CNS Anomalies Research Articles

Fetal Brain Structure and CNS Anomalies

Fetal Brain Structure and CNS Anomalies

Role of fetal MRI to diagnose abnormal cerebral ventricular system and associated fetal brain anomalies

BackgroundAbnormal cerebral ventricular system is one of the most common clinical indications for fetal MRI, mainly to detect other associated abnormalities that can be occult on prenatal ultrasonography. Although using ultrasound can identify most anomalies, MRI is known to be superior in identifying CNS anomalies as it has higher contrast resolution for brain parenchymal assessment added to the fact of being less affected by fetal positioning, oligohydramnios, maternal obesity, and reverberation artifacts. Fetal brain ventriculomegaly is defined as atrial width of > 10 mm on sonography, measured in the axial plane, at the level of the frontal horns, cavum septi pellucidi, and glomus of the choroid plexus perpendicular to the long axis of the lateral ventricle. One of the most important factors determining the fetal neurological outcome is the presence and severity of additional CNS anomalies that are better clarified by MRI. The aim of this study is to establish the role of fetal MRI in detecting the association between abnormal cerebral ventricular system and other CNS anomalies, correlation with the severity of ventriculomegaly and ventricle asymmetry.ResultsThirty pregnancies with fetal brain abnormal ventricular system were included in this study, 5 cases with isolated corpus callosum (CC) agenesis (16.666%); 2 cases with cystic lesions [one interhemispheric and the other dorsal] (6.666%) both associated with CC agenesis; 1 case with alobar holoprosencephaly (3.333%) associated with CC agenesis; 2 cases with semi-lobar holoprosencephaly (6.666%) [associated with CC agenesis and one of them is also associated with lissencephaly]; 3 cases with Dandy–Walker Malformation (DWM) (10%) [2 isolated and 1 associated with CC agenesis]; 3 cases with Dandy–Walker Variants (DWV) (10%) [1 isolated and 2 associated with CC agenesis]; 2 cases with Joubert syndrome (6.666%); 1 case isolated lissencephaly (3.333%); 4 cases of obstructive ventriculomegaly (13.333%) (1 of which associated with CC agenesis); 1 case of Arnold Chiari malformation type II (3.333%) associated with CC agenesis; 2 cases with meningoceles (6.666%) (occipital and parieto-occipital); 1 case with Mega cisterna Magna (3.333%); 1 case with anencephaly (3.333%); 1 case with right hemimegalencephaly (3.333%) (associated with frontal meningocele and CC agenesis); and 1 case with grade IV germinal matrix hemorrhage (3.333%). The pregnancies resulted in 20 births (66.66%), 2 died directly after birth (6.66%), 5 terminations (16.66%), and 3 intrauterine fetal deaths (IUFD) (10%). We found that the frequency of associated CNS anomalies was strongly related to the width of the ventricle. The association between CNS findings and ventricle width was particularly evident in sever ventriculomegaly. The greater the width of the ventricular system, the more the risk of associated CNS anomalies. Only one case showed diffusion restriction and was diagnosed to be of hemorrhagic nature. The relation between symmetry and degree of ventriculomegaly was found to be statistically insignificant (P = 0.115). Assessment of different fetal brain congenital anomalies was not significantly affected by the using of DWI sequence as it is a functional modality rather than being a tool for assessment of anatomical gross abnormalities.ConclusionsFetal MRI is an important adjuvant to US in cases of ventriculomegaly particularly those associated with complex CNS anomalies. The association between CNS findings and ventricular dilatation was particularly evident in sever ventriculomegaly. The greater the width of the ventricular system, the more the risk of associated CNS anomalies. Fetal MRI may also be helpful in doubtful cases that could be misdiagnosed as ventriculomegaly including holoprosencephaly, hydranencephaly, porencephaly, and various supratentorial cystic lesions. DWI confirms the diagnosis of hemorrhage.

