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.

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.

SMARCC1 is a susceptibility gene for congenital hydrocephalus with an autosomal dominant inheritance mode and incomplete penetrance.

A Jewish couple of mixed origin was referred for genetic counseling following termination of pregnancy at 18 weeks of gestation due to severe ventriculomegaly with aqueduct stenosis. Trio exome sequencing revealed a loss-of-function heterozygous variant in the SMARCC1 gene inherited from an unaffected mother. The SMARCC1 gene is associated with embryonic neurodevelopmental processes. Recent studies have linked perturbations of the gene with autosomal dominant congenital hydrocephalus, albeit with reduced penetrance. However, these studies were not referenced in the SMARCC1 OMIM record (*601732) and the gene was not considered, at the time, an OMIM morbid gene. Following our case and appeal, SMARCC1 is now considered a susceptibility gene for hydrocephalus. This allowed us to reclassify the variant as likely pathogenic and empowered the couple to make informed reproductive choices.

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.

Procedure-to-delivery interval after late amniocentesis and the need for routine antenatal corticosteroids.

OBJECTIVES: The aim of this study is to assess the procedure-to-delivery interval (PDI), the obstetric complications, and the early neonatal outcome in patients that did or did not receive glucocorticosteroids (GCSs) before third-trimester amniocentesis (TTA). METHODS: A retrospectively analysis of 445 TTA procedures divided into two groups based on the administration (study group = 220 patients) or not (control group = 225 patients) of GCSs before TTA. The PDI was calculated for all patients. Obstetric and neonatal outcomes were compared between the groups. RESULTS: The rate of procedure-associated complications was similar between the groups. The mean PDI was 47.2 ± 16.8 days. The overall incidence of preterm birth was 11.7%; 9% delivered between 34 and 37 weeks and 2.7% between 28 and 34 weeks. Only nine patients (2%) delivered within seven days following TTA. The incidence of respiratory distress syndrome in the study and control groups was 1.8% and 1.3%, p = .71, respectively. There were no significant differences in other neonatal outcomes in term and preterm deliveries between the study and control groups. CONCLUSIONS: In the present study, the administration of glucocorticoids prior to TTA did not reduce the rates of neonatal complications, which was similar in both groups and not higher than the general population.

Early term birth is associated with the risk of preterm and recurrent early term birth in women with 3 consecutive deliveries.

BACKGROUND: We assessed the association of early term at first birth (ETB) with the risk of preterm birth (PTB) and ETB in women with 3 consecutive deliveries. METHODS: We conducted a retrospective cohort study of all women with 3 consecutive singleton births at a single institute from 1994 to 2013. The risk of PTB (<37 weeks), spontaneous PTB and ETB (37-38 weeks) in the 3rd delivery was explored. RESULTS: Of 49,259 women delivered in our center during the study period, 4038 met inclusion criteria. The rate for subsequent PTB, spontaneous PTB and recurrent ETB in the 3rd delivery significantly increased as the number of prior ETBs increased. The order of a single prior ETB in one of the first two deliveries was differently associated with the risk of complications in the 3rd delivery, which was higher when the prior ETB was more recent to the third delivery. CONCLUSION: A history of ETB is associated with the risk of future PTB and recurrent ETB. The risk is related to the number and order of prior ETBs.

Ultrasound Nomograms of the Fetal Optic Nerve Sheath Diameter.

OBJECTIVE: To construct prenatal age-specific reference intervals for sonographic measurements of the optic nerve sheath diameter (ONSD) during gestation in normal fetuses. MATERIALS AND METHODS: Prospective cross-sectional study of fetuses assessed in antenatal ultrasound units between 2010 and 2014. The examination was based on a technique for the sonographic assessment of ONSD previously published by our group. The mean values and SDs of the ONSD were modeled as a function of the gestational week by curve estimation analysis based on the highest adjusted R2 coefficient. Repeatability tests were performed to assess intraobserver variability and interobserver agreement. RESULTS: During the study period 364 healthy fetuses were enrolled. The mean values for the ONSD varied from 0.6 mm at 15-16 weeks to 2.8 mm at 37-38 weeks. The ONSD grows in a linear fashion throughout gestation, with a quadratic equation providing an optimal fit to the data (adjusted R2 = 0.957). CONCLUSION: Sonographic age-specific references for the fetal ONSD are presented. This data may assist in the decision-making process in fetuses with a suspected increase in intracranial pressure, or anomalies affecting the development of optic stalks, such as optic hypoplasia and septo-optic dysplasia.

