Inborn Defects Research Articles

European Society for Immunodeficiencies guidelines for the management of patients with congenital athymia

Congenital athymia is a life-limiting disorder due to rare inborn errors of immunity causing impaired thymus organogenesis or abnormal thymic stromal cell development and function. Athymic infants have a T-B+NK+ immunophenotype with profound T lymphocyte deficiency and are susceptible to severe infections and autoimmunity. Patients variably display syndromic features. Expanding access to newborn screening for severe combined immunodeficiency (SCID) and T lymphocytopaenia and broad genetic testing, including next-generation sequencing technologies, increasingly facilitate their timely identification. The recommended first-line treatment is allogeneic thymus transplantation, which is a specialized procedure available in Europe and the United States. Outcomes for athymic patients are best with early diagnosis and thymus transplantation before the development of infectious and inflammatory complications. These guidelines on behalf of the European Society of Immunodeficiencies provide a comprehensive review for clinicians who manage patients with inborn thymic stromal cell defects, and offer clinical practice recommendations focused on the diagnosis, investigation, risk stratification and management of congenital athymia, with the aim of improving patient outcomes.

Machine Learning in Identifying Marker Genes for Congenital Heart Diseases of Different Cardiac Cell Types.

Congenital heart disease (CHD) represents a spectrum of inborn heart defects influenced by genetic and environmental factors. This study advances the field by analyzing gene expression profiles in 21,034 cardiac fibroblasts, 73,296 cardiomyocytes, and 35,673 endothelial cells, utilizing single-cell level analysis and machine learning techniques. Six CHD conditions: dilated cardiomyopathy (DCM), donor hearts (used as healthy controls), hypertrophic cardiomyopathy (HCM), heart failure with hypoplastic left heart syndrome (HF_HLHS), Neonatal Hypoplastic Left Heart Syndrome (Neo_HLHS), and Tetralogy of Fallot (TOF), were investigated for each cardiac cell type. Each cell sample was represented by 29,266 gene features. These features were first analyzed by six feature-ranking algorithms, resulting in several feature lists. Then, these lists were fed into incremental feature selection, containing two classification algorithms, to extract essential gene features and classification rules and build efficient classifiers. The identified essential genes can be potential CHD markers in different cardiac cell types. For instance, the LASSO identified key genes specific to various heart cell types in CHD subtypes. FOXO3 was found to be up-regulated in cardiac fibroblasts for both Dilated and hypertrophic cardiomyopathy. In cardiomyocytes, distinct genes such as TMTC1, ART3, ARHGAP24, SHROOM3, and XIST were linked to dilated cardiomyopathy, Neo-Hypoplastic Left Heart Syndrome, hypertrophic cardiomyopathy, HF-Hypoplastic Left Heart Syndrome, and Tetralogy of Fallot, respectively. Endothelial cell analysis further revealed COL25A1, NFIB, and KLF7 as significant genes for dilated cardiomyopathy, hypertrophic cardiomyopathy, and Tetralogy of Fallot. LightGBM, Catboost, MCFS, RF, and XGBoost further delineated key genes for specific CHD subtypes, demonstrating the efficacy of machine learning in identifying CHD-specific genes. Additionally, this study developed quantitative rules for representing the gene expression patterns related to CHDs. This research underscores the potential of machine learning in unraveling the molecular complexities of CHD and establishes a foundation for future mechanism-based studies.

Elevated Immunoglobulin E Serum Levels: Possible Underlying Factors That Can Cause an Inborn Error of Immunity in the Pediatric Population with Recurrent Infections.