Association of folic Acid deficiency with Central Nervous System Anomalies, Anencephaly, Spina bifida and Hydrocephalous Diagnosed by Ultrasonography during Embryonic and Fetal period

Aim: To see central nervous system anomaly during pregnancy (anencephaly, hydrocephalus and spina bifida) by ultrasonography associated with folic acid deficiency/ low intake. Study design: cross sectional Site and duration: one year from Jan 2021 to Dec 2021 at Pak Red Crescent Medical & Dental College and teaching Hospital Dina Nath Multan Road Kasur. Method: There was convenient sampling. Written Consent was taken from mothers for participation in study. Pregnant mothers were examined by ultrasonography and color Doppler Machine. Designated proforma was filled by taking history of pregnant mother. Results: The mean age of mothers was 25.oo + 5.00. Most of mothers were in 3rd trimester and Gravida 2. In eleven percent cases CNS anomalies were seen among these 6% were anencephaly and 5% were Spina bifida and hydrocephalus. Conclusion: Central nervous system anomalies were found associated with folic acid low intake by mothers during pregnancy. Keywords: Anencephaly, Hydrocephalus, Spina bifida, Folic acid intake, Ultrasonography.

Ultrasound markers of chromosome aberrations on routine second trimester screening

Second trimester ultrasound examination for risk assessment of chromosomal abnormalities remains an important component of prenatal evaluation. We have conducted a retrospective study to evaluate the efficiency of ultrasonographic screening for the markers of chromosomal aberrations and to classify ultrasonographic markers according to the aberration they were found with. Over a 10 year period we performed 620 karyotype analyses of fetal blood taken by cordocentesis after detection of fetal anomalies in a second trimester scan in unselected population and 216 samples of peripheral blood of neonates having phenotypic features suspected for chromosomopathies. Ultrasound examination and cytogenetic data were obtained from the laboratory database. Chromosomal abnormalities were found in 36 (5,8%) fetuses with anomalies. Most frequently chromosomal aberrations were detected in fetuses with multiple anomalies (13,3%), heart anomalies (11,5%), short femurs (12,5%) and polyhydramnios (7,7%). The success rate of sonographic examination in detection of Down syndrome was 85%, and in detection of sex chromosome trisomies 80%. Trisomy 18, trisomy 13 and polyploidy were found prenatally in 100% each. Nearly 42% of trisomy 21 fetuses had heart anomaly, 35,3% polyhydramnios and 17,7% short femurs. Trisomy 18 fetuses had polyhydramnios in 87,5%, CNS anomalies in 62,5% and symmetrical IUGR in 50% of cases. All of the fetuses with monosomy X had short femurs. Ultrasonographic evaluation is the most sensitive screening method for the identification of fetuses having a high risk rate for chromosomal abnormalities in a low risk population.

Riscos dos efeitos teratogênicos da isotretinoína e suas propriedades farmacológicas em mulheres sexualmente ativas

Introduction: Isotretinoin, also known as 13-cis-retinoic acid, belongs to the group of compounds derived from vitamin A. Objective: This work aims at women with active sexual life and during pregnancy, the teratogenic effects of the drug, as well as how to describe your clinical indication. Methodology: This is a systematic review of the literature, of scientific articles, in the databases indexed in the SciELO, Google Scholar, Birene, VHL and PubMED data portal, between 2000 and 2020. Results: Isotretinoin can be used in various dermatoses. The main adverse reactions include: dryness of the mucous membranes and skin. Teratogenicity being the main adverse effect, causing craniofacial anomalies, cardiovascular defects, cleft palate, ocular, auricular, skeletal and CNS anomalies. The acne treatment protocol with the use of isotretinoin determines some restrictions; in women of childbearing age, requires that they undergo two pregnancy tests, both of which must be negative. This drug is subject to special control provided for in Ordinance 344/1998. Conclusion: Thus, isotretinoin requires greater care in women who are sexually active, due to its high teratogenicity, in which case it is necessary to advise them on the use of contraceptives during treatment with isotretinoin.

Fetal magnetic resonance imaging (MRI) enhances the diagnosis of congenital body anomalies

AimsWe sought to assess variability and concordance between fetal MRI and ultrasound (USS) in the evaluation of fetal body abnormalities. MethodsAll fetal body anomalies reported on F-MRI within the iFIND database (http://www.ifindproject.com) were included. Differences in findings regarding anomalies on contemporaneous USS were explored. Three clinical specialists evaluated each case independently, and the anomaly severity was graded: as “insignificant” to “lethal”. The value of MRI in alteration of either antenatal or postnatal care was established. ResultsFifty-four cases were identified consisting of 5 healthy controls, 37 with USS-identified body anomalies, and 12 with known CNS or cardiac anomalies. In fetuses with a known body anomaly, information on the MRI was relevant to change the clinical course in 59% of cases. There was also an incidental detection rate of 7% in fetuses with known cardiac or CNS anomalies, or 1.5% of normal control, although these were rarely clinically relevant.Importantly, fetuses undergoing MRI for cardiac concerns did have major anomalies that were missed (one case of oesophageal atresia and two cases of ARM). ConclusionsIn cases where fetal anomalies are suspected, F-MRI is a valuable means of further characterizing anomalies and may detect additional anomalies in fetuses with recognized cardiac or CNS anomalies. In fetuses with a recognized body anomaly, more than half of those scanned by MRI had information available which changed clinical management. Importantly there were also incidental findings in healthy control fetuses, so the management of these needs to be recognized in fetal MRI research. Level of evidenceII, Prospective cohort study.

