Central Nervous System Defects Research Articles

Features of gestational period and perinatal outcomes in women with insulin resistance

Aim. To study the course of pregnancy and perinatal outcomes in women with insulin resistance. Material and methods. A retrospective and prospective study of 102 women and their newborns who were born in the State Institution “Research Institute of Obstetrics, Gynecology, and Perinatology” for the period 2017-2019 was conducted. All pregnant women were divided into 3 groups according to the level of insulin resistance index (NOMA index). Group I - 42 pregnant women with developmental risk factors for diabetes with an insulin resistance index above 2.84. Group II consisted of 30 subjects with a NOMA index below 2.21, and Group III (n = 30) consisted of healthy pregnant women with a physiological course of pregnancy and labor. Results. Newborns born to women with a NOMA index above 2.84 (pathological insulin resistance) have a high incidence of perinatal complications: central nervous system defects, various degrees of asphyxia, hypotrophy, and immaturity. Conclusion. Insulin resistance in general affects pregnancy and has a negative impact on the course of pregnancy, causing a high incidence of complications such as threatened miscarriage, preeclampsia, chronic placental insufficiency and affecting perinatal outcomes.

Birth Defects among Newborns in a Tertiary Care Centre: A Descriptive Cross-sectional Study.

The incidence of birth defects is 2-3% in the general population but it is increasing. An estimated 303,000 newborns die within 4 weeks of birth every year, worldwide, due to congenital anomalies. The objective of this study was to find out the prevalence of birth defects among newborns in a tertiary care centre. A descriptive cross-sectional study was done in the Department of Obstetrics and Gynaecology and the Department of Paediatrics from 15 June 2016 and 14 June 2019. Ethical approval was obtained from the Institutional Review Committee (Reference number: 142/077/078-IRC). Data of newborns were collected from the hospital records. Convenience sampling method was used. Point estimate and 99% Confidence Interval were calculated. Among 32,695 newborns, birth defects were seen in 169 (0.51%) (0.41-0.61, 99% Confidence Interval). The most common birth defect was musculoskeletal defects seen in 60 (35.50%) newborns followed by central nervous system defect seen in 30 (17.75%) newborns. The prevalence of birth defects among newborns was lower than in other studies done in a similar setting. birth defect; congenital malformation; prevalence.

Risk of birth defects by pregestational type 1 or type 2 diabetes: National Birth Defects Prevention Study, 1997-2011.

Previous studies found consistent associations between pregestational diabetes and birth defects. Given the different biological mechanisms for type 1 (PGD1) and type 2 (PGD2) diabetes, we used National Birth Defects Prevention Study (NBDPS) data to estimate associations by diabetes type. The NBDPS was a study of major birth defects that included pregnancies with estimated delivery dates from October 1997 to December 2011. We compared self-reported PGD1 and PGD2 for 29,024 birth defect cases and 10,898 live-born controls. For case groups with ≥5 exposed cases, we estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the association between specific defects and each diabetes type. We calculated crude ORs (cORs) and 95% CIs with Firth's penalized likelihood for case groups with 3-4 exposed cases. Overall, 252 (0.9%) cases and 24 (0.2%) control mothers reported PGD1, and 357 (1.2%) cases and 34 (0.3%) control mothers reported PGD2. PGD1 was associated with 22/26 defects examined and PGD2 was associated with 29/39 defects examined. Adjusted ORs ranged from 1.6 to 70.4 for PGD1 and from 1.6 to 59.9 for PGD2. We observed the strongest aORs for sacral agenesis (PGD1: 70.4, 32.3-147; PGD2: 59.9, 25.4-135). For both PGD1 and PGD2, we observed elevated aORs in every body system we evaluated, including central nervous system, orofacial, eye, genitourinary, gastrointestinal, musculoskeletal, and cardiac defects. We observed positive associations between both PGD1 and PGD2 and birth defects across multiple body systems. Future studies should focus on the role of glycemic control in birth defect risk to inform prevention efforts.

