Prenatal Diagnosis最新文献

Introduction: Fetal neck masses are rare but can be life-threatening if causing airway compromise. Early and accurate diagnosis of these masses allows life-saving interventions to be undertaken at birth in the form of the EXIT procedure.

Methods: A single institution case series of all patients referred for fetal MRI to a tertiary center in the North of England due to presence of a neck mass on antenatal ultrasound. Data concerning the MRI findings for each patient and their final diagnosis were collected to create a flow chart proposing the most likely diagnosis based on fetal MRI features.

Results: 13 patients who underwent fetal MRI for a neck mass with a final diagnosis available were included in the analysis. This review shows the range of diagnoses in these patients and that MRI was accurate in predicting airway compression and the need for the EXIT procedure.

Conclusion: Fetal MRI is a valuable tool in addition to ultrasound for refining the diagnosis of masses of the fetal neck and assessment of airway patency to allow planning for management at birth.

We report a case of a male fetus born to an unrelated couple with a fetal phenotype of an omphalocele and inferior vermian hypoplasia. Prenatal trio exome sequencing identified a maternally inherited pathogenic CDKN1C variant consistent with Beckwith-Wiedemann syndrome (BWS). This finding prompted targeted testing of the proband's sibling, who was confirmed to carry the same variant. Posterior fossa abnormalities have been reported in cases with BWS, and specifically in children with the CDKN1C loss-of-function variant.

Objective: To evaluate the yield of prenatal genetic testing in infants with a confirmed genetic diagnosis.

Methods: We retrospectively reviewed records of infants with a genetic diagnosis who were evaluated using a standardized genetic consult and testing approach. The predicted yield of various prenatal genetic sceening and diagnostic tools in this cohort was determined and compared.

Results: Genome sequencing had the highest predicted diagnostic yield (96.9%), followed by CMA with reflex to exome sequencing (95.5%), exome sequencing alone (93.8%) and CMA alone (43.6%). ACOG-recommended NIPT and carrier screening could have detected 25.4% of diagnoses, while 55.3% were detectable through genome-wide NIPT and a large carrier screening panel. Genome-wide NIPT improved chromosomal abnormality detection by ∼30% compared with ACOG-recommended NIPT. A large commercial carrier screening panel detected 26.1% of single-gene conditions, versus 6.1% with the ACOG-recommended panel. Overall, 62% of single-gene conditions were undetectable with current screening tools.

Conclusion: Prenatal ES or GS offers high diagnostic yields and a streamlined approach, suggesting that CMA may not be the most appropriate first-line test unless there is strong suspicion of a chromosomal diagnosis. Although prenatal genetic screening is valuable, its ability to identify rare genetic conditions remains limited. Our findings support revising the ACOG/ACMG guidelines to align with postnatal testing recommendations, particularly in high-risk pregnancies.

Objective: To determine whether invasive genetic testing should be systematically proposed in cases of FGR.

Methods: Descriptive retrospective study of 159 FGR cases (defined by an estimated fetal growth < 3rd percentile, regardless of Doppler findings) managed at the Toulouse Fetal Medicine Center (TFMC) during 2022-2023.

Results: Mean gestational age at diagnosis was 23.7 weeks. Head circumference < 3rd percentile was observed in 35% of cases, hemodynamic signs in 57%, and oligohydramnios in 11%. Invasive testing was performed in 56% (n = 89) of cases, with a diagnostic yield in cases with hemodynamic signs of 19% for genetic syndromes (whether chromosomal or monogenic), which dropped to 11% (n = 8) in isolated FGR. Postnatally, 50% (n = 67) of cases were attributed to placental causes, 31% (n = 41) to genetic disorders (of which 41% had a negative prenatal genetic workup), while 13% remained unexplained. Placental causes were most often due to chronic maternal vascular malperfusion (72%).

Conclusion: Findings support the systematic offer of exome sequencing in second-trimester FGR, regardless of whether it is isolated, associated with head circumference < 3rd percentile, or with abnormal hemodynamic profiles.

Objective: To evaluate whether the causative variants found upon clinical exome sequencing in fetuses affected with selected structural anomalies would also be detected if PanelApp-R21 or Human Phenotype Ontology (HPO)-driven gene selection terms were applied instead.