Prenatal diagnosis of brainstem anomalies.

Prenatal diagnosis of brainstem anomalies is important due to the usually associated neurodevelopmental impairment and genetic implications. The extreme developmental changes that the brainstem and cerebellum undergo during fetal life pose a challenge for the characterization and definition of the different malformations. The present review aims to demonstrate the normal development of the fetal brainstem and to present the main features required for diagnosis of its anomalies according to available data in the medical literature.

Comparison between 2D ultrasonography and magnetic resonance imaging for assessing brain and spine parameters in fetuses with spina bifida.

PURPOSE: To compare two-dimensional ultrasonography (2DUS) and magnetic resonance imaging (MRI) for assessing brain and spine parameters in fetuses with spina bifida. METHODS: A cross-sectional study was conducted on 15 fetuses with spina bifida (one with encephalocele, four with rachischisis and 10 with myelomeningocele). The size of the atrium of the lateral ventricle, percentage shortening of the cerebellum, degree of compromising of the first vertebra and total number of vertebras affected by herniation were assessed. The MRI examination was performed not more than 7 days after the 2DUS. To compare and correlate the parameters from the two techniques, the paired Student's t test and intraclass correlation coefficient (ICC) were used. To assess the correlations of atrium measurements from 2DUS and MRI with other parameters, Pearson's correlation coefficient (r) was used. RESULTS: No significant difference was observed in any of the means of the parameters assessed using the two techniques (p > 0.05). Both 2DUS and MRI seemed to present satisfactory reliability in measurements on the size of the atrium of the lateral ventricle and the first vertebra affected (ICC = 0.88 and 0.75, respectively). Measurements on the atrium of the lateral ventricle from 2DUS correlated better with the other parameters than did measurements from MRI. CONCLUSIONS: In fetuses with spina bifida, 2DUS and MRI present similar results, but measurements on the atrium of the lateral ventricle from 2DUS correlated better with the other parameters.

Reference intervals for fetal heart volume from 3-dimensional sonography using the extended imaging virtual organ computer-aided analysis method at gestational ages of 20 to 34 weeks.

OBJECTIVES: The purpose of this study was to establish the reference range for fetal heart volume from 3-dimensional (3D) sonography using the extended imaging virtual organ computer-aided analysis method. METHODS: The fetal heart volume was measured in 303 normal singleton pregnancies at gestational ages of 20 to 34 weeks using 3D sonography. The extended imaging virtual organ computer-aided analysis method was used to obtain a sequence of 10 parallel symmetric sections through the heart, according to examiner-determined limits (the apex at one extremity and the connection to the great vessels at the other). Heart contours were drawn manually in all sections to obtain the 3D volume measurement, which was provided automatically by the software. Normal z scores and percentile reference ranges for each gestational age were constructed. RESULTS: The fetal heart volume increased with gestational age. The mean values were 3.09 mL at 20 weeks, 9.18 mL at 26 weeks, and 24.89 mL at 34 weeks, according to the following formulas: fetal heart volume (mL) = 18.0076 - 2.1005 × gestational age + 0.0677 × gestational age2 (R(2) = 0.922); and SD (mL) = (4.5038 - 0.4281 × gestational age + 0.0114 × gestational age2) × âˆš1.495808 (R(2) = 0.922). CONCLUSIONS: A reference range for fetal heart volume using the 3D sonographic extended imaging virtual organ computer-aided analysis method at gestational ages of 20 to 34 weeks was established.

Assessment of cerebral circulation in normal fetuses by three-dimensional power Doppler ultrasonography.

