Clinical, Immunological, and Genetic Features in Patients with NFKB1 and NFKB2 Mutations: a Systematic Review.

BACKGROUND: Inborn errors of immunity (IEIs) encompass various diseases with diverse clinical and immunological symptoms. Determining the genotype-phenotype of different variants in IEI entity precisely is challenging, as manifestations can be heterogeneous even in patients with the same mutated gene. OBJECTIVE: In the present study, we conducted a systematic review of patients recorded with NFKB1 and NFKB2 mutations, two of the most frequent monogenic IEIs. METHODS: The search for relevant literature was conducted in databases including Web of Science, PubMed, and Scopus. Information encompassing demographic, clinical, immunological, and genetic data was extracted from cases reported with mutations in NFKB1 and NFKB2. The comprehensive features of manifestations in patients were described, and a comparative analysis of primary characteristics was conducted between individuals with NFKB1 loss of function (LOF) and NFKB2 (p52-LOF/IκBδ-gain of function (GOF)) variants. RESULTS: A total of 397 patients were included in this study, 257 had NFKB1 mutations and 140 had NFKB2 mutations. There were 175 LOF cases in NFKB1 and 122 p52LOF/IκBδGOF cases in NFKB2 pivotal groups with confirmed functional implications. NFKB1LOF and p52LOF/IκBδGOF predominant cases (81.8% and 62.5% respectively) initially presented with a CVID-like phenotype. Patients with NFKB1LOF variants often experienced hematologic autoimmune disorders, whereas p52LOF/IκBδGOF patients were more susceptible to other autoimmune diseases. Viral infections were markedly higher in p52LOF/IκBδGOF cases compared to NFKB1LOF (P-value < 0.001). NFKB2 (p52LOF/IκBδGOF) patients exhibited a greater prevalence of ectodermal dysplasia and pituitary gland involvement than NFKB1LOF patients. Most NFKB1LOF and p52LOF/IκBδGOF cases showed low CD19 + B cells, with p52LOF/IκBδGOF having more cases of this type. Low memory B cells were more common in p52LOF/IκBδGOF patients. CONCLUSIONS: Patients with NFKB2 mutations, particularly p52LOF/IκBδGOF, are at higher risk of viral infections, pituitary gland involvement, and ectodermal dysplasia compared to patients with NFKB1LOF mutations. Genetic testing is essential to resolve the initial complexity and confusion surrounding clinical and immunological features. Emphasizing the significance of functional assays in determining the probability of correlations between mutations and immunological and clinical characteristics of patients is crucial.

A systematic review regarding the prevalence of malignancy in patients with the hyper-IgE syndrome.

The hyper-immunoglobulin E syndrome (HIES) is a primary immunodeficiency disease originally described as Job syndrome. The fundamental causative variant of the HIES is an autosomal dominant mutation in the signal transducer and activator of transcription 3 (STAT3) gene. It is characterized by recurrent staphylococcal cold skin abscess, sinopulmonary infection, eczema, head and face anomalies, frequent bone fractures, eosinophilia and extremely high serum IgE levels (IgE ≥ 2000 IU/mL). However, multiple other genetic defects are also known as HIES-like disorders. Apart from infectious manifestations, STAT3, DOCK8 and TYK2 gene mutations are associated with various malignancies. The most common malignancies reported in these patients are lymphomas, including Hodgkin's and non-Hodgkin's lymphomas (NHL) of B and T cells. This systematic review aimed to investigate the prevalence of malignancies in HIES and the factors associated with malignancy in these patients. In this survey, all articles published until April 1st, 2023, in Scopus, PubMed and Web of Science databases based on three groups of keywords related to HIES syndrome and malignancy were reviewed by three different researchers. Finally, 26 articles were evaluated from which 24 papers were meta-analyzed. In the current study, the demographic information of 1133 patients with HIES, which was mentioned in 24 articles enrolled in the project, was collected, and the information related to patients who had malignancy was analyzed and meta-analyzed. A total of 96 patients out of 1133 studied patients had at least one type of malignancy, the overall prevalence of malignancies reported in the articles was 6.5% (95% confidence interval 4.1-9%), and the total prevalence of malignancy in patients with NHL type and patients with squamous cell carcinoma (SCC) was 2.9% (95% confidence interval 1.7-4.4%) and 2.2% (95% confidence interval 0.3-4.1%), respectively. The results of this study indicated that in 6.5% of cases, HIES was complicated with malignancy, and considering the higher rate of these malignancies in women as well as in DOCK8 mutation sufferers, it is necessary for physicians to be aware of this association and includes malignancy screening in follow-up and periodic examinations of these patients. Indeed, more studies in this field will help to clarify the precise figures and predisposing factors of the relationship between HIES and malignancy.