Elevated immunoglobulin E (IgE) levels are commonly associated with allergies. However, high IgE levels are also found in several other infectious and non-infectious disorders. Elevated IgE levels typically suggest allergies, eczema, or recurrent skin infections. Hyperimmunoglobulin E (hyper-IgE) levels typically reflect a monogenic atopic condition or inborn immune defects with an atopic phenotype. The aim of our research is to investigate and observe the clinical characteristics of children with increased IgE levels who have previously manifested infectious diseases. Furthermore, the retrospective study considers other factors, such as demographic characteristics (sex, area/environment, and age), and their effect on IgE serum levels. To answer this question, we conducted a one-year hospital-based retrospective study that included 200 hospitalized children who had at least two viral or bacterial infections in the six months preceding hospitalization. Measurements of IgE and allergen panels (respiratory and digestive) using blood samples revealed that individuals who tested positive for the body's synthesis of hyper-IgE were not observably allergic to any potential allergens despite having higher total serum IgE. According to the results, there was a strong correlation between elevated IgE serum levels and a history of infectious diseases among the patients.

ДИФФЕРЕНЦИАЛЬНАЯ ДИАГНОСТИКА ПРИОБРЕТЕННОЙ АПЛАСТИЧЕСКОЙ АНЕМИИ У ДЕТЕЙ: АНАЛИЗ ДАННЫХ РЕГИСТРОВОГО ИССЛЕДОВАНИЯ

Acquired aplastic anemia (AA) is still the diagnosis of exclusion. The purpose of the research was to identify clinical and laboratory signs that do not correspond to acquired AA allowing to diagnose other diseases accompanied by cytopenia. Materials and methods used: Authors represent the results of diagnostic search in pediatric patients (0 to 18 y/o) with a suspected diagnosis of acquired AA who underwent remote diagnosis in the laboratories of the National Scientific and Practical Center for Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev (Moscow, Russia) as part of the Register Study in Sep. 1, 2017-May 1, 2022. Results: in retrospective analysis of 523 children records, 104 (20%) patients had other diagnoses. In 29 (27.9%) patients were diagnosed with inherited bone marrow failure syndromes (IBMFS), in 11 (10.6%) with myelodysplastic syndrome, in 11 (10.6%) with deficiency anemia, in 10 (9.6%) with congenital unspecified AA, in 7 (6.7%) with immune cytopenia, in 7 (6.7%) with inborn defects of immunity, in 6 (5.8%) with secondary AA, in 6 (5.8%) with acute leukemia, in 2 (1.9%) with paroxysmal nocturnal hemoglobinuria and in 15 (14.4%) cases with other unspecified diseases. Fanconi anemia (n=15/29 patients) was the most common disease in the IBMFS group; this group had also included: dyskeratosis congenita (n=9), Schwachman-Diamond syndrome (n=2), amegakaryocytic thrombocytopenia (n=2), Diamond-Blackfan anemia in combination with congenital neutropenia (n=1). Conclusion: differential diagnosis of acquired AA can be difficult though it is undoubtedly must-do for successful treatment. Verification of other alternative diseases, including genetically determined syndromes, contributes to the choice of optimal patient management tactics.

Broken strands, broken minds: Exploring the nexus of DNA damage and neurodegeneration

Neurodegenerative disorders are primarily characterized by neuron loss progressively leading to cognitive decline and the manifestation of incurable and debilitating conditions, such as Alzheimer's, Parkinson's, and Huntington's diseases. Loss of genome maintenance causally contributes to age-related neurodegeneration, as exemplified by the premature appearance of neurodegenerative features in a growing family of human syndromes and mice harbouring inborn defects in DNA repair. Here, we discuss the relevance of persistent DNA damage, key DNA repair mechanisms and compromised genome integrity in age-related neurodegeneration highlighting the significance of investigating these connections to pave the way for the development of rationalized intervention strategies aimed at delaying the onset of neurodegenerative disorders and promoting healthy aging.