OC01.06: Clinical utility of assessing the embryonic brain by ultrasound at 7–10 weeks of gestation

To assess the clinical utility of assessing the embryonic brain and cranium by ultrasound at 7–10 weeks of gestation. 1000 consecutive cases of clinically indicated scans at 7-10 weeks were evaluated prospectively to assess the clinical utility of evaluating cranial and brain morphology in cases with bleeding, pelvic pain, previous pregnancy losses, and those requesting for reassurance scans or an early scan. All embryos were assessed by transabdominal scans, supplemented by transvaginal scans. 3D studies were utilised routinely. The evaluation was part of a larger study of complete embryonic morphology. Observations were categorised into normal studies, conclusive abnormal morphology, need for follow up at 11-14 weeks to confirm an anomaly and early genetic consultation. All patients were followed up with an 11-14 weeks and an 18-22 weeks' study unless there was a fetal demise or termination of pregnancy. All pregnancies that went to term were assessed by a clinical neonatal evaluation. A total of 61 embryos had an abnormal morphology and 19 of these had a cranial/brain anomaly. Of the 19 cranial and brain anomalies, seven embryos were non-viable at the time of scanning. Seven embryos had acrania, four anencephaly, three holoprosencephaly, one occipital encephalocele and four ventriculomegaly. 21 embryos in the original cohort had gray zone findings, of which 11 were normal on follow up and 10 were abnormal, all at the 11-14 week window. Of these five had CNS anomalies. There is a significant number of embryos with brain/cranial anomalies recognisable in early pregnancy in patients with clinically indicated scans at 7-10 weeks. It is prudent to include embryonic morphology at this period of ultrasound evaluation to triage pregnancies towards definitive management, early follow up, initiation of genetic evaluation or follow up at 12-14 weeks. Importantly, a change in management direction from routine NIPT at 10-11 weeks to a genetic consultation is possible.

VP53.02: Clinical characteristics and outcome of fetal partial agenesis of septum pellucidum

Agenesis of septum pellucidum (ASP) has an excellent prognosis when is isolated. Available series in ASP include few cases of the partial ASP (pASP) subgroup, probably because it is a very uncommon and misdiagnosed condition. Thus, our objective was to describe clinical characteristics and outcomes of pSAP. Retrospective study including fetuses diagnosed of pASP in our neurosonography unit from January 2019 to December 2020. Cases secondary to destructive origin were excluded. We collected data from advanced neurosonography and magnetic resonance including gestational age (GA) at diagnose, the evaluation of the optic nerves and chiasma, the presence of associated CNS and non-CNS anomalies and the presence of the pituitary gland. All cases have genetic study with array-CGH. pASP was considered as isolated when no other prenatal findings were detected. Postnatal data included MRI after delivery, evaluation of the visual system, endocrine tests and clinical neurologic follow-up. Seven patients with a prenatal diagnosis of pASP were included. Mean GA at diagnose was 27.2 weeks (range 24.1-30.7). pASP was considered isolated in 4 fetuses and all are developing normally at 13 months (range 8-16). From the three fetuses considered non-isolated, one with other CNS findings (mild ventriculomegaly, cortical maturation delay in operculum area and cerebellar growth in the lower limit) presents delay in language acquisition at 17 months; one with other CNS and non-CNS findings (column fornix fusion, dilatation of anterior horns, short corpus callosum, ARSA and low implantation ears) is considered as SOD spectrum at 12 months; and one with non-CNS findings (unilateral cleft lip and palate) is developing normal at 18 months. pASP has a good prognosis when isolated and the presence of associated findings increases the risk of abnormal neurodevelopment. pASP is an underdiagnosed condition and further research is warranted to explore its incidence and specific prognosis.

