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Clinics in Perinatology Mar 2020Severe combined immunodeficiency (SCID) encompasses a group of genetic defects. T cell development is universally affected and has alteration of B and/or NK cells. We... (Review)
Review
Severe combined immunodeficiency (SCID) encompasses a group of genetic defects. T cell development is universally affected and has alteration of B and/or NK cells. We present the case of a 5-day-old boy with combined heterozygous frame shift (c.256_257del, p.(Lys86Valfs*33)) and missense (c.1186C>T, p.(Arg396Cys)) variations in the RAG1 gene. He was admitted to our institution because of 0 TREC on Newborn Screen and worsening rash. Initially thought to have Omenn syndrome versus maternal engraftment with graft versus host disease, DNA analysis identified the noted mutations and he subsequently received a bone marrow transplant from a matched sibling.
Topics: Diagnosis, Differential; Humans; Infant, Newborn; Neonatal Screening; Rare Diseases; Severe Combined Immunodeficiency
PubMed: 32000930
DOI: 10.1016/j.clp.2019.09.004 -
Pediatric Dermatology Mar 2021Omenn syndrome is a rare combined immunodeficiency mostly associated with RAG1 and RAG2 mutations; the clinical manifestations are well-described and include neonatal...
Omenn syndrome is a rare combined immunodeficiency mostly associated with RAG1 and RAG2 mutations; the clinical manifestations are well-described and include neonatal erythroderma. Mortality due to opportunistic infections is a serious risk, and a timely diagnosis with a skin biopsy is an important part of the diagnostic workup. We wish to highlight key clinical features of Omenn syndrome and discuss the relevance of a skin biopsy.
Topics: Dermatitis, Exfoliative; Homeodomain Proteins; Humans; Infant, Newborn; Mutation; Severe Combined Immunodeficiency; Syndrome
PubMed: 33511666
DOI: 10.1111/pde.14401 -
Nihon Rinsho Men'eki Gakkai Kaishi =... 2017Mutations in the RAG1/RAG2 genes are associated with a broad spectrum of clinical phenotypes, ranging from severe combined immunodeficiency to various autoimmune... (Review)
Review
Mutations in the RAG1/RAG2 genes are associated with a broad spectrum of clinical phenotypes, ranging from severe combined immunodeficiency to various autoimmune diseases. The diversity of the clinical symptoms is determined not only by the residual RAG recombinase enzyme activity as determined by the mutations, but also by multiple environmental factors and, in rare cases, by second site mutations within the RAG1/RAG2 genes. The residual recombinase activity is responsible for the oligoclonal expansion of autoreactive T cells. Omenn syndrome is the result of intense Th2 type inflammation involving the skin and multiple other organs triggered by these T cells. In this review, the molecular pathology of diseases caused by RAG1/RAG2 mutations, in particular Omenn syndrome, will be discussed. Furthermore, abnormalities in other molecules involved in V(D)J recombination will be discussed in relation to Omenn-like syndrome.
Topics: DNA; DNA-Binding Proteins; Genetic Association Studies; Homeodomain Proteins; Humans; Mutation; Nuclear Proteins; Severe Combined Immunodeficiency; Th2 Cells; V(D)J Recombination
PubMed: 28747605
DOI: 10.2177/jsci.40.179 -
Current Opinion in Allergy and Clinical... Dec 2011During the past decade, easy access to sequence analyses has allowed us to increase our understanding of the pathogenesis of severe combined immunodeficiencies. Here, we... (Review)
Review
PURPOSE OF REVIEW
During the past decade, easy access to sequence analyses has allowed us to increase our understanding of the pathogenesis of severe combined immunodeficiencies. Here, we describe the expanding clinical and immunological spectrum associated with Omenn syndrome phenotype. In particular, we review the cellular and molecular mechanisms involved in the pathophysiology of 'classical' Omenn syndrome due to the recombination activating gene (RAG) defects and of a new subgroup of Omenn-like disorders.
RECENT FINDINGS
Different types of mutations are associated with the Omenn phenotype characterized by skin erythroderma, oligoclonal-activated T cells and elevated IgE in the absence of circulating B cells. Extensive studies conducted over the last few years have allowed the definition of the 'classical form' of Omenn syndrome due to hypomorphic defects in genes involved in V(D)J recombination, mainly RAG genes, and 'Omenn-like' features associated with mutations in genes involved in the maturation steps of lymphoid cells other than V(D)J recombination. Moreover, an increasing number of diseases other than those due to V(D)J recombination defects develop Omenn signs.