OBJECTIVE: To assess the three-dimensional power Doppler ultrasonography (3D power Doppler) vascular indices in the middle cerebral artery (MCA), anterior cerebral artery (ACA) and posterior cerebral artery (PCA) territories. METHODS: A cross-sectional study was carried out on 111 normal pregnancies between 26 and 34 weeks. The MCA, ACA and PCA territories closest to the transducer were scanned and volumes were calculated by using the VOCAL (Virtual Organ Computer-aided Analysis) program. The 3D power Doppler indices--vascularization index (VI), flow index (FI) and vascularization-flow index (VFI) were calculated. Scatter graphs, Pearson correlation coefficients (r) and linear regression models were used. RESULTS: Only the FI-MCA (r=0.38 and p<0.001), VFI-MCA (r=0.23 and p=0.016) and FI-PCA (r=0.191 and p=0.040) had a low correlation with gestational age. The other 3D power Doppler indices VI-MCA (r=0.153 and p=0.150), VI-ACA (r=0.105 and p=0.271), FI-ACA (r=0.154 and p=0.106), VFI-ACA (r=0.134 and p=0.161), VI-PCA (r=0.105 and p=0.270) and VFI-PCA (r=0.126 and p=0.180) showed no statistically significant correlation with gestational. CONCLUSION: It was observed a low correlation between gestational age and the FI-MCA, VFI-MCA and FI-PCA.

Assessment of yolk sac volume by 3D-sonography using the XI VOCAL method from 7 to 10 + 6 weeks of pregnancy.

PURPOSE: To access the yolk sac (YS) volume between 7 and 10 + 6 gestational weeks of pregnancy by threedimensional (3D) ultrasonography using extended imaging virtual organ computer-aided analysis (XI VOCAL) method. METHODS: For this cross-sectional study, 64 pregnant patients between 7 and 10 + 6 gestational weeks were enrolled and normal pregnancies were included. The XI VOCAL 10 slices manual method was used for the YS volumetry by 3D ultrasonography. The statistical analysis first obtained the means, medians, standard deviation, and maximum and minimum volume values. The correlation of YS volume to the gestational age (GA) and the crown-rump length (CRL) was evaluated by models of polynomial regression, being adjusted by determination coefficient (R (2)). RESULTS: The mean YS estimated volume ranged from 0.06 ± 0.03 cm(3) [0.02-0.11 cm(3)] to 0.16 ± 0.12 cm(3) [0.01-0.38 cm(3)] and showed to be weakly correlated to the GA [YS volume = exp(0.261 × GA + 0.008); R (2) = 0.14] and the CRL [YS volume = exp(0.033 × CRL + 0.035); R (2) = 0.13]. CONCLUSIONS: The YS volume estimated by 3D ultrasonography using the method XI VOCAL correlated weakly with GA and CRL in normal singleton pregnancies between 7 and 10 + 6 gestational weeks.

Morphological evaluation of lateral ventricles of fetuses with ventriculomegaly by three-dimensional ultrasonography and magnetic resonance imaging: correlation with etiology.

PURPOSE: To evaluate morphology of lateral ventricles of ventriculomegaly/hydrocephaly fetuses using 3D-sonography by virtual organ computer-aided analysis (VOCAL) technique and magnetic resonance imaging (MRI) and verify morphologic patterns related to etiology. METHODS: Seventeen fetuses presenting with ventricular enlargement (atria > 10 mm) were evaluated. 3D datasets were acquired from a coronal reference plane and post-processed by the rotational imaging using VOCAL 30°. MRI study was analyzed in the three plans in all sequences. Morphologic aspects such as global shape, anterior, posterior and inferior horn characteristics, wall irregularities and deformities were analyzed and related to etiology factor. RESULTS: Twenty-nine percent of the cases were secondary to Arnold-Chiari syndrome and presented with global dilation of the three-horns. Cases related to aqueduct stenosis presented with ependymal rupture and wall irregularities in advanced cases. Corpus callosum agenesis cases presented with small ventricular volumes, thin shape, normal or slightly enlarged anterior and inferior horns with dilation restricted to posterior horn. Cases related to trisomy 18 and cytomegalovirus presented irregular ventricular walls associated with anomalous ventricular shapes, suggesting parenchymal destruction. CONCLUSION: Ventricular morphology evaluation gives important information on etiology of ventricular enlargement, supporting prognosis prediction and decision making process of the affected fetuses and their families.