Mechanical properties of fabric-reinforced geocomposites in accordance with novel size-independent flexure-test technique

In this paper, two silica-based geopolymer matrix systems reinforced composites were synthesized and fabricated at optimal conditions. The composites contained approximately 40 wt.% of Carbon HTA twill (TohoTenax) and 48 wt.% of advanced S-glass twill (Saint-Gobain, Vetrotex), respectively. The resulting composites exhibited quite high toughness, with the shear stress playing a greater role compared to other ceramic matrix composites. To determine the flexural properties of the composites, a universal testing machine was used under the three-point bending mode. This evaluation was conducted using a novel size-independent technique based on testing specimens at different scales of the sample height (H) to span length (L) ratio. Microstructure analysis of the composites was performed using a scanning electron microscope (SEM). The analysis aimed to assess the effective impregnation and adhesion between the fiber and geopolymer matrix, as well as to identify micro-cracks, which are inborn defects in inorganic matrix composites. The findings presented in this study highlight the potential of the synthesized silica-based geopolymer matrix composites and their applicability in various engineering fields. Keywords: Geopolymer composite, fabric fiber, Size-independent flexure-test technique, flexural properties and microstructure.

Food allergy as one of the faces of primary immunodeficiency

Food allergy is characterized by an abnormal immune reaction that occurs reproducibly upon exposure to a specific food. This immune response can lead to a variety of symptoms, the prevalence of food allergies has increased in recent decades, most likely due to environmental factors that likely play a role in the expression of genetic susceptibility. Recent understanding of the immunopathogenesis of allergic diseases has suggested that these atopic diseases may be due to monogenic mutations associated with inborn errors of immunity (IEI). Aspects to be assessed in suspected IEI involve the onset of atopic disease within the initial months of life, the progression of the condition, and the response to conventional therapy. A prospective study was conducted on 385 patients admitted to the clinic with suspected immunodeficiency. Most children were referred for recurrent respiratory infections, but almost half had concurrent atopy (44%), atopy and autoimmunity (3%), autoimmunity (6%) and malignancy (1%). The results of the study underline the importance of the allergic phenotype and suggest that children with more severe allergic diseases should be screened for possible underlying inborn defects of immunity. If a congenital disorder of immunity is suspected, comprehensive immunologic testing is required, and genetic testing is essential to identify the specific genetic abnormalities. Molecular diagnosis provides a comprehensive understanding of congenital immune disorders, allowing tailored interventions and personalized surveillance strategies.

Chromatinopathies: insight in clinical aspects and underlying epigenetic changes.

Chromatinopathies (CPs), a group of rare inborn defects characterized by chromatin state imbalance, have evolved from initially resembling Cornelia de Lange syndrome to encompass a wide array of genetic diseases with diverse clinical presentations. The CPs classification now includes human developmental disorders caused by germline mutations in epigenes, genes that regulate the epigenome. Recent advances in next-generation sequencing have enabled the association of 154 epigenes with CPs, revealing distinctive DNA methylation patterns known as episignatures.It has been shown that episignatures are unique for a particular CP or share similarities among specific CP subgroup. Consequently, these episignatures have emerged as promising biomarkers for diagnosing and treating CPs, differentiating subtypes, evaluating variants of unknown significance, and facilitating targeted therapies tailored to the underlying epigenetic dysregulation.The following review was conducted to collect, summarize, and analyze data regarding CPs in such aspects as clinical evaluation encompassing long-term patient care, underlying epigenetic changes, and innovative molecular and bioinformatic methodologies that have been devised for the assessment of CPs. We have also shed light on promising novel treatment options that have surfaced in recent research and presented a synthesis of ongoing clinical trials, contributing to the current understanding of the dynamic and evolving nature of CPs investigation.

