A de novo pathogenic variant in DHX30 gene in a fetus with isolated dysgenesis of the corpus callosum.

A 36 years old woman in her first pregnancy was referred at 24w3d for a dedicated neurosonographic examination due to a suspected short corpus callosum (CC). The examination depicted a dysgenetic CC with asymmetric thickness at the level of the body in coronal views, very thin in the midline and thicker in both sides, suggesting bilateral formation of Probst bundles. The BPD, HC, and transverse cerebellar diameters were in the normal low range without associated growth restriction. Associated anomalies were not detected in the brain or other organs. Following genetic consultation and a normal CMA, trio exome sequencing was performed and a de novo missense pathogenic mutation c.2353 C > T in the DHX30 gene was detected. This variant has been previously reported in children and adults, mostly with a severe phenotype including neurodevelopmental disorder with variable motor and language impairment, but also mild phenotypes have been reported. MRI describes delayed myelination, ventriculomegaly, and cortical and cerebellar atrophy as imaging features in affected patients. This is the first prenatal report of a DHX30-associated neurodevelopmental disorder in which the fetus presents with isolated callosal dysgenesis, stressing the importance of exome sequencing in fetuses with this condition, as far as it is phenotypic presentation of numerous syndromes with different outcomes.

Prenatal Diagnosis of a KIDINS220 De Novo Heterozygous Variant in a Fetus With a Complex CNS Anomaly.

Following termination of pregnancy due to multiple brain malformations, a non-consanguineous couple of Jewish descent sought genetic counseling. Brain malformations identified on neurosonogram included corpus callosum dysgenesis, abnormal brain stem morphology, abnormal cortical sulcation and hypertelorism. Trio exome sequencing revealed a heterozygous de novo likely pathogenic variant in KIDINS220 gene. Heterozygous variants in KIDINS220 have been linked to spastic paraplegia, intellectual disability, nystagmus, and obesity syndrome (SINO). Reports on prenatal findings are limited and primarily consist of cases of ventriculomegaly. We describe a more severe clinical presentation in a case with a heterozygous variant.

Callosal injuries in cytomegalovirus fetopathy: a neurosonographic study.

Introduction - This study aimed to describe the rate and pattern of callosal injury in CMV fetopathy. Methods - This retrospective study included fetuses with confirmed CMV-PCR. Dedicated US including neurosonography was performed. Callosal Length below the 5th centile or morphological abnormalities were considered abnormal. Any additional abnormal findings were reported. Results - Seventy-two patients were included. In 76% infection occurred in the 1stT or periconceptional. In 34.7% a callosal anomaly was observed and it was never isolated. CNS abnormalities included: periventricular hyperechogenicity (PVHE) 55.5%, calcifications 52%, ventriculomegaly 33%, periventricular pseudocysts 31.4%, occipital cysts 22.2%, echogenic precaudate germinal matrix 30.5%, LSV 26.4%, sulcation abnormalities 22.2%, cerebellar findings 18% and HC below -2SD 18%. The most common association with CC insult was PVHE (56%) and calcifications (52%). Conclusion - Although not referred to as a classic brain structure affected by CMV infection, the CC was injured in one-third of our patients, including cases of late infection. The mechanism of disease and the prenatal patterns of callosal involvement in these cases appear to be different from the postnatal patterns and are not reversible. The presence of a callosal injury would imply a worse prognosis and a significant increment in the risk of neurodevelopmental impairment.

Clinical Practice Guidelines and Recommendations by the World Association of Perinatal Medicine and Perinatal Medicine Foundation: Reporting Suspected Findings from Fetal Central Nervous System Examination.

These guidelines follow the mission of the World Association of Perinatal Medicine, in collaboration with the Perinatal Medicine Foundation, which brings together groups and individuals worldwide, with the aim to improve prenatal detection of central nervous system anomalies and the appropriate referral of pregnancies with suspected fetal anomalies. In addition, this document provides further guidance for healthcare practitioners with the goal of standardizing the description of ultrasonographic abnormal findings.

The normal 14-18 gestational weeks "parasagittal complex" view of the fetal brain. A 3D transvaginal neurosonographic study.

