Immunological Markers in Children with Genetic Disorders and Recurrent Respiratory Tract Infections

BACKGROUND: Recurrent respiratory tract infections (RRI) are one of the extremely high common reasons for pediatric visits and hospitalization. Immunodeficiencies are considered as important conditions that may increase the probability of occurrence of RRI. Mannose-binding lectin (MBL2) is a protein of the innate immune system involved in the opsonization and the complement activation. MBL2 deficiency is associated with infectious diseases mainly chest infections; however, subnormal MBL2 levels are also seen in healthy subjects. Primary immunedeficiencies are associated with recurrent infections which mainly appear in early childhood. AIM: The aim of the study was to estimate T and B and natural killer cells percentage and to investigate the MBL2 and immunoglobulins (Igs) serum levels in children with recurrent RRIs in different genetic disorders compared to normal control. METHODS: This study included 50 children having a history of recurrent RRIs. All patients had genetic disorders and referred to National Research Centre for follow-up, in addition to, 25 children, age- and sex-matched as a healthy control group. They were subjected to full clinical examination and laboratory investigations including complete blood count (CBC), CD3, CD4, CD8, CD16, and CD19 by flow cytometry, MBL2 by enzyme-linked immunosorbent assay (ELISA), and Igs serum concentrations by nephelometry. RESULTS: CD16 showed a non-statistical significant difference between both patient groups. Serum levels of IgA in patient groups showed a significant decrease compared to the control group. Moreover, the serum level of IgM results shows a highly significant decrease when compared with the control group. There was no statistically significant difference in MBL2 and IgG serum levels between patient groups and control group. CONCLUSION: Children with genetic disorders and recurrent RRIs showed a statistically significant decrease of IgA and IgM serum levels as compared to the control group, while the serum level of MBL2 did not show significant results

Altered Adaptive Cellular Immune Function in a Group of Egyptian Children with Autism

Introduction: There is a growing evidence of immune system alteration in children with Autism Spectrum Disorder (ASD). These changes may include higher levels of pro-inflammatory cytokines in plasma, Cerebrospinal Fluid (CSF) and brain cells. Aim: To evaluate the imbalance of the immune system in autism through correlating some immunological markers (C3, C4, CD4, IL12 and IL17) with severity of ASD. Materials and Methods: The current case-control study included 120 subjects, 60 autistic children and 60 healthy control obtained from the Clinical Genetics Clinic, National Research Centre, Egypt from the period between December 2014 to December 2016. All candidates were subjected to full clinical evaluation in addition to ElectroEncephaloGraphy (EEG), hearing test and estimation of interleukins (IL12- IL17), C3-C4, CD4 levels in blood samples. Independent t-test, Chi-square test or McNemar test were used to analyse the data. Results: The levels of IL12 (27.47 ±7.15) and IL17 (1630.46±310.42) were significantly higher, (p= 0.026, 0.005) respectively, while levels of CD4 were significantly lower (37.93±3.25), (p<0.001) in autistic children compared to controls; however, there was no significant difference in C3 and C4 between the two groups. High statistically significant difference between autistic children with moderate and severe ASD in CD4 levels were seen, (p=0.018). Conclusion: Autistic children may suffer from immunological dysfunction. Further efforts should be exerted to find out the relation between immune imbalance and the progression of ASD

Association between MTHFR C677T variant and risk for congenital heart defects in Egyptian children: a case–control study including meta-analysis based on 147 cases and 143 controls

Abstract Background Stratification analysis studies showed that ethnicity has a significant association regarding MTHFR C677T variant and congenital heart diseases (CHDs) risk, and many published studies have controversial conclusions toward this association. Methods In this study, the association between the MTHFR C677T variant and the risk for CHDs was evaluated in 91 children with CHD and 95 healthy controls, as new cases, by using restriction fragment length polymorphism (RFLP) technique. Besides that, 2 case–control studies in the Egyptian population published before 2021 were included in this meta-analysis. The association was assessed by the odds ratio (OR) with a 95% confidence interval (CI) based on 294 alleles in CHD cases and 286 alleles in controls. Results The overall meta-analysis showed a significant association between MTHFR C677T variant and CHDs risk in Egyptian children with heterogeneity (Heterogeneity = 0.001) in all the genetic models with the highly significant association in T versus C allele (pooled OR 1.89, 95% CI 1.31–2.74; p value < 0.0004). The consistency of the genotypes was detected by Hardy–Weinberg equilibrium (HWE). Conclusions Our results support the MTHFR -677T allele as a susceptibility factor for CHDs in the Egyptian pediatric patients

