was administered in 6/12 FETO (50%) infants compared to 2/35 (6%) in the SOC group. Extracorporeal membrane oxygenation use was lower at 25% and survival was higher at 92% compared to 60% and 71% in the SOC infants, respectively. CONCLUSION: The delivery room resuscitation of infants treated with FETO requires thoughtful preparation with an experienced multidisciplinary team. Given increased survival, FETO should be offered to infants with severe isolated left-sided CDH, but only in high-volume centers with the experience and capability of removing the balloon, emergently if needed. The neonatal clinical team must be skilled in managing the unique postnatal physiology inherent to FETO where effective interdisciplinary teamwork is essential. Empiric and immediate surfactant administration should be considered in all FETO infants to lavage thick airway secretions, particularly those delivered <48 h after balloon removal.

Progesterone for Neurodevelopment in Fetuses With Congenital Heart Defects: A Randomized Clinical Trial.

Importance: Neurodevelopmental outcomes for children with congenital heart defects (CHD) have improved minimally over the past 20 years. Objectives: To assess the feasibility and tolerability of maternal progesterone therapy as well as the magnitude of the effect on neurodevelopment for fetuses with CHD. Design, Setting, and Participants: This double-blinded individually randomized parallel-group clinical trial of vaginal natural progesterone therapy vs placebo in participants carrying fetuses with CHD was conducted between July 2014 and November 2021 at a quaternary care children's hospital. Participants included maternal-fetal dyads where the fetus had CHD identified before 28 weeks' gestational age and was likely to need surgery with cardiopulmonary bypass in the neonatal period. Exclusion criteria included a major genetic or extracardiac anomaly other than 22q11 deletion syndrome and known contraindication to progesterone. Statistical analysis was performed June 2022 to April 2024. Intervention: Participants were 1:1 block-randomized to vaginal progesterone or placebo by diagnosis: hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and other CHD diagnoses. Treatment was administered twice daily between 28 and up to 39 weeks' gestational age. Main Outcomes and Measures: The primary outcome was the motor score of the Bayley Scales of Infant and Toddler Development-III; secondary outcomes included language and cognitive scales. Exploratory prespecified subgroups included cardiac diagnosis, fetal sex, genetic profile, and maternal fetal environment. Results: The 102 enrolled fetuses primarily had HLHS (n = 52 [50.9%]) and TGA (n = 38 [37.3%]), were more frequently male (n = 67 [65.7%]), and without genetic anomalies (n = 61 [59.8%]). The mean motor score differed by 2.5 units (90% CI, -1.9 to 6.9 units; P = .34) for progesterone compared with placebo, a value not statistically different from 0. Exploratory subgroup analyses suggested treatment heterogeneity for the motor score for cardiac diagnosis (P for interaction = .03) and fetal sex (P for interaction = .04), but not genetic profile (P for interaction = .16) or maternal-fetal environment (P for interaction = .70). Conclusions and Relevance: In this randomized clinical trial of maternal progesterone therapy, the overall effect was not statistically different from 0. Subgroup analyses suggest heterogeneity of the response to progesterone among CHD diagnosis and fetal sex. Trial Registration: ClinicalTrials.gov Identifier: NCT02133573.