Neurodevelopmental proteasomopathies constitute a recently defined class of rare Mendelian disorders, arising from genomic alterations in proteasome-related genes. These alterations result in the dysfunction of proteasomes, which are multi-subunit protein complexes essential for maintaining cellular protein homeostasis. The clinical phenotype of these diseases manifests as a syndromic association involving impaired neural development and multisystem abnormalities, notably craniofacial anomalies and malformations of the cardiac outflow tract (OFT). These observations suggest that proteasome loss-of-function variants primarily affect specific embryonic cell types which serve as origins for both craniofacial structures and the conotruncal portion of the heart. In this hypothesis article, we propose that neural crest cells (NCCs), a highly multipotent cell population, which generates craniofacial skeleton, mesenchyme as well as the OFT of the heart, in addition to many other derivatives, would exhibit a distinctive vulnerability to protein homeostasis perturbations. Herein, we introduce the diverse cellular compensatory pathways activated in response to protein homeostasis disruption and explore their potential implications for NCC physiology. Altogether, the paper advocates for investigating proteasome biology within NCCs and their early cranial and cardiac derivatives, offering a rationale for future exploration and laying the initial groundwork for therapeutic considerations.

BACKGROUND: The increasing and prevalent use of gabapentin among pregnant people highlights the necessity to assess its neonatal safety.
OBJECTIVE: This study aimed to investigate the foetal safety of gabapentin during pregnancy using a cohort study and scoping review with a meta-analysis of published evidence.
METHODS: We conducted a population-based cohort study using the Manitoba health databases between 1995 and 2019. We examined the association between gabapentin use during pregnancy and the prevalence of major congenital malformations, cardiac and orofacial malformations, and neonatal intensive care unit (NICU) admissions using multivariate regression models. We searched the literature in MEDLINE and EMBASE databases from inception to October 2022 to identify relevant observational studies and conducted a meta-analysis using random-effects models, including our cohort study results.
RESULTS: Of the 289,227 included pregnancies, 870 pregnant people were exposed to gabapentin. Gabapentin exposure during the First trimester was not associated with an increased risk of any malformations (adjusted relative risk [aRR]) 1.16 (95% confidence interval [CI] 0.92, 1.46), cardiac malformations (aRR 1.29, 95% CI 0.72, 2.29), orofacial malformations (aRR 1.37, 95% CI 0.50, 3.75), and major congenital malformations (aRR 1.00, 95% CI 0.73, 1.36). whereas exposure during any trimester was associated with an increased NICU admission risk (aRR, 1.99, 95% CI 1.70, 2.32). The meta-analysis of unadjusted results revealed an increased risk of major congenital malformations (RR 1.44, 95% CI 1.28, 1.61, I2 = 0%), cardiac malformations (RR 1.66, 95% CI 1.11, 2.47, I2 = 68%), and NICU admissions (RR 3.15, 95% CI 2.90, 3.41, I2 = 10%), and increased trend of orofacial malformations (RR 1.98, 95% CI 0.79, 5.00, I2 = 0%).
CONCLUSIONS: Gabapentin use was associated with an increased risk of NICU admissions in the cohort study and pooled meta-analysis. Clinicians should prescribe gabapentin with caution during pregnancy and further studies are warranted.

UNASSIGNED: Fetal cardiac safety of sertraline is controversial even though it is among the most frequently used antidepressants in pregnancy. Sertraline could theoretically affect the fetal heart resulting in malformations or more subtle changes, but studies evaluating fetal cardiac safety are prone to a number of systematic and random errors.
UNASSIGNED: The objective of this review is to evaluate the fetal cardiac safety profile of sertraline in pregnancy. A literature review included articles until November 2022 in Medline with no time or language limitations.
UNASSIGNED: Sertraline is associated with septal heart malformations, but not with more severe heart malformations. The association may be causal or at least partly related to systematic errors, including confounding by indication. Regardless of the causal mechanism, the association should not limit well-indicated treatments of maternal depression. The few available studies on fetal heart function is reassuring. There are no human data on the long-term effects on offspring cardiac function, but the teratogenic and fetal heart function studies do not imply risks of any major cardiac problems later in life. Interactions with other medication may, however, alter the risks associated with any medication in pregnancy, and information and surveilence systems taking this into account is much needed.