Correlating SFTPC gene variants to interstitial lung disease in Egyptian children

Abstract Background Interstitial lung disease (ILD) is a broad heterogeneous group of lung disorders that is characterized by inflammation of the lungs. Surfactant dysfunction disorders are a rare form of ILD diseases that result from mutations in surfactant protein C gene (SFTPC) with prevalence of approximately 1/1.7 million births. SFTPC patients are presented with clinical manifestations of ILD ranging from fatal respiratory failure of newborn to chronic respiratory problems in children. In the current study, we aimed to investigate the spectrum of SFTPC genetic variants as well as the correlation of the SFTPC gene mutations with ILD disease in twenty unrelated Egyptian children with diffuse lung disease and suspected surfactant dysfunction using Sanger sequencing. Results Sequencing of SFTPC gene revealed five variants: c.42+35G>A (IVS1+35G>A) (rs8192340) and c.43-21T>C (IVS1-21T>C) (rs13248346) in intron 1, c.436-8C>G (IVS4-8C>G) (rs2070687) in intron 4, c.413C>A p.T138N (rs4715) in exon 4, and c.557G>Ap.S186N (rs1124) in exon 5. Conclusion The present study confirms the association of detecting variants of SFTPC with surfactant dysfunction disorders

New drug-like small molecule antagonizes phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in patients with conotruncal heart defects