Association between IL-10 (at position -592) and IL-4 (at position -589) genotype polymorphism with atopic and non-atopic asthma in children.

OBJECTIVES: Asthma is the most prevalent respiratory disease, caused by chronic bronchial inflammation. Cytokines are known to play an important role in the pathophysiology of asthma. This study aimed to compare interleukin-4 (IL-4) and interleukin-10 (IL-10) gene polymorphisms between Iranian pediatric asthmatic patients and healthy controls and to investigate IL4 and IL10 gene variations in children with atopic and non-atopic asthma phenotypes. METHODS: In this prospective case-control study, a total of 95 unrelated pediatric asthmatic patients were recruited according to the Global Initiative for Asthma (GINA) criteria. The control group comprised two subgroups of 538 and 491 healthy individuals, undergoing IL4 and IL10 polymorphism assessments, respectively. The IL4 -589C/T (rs2243250) and IL10 -592A/C (rs1800872) gene polymorphisms were evaluated using the tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) assay. RESULTS: The findings indicated a significant difference in IL4 gene polymorphisms at position -589 between the asthmatic and healthy control groups. However, no significant difference was found in terms of IL10 gene polymorphisms, and they were not associated with atopy in the patients. CONCLUSION: The IL4 -589C/T polymorphism (rs2243250) can be a risk factor for asthma susceptibility, whereas the IL10 -592A/C polymorphism (rs1800872) is not a risk factor in the Iranian pediatric population. The results also showed that these polymorphisms are not risk factors for atopy in asthmatic children.

A case of Familial Mediterranean Fever presented with recurrent infection.

INTRODUCTION: The periodic fever syndrome Familial Mediterranean Fever (FMF) is caused by mutations in MEFV, which promote inflammation and present with uncontrolled systemic and organ-specific inflammation that can resemble infectious conditions. It is diagnosed based on clinical criteria, including frequent symptoms such as abdominal and thoracic pain, family history, and response to treatment with colchicine, which is confirmed by genetic assessment. Herein, we present a case of FMF with a relatively uncommon presentation. CASE PRESENTATION: A 22-month-old female was referred to the allergy and clinical immunology clinic with eczematoid skin rashes. She was admitted to the hospital several times since the 2nd day of life with different complaints like fever, seizure, and restlessness, and treated with the diagnosis of septicemia. Endoscopy and colonoscopy were done at the age of 6 months due to poor weight gain and bloody diarrhea, which revealed active crypt-destructive colitis with foci of erosion in favor of infectious or allergic colitis. The colon biopsy was negative for Cytomegalovirus (CMV). Regarding family history, she was the second child of the first cousins parents and had a healthy 12-year-old sister. There was a history of death for unknown reasons of her cousin, whose parents were related. The immunologic evaluation was done, which showed a relatively normal immunoglobulin level, antibody response, flow cytometry, and lymphocyte transformation test. Nonetheless, a genetic study was done, which showed a homozygote mutation in exon 10 of the MEFV gene in the patient and a heterozygote mutation in both her parents. CONCLUSION: The periodic fever syndrome Familial Mediterranean Fever (FMF) is caused by mutations in MEFV, which promote inflammation and present with uncontrolled systemic and organ-specific inflammation that can resemble infectious conditions. The patient was diagnosed with FMF, and treatment was started using colchicine, which successfully controlled the patient's symptoms and prevented the recurrence of fever and other inflammatory manifestations.

Evaluation of the frequency of attention deficit hyperactivity disorder in patients with asthma.

BACKGROUND: Asthma is the most prevalent respiratory disease caused by chronic airway inflammation. Attention Deficit Hyperactivity Disorder (ADHD) is children's most common psychological and neurodevelopmental disorder. Increased risk for ADHD in patients with inflammatory and autoimmune diseases supports the role of inflammatory mechanisms in the occurrence of ADHD. However, the association between asthma and ADHD remains unclear. OBJECTIVE: This study was designed to evaluate the prevalence of ADHD in patients with asthma who were referred to the clinic of allergy and clinical immunology. METHODS: This cross-sectional study was conducted on children aged 6 to 18 with asthma at Imam Ali hospital, Karaj, Iran. The patient's demographic data, history of childbirth delivery type, premature birth, hospital admission, family income, birth rate, and family history information related to the patient's asthma and medicines were recorded. ADHD diagnosis was made using the Persian version of Conners Parent Behavioral Problems Rating Scale (CPRS-26). RESULTS: In this study, 677 asthmatic patients were enrolled; 46 patients (6.8%) had ADHD. The probability of ADHD in asthmatic patients inhabited in a rural area, males, and patients with a history of food allergy, allergic rhinitis, urticaria, and eczema was significantly higher (p < 0.05). In addition, our result demonstrated that the likelihood of ADHD in patients with asthma and a history of PICU admission was significantly higher (p < 0.05). CONCLUSIONS: The present study showed that severe asthma, was the risk factor for ADHD in patients with asthma. Physicians should be aware of this co-morbidity to refer asthmatic patients who have the symptoms of ADHD to a psychologist.