OBJECTIVE: To study the early second trimester development of brain hemispheres, lateral ventricles, choroid plexus, and ganglionic eminence/basal ganglia complex (GEBG). METHODS: A retrospective analysis of TVUS 3D volumes of 14-18 gestational weeks (GW) fetuses. Hemispheres were analyzed for wall thickness, choroid plexus extension, GEBG height and length, lamination pattern (intermediate zone and the subplate border, IZ-SP), ventricle height, width, and angle. Measurements were correlated with GW and assessed for symmetry and impact of probe resolution. RESULTS: We included 84 fetuses (168 hemispheres). The CP location is variable at 14-16 GW, becoming consistently and symmetrically posterior at 18 GW. Hemispheric thickness, GEBG height and length grow significantly with fetal age, whereas ventricle height, width, and angle regress. The detection rate of the IZ-SP line at 14, 15, 16, 17, and 18 weeks was 0%, 24%, 78.26%, 100%, and 100%, respectively. The ratio between the upper and lower segments of the cerebral lamination grows with GW. For all brain structures, the asymmetry between sides was significant only for ventricular height. The transducer type did not have a significant effect on any outcome except for ventricle height. CONCLUSION: These normal features of the parasagittal view should aid clinicians in fetal brain assessment during the early weeks of the second trimester.

Myocardial Function in Fetuses with Congenital Cytomegalovirus Infection.

INTRODUCTION: The objective of this study was to investigate myocardial deformation of left (LV) and right ventricle (RV) using 2-dimensional speckle-tracking echocardiography (2D-STE) in fetuses with and without congenital cytomegalovirus (CMV) infection. METHODS: This was a prospective single-center study. Vertical transmission was defined by a positive CMV polymerase chain reaction (PCR) test on the amniotic fluid or on the neonate's urine. Fetuses were divided into group 1 and group 2 if CMV-PCR was positive or negative, respectively. LV and RV global longitudinal strain (GLS) values were obtained and adjusted for gestational age by calculating Z-scores. Univariate analysis was carried out to compare cardiac indices between group 1 and group 2. RESULTS: Fetuses from group 1 (n = 11) had a significantly lower LV myocardial shortening than those from group 2 (n = 32). GLS was -20.7 ± 5.2% and -26.3 ± 4.1%, respectively (p = 0.001). Similarly, GLS Z-score was lower (0.02 ± 0.72) in group 1 than in group 2 (-0.80 ± 0.59) (p = 0.001). Similarly, RV GLS Z-score was significantly impaired in group 1 compared to group 2 (-0.44 ± 1.03 vs. -1.04 ± 0.71, p = 0.041). CONCLUSION: Fetuses with congenital CMV showed subclinical biventricular myocardial dysfunction. Further studies are needed to confirm the potential role of 2D-STE in identifying fetuses with congenital CMV at risk of postnatal cardiovascular morbidities.

Prenatal diagnosis of a likely pathogenic variant in ZBTB18: Natural evolution of fetal phenotype including the long bones and corpus callosum.

Pathogenic variants in ZBTB18 gene have been described only postnatally with a variable phenotypic spectrum that includes intellectual disability, microcephaly, hypotonia, poor growth, corpus callosum abnormalities, seizures, and dysmorphic facial features. These features overlap with the phenotype of 1q43-q44 deletion syndrome (OMIM #612337). There are several genes within the 1q43-q44 deletion region, and ZBTB18 is of particular interest due to its known involvement in neuronal differentiation and migration. We describe here a fetus presenting with an intrauterine growth restriction, diminished long bones growth, single umbilical artery, and a short corpus callosum. On mid pregnancy ultrasound, all biometric parameters including the corpus callosum were relatively small but still within the normal range. Only a targeted follow-up during the third trimester, including neurosonographic and MRI exams, revealed the full extent of the malformation, leading to amniocentesis and a genetic workup that led to the identification of a de novo likely pathogenic variant in ZBTB18 gene. This is the first description of the evolving phenotype of a ZBTB18-related disorder in a fetus, which emphasizes the challenging diagnosis of subtle findings, that mandates a high level of clinical suspicion and a targeted follow-up throughout pregnancy.

Fetal cerebral ventriculomegaly: What do we tell the prospective parents?

Fetal cerebral ventriculomegaly is a relatively common finding, observed during approximately 1% of obstetric ultrasounds. In the second and third trimester, mild (≥10 mm) and severe ventriculomegaly (≥15 mm) are defined according to the measurement of distal lateral ventricles that is included in the routine sonographic examination of central nervous system. A detailed neurosonography and anatomy ultrasound should be performed to detect other associated anomalies in the central nervous system and in other systems, respectively. Fetal MRI might be useful when neurosonography is unavailable or suboptimal. The risk of chromosomal and non-chromosomal genetic disorders associated with ventriculomegaly is high, therefore invasive genetic testing, including microarray, is recommended. Screening for prenatal infections, in particular cytomegalovirus and toxoplasmosis, should also be carried out at diagnosis. The prognosis is determined by the severity of ventriculomegaly and/or by the presence of co-existing abnormalities. Fetal ventriculoamniotic shunting in progressive isolated severe ventriculomegaly is an experimental procedure. After delivery, ventricular-peritoneal shunting or ventriculostomy are the two available options to treat hydrocephalus in specific conditions with similar long-term outcomes. A multidisciplinary fetal neurology team, including perinatologists, geneticists, pediatric neurologists, neuroradiologists and neurosurgeons, can provide parents with the most thorough prenatal counseling. This review outlines the latest evidence on diagnosis and management of pregnancies complicated by fetal cerebral ventriculomegaly.