Morphology and Morphometry of Foetal Corpus Callosum Using MRI – A Retrospective Study

Introduction: Corpus callosum (CC) is the largest commissural white fibres interconnecting cerebral hemispheres. The corpus callosum is responsible for interhemispheric transfer of information which is essential for cognitive function. The foetal corpus callosum serves as sensitive indicator for normal brain development and maturation. As the corpus callosum is a part of the highest order latest maturing mental network of the brain, its measurements are important to assess normal brain development and to locate structural changes. A comprehensive evaluation of normal human foetal corpus callosal development is essential to detect and understand the congenital anomalies of the brain. Thus, the prenatal diagnosis of partial or complete agenesis of the corpus callosum is important for predicting the normal development of the foetus. Foetal neural anomalies that are suspected on prenatal ultrasonography (USG) can be detected in early stage using foetal MRI. This imaging technique is highly useful for detailed visualization of normal neural development. Certain conditions like colpocephaly and widening of interhemispheric fissure can be clearly visualized using foetal MRI when compared to prenatal ultrasonography. Aim and objective: Was to establish the normal reference values for the measurement of foetal corpus callosum. The length and thickness of the foetal CC was measured corresponding to gestational age (GA) between 18-36weeks. Materials and methods: A retrospective MRI study was carried out in Radiology department of Sri Ramachandra Hospital. The study was conducted on 50 pregnant women with GA of 18-32 weeks and morphology of foetal corpus callosum was measured using MRI. The corpus callosum was visualized in a mid-sagittal plane as an anechoic structure, delimited by two echogenic lines superiorly by sulcus of the corpus callosum and inferiorly by the septum pellucidum. The length of corpus callosum was measured from the anterior most aspect of genu to the posterior most aspect of the splenium and the width of individual parts were measured and correlated with gestational age. The values obtained from the study were statistically calculated using regression coefficient method. Results: In the present study following parameters were observed such as length and width of diverse parts of Corpus callosum. The length of foetal CC ranged from 25.96 to 47.2 mm in 18 to 32 weeks of gestational age. The range of width of rostrum, genu, body and splenium were 1.2 to 2.2 mm, 1.2-2.8mm, 1.3-3.1mm and 1.36-3.2mm respectively. Conclusion: The periodic development of nervous system can be calculated more effectively with the morphometric measurement of foetal CC and its correlation with BPD. It is considered to be accurate than using BPD measurement of head circumference in USG. Hence, with the normative data of foetal CC measurements correlated with gestational age would give us accurate details of neuronal growth rather than measuring biparietal diameter (BPD) alone using USG. This knowledge will be highly helpful for the gynaecologists to predict the abnormal development of the foetus and it is advised to include foetal CC parameters as a one of the tools for early detection of CNS anomalies.

Detection rate of fetal CNS anomalies by first and second trimester ultrasound screening

Objectives: The aim of this study was to detect CNS abnormalities in the first and second trimester by ultrasound. Methods: This cross-sectional study was performed on pregnant women who referred to the radiology department of Imam Reza and Valiasr hospitals in Tehran-Iran during 2019-2020. After obtaining informed consent, pregnant women were screened in the first trimester at week 13-13 and then in the second trimester at week 18-20 by a 5-8 MHz Ultrasound Transducer. Each ultrasound included examination of the fetal brain and vertebrae at the axial coronal and sagittal planes in the most important anatomical areas, including the trans-thalamic (TT) or the trans-ventricular (TV) plane, transverse cerebellar, and vertebral canal plan. Ultrasound of the first and second trimesters of all mothers was performed. Information of all pregnant mothers was collected and recorded. Data analysis was performed using SPSS software version 25. Results: In this study, 2234 pregnant women were included in the study. The total rate of detected anomalies was found to be 1.3%. The rate of abnormalities detected in the first trimester was far less than in the second trimester. The prevalence of CNS anomalies in the population under 30 years of age was also found 0.9%, while it was 1.6% in the population over 30 years of age. Conclusion: Second-trimester ultrasound is the method of choice in diagnosing central nervous system abnormalities. However, first-trimester ultrasound is the diagnostic method for structural abnormalities of the skull.

Chromosomal Microarray Analysis in Pregnancies With Corpus Callosum or Posterior Fossa Anomalies.