Accuracy and clinical utility of standard postmortem radiological imaging after early second trimester termination of pregnancy

ObjectiveThis study aims to assess accuracy and clinical utility of postmortem radiological exams [Magnetic Resonance Imaging (MRI), Computed Tomography (CT) and Radiography (XR)] after termination of pregnancy at <23 weeks’ gestation for congenital fetal malformations in comparison to autopsy. Study designThis a prospective single-center study on fetuses underwent termination of pregnancy for fetal defects. Overall concordance between any radiological exam and autopsy was evaluated. For postmortem MRI only, the following subgroups were analyzed: 1) total agreement; 2) agreement for main findings; 3) agreement for main findings but major relevant additional findings at autopsy; 4) total disagreement. Results174 cases were collected. The overall concordance with autopsy for main findings was 71% (115/163) for postmortem MRI and 99% (173/174) for prenatal ultrasound (US). Postmortem MRI detection rate was high for central nervous system (CNS) defects (98%), gastrointestinal, genitourinary and respiratory defects (100%), while it was poor for cardiovascular and musculoskeletal defects (25% and 42%, respectively). For musculoskeletal abnormalities, the performance of postmortem XR and postmortem CT exams improved the detection rate from 42% for postmortem MRI alone to 92%. ConclusionsPostmortem MRI has a good overall concordance for fetal defects after termination of pregnancy performed at <23 weeks. Along with autopsy, postmortem MRI may be offered for all cases of CNS defects in order to prevent inconclusive exams due to autolysis of the brain tissue, while postmortem CT and postmortem XR are indicated for musculoskeletal defects. In the presence of multiple abnormalities or cardiac defects the couple should be counseled on the poor performance of radiological investigations.

Benzoresorcinol induces developmental neurotoxicity and injures exploratory, learning and memorizing abilities in zebrafish

Benzophenones (BPs) are a class of UV absorber commonly used in skin care products like sunscreens. With its wide range of application, its environmental and human hazards have received much attention in recent days. Previous studies on the toxicity of BPs mainly focused on its endocrine-disrupting effects, but there are limited studies on its neurodevelopment and neurotoxicity. Herein, using the zebrafish model we studied the neurodevelopmental- and neuro-toxicity of benzophenone 1 (BP1) (0.8, 1.0, 1.2, 1.6, and 2.4 μg/mL). As a result, BP1 led to an increase of embryo mortality, a decrease in hatching rate, and an increase in the rate of developmental abnormalities in a concentration-dependent manner. BP1 also caused developmental defects in the central nervous system (CNS) and dopaminergic (DA) neurons. Accordingly, BP1 injured larval zebrafish general locomotion and response to stimuli in light/dark challenge. In adult zebrafish, BP1 exposure (1, 10, 100, 1000 μg/L) caused inhibition of learning and memory abilities in the T-maze tests, and inhibited exploratory behavior and activity in the novel tank diving tests. Further, transcription levels of genes related to neurotoxicity, neurodevelopment, and anxiety revealed that BP1 may affect the development and function of the myelin sheath, inducing structural and functional defects of CNS, manifested as abnormal behaviors such as anxiety. Hence, the current study revealed the neurodevelopmental toxicity and neurotoxicity of BP1, expanded our knowledge about the toxic effects of BP1 on organisms, posing a possible threat to the environment and human health.

Retrospective clinical evaluation of indications for termination of pregnancies due to fetal anomaly

Objective:To assess the indications for termination of pregnancy (TOP) in pregnant patients who were followed up with suspicion of fetal anomaly in a Turkish tertiary referral center.Material and Methods:This retrospective study was carried out in patients who were followed up with suspicion of fetal anomaly between May 2016 and May 2019 at the Perinatology Clinic of Obstetrics and Gynecology Department in Pamukkale University Hospital, which is a tertiary hospital in Denizli province in Turkey. Women were divided into two depending on gestational period: group 1 ≤22 weeks; and group 2 (>23 weeks of gestation).Results:Four hundred and seventeen pregnant women were evaluated and TOP was performed at a mean gestational age of 27.7±6.3 weeks. There were 308 (73.8%) women in group 1 and 109 (26.2%) in group 2. The decision to terminate pregnancy was due to fetal anomaly in 117 (28.1%). The majority of termination pregnancies in group 2 were performed because of multiple malformations and/or central nervous system defects. All chromosomal diseases were detected in group 1.Conclusion:With a good perinatal screening program, fetal anomalies can be diagnosed early. Therefore, early TOP is possible. Thus, pregnancy termination can be made before reaching the life limit.