Fatel Medicine in Clinical Practice

Fetal medicine is a specific field of medicine dedicated to the care and management of the expanding blastula during pregnancy. It contains an off-course range of demonstrative and therapeutic methods proposed to guarantee the health and happiness of two together, the future baby and the expectant parent. This abstract investigates the relevance and meaning of the before-birth cure in contemporary dispassionate practice.In the current age, fetal medicine has supported extraordinary advancements on account of contemporary technologies and a deeper understanding of what happens before birth. Ultrasound imaging, for instance, has enhanced the necessary finish for monitoring before birth, detecting irregularities, and assessing the overall energy of the embryo. Non-obtrusive prenatal experimentation (NIPT) has transformed the early detection of ancestral disorders, permissive prompt interventions, and cognizant accountability for persons. Fetal medicine offers further conditions; it offers a spectrum of healing attacks that can significantly impact gestational consequences. Intrauterine before-birth surgeries, such as curing processes for inborn heart defects or spina bifida, elucidate the field’s volume to mediate and improve the value of history for affected babies. Furthermore, before birth, the cure plays an important role in directing extreme-risk pregnancies. It authorizes close monitoring of motherly and prenatal well-being, ensuring that potential problems are recognized and addressed immediately. This is specifically critical in cases of multiple pregnancies, motherly healing environments, or fetal tumor limits. The field’s significance is further underscored by allure skills to foster early sticking between persons and the unborn adolescent. Seeing the embryo through ultrasound scans and engaging in discussions about allure, fitness, and what’s happening can enhance the heated relationship ‘between expectant parents and their babies. In conclusion, before birth, medicine has enhanced a necessary component of new clinical practice. It offers an inclusive approach to fetal care, including diagnostics, healing interventions, and psychological support for expectant parents. As electronics continue to advance and our understanding of before-birth incidents deepens, before-birth medicine’s part in guaranteeing healthy pregnancies and improving neonatal consequences will certainly stretch to expand and develop.

Cellular immune response to SARS-CoV-2 in patients with primary antibody deficiencies.

Primary antibody deficiencies (PAD) are inborn defects of the immune system that result in increased susceptibility to infections. Despite the reduced response to vaccination, PAD patients still benefit from it by reducing the risk of severe infections and complications. SARS-CoV-2 vaccines are recommended in PAD patients, but their immune effects are poorly studied. Here, we analyze virus-specific T-cell responses in PAD patients after booster vaccination against SARS-CoV-2. The study included 57 adult PAD patients on long-term immunoglobulin replacement therapy (IgRT) diagnosed with X-linked agammaglobulinemia (XLA; n = 4), common variable immunodeficiency (CVID; n = 33), isotype defects or IgG subclass deficiency (n = 6), and unclassified IgG deficiency (n = 14). Of those, 49 patients (86%) received vaccination against SARS-CoV-2 using mRNA vaccine (Pfizer-BioNTech). T-cell responses were assessed at a median of 21 (13 - 30) weeks after the booster dose (mainly the third dose) using commercially available interferon-gamma release assay (IGRA) with recombinant SARS-CoV-2 spike S1 protein. Vaccinated PAD patients showed an increased (3.8-fold, p = 0.004) release of IFN-γ upon S1 stimulation. In this group, we also documented higher serum levels of anti-SARS-CoV-2 IgG (4.1-fold, p = 0.01), although they were not associated with IGRA results. Further subgroup analysis revealed very similar IGRA responses in CVID and unclassified IgG deficiencies that were 2.4-fold increased compared to XLA and 5.4-fold increased compared to patients with isotype defects or IgG subclass deficiencies (e.g., vs. CVID: p = 0.016). As expected, CVID and XLA patients showed decreased serum titers of anti-SARS-CoV-2 antibodies compared to other studied groups (e.g., CVID vs. unclassified IgG deficiency: 4.4-fold, p = 0.006). The results did not depend directly on IgRT mode or dose, number of vaccine doses and time from the last booster dose, and clinical manifestations of PAD. Interestingly, anti-SARS-CoV-2 titers were positively correlated with serum immunoglobulin levels before IgRT (e.g., for IgA: r = 0.45, p<0.001; for IgG: r = 0.34, p = 0.009) and the percentage of peripheral blood NK cells (r = 0.48, p<0.001). Our results documented satisfactory in vitro cellular immune response in PAD patients after booster SARS-CoV-2 vaccination. Therefore, even patients with agammaglobulinemia should benefit from vaccination due to the apparent induction of cell-mediated immunity, which, together with IgRT, grants comprehensive protection against the pathogen.