ObjectiveWe investigated the detection rate of clinically significant chromosomal microarray analysis (CMA) results in pregnancies with sonographic diagnosis of fetal corpus callosum anomalies (CCA) or posterior fossa anomalies (PFA).MethodsAll CMA tests in pregnancies with CCA or PFA performed between January 2015 and June 2020 were retrospectively evaluated from the Israeli Ministry of Health database. The rate of CMA with clinically significant (pathogenic or likely pathogenic) findings was calculated and compared to a local Israeli cohort of 5,541 pregnancies with normal ultrasound.ResultsOne hundred eighty-two pregnancies were enrolled: 102 cases with CCA and 89 with PFA (9 cases had both). Clinically significant CMA results were found in 7/102 of CCA (6.9%) and in 7/89 of PFA (7.9%) cases. The CMA detection rate in pregnancies with isolated CCA (2/57, 3.5%) or PFA (2/50, 4.0%) was lower than in nonisolated cases, including additional CNS and/or extra-CNS sonographic anomalies (CCA-5/45, 11.1%; PFA-5/39, 12.8%), but this was not statistically significant. However, the rate among pregnancies that had extra-CNS anomalies, with or without additional CNS involvement (CCA-5/24, 20.8%; PFA-5/29, 17.2%), was significantly higher compared to all other cases (p = 0.0075 for CCA; p = 0.035 for PFA). Risk of CMA with clinically significant results for all and nonisolated CCA or PFA pregnancies was higher compared to the background risk reported in the control cohort (p < 0.001), but was not significant for isolated cases.ConclusionsOur findings suggest that CMA testing is beneficial for the genetic workup of pregnancies with CCA or PFA, and is probably most informative when additional extra-CNS anomalies are observed.

PTPN4 germline variants result in aberrant neurodevelopment and growth.

SummaryProtein-tyrosine phosphatases (PTPs) are pleomorphic regulators of eukaryotic cellular responses to extracellular signals that function by modulating the phosphotyrosine of specific proteins. A handful of PTPs have been implicated in germline and somatic human disease. Using exome sequencing, we identified missense and truncating variants in PTPN4 in six unrelated individuals with varying degrees of intellectual disability or developmental delay. The variants occurred de novo in all five subjects in whom segregation analysis was possible. Recurring features include postnatal growth deficiency or excess, seizures, and, less commonly, structural CNS, heart, or skeletal anomalies. PTPN4 is a widely expressed protein tyrosine phosphatase that regulates neuronal cell homeostasis by protecting neurons against apoptosis. We suggest that pathogenic variants in PTPN4 confer risk for growth and cognitive abnormalities in humans.

265 Hemivertebra: systematic review of cases with cytogenetic abnormalities, associated anomalies and proposed prenatal management

To identify cases of hemivertebra with abnormal cytogenetic studies and assess for other associated anomalies in order to provide more accurate patient counseling and prenatal management. This systematic review was conducted using PubMed (including Cochrane database) and Ovid Medline from inception through November 2019. Studies were deemed eligible for inclusion if hemivertebra with abnormal cytogenetic studies was identified in the fetal, neonatal, or infant period. Studies that described other vertebral anomalies were excluded. We identified 17 cases of hemivertebra with cytogenetic abnormalities among a total of 324 cases (5%) in our review. These include partial tetrasomy 4q, mosaic trisomy 4, mosaic trisomy 7, mosaic trisomy 9, mosaic trisomy 18q, mosaic trisomy 18; trisomy 7, trisomy 15q with monosomy 6q, partial trisomy 22; duplication of 2p; 4p- deletion, 17p deletion, 18p deletion, 18q22.2 deletion, 22q13.3 deletion; ring chromosome 21, and Fanconi’s anemia. 29% (5/17) were diagnosed prenatally, 47% (8/17) at birth, and 18% (3/17) postnatally. All cases had prenatally or postnatally diagnosed associated anomalies. 29% (5/17) had associated anomalies identified prenatally, including ear anomalies, CNS abnormalities, micrognathia, congenital heart defects, renal anomalies, clubfeet, and fetal growth restriction. Postnatally diagnosed anomalies commonly included: CNS (41%, 7/17), cardiac (53%, 9/17), skeletal (71%, 12/17) and genitourinary (59%,10/17). Hemivertebra with abnormal cytogenetic testing was always associated with malformations from other organ systems that could be missed by prenatal ultrasound alone. Those include CNS, cardiovascular, musculoskeletal, and genitourinary anomalies. Fetal echocardiogram is recommended due to the considerable association with congenital heart defects. Fetal neurosonography or MRI should be considered. Of those receiving genetic testing, karyotype or SNP microarray should be considered due to the common presence of mosaicism.

