Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations.

Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their in vivo relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis. Although the loss of Cdc42 seems generally compatible with apical-basal polarization and lumen formation in retinal blood vessels, it leads to defective endothelial axial polarization and to the formation of severe vascular malformations in capillaries and veins. Tracking of Cdc42-depleted endothelial cells in mosaic retinas suggests that these capillary-venous malformations arise as a consequence of defective cell migration, when endothelial cells that proliferate at normal rates are unable to re-distribute within the vascular network.

Genes and phenotypes in vascular malformations.

Vascular malformations (VMs) are caused by localized defects of vascular development. Most VMs are due to sporadic, postzygotic mutations, while some are the result of autosomal dominant germline mutations. Genotype-phenotype correlation is influenced by many factors. Individual genes can induce different phenotypes (pleiotropy), and similar phenotypes can be due to different genes/mutations (redundancy). The phenotypic spectrum of somatic mutations is wide, and depends on variant allele frequency, timing during embryogenesis, cell type(s) involved and type of mutation. The phenotype of germline mutations is determined by penetrance and expressivity, and is influenced by epigenetic factors (DNA methylation, histone modification) or 'second-hit' somatic mutations. Except for disorders with pathognomonic phenotypes such as Proteus syndrome or a characteristic constellation of symptoms such as CLOVES [congenital lipomatous (fatty) overgrowth, vascular malformations, epidermal naevi and scoliosis/skeletal/spinal anomalies] or PIK3CA-related overgrowth spectrum syndrome, differential diagnosis of VM is therefore difficult. It will be greatly facilitated with increasing analytic sensitivity of sequencing techniques such as next-generation sequencing. High-sensitivity molecular techniques are a prerequisite for targeted pharmacotherapy, i.e. selective therapeutic inhibition of activating mutations underlying VM, which has shown promising results in preliminary studies.

Venous pathologies in paediatric neuroradiology: from foetal to adolescent life.

The interpretation of cerebral venous pathologies in paediatric practice is challenging as there are several normal anatomical variants, and the pathologies are diverse, involving the venous system through direct and indirect mechanisms. This paper aims to provide a comprehensive review of these entities, as their awareness can avoid potential diagnostic pitfalls. We also propose a practical classification system of paediatric cerebral venous pathologies, which will enable more accurate reporting of the neuroimaging findings, as relevant to the underlying pathogenesis of these conditions. The proposed classification system comprises of the following main groups: arterio-venous shunting-related disorders, primary venous malformations and veno-occlusive disorders. A multimodal imaging approach has been included in the relevant subsections, with a brief overview of the modality-specific pitfalls that can also limit interpretation of the neuroimaging. The article also summarises the current literature and international practices in terms of management options and outcomes in specific disease entities.

Left Superior Vena Cava in the Fetus: A Rarely Isolated Anomaly.

The frequency of chromosomal anomalies among fetuses with isolated persistent left superior vena cava (PLSVC) is still debated. The objective of the present study was to assess the prevalence of genetic and morphological anomalies identified in fetuses with PLSVC. We conducted a single-center retrospective study including all fetuses diagnosed with a PLSVC between 2010 and 2017. PLSVC was categorized as isolated or associated according to antenatal diagnosis of associated congenital heart defects, hypoplastic aortic isthmus, abnormal venous/arterial connections, and extracardiac anomalies. Among 229 fetuses diagnosed with PLSVC, 39 cases (17%) were strictly isolated and no syndromic/genetic anomaly or aortic coarctation was diagnosed. Seventy-two fetuses had a cardiovascular defect with a rate of genetic anomalies of 22%, 29 had an extracardiac malformation, and 89 had both an extracardiac and a cardiovascular defect. Among fetuses with abnormal development of the arterial/venous system as the only associated anomaly such as aberrant right subclavian artery or absent ductus venosus, 22% had a genetic anomaly. Overall, sixty-five fetuses or infants had a genetic concern, including 23 aneuploidies, 15 pathogenic micro-deletions/duplications, and 5 variants of unknown significance; 12 patients had VACTERL association, and 12 heterotaxy syndrome. Seven infants had an aortic coarctation diagnosed at birth.In conclusion, a thorough prenatal ultrasound examination is paramount, and the identification of variants of the venous/arterial system in addition to PLSVC should raise suspicion for genetic or morphologic abnormalities. Invasive prenatal diagnosis with array-CGH should be offered when PLSVC is non-isolated, after a detailed ultrasound evaluation in a tertiary center.