Pregnancy in primary immunodeficiency diseases: The PREPI study

Primary immunodeficiencies (PID) are a heterogeneous group of rare inborn immunity defects. As management has greatly improved, morbidity and mortality are reduced in this population, while our knowledge on pregnancy's unfolding and outcome remains scarce. We conducted a retrospective monocentric study to study pregnancy outcomes in women with PID. The study cohort consisted of women over 18 included in the national registry for PID (CEREDIH), living in the greater Paris area, reporting ≥1 pregnancy. Data were collected through a standardized questionnaire and medical records. We analyzed PID features, pregnancy course and outcome, and neonatal features (NCT04581460). We studied 93 women with PID (27 combined immunodeficiencies, 51 predominantly antibody deficiencies, and 15 innate immunodeficiencies) and their 222 pregnancies (67, 119, and 36 in each group, respectively). One hundred fifty-four (69%) of 222 pregnancies led to 157 live births, including 4 severe preterm births (3%), in the range of pregnancy outcome in the French general population. In a multivariate model, poor obstetrical outcome (fetal loss or pregnancy termination) was associated with history of severe infection (adjusted odds ratio 0.28, 95% confidence interval 0.11-0.67, P= .005). Only 59% pregnancies were led with optimal anti-infective prophylaxis; severe infections were reported in only 2 pregnancies (1%). One infant died during the neonatal period. Pregnancy is achievable in women with a wide group of PID. Prematurity is increased and history of severe infection is associated with significant increase of fetal loss/pregnancy termination. Adjustment of care during pregnancy needs to be better delivered.

The Role of Gene Therapy for Primary Immunodeficiency

Primary Immunodeficiency disease (PID) is a wide genre of inborn defects that affect the patients immune system. More than 430 distinct phenotypes have been reported and more are being identified. Traditional treatments to PID include clearance or prevention of infections, avoidance of exposure to pathogen and live vaccines, immunoglobulin replacement therapy, and haematopoietic stem cell transplantation (HSCT). Mostly HSCT would be the only feasible radical solution, while others only offer temporary suppression of the condition. On the other hand, with the advancements in technology, gene therapy starts to show promising effects in multiple diseases including PID. In this review, we mainly discussed the effect and resent progresses of gene therapy on two common kinds of PID, SCID and WAS.

Relationship between Bone Mineral Density and Selected Parameters of Calcium-Phosphate Economy with Dietary Management and Metabolic Control in Polish Pediatric Patients with Classical Homocystinuria-A Preliminary Study.

Classical homocystinuria (HCU) is an inborn defect of methionine metabolism caused by a deficiency of the enzyme cystathionine β-synthase (CBS). The main symptoms of classical homocystinuria are lens subluxation, bone lesions, vascular disease and developmental delay/intellectual disability. The treatment method for HCU is a methionine-poor diet supplemented with amino acid preparations. The aim of the study was to examine the relationship of dietary factors, metabolic compensation and selected skeletal parameters in patients with HCU. Bone mineral density measurements (DXA) were performed in pediatric patients with HCU, and blood levels of selected amino acids, minerals and vitamins, as well as dietary nutritional value, were analyzed. A total of 11 patients with HCU whose median age was 9.3 years were enrolled in the study. The median DXA total body less head of HCU patients was -0.4 z-score, and the lumbar spine was -1.4 z-score. Despite supplementation, calcium intake was below the age norm. Average vitamin D3 intake was in line with recommendations, but 36% of patients had reduced blood levels. Bone mineral density depended on blood levels of 25-hydroxyvitamin D, homocysteine and methionine, as well as on BMI, age and intake of natural protein (R2 = 98.5%, p = 0.015; R2 = 86.7%, p = 0.0049) and protein from an amino acid preparation (r = 0.69, p = 0.026). The results of the study indicate the need for regular densitometry in patients with HCU and also the use of additional calcium and vitamin D3 supplementation. It is also necessary to perform a comprehensive analysis of the diet and metabolic controls.