The Effect of Using Dexamethasone Tablets Vaginally for Improving Cervical Bishop Score in Nulliparous Pregnant Women: A Randomized Clinical Trial.

Background: Cervix ripening and labor induction are common interventions in obstetrics. For optimal maternal health, labor may be induced under certain situations to improve fetal survival outcomes. Labor induction of an unripe cervix can lead to complications; therefore, several approaches can facilitate the ripening process. Methods: This randomized clinical trial was a triple-blind study that involved 84 pregnant nulliparous women enrolled between October 2019 and June 2021 in the labor ward of Kamali Hospital, Karaj, Iran. The pregnant women in the study underwent labor induction and were randomized into 2 groups: 1 group received vaginal dexamethasone and the other group was given a placebo. Results: There was no significant difference between the groups regarding maternal age, demographic characteristics, and initial Bishop score. The median second Bishop score (6 hours after intervention) was 3.5 in dexamethasone recipients and 3 in placebo recipients (P = 0.48). The median labor latent phase duration was 4 hours in dexamethasone recipients and 5 hours in placebo recipients (P = 0.57). Conclusions: This randomized clinical trial demonstrated that administering dexamethasone tablets vaginally did not significantly improve cervical Bishop scores. (Curr Ther Res Clin Exp. 2023; 84:XXX-XXX). ClinicalTrials.gov identifier: NCT05070468.

Cavernous sinus thrombosis in ulcerative colitis recurrent after pregnancy: A case report.

Inflammatory bowel disease and pregnancy are risk factors for increased hyper coagulopathy state. A 35-year-old woman with ulcerative colitis was presented in this study. She had the recurrence of the disease during pregnancy. She suffered cavernous sinus thrombosis simultaneously.

Cerebral venous sinus thrombosis following intracerebral hemorrhage after COVID-19 AstraZeneca vaccination: A case report.

The patient was a 55-year-old female patient who presented with sudden onset of left hemiplegia, facial hemiparesis, and hypoesthesia. She has received her first dose of the AstraZeneca COVID-19 vaccine. This case indicates that vaccination may raise the hypercoagulable state even in a condition of post-ICH and anticoagulant prophylaxis.

Niemann-Pick type A disease with new mutation: a case report.

BACKGROUND: Niemann-Pick type A (NP-A) is a congenital, hereditary disease caused by a deficiency in acid sphingomyelinase, a lysosomal enzyme. This deficiency results in an accumulation of sphingomyelin in lysosomes, leading to cellular apoptosis and ultimately to hepatosplenomegaly, neurodegenerative disorder and failure to thrive. Cherry-red spots in the macula and foamy cells in the bone marrow are other manifestations of the disease that help with diagnosis. Type A is a rare, untreatable disease with early manifestations and a poor prognosis, with newborns rarely surviving for 2-3 years. CASE PRESENTATION: A 1-year-old Persian boy was referred to our clinic due to abdominal distention and poor weight gain. He was the first male offspring of consanguineous parents. Other findings were neurodevelopmental delay, hepatosplenomegaly, severe hypotonia, difficulty in breathing, and a slightly coarse face with an open mouth and protruding tongue. The initial diagnosis was clinical mucopolysaccharidosis (MPS) based on the coarse facial features, but further workup ruled out this inherited disorder. Enzyme histochemistry revealed that the level of acid sphingomyelinase was lower than normal. In the genetic study, next-generation sequencing of all coding exons and flanking intronic regions of the patient's DNA demonstrated a homozygous c.682T>G variant in the SMPD1 gene. This variant was classified as a variant of unknown significance. Further evaluation of DNA extract from his parents and examined using Sanger sequencing showed a heterozygous c.682T>G variant in the SMPD1 gene of both parents. CONCLUSIONS: We describe a 1-year-old boy with neurodevelopmental delay, hepatosplenomegaly, and severe hypotonia. Further investigation demonstrated a new mutation for Niemann-Pick disease.

The effect of magnesium sulfate on maternal serum electrolytes and parathyroid hormone in pre-eclampsia.