The Frequency, Types and Risk Factors of Congenital Anomalies in a Tertiary Neonatal Intensive Care Unit (A hospital based study)

Background: Congenital anomalies (CA) are common causes of infant’s and childhood deaths and disability. Objectives: The aim of the study is to determine the frequency, describe the types and risk factors of congenital anomalies among newborns admitted to Neonatal Intensive Care Unit (NICU) of Assiut University Children's Hospital. Study design: It is a prospective observational study (analytic cross sectional study) was performed and screening of the newborns admitted at NICU of Assiut University Children's Hospital (for 6 months) during the period from 1st December 2017 to 31st May 2018. The sample included 346 newborns, 173 cases and 173 controls. We collected data using a record checklist and an interviewing questionnaire.Results: There were significant differences between cases and controls concerning gestational age (P=0.001), single or multiple babies (P=0.002), residence (P=0.001), consanguineous marriage (P=0.01) and family history of unfavorable outcome (P=0.001). We also found that the most common type of congenital anomalies was gastrointestinal anomalies 63 cases (36.4%) with tracheoesophageal fistula 17 cases (27%) being the most common GIT anomalies. Then the musculoskeletal anomalies being the second common anomalies 14.5% with diaphragmatic hernia 10 cases being the most common in musculoskeletal anomalies followed by other anomalies (22 multiple and 1Conjoined Twins) 23 cases (13.3%) followed by cardiovascular anomalies 22 cases (12.7%), followed by CNS anomalies 18 cases (10%). Conclusions: The frequency of congenital anomalies was 22.97%. The most common anomalies were gastrointestinal anomalies (GIT), musculoskeletal anomalies, multiple anomalies and cardiovascular system anomalies. The risk factors were consanguineous marriage, positive family history, urban areas, full-term and singleton pregnancies.

Intracranial and extracranial vascular manifestations of patients with a clinical diagnosis of Klippel-Trenaunay syndrome.

While numerous reports have demonstrated intracranial CNS anomalies associated with Klippel-Trenaunay syndrome, to our knowledge, there has not been a large consecutive study examining these anomalies. The aim of this study was to determine the spectrum of intracranial neurovascular manifestations in patients with a clinical diagnosis of Klippel-Tranaunay syndrome. Consecutive patients with a clinical diagnosis of Klippel-Trenaunay syndrome, as defined by the International Society for the Study of Vascular Anomalies, who underwent brain contrast-enhanced CT/computed tomography angiography, MRI/magnetic resonance angiography, or digital subtraction angiography at our institution from 2000 to 2019 were included. Studies were evaluated by a neuroradiologist and a senior radiology resident for the presence of cavernous malformations, developmental venous anomalies, venous sinus developmental abnormalities, craniofacial venous malformations, intraosseous venous malformations, and intracranial/extracranial venous abnormalities. Fifty patients with definite KTS were included. Thirty-four neurovascular anomalies were found in 17 patients (34.0%), including 8 with multiple anomalies. Nine patients had developmental venous anomalies (18.0%), 7 had craniofacial venous malformations (14.0), 6 had venous sinus developmental abnormalities (12.0%), 7 had intraosseous venous malformations (14.0%), and 2 had cavernous malformations (4.0%), and 9 patients had both intracranial venous abnormalities and craniofacial or calvarial findings (13.0%). Our findings demonstrate that Klippel-Trenaunay syndrome can involve a wide spectrum of intracranial neurovascular anomalies predominantly involving the venous system.

Neurological Damage by Coronaviruses: A Catastrophe in the Queue!

Neurological disorders caused by neuroviral infections are an obvious pathogenic manifestation. However, non-neurotropic viruses or peripheral viral infections pose a considerable challenge as their neuropathological manifestations do not emerge because of primary infection. Their secondary or bystander pathologies develop much later, like a syndrome, during and after the recovery of patients from the primary disease. Massive inflammation caused by peripheral viral infections can trigger multiple neurological anomalies. These neurological damages may range from a general cognitive and motor dysfunction up to a wide spectrum of CNS anomalies, such as Acute Necrotizing Hemorrhagic Encephalopathy, Guillain-Barré syndrome, Encephalitis, Meningitis, anxiety, and other audio-visual disabilities. Peripheral viruses like Measles virus, Enteroviruses, Influenza viruses (HIN1 series), SARS-CoV-1, MERS-CoV, and, recently, SARS-CoV-2 are reported to cause various neurological manifestations in patients and are proven to be neuropathogenic even in cellular and animal model systems. This review presents a comprehensive picture of CNS susceptibilities toward these peripheral viral infections and explains some common underlying themes of their neuropathology in the human brain.

