Hemophagocytic lymphohistiocytosis as presenting manifestation of profound combined immunodeficiency due to an ORAI1 mutation
Christian KlemannSandra AmmannMiriam HeizmannSebastian FuchsSebastian F. N. BodeMaximilian HeegHans FuchsKai LehmbergUdo zur StadtClaudia RollThomas VraetzCarsten SpeckmannMyriam Ricarda LorenzKlaus SchwarzJan RohrStefan FeskeStephan Ehl
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Hemophagocytic Lymphohistiocytosis
Primary Immunodeficiency
Macrophage Activation Syndrome
Pathogenesis
Primary Immunodeficiency
Hematopoietic stem cell
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Introduction and objectives: Severe combined immunodeficiency (SCID) is a subset of primary immunodeficiency diseases caused by a hereditary deficiency of the adaptive immune system. Mutation in recombination activating gene (RAG) is known as the underlying genetic cause of SCID. RAG protein plays a pivotal role in V(D)J recombination which is the main process to assemble lymphocyte antigen receptors during T- and B-cell development. The patients are characterized by recurrent infections, failure to thrive, chronic diarrhea, and fever, in early infancy. Herein, we present a case of SCID with rare neurological manifestations affected by a mutation in RAG1.Patients and methods: The patient was a 15-month-old infant born to a consanguineous family. She was presented with neurological abnormalities including facial nerve palsy, seizure, and decreased consciousness. Next-generation sequencing (NGS)-based primary immunodeficiency disease (PID)-gene panel screen and Sanger sequencing were performed to identify the genetic mutation.Results: We found a novel homozygous missense mutation in RAG1, c.1210C>T,p.Arg404Trp, which was predicted to be deleterious (combined annotation dependent depletion, CADD score of 27.4). Both parents were heterozygous carriers for this mutation. According to her laboratory data, both T cell and B cell numbers were decreased and the patient was diagnosed as RAG1- SCID.Conclusions: SCID is a pediatric emergency with a variety of manifestations in infants. Therefore, accurate diagnosis importantly in the case of rare manifestations must be considered in these patients. Our findings point toward the importance of genetic assessment for early diagnosis and timely treatment of this disorder.
Primary Immunodeficiency
RAG2
Sanger sequencing
Failure to Thrive
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Hemophagocytic lymphohistiocytosis (HLH), also known as cytokine storm, hemophagocytic lymphohistiocytosis, and macrophage activation syndrome, is a life-threatening disorder caused by a congenital or acquired defect in the cytolytic activity of cytotoxic T-lymphocytes (CD8+) and natural killers, as well as hyperproduction of interleukins-1, -6, -18, and interferon-γ. HLH develops in children with systemic juvenile idiopathic arthritis (sJIA), often resulting in multiple organ failure, and is characterized by a high risk of death. This article discusses the mechanisms underlying the development of primary and secondary HLH and sJIA, as well as clinical and laboratory manifestations of HLH. It summarizes the information on diagnostic criteria and analyzes therapeutic approaches used for HLH. Key words: hemophagocytic lymphohistiocytosis, systemic juvenile idiopathic arthritis, biologicals, rheumatology, children
Hemophagocytic Lymphohistiocytosis
Macrophage Activation Syndrome
Cytokine Storm
Tocilizumab
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Severe combined immunodeficiency (SCID) is the most life-threatening form of primary immunodeficiency, fatal within the first years of life if hematopoietic stem cell transplantation (HSCT) is not performed. Early diagnosis is crucial for prevention of multiple life-threatening complications, which in turn allows for successful HSCT. Current publication contains clinical recommendations for diagnosis of SCID and its complications, complex treatment, including HSCT, prenatal diagnostics and genetic family counselling.
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Immunodeficiency Syndrome
Immunologic Deficiency Syndromes
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The designation primary immunodeficiency embraces a multiplicity of diseases of which only the more severe constitute indications for BMT (bone marrow transplantation)--e.g. severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, familial haemophagocytic lymphohistiocytosis and malignant osteopetrosis. In cases of immunodeficiency, the outcome of BMT is strongly dependent on the patient's age, clinical status at transplantation and the type of immunodeficiency. In children with SCID who undergo BMT during the first few months of life, lasting cures can be obtained in almost 100 percent of the cases, whereas there is only a 15 percent probability of success if the child is older, infected, cannot undergo cytostatic preconditioning or cannot be given T-cell depleted bone marrow.