EP171: Family of three with truncating pathogenic variant in NFIA leading to central nervous system and urinary tract defects

The nuclear factor I type A (NFIA) protein is part of a family of DNA-binding proteins that act as transcription factors that are pivotal to the proper development of the central nervous system, particularly neuronal and glial cell differentiation and migration. Previous studies have demonstrated that heterozygous NFIA gene variants cause Brain Malformation with or without Urinary tract defects (BRMUTD, OMIM 613735) which is associated with hypoplasia of the corpus callosum, hydrocephalus, urinary tract defects, and developmental delays.

A new association of Oculoauriculovertebral spectrum and persistent fifth aortic arch -double lumen aorta: a case report

BackgroundOculo-auriculo-vertebral spectrum is a heterogeneous group of genetic disorder, also known as Goldenhar Syndrome, which has several phenotypic features including craniofacial anomalies, cardiac, vertebral and central nervous system defects. Cardiovascular anomalies include ventricular septal defects, atrial septal defects, patent ductus arteriosus, Tetralogy of Fallot, double outlet right ventricle, aberrant right subclavian artery, coarctation of aorta, transposition of the great arteries, double inlet left ventricle, cor triatriatum, pulmonary artery stenosis, aortic stenosis, persistent left superior vena cava, partially or totally abnormal pulmonary venous return and bicuspid aortic valve. Persistent fifth aortic arch, also named as double lumen aortic arch, is a very rare cardivascular anomaly and usually associate other cardiac defects.Case presentationWe present a 7 month old patient with oculo-auriculo-vertebral spectrum signs as facial asymmetry, short neck, choanal atresia, cleft palate, bilateral preauricular skin tags, bilateral hypoplastic ear lobes, epibulbar dermoid cyst, rib, vertebrae and cardiovascular anomalies. Cardiovascular anomalies detected with echocardiography and computed tomography were malalignment ventricular septal defect and double lumen aorta, known as persistent fifth aortic arch.ConclusionVarious cardiovascular anomalies may accompany Goldenhar Syndrome. We present a case with persistent fifth aortic arch and Oculo-auriculo-vertebral spectrum and this is a new association that was not reported before in the literature.

Corticomuscular Adaptations in the SingleLeg Jump Task in Response to Progressive Mechanical Perturbation Training in Individuals With Anterior Cruciate Ligament Deficiency

Introduction: Studies have repeatedly discussed the importance of training with sufficient cognitive and sensory-motor challenges in successfully transferring Anterior Cruciate Ligament Deficiencies (ACLDs) from rehabilitation centers to sports facilities. For this purpose, this study investigated the effect of mechanical perturbation training and standard training on the brain and muscle activity of these individuals while jumping on one leg. Materials and Methods: A total of 30 athletes with unilateral Anterior Cruciate Ligament (ACL) rupture (in the coper classification) were randomly assigned to perturbation and standard training groups. To compare the effect of two types of intervention training methods, we examined the Similarity Index (SI) and Voluntary Response Index (VRI) in surface Electromyography (sEMG) tests of eight muscles in the lower extremities and relative power of alpha and beta spectra in Quantitative Electroencephalographic (QEEG) tests between two groups and between two limbs of each group members in the single-leg jump task. Results: Both training groups showed improved neuromuscular control and increased SI on sEMG tests between the two limbs. However, this improvement in the perturbation training group showed an excellent increase in Effect Size (ES) (intra-group comparison values of SI for perturbation training group P=0.0001, ES=3.6; and P=0.008, ES=1.24 in the standard training group; and P=0.04, ES=0.87 in the inter-group comparison). Regarding the post-test of QEEG tests, no significant difference was found between the two groups (alpha P-value: 0.13, beta P-value: 0.07). However, in the intra-group comparison, the perturbation training group achieved excellent symmetry for the relative power spectrum of alpha and beta signals (the similarity values between the two limbs in the perturbation training group for alpha were P=0.92, ES=0.04 and for beta were P=0.92, ES=0.02; and these values for standard training group for alpha were P=0.07, ES=0.86 and for beta as P=0.08, ES=0.87). Conclusion: The present study results showed that mechanical perturbation and standard training are suitable for transporting ACLDs to sports environments. Furthermore, in comparing these two training methods, mechanical perturbation training in the manner used in this study has higher adequacy to eliminate motor control and central nervous system defects.