Prenatal two-and three-dimensional echocardiographic diagnosis of anomalous origin of one pulmonary artery from the ascending aorta: Case report and literature review.

In utero diagnosis of anomalous origin of one pulmonary artery from the ascending aorta (AOPA) has been rarely reported, although this malformation has a high mortality rate due to the rapid development of pulmonary hypertension. We report two cases of AOPA, in which either the left or the right pulmonary artery originated from the distal part of the ascending aorta. Scanning around the three-vessel view to search for the origin of the left and right pulmonary arteries is essential for the diagnosis. In addition, recognition of an abnormal vessel at the three-vessel tracheal view is also useful. Three-dimensional echocardiography with high-definition flow imaging and spatiotemporal image correlation technique facilitates the identification of the anomalous origin of the pulmonary artery and should be considered a complementary modality in fetal cardiac examinations.

Parvins Are Required for Endothelial Cell-Cell Junctions and Cell Polarity During Embryonic Blood Vessel Formation.

OBJECTIVE: During vascular development, integrin-mediated signaling regulates the formation and stabilization of cell-cell junctions, which are required for endothelial cell (EC) apical-basal polarity and proper deposition of the vascular basement membrane. Parvins are actin-binding proteins that facilitate the interaction of integrins with the actin cytoskeleton. The endothelium expresses 2 parvin isoforms: α-pv (α-parvin) and ß-pv (ß-parvin). Recently, we have shown that α-pv is critical for vessel growth and vessel stability at late embryonic developmental stages. The role of parvins during early embryonic development is unknown. APPROACH AND RESULTS: To investigate the role of endothelial parvins in the developing vasculature, we generated mice with ECs lacking both parvin isoforms by deleting α-pv in ECs in global ß-pv-/- mice (α-pvΔEC;ß-pv-/- mice). Here, we show that α-pvΔEC;ß-pv-/- mice die around embryonic day 11.5 and exhibit hemorrhages, immature capillary beds, and severe vascular defects in the central nervous system, including reduced vessel branching, increased vessel diameter, and balloon-like hemorrhagic clusters of ECs. Vessels in α-pvΔEC;ß-pv-/- embryos display disorganized cell-cell junctions, impaired endothelial apical-basal polarity, and discontinuous basement membranes. These vascular defects are accompanied by defective pericyte-vessel interaction. CONCLUSIONS: Our results show that parvins are critical for the organization of endothelial cell-cell junctions, the establishment of endothelial apical-basal polarity, and the integrity of the basement membrane.

Prenatal diagnosis of tetralogy of Fallot associated with pulmonary artery sling: Two case reports.

Tetralogy of Fallot (TOF) is a common condition accounting for 10%-20% of all fetal cyanotic congenital heart disease cases. Pulmonary artery sling (PAS), or aberrant left pulmonary artery, is a rare congenital cardiovascular malformation. Approximately 58%-83% of PAS is associated with other cardiovascular malformations, TOF being rarest. The diagnosis of PAS is generally incidental or made at autopsy. Cases of prenatal diagnoses of TOF associated with PAS have not yet been reported. Here, we report two cases of TOF associated with PAS diagnosed prenatally in our hospital.

Prenatal ultrasound diagnosis of fetal isolated right ventricular noncompaction with pulmonary artery sling: A rare case report.

Noncompaction of the ventricular myocardium (NVM), also known as spongy myocardium, is a rare type of cardiomyopathy that has a serious impact on fetuses, children, and adults. NVM mainly affects the left ventricle, as isolated right ventricular noncompaction (IRVNC) is rare. Pulmonary artery sling (PAS) is a rare condition in which the left pulmonary artery anomalously originates from a normal positioned right pulmonary artery, and only a few studies have reported PAS in fetuses. Fetal IRVNC complicated with PAS has not been reported yet. Here, we report a case of IRVNC complicated with PAS that was diagnosed prenatally at 30 weeks gestation and confirmed by postpartum anatomy and pathology.

Congenital jugular vein phlebectasia or aneurysma: A rare entity in prenatal diagnosis.

Vascular malformations arising from the wall of the external jugular vein are rare and appeared most commonly in pediatric population. Here, we present a case of vascular malformation in the left external jugular vein diagnosed in a fetus during third trimester ultrasound. This is the first described case in prenatal diagnosis.

Fetal case of right atrial isomerism with infracardiac total anomalous pulmonary venous connection and agenesis of the ductus venosus.