Primary Immunodeficiency
Osteopetrosis
Wiskott–Aldrich syndrome
Immunodeficiency Syndrome
Hemophagocytic Lymphohistiocytosis
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Adenosine deaminase deficiency
Primary Immunodeficiency
Immunologic Deficiency Syndromes
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One of the well-known groups of primary immunodeficiency conditions includes primary immunodeficiencies with impaired DNA repair. Primary immunodeficiencies with impaired DNA repair include immunodeficiency with Cernunnos protein deficiency. Pathogenic biallelic genetic variants in the NHEJ1 gene lead to the development of this immunodeficiency. The Cernunnos protein is involved in the processes of non-homologous DNA repair and V(D)J recombination of T- and B-lymphocyte receptors. In the clinical picture of patients with Cernunnos protein deficiency, the leading manifestations are the following: infectious complications within the framework of combined immunodeficiency, cytopenia, autoimmune complications. Like most primary immunodeficiencies with impaired DNA repair, immunodeficiencies with a defect in the NHEJ1 gene are characterized by a predisposition to the development of malignant neoplasms. The only curative treatment for patients with primary immunodeficiency conditions associated with Cernunnos protein deficiency is allogeneic hematopoietic stem cell transplantation.
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Immunodeficiency Syndrome
Cytopenia
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Abstract Immunodeficiency is a condition caused by a defect in the immune system, leading to a failure to protect the body adequately from infection. It should be considered in anybody with a history of recurrent infections, two or more episodes of life‐threatening infections, infections with unusual or opportunistic organisms or with unexpected or severe complications. Immunodeficiency may be either primary or secondary in origin. Primary immunodeficiency (PID) may present as early as the first 3–4 weeks of life with severe diarrhoea, resulting in failure to thrive, recurrent infections and severe eczema. However, it may also manifest in early childhood or later, depending on the nature of the underlying disease and genetic mutation. It is essential to diagnose PID early, particularly severe combined immune deficiency (SCID), in order to prevent infections and organ damage and offer curative treatment such as haematopoietic stem cell transplantation (HSCT) or gene transfer (GT). Key Concepts Defects in the immune system can put patients at risk of life‐threatening infections. Primary immunodeficiency consists of a wide range of disorders that affect adaptive or innate immunity. Early diagnosis of primary immunodeficiency is essential for successful outcome. The most common manifestation of immunodeficiency is recurrent respiratory infections. The most predictive of 10 warning signs for a diagnosis of PID are family history, need for intravenous antibiotics for sepsis and failure to thrive. Next‐generation sequencing has led to the discovery of novel genetic causes of known and new PIDs. Outcome of haematopoietic stem cell transplantation has greatly improved. Gene therapy is successful and increasingly available for a number of disorders. Secondary immunodeficiency can be caused by infection such as HIV.
Primary Immunodeficiency
Immune Dysregulation
Failure to Thrive
Common Variable Immunodeficiency
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Primary Immunodeficiency
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Primary immunodeficiency syndromes may be seen as "experiments of nature", giving insights into the organization and function of the human immune system. The principal categories of primary immunodeficiency syndromes: severe combined immunodeficiency, agammaglobulinemia and isolated T-cell defects (e.g. Di George Syndrome) are still used in view of their leading clinical presentations. However, detailed analysis of individual cases and families now shows a plethora of different diseases in each category. In this review the relationship of primary immunodeficiency diseases of the B-cell system and autoimmune phenomena are discussed. The pathology of thymus in severe combined immunodeficiency is shown: central maturation defects of the T-cell system are not due to "dysplasia" of the thymus but rather to enzyme defects of the lymphatic cells. Severe alterations of the thymus may also be caused by graft versus host disease. The clarification of genetic defects of lymphoid differentiation and maturation today may lead to improved early and prenatal diagnosis as well as specific gene therapy. The success of bone marrow transplantation in many cases of primary immunodeficiency disease syndromes may be considered as a consequence of successful gene therapy.
Primary Immunodeficiency
Immunodeficiency Syndrome
Immunologic Deficiency Syndromes
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