Upgrading an intronic TMEM67 variant of unknown significance to likely pathogenic through RNA studies and community data sharing.

FETAL PHENOTYPE: A couple of Ashkenazi Jewish descent was referred for an early anatomy scan at 14 + 2 weeks of gestation following a previous pregnancy termination due to posterior encephalocele and enlarged kidneys. The index pregnancy was also positive for several fetal abnormalities, including enlarged kidneys with cystic dysplasia and abnormal cerebellar morphology highly suggestive of Joubert syndrome. GENETIC DIAGNOSTIC TEST PERFORMED, RESULT, AND INTERPRETATION: Trio exome sequencing revealed compound heterozygosity for variants in the TMEM67 gene: a known pathogenic maternally inherited variant found in trans with a paternal intronic variant of unknown significance. RNA analysis revealed that the intronic variant creates a cryptic acceptor splice site in intron 12, leading to the insertion of 22 bp and causing a frameshift with a premature stop codon. This analysis enabled the reclassification of the intronic variant to likely pathogenic. IMPLICATIONS AND NOVELTY: This information empowered the couple to make informed reproductive choices and opt for preimplantation genetic testing (PGT) for future pregnancies.

A unique brain germinal matrix involvement in cytomegalovirus infected fetuses: A retrospective neurosonographic analysis with outcome correlation.

OBJECTIVE: To study the clinical significance of brain germinal matrix (GM) changes in cytomegalovirus (CMV) infected fetuses. METHOD: This is a retrospective analysis. Group A; isolated GM finding, with or without lenticulostriatal vasculopathy (LSV). Group B; non-isolated lesion. Amniocentesis, urinalysis, postnatal US and developmental assessment, were obtained. RESULTS: Group A and B included 18 and four fetuses, respectively. In group A, mean fetal age at diagnosis was 34.3 weeks (31-38 weeks). In 15/18 (83.3%), the lesion was bilateral and LSV was present in 8/18 (44.4%). Small cysts appeared inside the lesion in 5/18 (27.7%). MRI was normal in 8/18 (44.4%). Subtle or inconclusive findings were reported in the remaining fetuses. Brain ultrasound was normal in 10/18 (55.5%) of newborns. In the remaining, caudothalamic cyst with or without LSV, or isolated LSV were found. All newborns are developing normally at a mean follow-up age of 33.3 months (+/- 19.6 moths). In group B, all four patients requested for termination of pregnancy. CONCLUSION: Fetal CMV infection may cause focal GM changes, frequently accompanied by LSV, late in pregnancy. These changes may be isolated, or as part of a more generalized brain damage. When isolated, favorable prognosis is expected.

WAPM-World Association of Perinatal Medicine Practice Guidelines: Fetal central nervous system examination.

These practice guidelines follow the mission of the World Association of Perinatal Medicine in collaboration with the Perinatal Medicine Foundation, bringing together groups and individuals throughout the world, with the goal of improving the ultrasound assessment of the fetal Central Nervous System (CNS) anatomy. In fact, this document provides further guidance for healthcare practitioners for the evaluation of the fetal CNS during the mid-trimester ultrasound scan with the aim to increase the ability in evaluating normal fetal anatomy. Therefore, it is not intended to establish a legal standard of care. This document is based on consensus among perinatal experts throughout the world, and serves as a guideline for use in clinical practice.

The early pattern of human corpus callosum development: A transvaginal 3D neurosonographic study.