OBJECTIVE: To evaluate possible interactions of magnesium sulfate-the drug of choice in the management of pre-eclampsia/eclampsia-in response to a few case reports that revealed maternal electrolyte disturbances, especially symptomatic changes, following magnesium sulfate administration in pre-eclampsia. METHODS: Prospectively, women with pre-eclampsia were given 4 g of intravenous magnesium sulfate followed by a 2 g/h infusion up to 24 h after delivery. Sequential blood samples were drawn from each patient and used to measure the serum levels of sodium, potassium, calcium, phosphorus, magnesium, and parathyroid hormone. RESULTS: A total of 30 pregnant women with pre-eclampsia were evaluated. They were aged between 20 and 41 years with median gestational age of 37.6 (interquartile range 35.4-38.9) weeks. Only five patients reached the therapeutic window of magnesium in at least one of our measuring intervals during magnesium sulfate infusion. Plasma magnesium concentrations increased significantly during magnesium sulfate administration and dropped during the next 12 and 24 h after infusion discontinuation (P < 0.05). Fifteen of 30 (50%) patients developed asymptomatic hypocalcemia, mainly at hour 24 of infusion. Negative moderate correlations were detected between the calcium and magnesium concentrations at 12 and 24 hours of infusion (ρ = -0.390, P = 0.044 and ρ = 0.315, P = 0.096, respectively). None of the patients with hypocalcemia reached the therapeutic level of magnesium or experienced parallel hyperphosphatemia. Eleven of 30 (36.6%) patients developed hyperphosphatemia mainly at 2 and 12 h of magnesium sulfate infusion. CONCLUSIONS: Our study implies that magnesium sulfate could cause hypermagnesemia-induced hypocalcemia in women with pre-eclampsia, independent from parathyroid hormone. The negative correlations between calcium and magnesium concentrations could be indicative of dose-dependent associations between serum magnesium level and degree of hypocalcemia in our study.

Acute polyneuropathy as the main manifestation of primary Sjogren's syndrome: A case report.

Sjogren's syndrome is an inflammatory disease affecting many systems. We report a Sjogren case with the presenting feature of an acute motor-predominant polyneuropathy resembling Guillain-Barre syndrome. Upon further investigation, it was found that the patient had sicca symptoms for months. Scrupulous history should be taken to prevent a missed diagnosis.

Giant cell arteritis with rare manifestations of stroke and internal carotid artery dissection: A case study.

Giant cell arthritis is a systemic vasculitis. A 51-year-old man was presented with sudden onset of right-side blurred vision, frozen movements, and ptosis in the right eye and left side paresis. The diagnosis of GCA with first manifestations of stroke and carotid dissection may be neglected as an underlying cause.

Ruled out of preeclampsia-like syndrome due to COVID-19: A case study.

Coronavirus disease (COVID-19) is an infectious disease. In this study, we report a 28-year-old pregnant woman who had a postpartum seizure with a background of HELLP syndrome and a proven COVID-19 infection. Her child survived, and at 12-week postpartum, all maternal COVID-19-related symptoms vanished, and she was cured.

A pregnant woman with a history of SLE with PPROM and severe thrombocytopenia: A case study.

This study discusses the management of a pregnant woman with PPROM and a history of lupus. She was found to be severely thrombocytopenic which was unresponsive to prednisolone. During cesarean section, placental abruption was found and postpartum hemorrhage ensued.

Clinical, immunological, and genetic features in 780 patients with autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like diseases: A systematic review.

BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a group of genetic disorders characterized by early-onset lymphoproliferation, autoimmune cytopenias, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline mutations in the TNFRSF6 gene. In this study, we conducted a systematic review of patients with ALPS and ALPS-like syndrome. METHODS: The literature search was performed in Web of Science, Scopus, and PubMed databases to find eligible studies. Additionally, the reference list of all included papers was hand-searched for additional studies. Demographic, clinical, immunological, and molecular data were extracted and compared between the ALPS and ALPS-like syndrome. RESULTS: Totally, 720 patients with ALPS (532 genetically determined and 189 genetically undetermined ALPS) and 59 cases with ALPS-like phenotype due to mutations in genes other than ALPS genes were assessed. In both ALPS and ALPS-like patients, splenomegaly was the most common clinical presentation followed by autoimmune cytopenias and lymphadenopathy. Among other clinical manifestations, respiratory tract infections were significantly higher in ALPS-like patients than ALPS. The immunological analysis showed a lower serum level of IgA, IgG, and lymphocyte count in ALPS-like patients compared to ALPS. Most (85%) of the ALPS and ALPS-like cases with determined genetic defects carry mutations in the FAS gene. About one-third of patients received immunosuppressive therapy with conventional or targeted immunotherapy agents. A small fraction of patients (3.3%) received hematopoietic stem cell transplantation with successful engraftment, and all except two patients survived after transplantation. CONCLUSION: Our results showed that the FAS gene with 85% frequency is the main etiological cause of genetically diagnosed patients with ALPS phenotype; therefore, the genetic defect of the majority of suspected ALPS patients could be confirmed by mutation analysis of FAS gene.