Methods: During 9 years (2016-2024), the whole exome was sequenced in 206 pregnancies with selected fetal structural anomalies, with prospective interpretation of about 5000 morbid OMIM genes. Retrospectively, 79 causative and 19 incidental findings were reviewed and assessed for their detectability under two alternative strategies: PanelApp-R21 or HPO-driven gene lists.

Results: Among the 79 causative genes identified by interpreting morbid OMIM genes in 78 structurally abnormal fetuses, PanelApp-R21 was able to detect 76 (96%) genes, while HPO-driven terms identified only 56 (71%). For 19 incidental findings, the PanelApp-R21 pathway could identify eight (42%), while HPO terms captured only one (5.3%).

Conclusions: In prenatal ES, reliance on HPO-driven gene selection significantly lowers diagnostic yield compared with clinical ES, with nearly one-third of primary findings and most incidental findings missed. PanelApp represents a pragmatic alternative, preserving a high primary diagnostic yield while limiting incidental findings.

Objective: To explore our simulation model's ability to ascertain changes in surgical performance in practitioners with varying levels of expertise.

Methods: A fetal surgeon, a fetal surgery fellow, and a medical student performed fetoscopic spina bifida repairs using our simulator. During each session, we assessed fetoscopic skills using a Global Rating Scale (GRS) (minimum and maximum score was 9 and 45, respectively), time to completion, and watertightness of the closure. A mixed linear model assessed the influence of expertise level and session number on GRS scores and operation time. We evaluated the frequency of water tightness, defined as no leakage at the suture line after injecting a pre-specified water volume beneath the repaired layer. A generalized linear mixed model assessed changes in the likelihood of achieving a watertight closure over time and according to expertise level.

Results: Each participant completed 10 simulation sessions. Expertise level influenced the GRS scores (F = 20.10, p = 0.04). Operation time decreased over time (F = 30.6, p = < 0.001). Optimal watertight closure was achieved in 60% of cases by the fetal surgeon and 30% of cases by the fetal surgery fellow and medical student. There was a non-significant increase in odds of achieving watertight closure with each session (odds ratio 1.27, p = 0.12).

Conclusions: Our fetoscopic spina bifida repair simulator demonstrated changes and may enhance surgical performance across varying expertise levels. However, larger studies are needed to validate our findings.

Objective: Congenital complete heart block (CHB) carries significant morbidity and mortality. Maternal Hydroxychloroquine may prevent CHB in subsequent pregnancies. No studies have explored the benefit of Hydroxychloroquine initiated after the diagnosis of CHB. We hypothesized fetuses exposed to Hydroxychloroquine, even after CHB diagnosis, will have improved outcomes using time to pacemaker placement as the primary outcome.

Methods: A single-center retrospective study was conducted on patients with CHB secondary to maternal anti-SSA antibodies approximately 2005-2024.

Results: All patients (n = 42) received prenatal Dexamethasone. Twenty-four patients received prenatal Dexamethasone + Hydroxychloroquine; nine were started on Hydroxychloroquine prior to CHB diagnosis, while 15 were started on Hydroxychloroquine after diagnosis. Fetal hydrops occurred more in patients treated with Dexamethasone alone (p = 0.004). Oligohydramnios occurred more in patients on Dexamethasone + Hydroxychloroquine (p = 0.003). There was a higher likelihood of pacing at birth in the Dexamethasone only group (p = 0.045), but no further significant differences in timing to pacemaker placement. Long-term survival was similar.

Conclusion: Increased rates of hydrops fetalis and the need for pacing at birth in the Dexamethasone only group suggest a possible positive effect of Hydroxychloroquine in utero, even if administered after the diagnosis of CHB. This study is limited by the small sample size and the inability to control for covariates. Further multicenter studies would help explore whether adjunctive treatment with Hydroxychloroquine improves outcomes, even when initiated after CHB diagnosis.

Objective: To evaluate the diagnostic value of prenatal exome sequencing (ES) integrated with copy number variant (CNV) and single nucleotide variant (SNV) analysis (ES-CNV/SNV) in fetuses with structural anomalies following negative chromosomal microarray analysis (CMA) and karyotyping, and to delineate the practical challenges encountered during its clinical implementation in prenatal settings.