Craniofacial Anomaly Association with the Internal Malformations in the Pediatric Age Group in Al-Fallujah City-Iraq

Objectives To estimate the prevalence of craniofacial anomalies among Iraqi people and its association with other congenital malformations. Methods A hospital-based cohort study. It was conducted in Iraq, Fallujah city from Jan 2019-April 2019. The pediatric age group below 16 years attending the consultation clinic. Results The prevalence rate of craniofacial anomalies was 2%. There were 43 (54%) males and 37 (46%) females. A 55 cases (69%) out of total 80 cases have an association with other internal congenital malformations, and 25 cases (31%) have no association. Those associated internal malformations were categorized according to their types into congenital heart disease 33(60%), Renal diseases 9 (16%), CNS anomalies 8(15%), and GIT anomalies 5(9%). Conclusions Craniofacial anomalies showed a relatively higher prevalence rate in comparison to other studies worldwide. It was found that the majority of craniofacial anomalies might be associated with other congenital systemic malformations. Furthermore, the necessary actions to identify the frequency and risk factors associated with craniofacial anomalies in the Iraqi population are emphasized to put a better strategy to establish future preventive programs and treatment.

OR02-01 Gene Dosage Changes in RBFOX-2 Can Affect Upper and Lower Tract Genitourinary Development

Searching for genetic and genomic alterations in patients with genitourinary (GU) birth defects can aid in the identification of genes that are important for normal GU development. Using data in DECIPHER, RBFOX-2, located at 22q12 was identified as one such candidate gene and the effect of haploinsufficiency in humans and a mouse model (Rbfox-2α/+) assessed. RBFOX2 is an RNA-binding protein regulating alternative splicing. It also impacts steroid receptor transcriptional activity. RBFOX family members are thought to affect different developmental programs via isoform-specific localization and splicing activities. RBFOX-2 plays a vital role in multiple developmental processes including heart, brain, muscle and testis development. “Non-syndromic” patients with congenital GU anomalies were more likely to harbor RBFOX-2 CNVs (2.4%; hypospadias, 21% cryptorchidism, 29% vesicoureteral reflux and 29% ureteropelvic junction obstruction) relative to the general population (0.11%) indicating that 22q12 is a hotspot genetic locus for GU anomalies. CNVs (microdeletions and microduplications) spanning RBFOX-2 were identified in twenty-seven humans with a wide range of birth defects(intellectual disability, CNS, cardiac, genitourinary, facial, hearing, vision, growth and stature anomalies) and the phenotype of the haploinsufficient Rbfox-2α/+mouse model closely correlated with the human phenotype, although Rbfox-2α/+ andRbfox-2α/α are neonatal lethal. By E18.5 day of development 100% of the Rbfox-2α/+ and null fetuses exhibited hypospadias, megacystis (50%) and bilateral hydroureteronephrosis. RNA Seq was performed on genital tubercles from three Rbfox2fl/fl, Gdf9 icre+ and three Rbfox2fl/fl P1 males. 377 genes were differentially expressed between the two groups including 212 genes which were upregulated and 165 genes which were downregulated. Hallmark gene set analysis revealed downregulation of Wnt/β-catenin signaling and hedgehog signaling, both pathways which are well defined in genital development. Gene ontology (GO) analysis further defined downregulation of pathways (fibroblast growth factor, retinoic, androgen, estrogen and G-protein receptor signaling) including those involving negative regulation of embryonic development, epithelial development, morphogenesis of epithelial tube, renal, ureter, limb and several other developmental pathways. These results support the hypothesis that loss of Rbfox2 during development leads to hypospadias through impaired development of the urethral epithelium.

Microcephalic osteodysplastic primordial dwarfism type II: Additional nine patients with implications on phenotype and genotype correlation.

PCNT encodes a large coiled- protein localizing to pericentriolar material and is associated with microcephalic osteodysplastic primordial dwarfism type II syndrome (MOPD II). We report our experience of nine new patients from seven unrelated consanguineous Egyptian families with the distinctive clinical features of MOPD II in whom a customized NGS panel showed homozygous truncating variants of PCNT. The NGS panel results were validated thereafter using Sanger sequencing revealing three previously reported and three novel PCNT pathogenic variants. The core phenotype appeared homogeneous to what had been reported before although patients differed in the severity showing inter and intra familial variability. The orodental pattern showed atrophic alveolar ridge (five patients), rootless tooth (four patients), tooth agenesis (three patients), and malformed tooth (three patients). In addition, mesiodens was a novel finding found in one patient. The novel c.9394-1G>T variant was found in two sibs who had tooth agenesis. CNS anomalies with possible vascular sequelae were documented in two male patients (22.2%). Simplified gyral pattern with poor development of the frontal horns of lateral ventricles was seen in four patients and mild thinning of the corpus callosum in two patients. Unilateral coronal craniosynstosis was noted in one patient and thick but short corpus callosum was an unusual finding noted in another. The later has not been reported before. Our results refine the clinical, neuroradiological, and orodental features and expand the molecular spectrum of MOPD II.