OBJECTIVE: To provide an in-vivo description of early corpus callosum (CC) development. METHODS: We reviewed 3D US volumes acquired transvaginally (TVUS) through the anterior fontanelle, between 14 to 17 weeks. The following landmarks were recognized: tela-choroidea (TC), foramina of Moro, early CC and the evolving cavum septi pellucidi. The following measurements were taken: total, anterior and posterior sections, and height of the CC (referenced to the anterior TC border). All measurements were correlated to both the gestational age and the transverse cerebellar diameter (TCD). RESULTS: Eighty nine volumes were included in the study (mean 15.1 weeks ± 0.84, TCD range, 13.1-18.4 mm) with high inter and intra observer correlation of the measurements. We found high correlation between CC length and height, and TCD. The anterior segment of the CC appear earlier than the posterior one, and growth continues bi-directionally. Initially, the posterior elongation is significantly larger than the anterior one. Association of all CC measurements with TCD remained significant when co-varying for maternal age and fetal sex. CONCLUSIONS: imaging the fetal CC is feasible from 14 weeks by TVUS, by following the suggested insonation approach. The early CC develops bi-directionally, and the posterior elongation is more significant than the anterior one.

Periventricular pseudocysts of noninfectious origin: Prenatal associated findings and prognostic factors.

OBJECTIVE: The purpose of this study was to establish prognostic factors in fetuses diagnosed with periventricular pseudocysts (PVPCs) without known congenital infection, between 28 and 37 weeks of gestation. METHODS: This retrospective study included cases of fetal PVPC from 2008 to 2018. PVPCs were classified according to location, number, extension, morphology, and size. Additional findings, MRI and genetic studies were recorded. Pregnancy outcome, postnatal, or postmortem results were obtained. Images from patients with normal (Group 1) and abnormal postnatal development (Group 2) were compared for analysis of factors predictive of outcome. RESULTS: One-hundred and fifteen pseudocysts were observed in 59 patients. In 34 fetuses (57%), the PVPC was an isolated finding. Thirty-nine patients delivered live newborns, 27% opted for termination of pregnancy, and 4 patients were lost to follow-up. Eighty-four percent of the liveborns had normal development. When assessing for the influence of pseudocyst characteristics, a wide CSP, or large head circumference, neither of these affected the outcome. The presence of additional anomalies was the only positive predictor for abnormal development regradless of specific PVPC characteristics (P = .002). CONCLUSIONS: In fetuses with PVPCs, the presence of additional anomalies was the only predictor for adverse postnatal outcome. No association between cystic characteristics and adverse outcome was observed.

Prenatal and postnatal presentation of PRMT7 related syndrome: Expanding the phenotypic manifestations.

Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-l-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 10 patients have been described with mutations in PRMT7. The shared findings include: hypotonia, intellectual disability, short stature, brachydactyly, and mild dysmorphic features. We describe the prenatal, postnatal, and pathological findings in two male sibs homozygote for a mutation in PRMT7. Both had intrauterine growth restriction involving mainly the long bones. In addition, eye tumor was found in the first patient, and nonspecific brain calcifications and a systemic venous anomaly in the second. The pregnancy of the first child was terminated and we describe the autopsy findings. The second child had postnatal growth restriction of prenatal onset, hypotonia, strabismus, sensorineural hearing loss, genitourinary and skeletal involvement, and global developmental delay. He had dysmorphic features that included frontal bossing, upslanting palpebral fissures, small nose with depressed nasal bridge, and pectus excavatum. Our patients provide additional clinical and pathological data and expand the phenotypic manifestations associated with PRMT7 homozygote/compound heterozygote mutations to include brain calcifications and delayed myelination, and congenital orbital tumor.

Ultrasound imaging of the fetal secondary palate: Methodological description of a two-dimensional approach and a case series.

OBJECTIVE: The study aims to describe our two-dimensional (2D) ultrasound approach to visualize the fetal secondary palate and plot its growth curve and to describe and demonstrate its clinical implementation. METHODS: This is a two parts retrospective study. First, we measured the antero-posterior length of the bony secondary palate, from the soft to hard palate interface (SHPI) line to the alveolar ridge, blindly by two operators during routine scans of low-risk fetuses, and plot a longitudinal growth curve. In the second part, we describe four cases of prenatal diagnosis of secondary palate cleft. RESULTS: Sixty-eight fetuses were included: 14 to 15 weeks (n = 20), 21 to 24 weeks (n = 32), and 29 to 35 weeks (n = 16). The bony secondary palate elongates along gestation from a mean of 5.3 mm (+/-0.46 mm) at 14 to 15 weeks to 15.9 mm (+/-1.7 mm) at 29 to 35 weeks. We found high intraobserver and interobserver correlation between measurements. All four cases diagnosed by this approach were confirmed postnatally. CONCLUSIONS: The SHPI, representing the normally developed secondary bony palate, can be imaged in the fetus by direct 2D ultrasound as early as 14 weeks. A gap within or nonvisualization of the SHPI is highly suggestive for a secondary palate cleft.