الملخص: أهداف البحث: عيوب القلب الوعائية وراثية بشكل كبير وحوالي ثلث عيوب القلب الخلقية ناتجة عن عيوب القلب الوعائية. باستخدام التحليل اللاحق لعيوب القلب المخروطية -بيانات دراسة الترابط الجينومي الكامل ذات الصلة، تم افتراض مسار جديد مفترض لنقل الإشارات، يسمى ''فارس2-بك3كا-أ ك ت''، المرتبط بعيوب القلب الوعائية. كنا نهدف بشكل أساسي إلى التحقق من مسار ''فارس2-بك3كا-أ ك ت” بشكل تجريبي باستخدام المقياسين ''فارس2” و ''بيب3” في كل من مرضى عيوب القلب والعينة الضابطة، وإنشاء مثبط ''بيب3''، كواحد من مسببات عيوب القلب الضارة ذات الصلة، باستخدام استراتيجية تصميم الأدوية القائمة على ''أ ك ت''. طرق البحث: تم إجراء التنميط الجيني ''ار اس 2517582” والتعبير النسبي لـ ''فارس2” في 207 أفراد باستخدام تفاعل البلمرة المتسلسل الكمي، إلى جانب ذلك تم أيضا قياس ''بيب3” المحررة فى البلازما لدى 190 فردا باستخدام تقنية المقايسة الامتصاصية المناعية للإنزيم المرتبط. استخدمنا نموذج ميزات ''أ ك ت''-حامل الخاصة الدوائية لاكتشاف خصم ''بيب3” باستخدام أدوات حسابية متعددة وأدوات تقدير شبيهة بالعقاقير. النتائج: تم تأكيد إمراض عيوب القلب الوعائية بسبب فرط التحفيز المفرط لـ ''فارس2-بك3كا-أ ك ت” عن طريق ''فارس2” المرتفع و ''بيب3” في مرضى عيوب القلب الوعائية. حددنا جزيئا صغيرا جديدا، يسمى ''بيسب322''، قادرا على أن يقاوم ارتباط ''بيب3''، وتم منحه الأولوية من خلال الفحص الافتراضي لـ 21 جزيئا صغيرا افتراضيا. أظهر ''بيسب322” الحد الأدنى من التغير النسبى لاختلاف موقع جزيئاته ''رمسد''، وتقارب ربط عال، وثابت تفكك أقل من مجمع بيب3-أ ك ت” بمقدار 1.99 كيلو كالوري/مول مما يؤدي إلى تحول التوازن التفضيلى نحو تكوين معقد ''بيسب322-أ ك ت''. عرضت ''بيسب322” الخصائص الدوائية المقبولة وخصائص تشابه الأدوية وفقا لقاعدة ليبنيسكي و قاعدة امتصاص وتوزيع وتمثيل الغذاء وإفرازه المكونة من خمسة مصنفات. هذا هو أول جزيء محتمل كشبيه علاجى الدواء لمرضى عيوب القلب الوعائية الذين يعانون من ارتفاع ''بيب3''. الاستنتاجات: ''بيب3” هي مؤشرات حيوية تشخيصية مفيدة لمرضى عيوب القلب. يعد نموذج ميزات ''أ ك ت''-حامل الخاصة الدوائية نهجا ممكنا لاكتشاف المزيد من مضادات تأثير''بيب3''. يوصى بإجراء المزيد من اختبارات التطوير لجزئ ''بيسب322''. Abstract: Objectives: Conotruncal heart defects (CTDs) are highly heritable, and approximately one-third of all congenital heart defects are due to CTDs. Through post-analysis of GWAS data relevant to CTDs, a new putative signal transduction pathway, called Vars2-Pic3ca-Akt, associated with CTD has been hypothesized. Here, we aimed to validate the Vars2-Pic3ca-Akt pathway experimentally by measuring Vars2 and PIP3 in patients with CTDs and controls, and to construct a PIP3 inhibitor, as one of harmful-relevant CTD pathogenesis, through an Akt-based drug design strategy. Methods: rs2517582 genotype and relative Vars2 expression in 207 individuals were determined by DNA sequencing and qPCR respectively, and free plasma PIP3 in 190 individuals was quantified through ELISA. An Akt-pharmacophore feature model was used to discover PIP3 antagonists with multiple computational and drug-like estimation tools. Results: CTD pathogenesis due to Vars2-Pic3ca-Akt overstimulation was confirmed by elevated Vars2 and PIP3 in patients with CTDs. We identified a new small molecule, 322PESB, that antagonizes PIP3 binding. This molecule was prioritized via virtual screening of 21 hypothetical small molecules and it showed minimal RMSD change, high binding affinity andlower dissociation constant than PIP3-Akt complex by 1.99 Kcal/Mol, thus resulting in an equilibrium shift toward 322PESB-Akt complex formation. Moreover, 322PESB exhibited acceptable pharmacokinetics and drug likeness features according to ADME and Lipinski's rule of five classifiers. This compound is the first potential drug-like molecule reported for patients with CTDs with elevated PIP3. Conclusion: PIP3 is a useful diagnostic biomarker for patients with CTDs. The Akt-pharmacophore feature model is a feasible approach for discovery of PIP3 signalling antagonists. Further 322PESB development and testing are recommended

Clinical and genetic characterization of ten Egyptian patients with Wolf–Hirschhorn syndrome and review of literature

Abstract Background Wolf–Hirschhorn syndrome (WHS) (OMIM 194190) is a multiple congenital anomalies/intellectual disability syndrome. It is caused by partial loss of genetic material from the distal portion of the short arm of chromosome. Methods We studied the phenotype–genotype correlation. Results We present the clinical manifestations and cytogenetic results of 10 unrelated Egyptian patients with 4p deletions. Karyotyping, FISH and MLPA was performed for screening for microdeletion syndromes. Array CGH was done for two patients. All patients exhibited the cardinal clinical manifestation of WHS. FISH proved deletion of the specific WHS locus in all patients. MLPA detected microdeletion of the specific locus in two patients with normal karyotypes, while array CGH, performed for two patients, has delineated the extent of the deleted segments and the involved genes. LETM1, the main candidate gene for the seizure phenotype, was found deleted in the two patients tested by array CGH; nevertheless, one of them did not manifest seizures. The study emphasized the previous. Conclusion WHS is a contiguous gene syndrome resulting from hemizygosity of the terminal 2 Mb of 4p16.3 region. The Branchial fistula, detected in one of our patients is a new finding that, to our knowledge, was not reported

National screening for developmental delays and their determinants among Egyptian school age children: A step towards implementing life skills programs.