Análise da reprodutibilidade do Doppler de amplitude tridimensional na avaliação da circulação do cérebro fetal / Analysis of three-dimensional power Doppler sonography reproducibility in the assessment of fetal brain circulation

OBJETIVO: Avaliar a reprodutibilidade intra e interobservador do Doppler de amplitude tridimensional (3D power Doppler) na avaliação do fluxo sanguíneo cerebral do território da artéria cerebral média. MATERIAIS E MÉTODOS: Foi realizado estudo transversal com 20 gestantes normais entre 26 e 34 semanas. O território da artéria cerebral média mais próximo ao transdutor foi selecionado e o volume foi calculado utilizando-se o método Virtual Organ Computer-aided AnaLysis. Posteriormente, obtiveram-se os índices do 3D power Doppler: índice de vascularização (VI), índice de fluxo (FI) e índice de vascularização-fluxo (VFI). Utilizaram-se, para os cálculos, o coeficiente de correlação intraclasse (CCI) e gráficos de Bland-Altman. RESULTADOS: Foi observada boa concordância intra e interobservador, com CCI > 0,90 para todos os índices do 3D power Doppler: VI [CCI = 0,992 (IC 95 por cento: 0,981-0,997)], FI [CCI = 0,999 (IC 95 por cento: 0,998-0,999)], VFI [CCI = 0,995 (IC 95 por cento: 0,987-0,998)]. Reprodutibilidade interobservador: VI [CCI = 0,988 (IC 95 por cento: 0,970-0,995)], FI [CCI = 0,999 (IC 95 por cento: 0,997-1,000)], VFI [CCI = 0,994 (IC 95 por cento: 0,994-0,998)]. CONCLUSÃO: O 3D power Doppler mostrou-se um método prático, fácil e com boa reprodutibilidade intra e interobservador, com o IF evidenciando a melhor concordância intra e interobservador.

OBJECTIVE: To evaluate the intra- and interobserver reproducibility of three-dimensional power Doppler sonography (3D power Doppler) in the assessment of fetal brain blood flow in the middle cerebral artery territory. MATERIALS AND METHODS: A cross-sectional study was developed with 20 healthy pregnant women between 26 and 34 gestational weeks. The middle cerebral artery territory closest to the transducer was scanned and the blood flow volume was calculated with the method Virtual Organ Computer-aided AnaLysis. The following 3D power Doppler indices were later obtained: vascularization index (VI), flow index (FI) and vascularization-flow index (VFI). The intraclass correlation coefficient (ICC) and Bland-Altman plots were utilized for calculating the intra- and interobserver variability. RESULTS: A good intra- and interobserver agreement was observed, with ICC > 0.90 for all the 3D power Doppler indices: VI [ICC = 0.992 (CI 95 percent: 0.981-0.997)], FI [ICC = 0.999 (CI 95 percent: 0.998-0.999)], VFI [ICC = 0.995 (CI 95 percent: 0.987-0.998)]. Interobserver reproducibility: VI [ICC = 0.988 (CI 95 percent: 0.970-0.995)], FI [ICC = 0.999 (CI 95 percent: 0.997- 1.000)], VFI [ICC = 0.994 (CI 95 percent: 0.994-0.998)]. CONCLUSION: 3D power Doppler has shown to be a practical and easy method in the assessment of fetal brain blood flow, with good intra- and interobserver reproducibility. The FI presented the best intra- and interobserver agreement.

Reliability and validity of in vitro volume calculations by 3-dimensional ultrasonography using the multiplanar, virtual organ computer-aided analysis (VOCAL), and extended imaging VOCAL methods.

OBJECTIVE: The purpose of this study was to assess the reliability and validity of in vitro volume calculations by 3-dimensional ultrasonography. METHODS: This observational study was performed by 2 examiners to obtain volumes of 3 objects of different shapes and sizes filled with ultrasound gel and immersed in water. The examiners used the multiplanar (5-mm interval), virtual organ computer-aided analysis (VOCAL, 30 degrees) and extended imaging (XI) VOCAL (5, 10, 15, and 20 planes) methods to estimate the volumes of each object. A paired Student t test (P) and intraclass correlation coefficients (ICCs) were used to assess reproducibility of the methods. Validity was assessed comparing the percent differences between the estimated and the real volumes using the P value, mean differences, and ICC for each method. RESULTS: All methods were highly reliable and valid. There were no significant differences in interobserver variability; there was a strong interobserver correlation. There were no significant differences in the percent differences between the estimated and real volumes of the objects using the 3 methods. The XI VOCAL method was superior to the multiplanar and VOCAL methods in the measurement of irregularly shaped objects. The XI VOCAL method with 10 planes estimated volumes closest to the real volumes. CONCLUSIONS: All 3 methods were reliable and valid; however, XI VOCAL was superior to the other methods in the measurement of irregularly shaped objects.