Methods: In this multicenter prospective cohort study (2018-2021), 275 fetuses with structural anomalies were categorized into three groups: sporadic single-system (n = 128), sporadic multisystem (n = 88), and recurrent anomalies (n = 59). Trio-based ES-CNV/SNV analysis was used to identify SNVs, CNVs, or compound heterozygous CNV/SNV combinations- the latter being defined as two distinct pathogenic variants (a CNV and an SNV) coexisting within the same gene, resulting in biallelic gene dysfunction, which is pivotal for autosomal recessive disorders. Incremental diagnostic yields across groups, the incidence of CNV/SNV combinations, and expanded prenatal phenotypic-genotypic correlations were analyzed.

Results: ES-CNV/SNV analysis improved the diagnostic yield to 29.45% (81/275) compared with conventional chromosome analysis combined with CMA in fetuses with malformations. The highest diagnostic yield was observed in the recurrent anomaly group (40.68%, 24/59), followed by the multisystem (28.41%, 25/88) and single-system anomaly groups (25.00%, 32/128). Notably, 1.45% of cases harbored compound CNV/SNV combinations, underscoring the diagnostic potential of ES-CNV/SNV in autosomal recessive disorders. In addition, this study expanded prenatal phenotypic-genotypic correlations for 36 variants and five genes.

Conclusion: ES-CNV/SNV analysis enhances prenatal diagnostic precision by detecting compound CNV/SNV combinations that are undetectable by standard testing. Recurrent anomalies demonstrated a greater diagnostic benefit than sporadic single-system or multisystem anomalies, underscoring the utility of this method in high-risk cases. This study broadens the prenatal phenotypic spectrum and deepens our understanding of developmental mechanisms.

Objective: We describe a series of pregnancies with autosomal dominant lymphedema and generalized lymphatic dysplasia in the fetus diagnosed with prenatal exome or genome sequencing. We focus on specific syndromes, fetal features, and parental symptoms to deepen our understanding of congenital lymphatic anomalies.

Methods: Pregnancies with one or more fetal effusions were prospectively enrolled from 2017 to 2024 and underwent exome or genome sequencing. Fetal effusions included increased nuchal translucency ≥ 3.5 mm, cystic hygroma, pleural effusion, pericardial effusion, ascites, and/or skin edema. Records were reviewed to extract personal and family history, ultrasound findings, and pregnancy outcomes.

Results: Among 303 pregnancies with one or more fetal effusions, eight (3%) had a molecular diagnosis of autosomal dominant lymphedema or generalized lymphatic dysplasia. Gestational age at detection of fetal effusion(s) ranged from the first through third trimesters. Four fetuses inherited the genetic variant(s) from a biological parent. Of these, one parent was asymptomatic, and three had largely milder symptoms than their fetus. Perinatal outcomes were more favorable for fetuses with heterozygous PIEZO1 variants.

Conclusion: Autosomal dominant lymphedema and generalized lymphatic dysplasia can present with a breadth of fetal effusions from the first through third trimesters and are frequently inherited from a biological parent with less severe symptoms. These data provide a deeper understanding of how congenital lymphatic anomalies manifest in utero and inform expectations about recurrence risk in future pregnancies.

Objective: Fetal macrocephaly (HC Z-score ≥ +2) is a common reason for referral for neurosonography. While most cases are benign and asymptomatic, syndromic macrocephaly poses a significant risk of abnormal neurodevelopment. This study aimed to describe the sonographic and genetic features of fetuses at the highest risk of syndromic macrocephaly.

Methods: We retrospectively analyzed 19 fetuses with either HC Z-scores ≥ +2.5 or those with ≥ +2 and associated anomalies, evaluated between January 2015 and October 2024. Assessments included fetal neurosonography, anomaly scans, MRI, and genetic work-up. Outcomes and postnatal/postmortem data were reviewed.

Results: Mean gestational age at the time of diagnosis was 29.6 weeks (range 23-35.4 weeks). Seventeen fetuses (89%) had associated anomalies: large for gestational age (12/19), callosal abnormalities (11/19), malformation of cortical development (13/19), and facial dysmorphism (11/19) were diagnosed. Genetic investigation results (CMA) were available for 17 of the 19 patients. Overall, 14 of the 17 patients had abnormal genetic findings, mostly involving mTOR pathway genes.

Conclusion: High Z-scores and additional imaging findings strongly correlate with genetic abnormalities, most often mTOR-related. These results support the integration of exome sequencing into prenatal evaluation of fetal macrocephaly.