AimThis study aimed to estimate the national prevalence of developmental delays (DDs) and their determinants among Egyptian children aged 6 to 12 years. Such estimation is a prerequisite step toward the application of Life Skill Education (LSE) programs that will potentiate children's future capabilities.MethodsVineland Adaptive Behavior Scales" was used as a reliable and diagnostic test for DDs screening during this national cross sectional study. Gross motor (GM), fine motor (FM), daily living skills, communication, and socialization skills were assessed. The multivariate logistic regression analysis was used to identify factors associated with DDs. The Adjusted Odds Ratio (AOR) with a 95% Confidence Interval was estimated to indicate the strength of association. A p-value of ResultsOut of the 20324 surveyed school-aged children, 7.4% were found to have at least one delay. Communication deficits were the most common (6.4%) followed by delay in daily living skills (2.0%). The final model of logistic regression had a good fit for seven variables out of the sociodemographic, epidemiological characteristics, maternal and perinatal problems that were associated with a higher likelihood of at least one DD: Children suffering from any convulsions (AOR = 4.32; 95% CI: 3.18-5.88), male gender (AOR = 1.86; 95% CI: 1.65-2.09), birth weight less than 2.5 kg (AOR = 1.77; 95% CI: 1.40-2.24), history of maternal health problem during pregnancy (AOR = 1.64; 95% CI:1.34-2.01), children staying in an incubator for more than two days (AOR = 1.57, 95% CI: 1.29-1.91), having less educated fathers (AOR = 1.55, 95% CI: 1.24-1.95) and belonging to the middle social class (AOR = 1.40, 95% CI: 1.24-1.58).ConclusionThe identified types and determinants for each DD are allowing for the implementation of tailored programs for school children's life skills promotion for achieving the most sustainable effects on children's biological and psychological health and well-being

Prevalence and risk factors of disabilities among Egyptian preschool children: a community-based population study

Abstract Background Child disability has significant implications on their well-being and healthcare systems. Aim: This survey aimed to assess the magnitude of seven types of disability among Egyptian children aged 1 < 6 years and their socio-demographic, epidemiological, and perinatal predictors. Methods A national population-based cross-sectional household survey targeting 21,316 children from eight governorates was conducted. The screening questionnaire was derived from the WHO ten-question survey tool validated for identifying seven disability categories. Results The percentage of children with at least one disability was 8.1% as follows: speech/communication (4.4%), Mobility/physical (2.5%), Seizures (2.2%), Comprehension (1.7%), Intellectual impairment (1.4%), Visual (0.3%) and Hearing (0.2%). Age was not found to affect the odds of disability except for visual disability (significantly increased with age (AOR = 1.4, 95% CI:1.1–1.7). Male sex also increased the odds of all disabilities except visual, hearing, and seizures. Convulsions after birth significantly increased the odds of disability as follows: hearing (AOR = 8.1, 95% CI: 2.2–30.5), intellectual impairment (AOR = 4.2, 95% CI: 2.5–6.9), and mobility/physical (AOR = 3.4, 95% CI: 2.3–5.0). Preterm delivery and being kept in an incubator for more than two days after birth increased the odds for visual disability (AOR = 3.7, 95% CI: 1.1–12.1 & AOR = 3.7, 95% CI: 1.7–7.9 respectively). Cyanosis increased the odds of seizures (AOR = 4.7, 95% CI: 2.2–10.3). Low birth weight also increased the odds for all disability domains except for visual and hearing. Maternal health problems during pregnancy increased the odds for all types of disability except hearing and seizures. Higher paternal education decreased the odds for all disabilities by at least 30% except for vision and hearing. Conclusion The study found a high prevalence of disability among Egyptian children aged 1–6 years. It identified a number of modifiable risk factors for disability. The practice of early screening for disability is encouraged to provide early interventions when needed

Additional file 2 of Prevalence and risk factors of disabilities among Egyptian preschool children: a community-based population study

Additional file 2: S Table 2. All data disability less than 6