SUMMARY
Impaired but not abolished V(D)J recombination process leads to the generation of a few T cells which expand in the periphery, infiltrate target organs such as skin and gut, resulting in severe erythroderma and colitis, both typical signs of Omenn syndrome. Extensive molecular studies now demonstrate that genes other than V(D)J molecules have a role in the pathogenesis of this disease, supporting the evidence that 'Omenn' defines an inflammatory condition associated with various genetic defects.
Topics: Adenosine Deaminase; B-Lymphocytes; Cell Differentiation; DNA-Binding Proteins; Homeodomain Proteins; Humans; Interleukin-7; Lymphocyte Activation; Mutation; Severe Combined Immunodeficiency; T-Lymphocytes; V(D)J Recombination
PubMed: 22001740
DOI: 10.1097/ACI.0b013e32834c311a -
European Journal of Pediatrics Dec 2001Omenn syndrome is a form of severe combined immunodeficiency associated with high mortality. Early recognition is required in order to initiate life-saving therapy. This... (Review)
Review
UNLABELLED
Omenn syndrome is a form of severe combined immunodeficiency associated with high mortality. Early recognition is required in order to initiate life-saving therapy. This review provides information on the clinical symptoms, laboratory parameters and pathology of the disease, supporting early diagnosis in suspected patients. A literature search was performed using Medline, encompassing the period 1965-1999. Sixty-seven cases were identified and with the addition of a recently diagnosed patient at our hospital, 68 children were included. Median age at onset of symptoms was 4 weeks. Key symptoms were erythematous rash (98%), hepatosplenomegaly (88%), lymphadenopathy (80%), often accompanied by recurrent infections (72%) and alopecia (57%). An elevated WBC (55%) was frequently observed, due to eosinophilia and/or lymphocytosis. B-cell counts were significantly decreased whereas T-cell counts were elevated. A high serum IgE was another frequent finding (91%). Therapeutic options include bone marrow transplantation or cord blood stem cell transplantation; however, the mortality still was 46%.
CONCLUSION
Omenn syndrome is a fatal disease if untreated. The mortality may be reduced when diagnosis is established early and treatment is initiated rapidly by using early compatible bone marrow transplantation or cord blood stem cell transplantation.
Topics: Bone Marrow Transplantation; Female; Fetal Blood; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Male; Practice Guidelines as Topic; Severe Combined Immunodeficiency; Treatment Outcome
PubMed: 11795679
DOI: 10.1007/s004310100816 -
Ryoikibetsu Shokogun Shirizu 2000
Review
Topics: Bone Marrow Transplantation; DNA Nucleotidyltransferases; Diagnosis, Differential; Gene Rearrangement, T-Lymphocyte; Genes, RAG-1; Graft vs Host Disease; Humans; Mutation, Missense; Prognosis; Severe Combined Immunodeficiency; Syndrome; T-Lymphocytes; VDJ Recombinases
PubMed: 11212702
DOI: No ID Found -
Current Opinion in Rheumatology Jul 2006Omenn syndrome is a rare inherited primary immunodeficiency characterized by severe combined immunodeficiency in combination with autoimmune features leading to squamous... (Review)
Review
PURPOSE OF REVIEW
Omenn syndrome is a rare inherited primary immunodeficiency characterized by severe combined immunodeficiency in combination with autoimmune features leading to squamous erythrodermia, alopecia, lymphadenopathy, hepatosplenomegaly, and intractable diarrhea. Recent advances include characterizing the genetic basis of the syndrome and integrating the genetic defects into knowledge of tolerance induction.
RECENT FINDINGS
Molecular studies have shown that besides the well-known hypomorphic recombination activating gene defects, mutations in the nonhomologous end-joining factor Artemis and in the interleukin-7 receptor alpha chain can contribute to the development of Omenn syndrome. These investigations established that Omenn syndrome is a genetically heterogeneous condition. Whereas the majority of patients with Omenn syndrome bear hypomorphic gene alterations, some exhibit somatic mosaicism due to second-site reversions of null alleles. A lack of central tolerance contributes to the autoimmune pathology of the disease.