MP65-12 MURINE RBFOX-2 HAPLOINSUFFICIENCY PARALLELS CONGENITAL ANOMALIES IN HUMAN PATIENTS WITH RBFOX-2 COPY NUMBER VARIANTS

You have accessJournal of UrologyPediatrics: Hypospadias and Penile Surgery (MP65)1 Apr 2020MP65-12 MURINE RBFOX-2 HAPLOINSUFFICIENCY PARALLELS CONGENITAL ANOMALIES IN HUMAN PATIENTS WITH RBFOX-2 COPY NUMBER VARIANTS Jeffrey White, Marisol O'Neill, Kunj Sheth, and Dolores Lamb* Jeffrey WhiteJeffrey White More articles by this author , Marisol O'NeillMarisol O'Neill More articles by this author , Kunj ShethKunj Sheth More articles by this author , and Dolores Lamb*Dolores Lamb* More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000940.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Copy number variants (CNVs) are micro-deletions or micro-duplications of a chromosome. When these occur in a dosage-sensitive gene, birth defects can develop. Hypospadias is a common, externally identifiable genitourinary birth defect. We hypothesized that, through a top-down approach utilizing CNVs from patients with hypospadias, novel genes in penile development can be discovered. METHODS: By searching CNV databases for hypospadias, candidate genes were identified. Four hypospadic patients had CNVs in the RNA binding FOX 2 (RBFOX-2) gene. TaqMan CNV assays identified the incidence of RBFOX-2 CNVs. By crossing Gdf9-Cre mice with conditional Rbfox-2-Flox mice, Rbfox-2Δ/+ mice (single copy deletion of Rbfox-2) were analyzed using microCT. Gene expression analyses were performed with in vitro and in vivo models. RESULTS: Seventeen patients with RBFOX-2 CNVs were identified in DECIPHER: 4 had hypospadias, 8 had intellectual disabilities, 7 had CNS anomalies, 7 had cardiac defects, and 3 had facial deformities. Though RBFOX-2 CNVs are not common in population-level database (Database of Genomic Variants, 0.11%, n=42,511, p=0.3), samples from patients with GU birth defects identified 11 (2.4%, n=450) with CNVs for RBFOX-2: 21% with hypospadias, 21% cryptorchidism, 29% vesicoureteral reflux and 29% ureteropelvic junction obstruction. When compared with controls (0.0%, n=64), an enrichment of RBFOX-2 CNVs was discovered in GU birth defect patients (p<0.01). A murine model of Rbfox-2 haploinsufficiency was analyzed at E14.5, E16.5 and E18.5. MicroCT was performed to assay for phenotypes. Head defects (hydrocephalus, branchial arch defects and facial asymmetry), chest anomalies (asymmetric cardiac hypertrophy and septal anomalies), abdominal phenotypes (bile duct anomalies and omphalocele), spinal anomalies (neural tube defects), kidney phenotypes (hydroureteronephrosis), and genital tubercle (GT) anomalies (hypospadias) were discovered. Through in vitro and in vivo studies, RBFOX-2 was discovered to have a role in FGFR2 splicing in penile development. CONCLUSIONS: RBFOX-2 gene dosage changes are enriched in patients with GU birth defects but several other organ systems may also be affected. Murine models of Rbfox-2 haploinsufficiency parallel anomalies of humans with RBFOX-2 CNVs. Our data suggest that RBFOX-2 regulates mesenchyme-to-epithelial transitions in the penis and may play a role in basic developmental programs which regulate many organ systems. Source of Funding: This project was supported by the Urology Care Foundation Research Scholar Award funded by the Society of Pediatric Urology and the Sushil Lacy, MD Foundation as well as NIH R01DK078121 © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e978-e978 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jeffrey White More articles by this author Marisol O'Neill More articles by this author Kunj Sheth More articles by this author Dolores Lamb* More articles by this author Expand All Advertisement PDF downloadLoading ...