inborn errors
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2022 ◽  
Vol 12 ◽  
Author(s):  
Lingtong Huang ◽  
Wei Wu ◽  
Yijing Zhu ◽  
Huili Yu ◽  
Lingling Tang ◽  
...  

Hemophagocytic lymphocytosis (HLH) is a rare disease caused by inborn errors of immunity (IEI), secondary to infection, lymphoma or autoimmune disorders, but we often overlook the fact that HLH can be secondary to inborn errors of metabolism (IEM). Here, we describe a patient who was diagnosed with glutaric aciduria type IIC complicated by features suggestive of possible HLH. The diagnosis of glutaric aciduria type IIC, a IEM, was confirmed by whole exome sequencing. The patient was treated with coenzyme Q10 and riboflavin which effectively improved her liver function. During treatment, the patient developed severe anemia and thrombocytopenia. Persistent fever, splenomegaly, cytopenias, increased ferritin, hypertriglyceridemia, hypofibrinogenemia, and hemophagocytosis in the bone marrow pointed to the diagnosis of HLH; however, the patient eventually died of gastrointestinal bleeding. After other potential causes were ruled out, the patient was diagnosed with glutaric aciduria type IIC complicated by features suggestive of possible HLH. When cytopenias occurs in IEM patients, HLH is a possible complication that cannot be ignored. This case suggests a possible relationship between IEM and risk for immune dysregulation.


2022 ◽  
Vol 12 ◽  
Author(s):  
Akihiro Hoshino ◽  
Etsushi Toyofuku ◽  
Noriko Mitsuiki ◽  
Motoi Yamashita ◽  
Keisuke Okamoto ◽  
...  

IKAROS and CTLA4 deficiencies are inborn errors of immunity and show similar clinical phenotypes, including hypogammaglobulinemia and autoimmune diseases (ADs). However, the differences in clinical features and pathogenesis of these are not fully understood. Therefore, we performed systematic literature reviews for IKAROS and CTLA4 deficiencies. The reviews suggested that patients with IKAROS deficiency develop AD earlier than hypogammaglobulinemia. However, no study assessed the detailed changes in clinical manifestations over time; this was likely due to the cross-sectional nature of the studies. Therefore, we conducted a retrospective longitudinal study on IKAROS and CTLA4 deficiencies in our cohort to evaluate the clinical course over time. In patients with IKAROS deficiency, AD and hypogammaglobulinemia often develop in that order, and AD often resolves before the onset of hypogammaglobulinemia; these observations were not found in patients with CTLA4 deficiency. Understanding this difference in the clinical course helps in the clinical management of both. Furthermore, our results suggest B- and T-cell-mediated ADs in patients with IKAROS and CTLA4 deficiencies, respectively.


2022 ◽  
Vol 12 ◽  
Author(s):  
Ebe Schiavo ◽  
Beatrice Martini ◽  
Enrico Attardi ◽  
Filippo Consonni ◽  
Sara Ciullini Mannurita ◽  
...  

Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.


Author(s):  
Thulasi Raman Ramalingam

AbstractInborn errors of immunity (IEI) are a group of inherited heterogeneous disorders affecting the immune system characterized by increased susceptibility to infections, immune dysregulation, and lymphoproliferation. Flow cytometry (FCM) is a rapid and reliable technique for evaluation and enumeration of immune cells. It also helps in understanding the functional and signaling pathways of the immune system. Lymphocyte subset analysis is a simple and effective screening tool in suspected combined and humoral immunodeficiency patients. Qualitative phagocytic defects such as chronic granulomatous disease and leucocyte adhesion defect are easily diagnosed by FCM. Study of intracellular proteins (e.g., BTK, WASP, DOCK8), cytokine production, and signaling molecules (e.g., STAT3) by FCM is very useful but also quite challenging to establish. T and B lymphocyte interaction for normal class switching of B cells can be assessed and can help in diagnosis of combined variable immunodeficiency and hyperimmunoglobulin M syndrome. FCM is also used in posttransplant monitoring of IEI patients and also in prenatal diagnosis in suspected cases. It is also useful in validation of variants of uncertain significance obtained in exome sequencing. FCM results should always be interpreted with clinical history and, if needed, should be confirmed with molecular genetic studies before establishing the final diagnosis. Ensuring good sample quality and running parallel controls with patient samples will avoid the preanalytical and analytical errors. This review describes the applications of FCM in the diagnosis of various IEI.