Development of gene therapy for hypophosphatasia

Hypophosphatasia (HPP) is a disease caused by an inborn defect in the production of alkaline phosphatase that affects bones and teeth. The six types are perinatal lethal form, perinatal benign form, infantile form, childhood form, adulthood form and odontohypophosphatasia. Treatments have historically been limited but, in 2015, an enzyme replacement therapy known as Asfotase Alfa was approved. This has improved life expectancy and quality of life but drawbacks such as requires 3-6 injections per week for life, injection pain and swelling at injection sites remain. Professor Koichi Miyake and his team at the Department of Gene Therapy at Nippon Medical School (NMS), Japan, are working to improve treatments for HPP. The researchers are developing novel therapeutic agents to potentially treat HPP by only single injection, one of which is ARU-2801. The hope is that this will not only prolong the life of HPP patients and improve their symptoms, but also improve their quality of life and will also improve the symptoms of patients with disease types that currently cannot be treated with enzyme replacement therapy. Miyake and the team have evaluated the efficacy and safety of ARU-2801 using non-human primates (NHPs). In their studies, ARU-2801 was able to maintain tissue nonspecific alkaline phosphatase (TNALP) expression in NHPs and mice for a long period, with no side effects. In future clinical trials the effectiveness of ARU-2801 will need to be confirmed in patients.

Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency in Zhejiang province, China.

3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is an autosomal recessive inborn defect of leucine catabolism caused by MCCC1 or MCCC2 variants. 3-MCCD is considered to be a relatively benign disorder with favorable outcome. We report the biochemical, clinical, and molecular features of patients with 3-MCCD. From January 2009 to August 2022, 4,402,587 newborns were screened by tandem mass spectrometry. Newborns with increased C5OH concentrations were recalled for repeated testing, urine organic acid analysis and molecular genetic analysis were performed if the second test was still positive. A total of 53 patients were diagnosed with 3-MCCD. The estimated incidence of 3-MCCD in Zhejiang Province was 1 in 83,068 newborns. All these 53 patients exhibited increased C5OH concentrations in blood. 94% (50/53) of the patients had markedly increased urinary 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. All these 53 patients did not present any clinical symptom. Twenty-three of 53 patients had secondary carnitine deficiency. Twenty-eight patients had variants in MCCC1 and 25 had variants in MCCC2. Eleven novel variants were found in MCCC1 and MCCC2. The c.639+2T>A and c.1144-1147delinsTTTT were the most common variant in MCCC1 and MCCC2 gene, respectively. We elucidated the incidence of 3-MCCD in Zhejiang province, China. All patients showed asymptomatic and present normal growth and development during follow-up. Eleven novel MCCC1 and MCCC2 variants were identified, which expanded the variant spectrum.

MoS2 Passivated Multilayer Graphene Membranes for Li-Ion Extraction From Seawater.

Abundant Li resources in the ocean are promising alternatives to refining ore, whose supplies are limited by the total amount and geopolitical imbalance of reserves in Earth's crust. Despite advances in Li+ extraction using porous membranes, they require screening other cations on a large scale due to the lack in precise control of pore size and inborn defects. Herein, MoS2 nanoflakes on a multilayer graphene membrane (MFs-on-MGM) that possess ion channels comprising i) van der Waals interlayer gaps for optimal Li+ extraction and ii) negatively charged vertical inlets for cation attraction, are reported. Ion transport measurements across the membrane reveal ≈6- and 13-fold higher selectivity for Li+ compared to Na+ and Mg2+ , respectively. Furthermore, continuous, stable Li+ extraction from seawater is demonstrated by integrating the membrane into a H2 and Cl2 evolution system, enabling more than 104 -fold decrease in the Na+ concentration and near-complete elimination of other cations.

Multiplex Snapshot minisequencing for detection of common PAH gene mutations in Iranian patients with Phenylketonuria.