The third ventricle of the human fetal brain: Normative data and pathologic correlation. A 3D transvaginal neurosonography study.

OBJECTIVE: The objective of the study are to describe (a) the technical aspects and (b) the anatomical boundaries of the fetal third ventricle (3V) on the midsagittal sonographic view and to assess (c) different biometric parameters in normal and abnormal fetuses and (d) and their reproducibility. METHODS: This study included 67 normal and 50 CNS anomalies fetuses which include (1) obstructive severe ventriculomegaly (SVM; atrial width ≥ 15 mm), (2) moderate ventriculomegaly (10-14.9 mm), and (3) corpus callosum agenesis (ACC). All underwent transvaginal 3D neurosonography of the midsagittal view of the 3V. The following parameters were measured: area, perimeter, craniocaudal and anteroposterior (AP) diameters, interthalamic adhesion diameter (ITAD), wedge angle, and the ratio between the last 2 variables (ITAD/WA). Repeatability was also assessed. RESULTS: The ITAD and the ITAD/WA are significantly different between normal fetuses and the SVM (P ≤ .001). Interthalamic adhesion diameter of ≤7.1 mm is able to identify SVM with 98.6% accuracy (CI: 0.92-0.99). In ACC cases, the AP diameter is significantly shorter than both normal fetuses and ventriculomegaly. Intraobserver/interobserver reliability was good for most variables. CONCLUSIONS: Transvaginal neurosonography enables visualization of the normal and abnormal fetal third ventricle. An ITAD <7.1 identifies aqueductal stenosis as the likely etiology of severe ventriculomegaly with an accuracy of 98.6%.

The use of fetal neurosonography and brain MRI in cases of cytomegalovirus infection during pregnancy: A retrospective analysis with outcome correlation.

OBJECTIVE: To analyze ultrasound (US) and magnetic resonance imaging (MRI) results and developmental outcome in cases of maternal primary cytomegalovirus (CMV) infection during pregnancy. METHODS: We retrospectively reviewed the results of fetal neurosonography and brain MRI of CMV-infected fetuses (Group 1). Cases of maternal infection in which the fetal status was unknown, and subsequently had a negative CMV postnatal urine analysis, were independently analyzed (Group 2). Imaging results were classified as follows: positive, negative, or inconclusive. Developmental landmarks were followed up. RESULTS: Eighty-one women were included in the study: 48 (59.2%) in Group 1 and 33 (40.8%) in Group 2. In Group 1, termination of pregnancy was performed in 8 cases (16.7%) following the diagnosis of brain abnormalities. Among the remaining cases, concordance rate between US and MRI was 78%. False negative rates for US and MRI were 5.5% and 6.4%, respectively (hearing deficits). For MRI, we found 17.5% of false positive/inconclusive results, while for the US, we found 5% of inconclusive results. In Group 2, false positive rates for US and MRI were 6.5% and 12.9%, respectively. CONCLUSIONS: Adding MRI in CMV-infected cases with a normal neurosonographic follow-up should be weighed against a nonnegligible rate of false positive and inconclusive findings.

Outcome of singleton pregnancy in women ≥ 45 years old: a retrospective cohort study.

OBJECTIVE: To investigate prematurity rate in women aged ≥ 45 carrying a singleton pregnancy. Other maternal and neonatal outcomes are also described. DESIGN: Retrospective cohort study. SETTING: Women delivering a singleton pregnancy at a single tertiary medical center. POPULATION: The study included all women aged 45 years and over who delivered at 20 weeks gestation or beyond over a 9-year period from May 2000 to May 2009. METHODS: Women aged 45 years and over were identified. The study group was compared to a control group of women <40 years with singleton pregnancies conceived by in vitro fertilization (IVF) who delivered during the same time period. MAIN OUTCOME MEASURE(S): Maternal complications during pregnancy and neonatal outcome. RESULTS: During the study period 278 women ≥ 45 years delivered a singleton pregnancy. The control group included 304 women. The rate of delivery before 37 weeks as well as before 32 weeks were very high in our study group (18.7 vs. 10.9%, p = 0.009 and 5.4 vs. 2.0%, p = 0.04, respectively). In multivariate analysis, older maternal age was not independently related to prematurity. Chronic hypertension (HTN) was found to be a major risk factor associated with prematurity in advanced maternal age. CONCLUSIONS: Women ≥ 45-years-old with a singleton pregnancy carry a higher risk of maternal and perinatal complications. Preterm birth is a significant complication in this age group and is associated with preexisting chronic HTN.