After birth, the ductus venosus becomes an important route connecting the pulmonary and systemic venous systems for survival in infracardiac total anomalous pulmonary venous connection. We encountered a fetal case of right atrial isomerism with infracardiac total anomalous pulmonary venous connection and agenesis of ductus venosus. Prenatal echocardiography suggested that the fetus had severe pulmonary venous obstruction; however, no obstructive lesions were detected at the level of the vertical vein that drained into the portal veins. Therefore, we concluded that emergency surgical pulmonary venous obstruction release was the only way for the fetus to survive. However, the saturation level was maintained above 70% due to the abundant communications via the hepatic sinusoid over 1 week after birth. In conclusion, hepatic sinusoids can be a sufficient route for pulmonary venous return and may not cause severe pulmonary venous obstruction in infracardiac total anomalous pulmonary venous connection with agenesis of ductus venosus.

Placental Pathology in Neonatal Stroke: A Retrospective Case-Control Study.

OBJECTIVE: To assess the association of placental abnormalities with neonatal stroke. STUDY DESIGN: This retrospective case-control study at 3 academic medical centers examined placental specimens for 46 children with neonatal arterial or venous ischemic stroke and 99 control children without stroke, using a standard protocol. Between-group comparisons used χ2 and Fisher exact t test. Correlations used Spearman correlation coefficient. RESULTS: Case placentas were more likely than controls to meet criteria for ≥1 of 5 major categories of pathologic abnormality (89% vs 62%; OR, 5.1; 95% CI, 1.9-14.0; P = .0007) and for ≥2 categories (38% vs 8%; OR, 7.3; 95% CI, 2.9-19.0; P < .0001). Fetal vascular malperfusion occurred in 50% of cases and 17% of controls (OR, 4.8; 95% CI, 2.2-10.5; P = .0001). Amniotic fluid inflammation occurred in 46% of cases with arterial ischemic stroke vs 25% of controls (OR, 2.6; 95% CI, 1.1-6.1; P = .037). There was evidence of a "stress response" (meconium plus elevated nucleated red blood cells) in 24% of cases compared with 1% of controls (OR, 31; 95% CI, 3.8-247.0; P < .0001). CONCLUSIONS: Placental abnormality was more common in children with neonatal stroke compared with controls. All placental findings represent subacute-to-chronic intrauterine stressors. Placental thrombotic processes were associated with both arterial and venous stroke. Our findings provide evidence for specific mechanisms that may predispose to acute perinatal stroke. Amniotic fluid inflammation associated with neonatal arterial ischemic stroke deserves further investigation.

Congenital portosystemic venous shunt.

Congenital portosystemic venous shunts are rare developmental anomalies resulting in diversion of portal flow to the systemic circulation and have been divided into extra- and intrahepatic shunts. They occur during liver and systemic venous vascular embryogenesis and are associated with other congenital abnormalities. They carry a higher risk of benign and malignant liver tumors and, if left untreated, can result in significant medical complications including systemic encephalopathy and pulmonary hypertension. CONCLUSION: This article reviews the various types of congenital portosystemic shunts and their anatomy, pathogenesis, symptomatology, and timing and options of treatment. What is Known: • The natural history and basic management of this rare congenital anomaly are presented. What is New: • This paper is a comprehensive review; highlights important topics in pathogenesis, clinical symptomatology, and treatment options; and proposes an algorithm in the management of congenital portosystemic shunt disease in order to provide a clear idea to a pediatrician. An effort has been made to emphasize the indications for treatment in the children population and link to the adult group by discussing the consequences of lack of treatment or delayed diagnosis.

Pathogenesis of solitary right aortic arch: a mass effect hypothesis based on observations of serial human embryonic sections.

In general, solitary right aortic arch carries the left-sided ductus arteriosus communicating between the left subclavian and pulmonary arteries or the right-sided ductus connecting the descending aorta to the left pulmonary artery. Serial sections of fifteen 5- to 6-week-old embryos and ten 8- to 9-week-old fetuses suggested that the pathogenesis was unrelated to inversion due to dysfunction in gene cascades that control the systemic left/right axis. With inversion, conversely, the ductus or the sixth pharyngeal arch artery should connect to the right pulmonary artery. The disappearance of the right aortic arch started before the caudal migration of the aortic attachment of the ductus. Sympathetic nerve ganglia developed immediately posterior to both aortae, with a single embryonic specimen showing a large ganglion at the midline close to the union of the aortic arches. These ganglia may interfere with blood flow through the distal left arch, resulting in the ductus ending at the descending aorta behind the oesophagus. In another fetus examined, a midline shift of the ductus course resulted in the trachea curving posteriorly. Therefore, solitary right arch is likely to accompany abnormalities of the surrounding structures. The timing and site of the obstruction should be different between types: an almost midline obstruction near the aortic union needed for the development of the left-sided ductus and a distal obstruction near the left subclavian arterial origin needed for the development of the right-sided ductus. A mass effect of the sympathetic ganglia may explain the pathogenesis of any type of anomalous ductus arteriosus shown in previous reports of the solitary right arch.