To review post-mortem findings among deaths presenting as sudden and/or unexpected deaths in two centers in the UK during a 16-year period in order to identify those related to cardiovascular conditions. The post-mortem databases of two tertiary referral institutions were searched, and all reports were reviewed. Histological features and results of ancillary investigations were noted. All cases of sudden and/or unexpected cardiac deaths (SCD) between 2003 and 2018 were identified. The study was PRISMA compliant and approved by clinical governance. 68/1129 cases of SCD (6.0%) were identified in one center and 83/753 cases (11%) in the other. These 151 cases constituted the study cohort. The mean annual incidence of SCD was 0.3 per 100,000 persons/annum. The three most prevalent groups of cardiac pathology were cardiac malformations (51/151; 33.8%), cardiomyopathies (32/151; 21.2%), and myocarditis (31/151; 20.5%). Mean age at death was 3.4 years. Prematurity was predominantly associated with deaths related to cardiac malformations (p < 0.001). Symptoms had been present for a mean of 3.8, 3.0, and 3.5 days before death for myocarditis, cardiomyopathy, and cardiac malformations/complications post-surgery. This retrospective comparative study represents the largest autopsy series of SCD in infants and children in the UK. Some entities are very infrequent. Several diseases could have been identified earlier in life allowing for the possibility of intervention. Limitation includes the retrospective nature of the study and that, as arrhythmogenic gene mutations are not yet routinely performed in unexplained deaths, the incidence of SCD in infants and children is most likely underestimated.

Nanomaterials are widespread in the human environment as pollutants, and are being actively developed for use in human medicine. We have investigated how the size and dose of polystyrene nanoparticles affects malformations in chicken embryos, and have characterized the mechanisms by which they interfere with normal development. We find that nanoplastics can cross the embryonic gut wall. When injected into the vitelline vein, nanoplastics become distributed in the circulation to multiple organs. We find that the exposure of embryos to polystyrene nanoparticles produces malformations that are far more serious and extensive than has been previously reported. These malformations include major congenital heart defects that impair cardiac function. We show that the mechanism of toxicity is the selective binding of polystyrene nanoplastics nanoparticles to neural crest cells, leading to the death and impaired migration of those cells. Consistent with our new model, most of the malformations seen in this study are in organs that depend for their normal development on neural crest cells. These results are a matter of concern given the large and growing burden of nanoplastics in the environment. Our findings suggest that nanoplastics may pose a health risk to the developing embryo.

Axenfeld-Rieger syndrome (ARS) is an autosomal dominant disorder that is primarily due to disruption of the development of neural crest cells. The onset of associated symptoms in both eyes accompanied by extraocular developmental defects is referred to as ARS. Cardiac defects associated with ARS have been reported, but the extent of the cardiac defects has yet to be defined. We report a case of a 17-year-old girl with ARS with typical facial malformations and severe mitral and tricuspid valve insufficiency. The patient was diagnosed with secondary glaucoma detected on ophthalmologic examination. Echocardiography showed severe mitral and tricuspid valve insufficiency. This case provides further evidence of the association of ARS with cardiac malformations and extends the reported range of cardiac malformations in patients with ARS.

The aim of this study is to identify the occurrence of cardiac malformations occurred in children conceived by assisted reproduction techniques (ART) in the international literature in Medline database from 1999 to 2012. The search returned data on 32,000 births, whose 21,000 were conceived naturally and 11,000 were conceived by ICSI and/or IVF. The incidence of cardiac malformations in general population situations was 0.4%. The incidence of cardiac malformations by ART was 1.8% from ICSI and IVF. Among the situations of conceived naturally was observed 88 cases of cardiac malformations, which were: Atrial Septal Defect: 26 cases 29.55%, Change in the interventricular septum: 18 cases 20.45%, coarctation of the aorta: 13 cases 14.77%, aortic stenosis: 11 cases 12.5%, tetralogy of Fallot: 5.68% 5 cases, stenosis of the pulmonary trunk: 5 cases 5.68% other: 11.37% 10 cases. In cases of cardiac malformations in children conceived by IVF and ICSI, 198 cases were found, which were: CIA: 58 cases 29.30%, Change in the interventricular septum: 37 cases 18.69%, coarctation of the aorta: 20 cases 10.10%, aortic stenosis: 18 cases 9.09%, tetralogy of Fallot: 11 cases 5.55%, stenosis of the pulmonary trunk: 6 cases 3.03%, Other: 48 cases 24.24%. There remain opened questions about infertility and risk factors involving ART. Further research is clearly required. Health care providers should counsel infertile couples seeking assisted reproduction by IVF and technology.