Phenylketonuria (PKU) is one of the most common inborn faults of amino acid metabolism in the world. It is caused by an autosomal recessive insufficiency of the hepatic enzyme phenylalanine hydroxylase (PAH) that catalysis the irreversible hydroxylation of phenylalanine to tyrosine. More than 950 different disease-causing mutations in the PAH gene have been identified. The most prominent complication of PKU if not diagnosed and treated is severe mental retardation. Early diagnosis and initiation of nutritional therapy are the most important measures in preventing this mental retardation. For this reason, we developed a simple and rapid molecular test for detection of the most frequent phenylalanine hydroxylase mutations. We have developed a PCR multiplex SNaPshot reaction that targets all 10 common mutations identified in PAH gene. Multiplex assays based on the SNaPshot minisequencing approach were developed to simultaneous genotype ten mutations at the PAH gene. We have optimized the detection of this mutations in one multiplex polymerase chain reaction (PCR) followed by ten single-nucleotide extension reactions. The different genotypes were determined based on the position and the fluorescent color of the peaks in a single electropherogram. DNA sequencing assay also were used to verify genotyping results obtained by SNaPshot minisequencing, all mutations were concordant. This method can be useful as secondary test in neonatal screening for hyperphenylalaninemia in neonates with a positive screening test and also be suitable for carrier screening. The assay can be easily applied for accurate, time and cost efficient genotyping of the selected SNPs in various populations.

Evaluation of the effects in the &lt;i&gt;in vitro&lt;/i&gt; system of synthetic thymic hexapeptide on the expression levels of NF-κB, IFNα/βR and CD119 neutrophilic granulocytes in patients with chronic herpes viral co-infections

Background. Strategies used by herpes viruses with human cells are complex and multifaceted. On one hand, inborn defects in antiviral immune defense have been unveiled, which also affect interferon (IFN) system underlying development of chronic recalcitrant relapsing viral infections such as remittent respiratory viral infections, herpesvirus infections, and papillomavirus infections. On the other hand, numerous viruses are able to damage both immune system and IFN network. During inborn and acquired defects in IFN network, inborn or induced mutation in gene products involved in signaling cascades aimed at upregulating gene expression responsible for IFN production are observed. One of the strategies used by diverse viruses is altering some signaling pathways resulting in activated transcription factors including nuclear factor NF-kB. However, antiviral mechanisms executed by neutrophilic granulocytes (NGs), particularly affecting NF-kB expression have not been elucidated. Aim of the study: to study in vitro features of NF-kB expression and number of neutrophilic granulocytes (NG) expressing membrane IFN/R and IFNR in patients with atypical chronic active herpes virus infections (AChA-HVI), followed by assessing an effect of arginyl-alpha-aspartyl-lysyl-valyl-tyrosyl-arginine hexapeptide (HP), a synthetic analogue of the active center of the thymopoietin (active substance of drug Imunofan, Russia), on the expression of NG NF-kB and IFN/R and IFNR. Materials and methods. We observed 25 patients of both sexes aged 23 to 64 years with AChA-HVI, manifested by chronic fatigue syndrome and cognitive disorders. Study design: stage 1 clinical, ELISA, PCR methods, FC was used. Stage 2 the in vitro experiment: 32 blood samples from 8 healthy adults and 375 blood samples from 25 patients with AChA-HVI were analyzed: % NG expressing NF-kB, IFN/R, IFNR and the relevant MFI levels by using FC before and after incubation with HP. Results. Our study demonstrated low level (MFI) of NF-kB expression in 100% NG associated with decreased % of NG expressing IFN/R and IFNR in all patients with AChA-HVI and low serum level for IFN and IFN in comparison with healthy individuals. In the in vitro experiment there was shown that 100% of NG expressed NF-kB after exposure to HP. However, only 48% patients (SG 2) restored NF-kB expression level (MFI) to normal range and 52% of cases (SG 1) had no response. HP increased % of NG expressing IFN/R in SG 2 and increased % of NG expressing IFNR in SG 1. Conclusions. It was shown, that influence of HP in vitro has ambiguous effects on the expression of NF-kB, % of NG expressing IFN/R and IFNR in patients with AChA-HVI. We assume that different NF-kB response to HP is associated with inborn or secondary NF-kB deficiency.