Hemodynamic studies of isolated absent ductus venosus.

OBJECTIVE: The objective of this article is to evaluate hemodynamic changes among fetuses with isolated absent ductus venosus (IADV) diagnosed by prenatal ultrasonography. PATIENTS AND METHODS: Fetuses with prenatal diagnosis of IADV were recruited and followed. Hemodynamic assessment was performed in all cases, including measurement of cardiac dimensions, shortening fraction, myocardial performance index, preload index in the inferior vena cava and the presence of venous pulsations in the umbilical vein (UV). RESULTS: Nine fetuses of IADV were assessed, including six cases with extra-hepatic UV drainage and three with intra-hepatic drainage. All fetuses with extra-hepatic UV drainage showed an elevated preload index in the inferior vena cava, venous pulsations in the UV and cardiomegaly. Of them, four had hydrops, two showed poor cardiac function and three resulted in perinatal mortality. Three cases with intra-hepatic drainage had continuous flow in the UV, normal in all hemodynamic parameters and all survived. CONCLUSION: Hemodynamic assessment of fetuses with IADV was helpful in predicting the development of hydrops and perinatal mortality. The poor prognostic factors included cardiac overload, cardiomegaly, poor myocardial performance, increased preload, the presence of venous pulsations and extra-hepatic UV drainage. © 2015 John Wiley & Sons, Ltd.

Azygos Vein Z Scores in Healthy Fetuses and Fetuses With Venous Malformations Related to the Azygos Vein.

OBJECTIVES: To establish fetal azygos vein and descending aorta sonographic Z score formulas based on femur length and gestational age and to determine the value of azygos vein diameter variation for potential use in the diagnosis of fetal venous malformations related to the azygos vein. METHODS: A total of 452 healthy singleton fetuses and 25 fetuses with venous malformations related to the azygos vein underwent prenatal sonography in this retrospective study. Azygos vein and descending aorta diameters were measured offline after spatiotemporal image correlation volume acquisition. Normal azygos vein and descending aorta Z score formulas were constructed for these measurements based on femur length by performing standard regression analysis followed by weighted regression of absolute residual values. The azygos vein-to-descending aorta ratio was calculated. Three parameters were compared between venous malformations related to the azygos vein and healthy fetuses. RESULTS: Azygos vein and descending aorta Z score formulas were constructed. Both showed a positive linear correlation with femur length (r = 0.79 and 0.90, respectively; P < .01) and gestational age (r = 0.79 and 0.91; P < .01). The azygos vein Z scores and azygos vein-to-descending aorta ratios of fetuses with malformations were significantly higher than those of healthy fetuses (P < .01). In the abnormal group, 96.0% of azygos vein Z scores (24 of 25) were greater than ±2, and 96.0% of azygos vein-to-descending aorta ratios (24 of 25) were greater than the 95% confidence interval. CONCLUSIONS: The azygos vein Z score formulas we developed can provide a quantitative basis for prenatal screening of venous malformations related to the azygos vein. Azygos vein dilatation and an abnormal azygos vein-to-descending aorta ratio may contribute to increasing the recognition of venous malformations involving the azygos vein.

Developmental venous anomalies of the brain in children -- imaging spectrum and update.

Developmental venous anomalies (DVAs) are the most common vascular malformation of the brain and are commonly identified on routine imaging of the brain. They are typically considered incidental findings, usually with no clinical significance. However the increasing identification of DVAs as a result of improved imaging technology has led to recognition of their association with a variety of abnormal imaging findings and clinically important conditions. This pictorial essay explores the suspected embryological origin, associated imaging features, and proposed pathophysiological mechanisms of DVAs in the pediatric population. This paper emphasizes newer physiological imaging data, which suggest that DVA drainage has less physiological flexibility than otherwise normal venous drainage development.