Oromandibular limb hypogenesis syndrome: a singular variation of a rare syndrome: a case report

Background:A positive prenatal history of maternal fever has been found to express as a range of defects in infants including limb reduction, central nervous system defects, facial dysmorphogenesis and foetal death. Oromandibular limb hypogenesis syndrome is a rare spectrum of congenital disorders characterised by malformations of the tongue, mandible, maxilla and limbs. They present as sporadic cases with extremely low incidence and seldom occur with associated syngnathia. Syngnathia can manifest as fibrous, bony or in combination.Observation:Here we represent a rare case of Oromandibular limb hypogenesis syndrome type IV E with combination of syngnathia, cleft palate, retrognathia and hypoglossia-hypodactylomelia. An early surgical release of syngnathia was undertaken on having features of failure to thrive, high risk of aspiration and related complications due to enteral feeding.Conclusion:Delaying the surgical procedure could result in growth restriction and progressive ankylosis of the Temporomandibular joint (TMJ). It is essential to document the singular variant of Oromandibular limb hypogenesis syndrome (OLHS) to the medical literature.

The use of hippotherapy in shaping the body posture and balance in children with Down syndrome

Down syndrome (DS) is one of the most common genetic developmental disorders that is caused by a trisomy of the 21st chromosome pair. The incidence of Down syndrome in the general population is estimated at 1/732 infants. This percentage increases significantly with the increasing age of women in labour. Down syndrome manifests itself in a variety of signs and symptoms. The signs mainly refer to abnormalities in the structure of the central nervous system, internal organs, eye and skeletal system defects. Both aspects of development, i.e., physical and mental, are delayed. One of the methods that supports the treatment of patients with DS is hippotherapy. It takes various forms, including: therapy in the form of contact with a horse, psycho-pedagogical horse riding and therapeutic horse riding. The purpose of the article was to present the influence of hippotherapy on the shaping of body posture and coordination skills with particular emphasis on body balance.

Anesthetic Management of a Patient with Goldenhar Syndrome Undergoing Emergency Caesarean Section: A Case Report

Goldenhar Syndrome (GS) is a relatively common developmental disorder characterized by craniofacial anomalies in association with vertebral, cardiac, renal, and central nervous system defects. A 24-year-old female patient reported to the Department of Obstetrics and Gynecology of with chief complaints of amenorrhea for 9 months and pain in abdomen. A provisional diagnosis of Goldenhar syndrome was made which was later confirmed by radiographic investigation Despite the presence of a difficult airway, awake fiber optic intubation was not possible as our patient refused to cooperate. We planned for general anesthesia as patient did not give consent for subarachnoid block. Patient was pre-oxygented with 100% oxygen for 3 min. Induction of patient was done with injection propofol 100mg and cricoid pressure was applied after loss of consciousness. Injection succinylcoline 100 mg was given intravenously and McGrathTM MAC video laryngoscope was used to intubate the patient. Anesthesia was maintained with nitrous oxide (60%), oxygen (40%). Atracurium was used as muscle relaxant during maintenance period. After extubation, patient was shifted to post anesthesia care unit for further observation and discharged later.

Eczema herpeticum subsequent to septic shock in early pregnancy: a first case report

BackgroundEczema herpeticum (EH) is a severe skin complication caused by human simplex virus (HSV) infection concomitant with immune dysfunction and dermatological conditions, mainly atopic dermatitis. We present the first case of EH subsequent to sepsis-related immunological suppression in pregnancy.Case presentationSeptic shock developed in a 30-year-old primiparous woman at 14 weeks of pregnancy during admission for hyperemesis gravidarum. Although her life-threatening status due to sepsis improved by prompt treatment, on day 3 of treatment in the intensive care unit, blisters suddenly erupted on her face and neck and spread over her body. EH was diagnosed according to HSV type-1 antigen positivity and a past medical history of EH and atopic dermatitis. Antiviral agents were administered immediately, with positive results. Her general condition improved quickly, without central nervous system defects. This is the first report of EH following septic shock in early pregnancy. At present, we speculate that EH develops as a complication due to immunological changes in the late phase of sepsis because sepsis is mainly characterized by both an inflammatory state in the acute phase and an immunosuppressive state in the late phase. Pregnancy can also contribute to its pathogenesis, as it causes an immunosuppressive state. Mortality due to EH is relatively high; in this case, a history of EH and atopic dermatitis contributed to the initiation of prompt medical interventions for the former, with improvement in the patient’s severe condition. The combination of immunological changes in sepsis and pregnancy can cause HSV reactivation, resulting in EH recurrence.ConclusionsIn conclusion, if dermatological symptoms develop in a pregnant woman with a history of EH and/or atopic dermatitis treated for sepsis, EH should be suspected based not only on clinical features but also on immunological changes along with sepsis, and prompt medical interventions should be initiated.