SUMMARY
Research has begun to clarify the genetic defects and the conditions underlying the lack of tolerance enforcement that predispose to Omenn syndrome. Clinical applications of this research include the identification of the causative genetic defect in the majority of Omenn syndrome cases and the use of this genetic knowledge in family and prenatal analyses and in difficult differential autoimmune diagnoses.
Topics: Autoimmune Diseases; DNA Repair; Humans; Immune Tolerance; Lymphocytes; Models, Immunological; Mutation; Recombination, Genetic; Severe Combined Immunodeficiency; Syndrome; T-Lymphocytes; VDJ Recombinases
PubMed: 16763459
DOI: 10.1097/01.bor.0000231907.50290.6f -
The Israel Medical Association Journal... Mar 2002Severe combined immunodeficiencies represent a heterogeneous group of hereditary defects of the immune system that affect both T and B cells and whose etiology has only... (Review)
Review
Severe combined immunodeficiencies represent a heterogeneous group of hereditary defects of the immune system that affect both T and B cells and whose etiology has only recently begun to be understood. A portion of these SCID patients bear a defect in either of the two recombination-activating genes, Rag-1 or Rag-2, while others have mutations in a newly identified gene, Artemis. Omenn syndrome is an unusual severe immunodeficiency with T cells but no B cells, and peculiar features also due to a defect in Rag-1 or Rag-2 genes. All these three forms are characterized by an impairment of the VDJ recombination, the process that insures the somatic diversification of immunoglobulin and T cell receptor-encoding genes. Recent findings have enabled us to better understand the pathophysiology of these three immunodeficiencies, which affect the V(D)J recombination process to a different extent and in different ways.
Topics: B-Lymphocytes; DNA-Binding Proteins; Endonucleases; Genes, RAG-1; Humans; Mutation; Nuclear Proteins; Severe Combined Immunodeficiency; beta-Lactamases
PubMed: 11908269
DOI: No ID Found -
The Journal of Allergy and Clinical... Dec 2008Omenn syndrome (OS) was reported until recently as a distinct form (phenotype and genotype) of severe combined immunodeficiency (SCID). Similar to other patients with... (Review)
Review
Omenn syndrome (OS) was reported until recently as a distinct form (phenotype and genotype) of severe combined immunodeficiency (SCID). Similar to other patients with SCID, patients with OS present early in infancy with viral or fungal pneumonitis, chronic diarrhea, and failure to thrive. Unlike typical SCID, patients with OS have enlarged lymphoid tissue, severe erythroderma, increased IgE levels, and eosinophilia. The inflammation observed in these patients is believed to be triggered by clonally expanded T cells, which are predominantly of the T(H)2 type. These abnormal T cells, in the absence of proper regulation by other components of the immune system, secrete a host of cytokines that promote autoimmune as well as allergic inflammation. The emergence of these T-cell clones occurs in patients with hypomorphic mutations in recombination activating gene 1 or 2, but not in patients with deleterious mutations in these enzymes which render them inactive. Recently, OS was also identified in a growing list of other leaky SCIDs with mutations in RNA component of mitochondrial RNA processing endoribonuclease, adenosine deaminase, IL-2 receptor gamma, IL-7 receptor alpha, ARTEMIS, and DNA ligase 4. This new information revealed OS is a distinct inflammatory process that can be associated with genetically diverse leaky SCIDS.
Topics: Autoimmune Diseases; Dermatitis, Exfoliative; Eosinophilia; Genotype; Humans; Immunoglobulin E; Inflammation; Mutation; Phenotype; Severe Combined Immunodeficiency; Th2 Cells
PubMed: 18992930
DOI: 10.1016/j.jaci.2008.09.037 -
International Journal of Dermatology Feb 1997
Topics: Biopsy, Needle; Dermatitis, Exfoliative; Dermatitis, Seborrheic; Diagnosis, Differential; Eosinophilic Granuloma; Fatal Outcome; Fever; Humans; Infant; Infections; Lymphatic Diseases; Male; Severe Combined Immunodeficiency; Syndrome
PubMed: 9109017
DOI: 10.1111/j.1365-4362.1997.tb03077.x