S1424 Porphyrias Are Linked to Primary Liver Cancer, Particularly Hepatocellular Carcinoma: A Systematic Review and Pooled Analysis

Introduction: Porphyrias are in-born defects in the heme biosynthesis pathway resulting in neurovisceral manifestations, cutaneous photosensitivity, and multi-systemic involvement. Its estimated prevalence nears 5 per 100,000 patients worldwide. Subclinical liver disease is common which carries a risk of malignancy. To this end, we aim to determine the risk of primary liver cancer and hepatocellular carcinoma (HCC) in patients with porphyria. Methods: We conducted a comprehensive search of several databases, including PubMed, EMBASE, and Web of Science.We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Keywords used in the literature search included “porphyria,” “hepatic porphyria,” “delta-aminolevulinate-dehydratase deficiency porphyria,” “acute intermittent porphyria,” “porphyria cutanea tarda,” “cirrhosis,” “hepatocellular carcinoma,” “cancer,” “transplant,” to identify relevant articles. Results: In total, 19 studies, which included 7,381 patients with porphyria (3476 females), were considered for the final review. In eight studies, alpha-fetoprotein levels were elevated between 200 and 1000 IU/ml. Elevated urinary delta-aminolevulinic acid dehydratase, prophobilinogen, and other uroporphyrins were observed. Median follow-up time ranged from 3 to 24 years. Of the total cohort of patients with porphyria, primary liver cancer was diagnosed in 351 patients (4.8%), of whom 243 (3.3% of the total) were found to have HCC. A small subset of patients was found to have cholangiocarcinoma (n=18; 0.3% of the total). Interestingly, progression to HCC was seen despite the development of advanced liver disease or cirrhosis. Of the total cohort, 30 patients underwent liver resection, 48 patients underwent liver transplantation, and 327 patients died. Compared to those who did not undergo periodic screening, only four patients (28.6%) underwent tumor resection with a recurrence rate of 75% (n=3/4). (Figure) Conclusion: Our study revealed that patients with porphyria are at increased risk for the development of primary liver cancer and HCC. Furthermore, we showed that malignancy can occur even in the absence of cirrhosis, supporting the need for appropriate screening. To this end, AFP should be used in conjunction with imaging modalities to screen for liver malignancy as frequently as every 6–12 months. Further studies should aim to develop diagnostic and prognostic models aimed at its early detection.Figure 1.: Flow chart of included studies

A neural stem cell paradigm of pediatric hydrocephalus.

Pediatric hydrocephalus, the leading reason for brain surgery in children, is characterized by enlargement of the cerebral ventricles classically attributed to cerebrospinal fluid (CSF) overaccumulation. Neurosurgical shunting to reduce CSF volume is the default treatment that intends to reinstate normal CSF homeostasis, yet neurodevelopmental disability often persists in hydrocephalic children despite optimal surgical management. Here, we discuss recent human genetic and animal model studies that are shifting the view of pediatric hydrocephalus from an impaired fluid plumbing model to a new paradigm of dysregulated neural stem cell (NSC) fate. NSCs are neuroprogenitor cells that comprise the germinal neuroepithelium lining the prenatal brain ventricles. We propose that heterogenous defects in the development of these cells converge to disrupt cerebrocortical morphogenesis, leading to abnormal brain-CSF biomechanical interactions that facilitate passive pooling of CSF and secondary ventricular distention. A significant subset of pediatric hydrocephalus may thus in fact be due to a developmental brain malformation leading to secondary enlargement of the ventricles rather than a primary defect of CSF circulation. If hydrocephalus is indeed a neuroradiographic presentation of an inborn brain defect, it suggests the need to focus on optimizing neurodevelopment, rather than CSF diversion, as the primary treatment strategy for these children.