Severe types of fetopathy are associated with changes in the serological proteome of diabetic mothers.

Pregestational or gestational diabetes are the main risk factors for diabetic fetopathy. There are no generalized signs of fetopathy before the late gestational age due to insufficient sensitivity of currently employed instrumental methods. In this cross-sectional observational study, we investigated several types of severe diabetic fetopathy (cardiomyopathy, central nervous system defects, and hepatomegaly) established in type 2 diabetic mothers during 30 to 35 gestational weeks and confirmed upon delivery. We examined peripheral blood plasma and determined a small proportion of proteins strongly associated with a specific type of fetopathy or anatomical malfunction. Most of the examined markers participate in critical processes at different stages of embryogenesis and regulate various phases of morphogenesis. Alterations in CDCL5 had a significant impact on mRNA splicing and DNA repair. Patients with central nervous system defects were characterized by the greatest depletion (ca. 7% of the basal level) of DFP3, a neurotrophic factor needed for the proper specialization of oligodendrocytes. Dysregulation of noncanonical wingless-related integration site signaling pathway (Wnt) signaling guided by pigment epithelium-derived factor (PEDF) and disheveled-associated activator of morphogenesis 2 (DAAM2) was also profound. In addition, deficiency in retinoic acid and thyroxine transport was exhibited by the dramatic increase of transthyretin (TTHY). The molecular interplay between the identified serological markers leads to pathologies in fetal development on the background of a diabetic condition. These warning serological markers can be quantitatively examined, and their profile may reflect different severe types of diabetic fetopathy, producing a beneficial effect on the current standard care for pregnant women and infants.

Early Detection of Central Nervous System Abnormalities by Neurosonography in Critically Ill Neonates

Background: Neurosonography has been widely used for screening and early detection of Central Nervous System (CNS) defects, such as intraventricular hemorrhage, hydrocephalus, cerebral edema, or any structural anomalies in the neonatal brain in the neonatal intensive care unit (NICU) of a tertiary level hospital. The present study aimed to assess the detection of CNS abnormalities by neurosonography in critically ill neonates.Methods: This prospective cross-sectional study at the Neonatology Unit of the Paediatric Department of Acharya Vinoba Bhave Rural Hospital (AVBRH). A neonate was described as “critically ill” based on detailed maternal history and clinical examination. These neonates were subjected to neurosonography according to the inclusion and exclusion criteria in accordance with the noted protocols and various anomalies. Gestational age, birth weight, clinical examination, investigation, neurosonography finding, and outcomes were evaluated.Results: Neurosonography was performed in 105 critically ill neonates, out of whom 21 cases had abnormal neurosonography findings. Abnormal neurosonography was not significantly correlated with birth weight and gestational age of high-risk neonates (P=0.538 &P=0.130). The most frequent clinical manifestation was respiratory distress syndrome, followed by a neonatal seizure. The mean scores of heart rate, respiratory rate, systolic blood pressure, diastolic blood pressure, and oxygen saturation were obtained at 140±19.81, 54.08±13.07, 90.96±8.66, 54.13±8.39, and 94.39±6.93, respectively.Conclusion: Neurosonography is a useful tool in NICU. It is an acceptable and reliable modality to screen critically ill neonates, assisting the early detection and management of these ill neonates.

AN INSIGHT INTO - HEMIFACIAL MICROSOMIA

Hemifacial microsomia is a common birth defect involving first and second branchial arch derivatives. The phenotype is highly variable. In addition to craniofacial anomalies, there may be cardiac, vertebral, and central nervous system defects. Most cases are sporadic, but there are rare familial cases that exhibit autosomal dominant inheritance.

The Assessment of the Usefulness of Prenatal Magnetic Resonance Imaging in the Diagnosis of Central Nervous System Defects.