Heterotaxy syndrome, also called atrial isomerism, is a rare congenital condition in which the internal organs are abnormally arranged across the left-right axis of the body. It is classified into polysplenia syndrome or left atrial isomerism and asplenia syndrome or right atrial isomerism. It is associated with high morbidity and mortality due to the severity of cardiac anomalies. It is important to be aware of the syndrome findings as they can be incidentally found on imaging in adults. Here, we report a case of a 33-year-old female who presented with worsening shortness of breath, found to have a pulmonary embolism, and heterotaxy was incidentally identified on her imaging. A concise review follows.

OBJECTIVE: To know the cardiac malformations frequency associated with esophageal atresia and its type in patients of the Children\'s Specialties Hospital of Chihuahua as well as related sociodemographic characteristics.
METHODS: The epidemiology, clinic and evolution of patients with esophageal atresia diagnosis who were admitted to this hospital for a period of two years were studied. Variables such as sex, gestational age, birth weight, Apgar score, atresia type, associated congenital malformations, hospital complications and parental related aspects were analyzed.
RESULTS: Twelve patients were studied, 50% of them were male, most of them were products of term pregnancies with adequate birth weight. There were mestizo ethnicity prevalence, young mothers children with a medium socio-economic level, without geographical predominance. 82% of the cases corresponded to type III esophageal atresia, the most frequent congenital malformations associated were cardiac in 83% of which 90% corresponded to atrial septum defects.
CONCLUSIONS: Esophageal atresia is a relatively common congenital malformation of multifactorial etiology. A complete approach to patients with this pathology is necessary to identify a concomitant illness and provide adequate treatment.
OBJECTIVE: Conocer la frecuencia de malformaciones cardiacas asociadas en pacientes con atresia de esófago y su tipo en el Hospital Infantil de Especialidades de Chihuahua, así como las características sociodemográficas relacionadas.
UNASSIGNED: Se estudiaron la epidemiología, la clínica y la evolución de los pacientes con diagnóstico de atresia esofágica que ingresaron a dicho nosocomio durante un periodo de 2 años. Se analizaron variables como sexo, edad gestacional, peso al nacer, Apgar, tipo de atresia, malformaciones congénitas asociadas, complicaciones durante la estancia hospitalaria y aspectos relacionados con los padres.
RESULTS: Se estudiaron 12 pacientes, de los cuales el 50% eran de sexo masculino, y la mayoría de ellos fueron producto a término con peso adecuado al nacimiento. Predominio de etnia mestiza, hijos de madres jóvenes con nivel socioeconómico medio, sin predominio geográfico. El 82% de los casos correspondían a atresia esofágica tipo III, y las malformaciones congénitas más frecuentes asociadas fueron las cardiacas en el 83% de los casos, de las cuales el 90% correspondían a defectos del tabique auricular.
CONCLUSIONS: La atresia esofágica es una malformación congénita relativamente común y de etiología multifactorial. Es necesario realizar un abordaje completo de los pacientes con esta patología para poder identificar otra afección y brindar el tratamiento adecuado.

In congenital heart disease, the presence of structural defects affects blood flow in the heart and circulation. However, because the fetal circulation bypasses the lungs, fetuses with cyanotic heart defects can survive in utero but need prompt intervention to survive after birth. Tetralogy of Fallot and persistent truncus arteriosus are two of the most significant conotruncal heart defects. In both defects, blood access to the lungs is restricted or non-existent, and babies with these critical conditions need intervention right after birth. While there are known genetic mutations that lead to these critical heart defects, early perturbations in blood flow can independently lead to critical heart defects. In this paper, we start by comparing the fetal circulation with the neonatal and adult circulation, and reviewing how altered fetal blood flow can be used as a diagnostic tool to plan interventions. We then look at known factors that lead to tetralogy of Fallot and persistent truncus arteriosus: namely early perturbations in blood flow and mutations within VEGF-related pathways. The interplay between physical and genetic factors means that any one alteration can cause significant disruptions during development and underscore our need to better understand the effects of both blood flow and flow-responsive genes.