2022 ◽  
Vol 50 (1) ◽  
pp. 80-84
Author(s):  
Mahshid Movahedi ◽  
Mahnaz Jamee ◽  
Hosseinali Ghaffaripour ◽  
Farzad Noori ◽  
Mehdi Ghaini ◽  
...  

Background: Inborn errors of immunity (IEIs) are a group of congenital diseases caused by genetic defects in the development and function of the immune system. The involvement of the respiratory tract is one of the most common presentations in IEIs.Methods: Overall, 117 patients with diagnosed IEIs were followed-up within 8 years at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD). Demographic, clinical, and laboratory data were collected in a questionnaire. Pulmonary function test (PFT), chest X-ray (CXR), and high-resolution computed tomography (HRCT) scans were obtained where applicable.Results: Our study population consisted of 48 (41%) patients with predominantly antibody deficiencies (PADs), 39 (32%) patients with congenital defects of phagocytes, 14 (11.9%) patients with combined immunodeficiency (CID), and 16 (14%) patients with Mendelian susceptibility to mycobacterial diseases (MSMD). . Recurrent pneumonia was the most common manifestation, while productive cough appeared to be the most common symptom in almost all diseases. PFT showed an obstructive pattern in patients with PAD, a restrictive pattern in patients with CID, and a mixed pattern in patients with CGD. HRCT findings were consistent with bronchiectasis in most PAD patients, whereas consolidation and mediastinal lesions were more common in the other groups.Conclusions: Pulmonary manifestations vary among different groups of IEIs. The screening for lung complications should be performed regularly to reveal respiratory pathologies in early stages and follow-up on already existing abnormalities.


Author(s):  
Kate F. Kernan ◽  
Lina Ghaloul-Gonzalez ◽  
Jerry Vockley ◽  
Janette Lamb ◽  
Deborah Hollingshead ◽  
...  

Abstract   Purpose Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown. Methods We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN’s Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype. Results More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12–7.10, p = 0.023, urine: OR: 8.23, 95% CI: 1.06–64.11, p = 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin $$\ge 500$$ ≥ 500 ng/mL, OR: 2.16, 95% CI: 1.28–3.66, p = 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 – 2.60, p = 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12–2.76, p = 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10–2.68, p = 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21–14.5, p = 0.019). Conclusion Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.


2022 ◽  
Author(s):  
Leanne van Leeuwen ◽  
Corine GeurtsvanKessel ◽  
Pauline Ellerbroek ◽  
Godelieve J. de Bree ◽  
Judith Potjewijd ◽  
...  

2022 ◽  
pp. 159-175
Author(s):  
Abdelmohcine Aimrane ◽  
Bilal El-Mansoury ◽  
Said Sabir ◽  
Soraia El Baz ◽  
Nadia Zouhairi ◽  
...  

The newly emerged pandemic of coronavirus-induced disease of the year 2019 (COVID-19) has become the utmost health concern worldwide. Patients with COVID-19 are highly susceptible to develop hypercoagulable state increasing the risk of causing venous and arterial thrombosis at both small and large vessels. Additionally, in patients showing co-morbidities, for instance patients with inborn errors of metabolism linked to heart failure, the complications and mortalities are even higher than in any other case. In such frail patients already showing health concerns, the COVID-19-induced pneumonia may cause acute or chronic cardiovascular complications. Indeed, several reports of thrombotic complications in association with other complications has been presented, such as large vessels storks, clotting of catheters, and myocardial injury. Nevertheless, knowledge on the COVID-19-associated cardiovascular diseases remains scarce. Thus, in this chapter, the authors represent an overview of the available data on the induced heart failure related to COVID-19.


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