Central nervous system (CNS) abnormalities cause about 40% of infant deaths in the first year of life. In case of the detection of abnormalities by ultrasound, a pregnant woman should be offered prenatal magnetic resonance imaging (pMRI). The aims of our study were: (1) to evaluate the effectiveness of pMRI in the diagnosis of selected fetal CNS defects; and (2) to assess the possibility of replacing postnatal tests with prenatal magnetic resonance. The prospective and observational study was conducted between 2014 and 2017 at the University Hospital in Krakow. Patients with suspected CNS defects of the fetus were qualified for pMRI in the third trimester of pregnancy. Sixty patients were included in the study group. Prenatal MRI was characterized by low accuracy in the diagnosis of complex brain defects. Cohen’s kappa coefficient κ = 0.21 (95% CI 0.00–0.46). No evidence was found suggesting the replacement of postnatal tests with pMRI. MRI was characterized by low consistency of diagnoses in the case of complex brain defects. The possibility of replacing postnatal studies with pMRI was not supported.

P–546 Exome sequencing and preimplantation genetic testing for unexplained recurrent fetal malformations

Abstract Study question Could patient suffering unexplained recurrent fetal malformations be benefit of PGT-M by exome sequencing mutations identification? Summary answer Patients suffering unexplained recurrent fetal malformations could be benefit of the use of exome sequencing in combination to PGT-M to have a healthy live birth. What is known already Fetal malformations account for approximately 3% of live births and causes include: chromosomal abnormalities, exposure to toxic substances or teratogens and infections. Recently, studies have shown that several monogenic diseases are linked to fetal abnormalities. However, because of the large number of potential genes, genetic testing is challenging. Exome sequencing is widely used to detect genetic mutations and has emerged as a useful tool for finding the genetic cause of fetal abnormalities. The aim of this study was to show how exome sequencing in patients suffering unexplained recurrent fetal malformations in combination to PGT-M could lead to successful healthy newborn. Study design, size, duration Case report of a non-consanguineous couple with unexplained, recurrent fetal malformations. Couple were recruited during clinical consultation for unexplained recurrent fetal malformations at a private reproductive medicine clinic. The couple had two malformed fetus with the same congenital abnormalities: hydrocephalus, cerebellar vermis agenesis, cerebellar hypoplasia and enlarged cisterna magna. Patients signed written informed consent regarding to exome testing. For fetal sample, informed consent was obtained from parents. Participants/materials, setting, methods Sample of the affected fetus were provided. Parental genomic DNA was extracted from peripheral blood. Exome sequencing was performed using TrusightOne (Illumina®). FASTAQ data were processed through BWA and GATK algorithm. VCF files were analysed using Variant Interpreter software. After genetic counselling, PGT-M was performed using linkage polymorphic markers analysis and mutation sequencing. Embryo biopsy was carried at blastocyst stage. Embryos were vitrified and one healthy embryo was thaw and transfer in a subsequent cycle. Main results and the role of chance An homozygous novel pathogenic mutation c.641 C&amp;gt;T (p.Ala214Val) in FVLCR2 gene was found. The parents were heterozygous carriers revealing that the detected variant follow an autosomal recessive pattern. The FLVCR2 (14q24.3) gene encodes a transmembrane protein that belongs to the major facilitator superfamily of secondary carriers that transport small solutes in response to chemiosmosis ion gradients, such as calcium. Mutations in this gene are related to fetal central nervous system defects. This disorder is diagnosed prenatally and is lethal. PGT-M was recommended during genetic counselling. After control ovarian stimulation 14 oocytes were retrieved and finally 4 embryos were suitable for embryo biopsy at blastocyst stage. One embryo was diagnosed as healthy, two affected and one heterozygous carrier. The healthy embryo was thaw and transferred and a healthy male baby was born. Limitations, reasons for caution Exome sequencing has technical limitations: only covers mutations in coding regions and does not cover noncoding regions of the genome. It also cannot reliably detect copy-number variants at single gene level. Wider implications of the findings: This study offers strong evidence of exome-sequencing as a new diagnostic strategy and powerful tool discovering the underlying etiology of recurrent fetal malformations and identifying new genes important for human development. Using this strategy in combination with PGT-M, clinicians can help couples with recurrent fetal malformations to have healthy newborns. Trial registration number Not applicable

Crown-Rump Length Discordance, Increased Nuchal Translucency, and Detection of Fetal Structural Anomalies in Twin Pregnancies in the First Trimester: 5 Years of Experience in a Tertiary Hospital in China.

To evaluate the efficacy of the first-trimester ultrasound scan in the detection of fetal structural anomalies in twin pregnancies. To examine the association between increased nuchal translucency (NT) thickness, crown-rump length (CRL) or NT discordance, and detection of structural anomalies in a large twin series in China. We performed retrospective analysis of twin pregnancies who underwent 11-13+6 -week and second-trimester anomaly scan and booked at Beijing Obstetrics and Gynecology Hospital between January 2012 and December 2016. Measurement of fetal CRL/NT and assessment of fetal anatomic structures were based on standard (not detailed) protocols. Conjoined twins and twin-reversed arterial perfusion sequence (TRAPS) were excluded from structural anomalies. The diagnostic performance of first-trimester ultrasound in detection of fetal structural anomalies in twins was determined and compared with that of second trimester. The accuracy of independent variates associated with structural anomaly detection was calculated. A total of 1442 women with twin pregnancies were included. In 40 women and 45 fetuses, structural anomalies were found. Fetal structural anomalies verified at delivery were detected in 42.5% (17/40) of affected pregnancies in the first trimester and 92.5% (37/40) of affected pregnancies when added second trimester (P=.13). The survival rate of pregnancies detected in second trimester was higher than that of pregnancies detected in first trimester (11.8% vs 65.2%). The mean value of intertwin CRL/NT discordance in cases with fetal structural anomalies was larger in monochorionic twins than dichorionic twins, but monochorionicity was not associated with structural anomalies. CRL discordance ≥10% (OR 3.1, 95%CI 1.5-6.3) and NT ≥95th centile (OR 20.0, 95%CI 9.0-44.2) were associated with fetal structural anomalies. In both dichorionic (DC) and monochorionic (MC) twins, the percentages of CRL discordance ≥10% was larger in twins with structural anomalies than those without structural anomalies (37.5% vs 13.4% in DC twins and 50.0% vs 12.5% in MC twins), and this was also true for NT ≥95th centile (31.3% vs 1.7% in DC twins and 37.5% vs 2.2% in MC twins). In the setting of CRL discordance ≥10%, 40.0% (16/40) of twins with structural anomalies were found, in which the predominant fetal structural anomalies were cardiovascular defects, abdominal wall defects, and central nervous system defects. The AUC for detecting structural anomalies by CRL discordance ≥10% was 0.63. In the setting of NT ≥95th centile, 32.5% (13/40) of twins with structural anomalies were found, in which the predominant fetal structural anomalies were cardiovascular defects, cystic hygroma, and abdominal wall defects. The AUC for detecting structural anomalies by NT ≥95th centile was 0.65. The detection rate of twins with fetal structural anomalies was 42.5% per pregnancy in the first trimester. CRL discordance ≥10% and NT ≥95th centile may indicate higher risk of fetal structural anomalies in twins, but their efficacy was limited.

Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease.

SummaryLeukodystrophies, genetic neurodevelopmental and/or neurodegenerative disorders of cerebral white matter, result from impaired myelin homeostasis and metabolism. Numerous genes have been implicated in these heterogeneous disorders; however, many individuals remain without a molecular diagnosis. Using whole-exome sequencing, biallelic variants in LSM7 were uncovered in two unrelated individuals, one with a leukodystrophy and the other who died in utero. LSM7 is part of the two principle LSM protein complexes in eukaryotes, namely LSM1-7 and LSM2-8. Here, we investigate the molecular and functional outcomes of these LSM7 biallelic variants in vitro and in vivo. Affinity purification-mass spectrometry of the LSM7 variants showed defects in the assembly of both LSM complexes. Lsm7 knockdown in zebrafish led to central nervous system defects, including impaired oligodendrocyte development and motor behavior. Our findings demonstrate that variants in LSM7 cause misassembly of the LSM complexes, impair neurodevelopment of the zebrafish, and may be implicated in human disease. The identification of more affected individuals is needed before the molecular mechanisms of mRNA decay and splicing regulation are added to the categories of biological dysfunctions implicated in leukodystrophies, neurodevelopmental and/or neurodegenerative diseases.