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Clinical and Experimental Immunology Feb 2024Recombination activating genes (RAG)1 and RAG2 deficiency leads to combined T/B-cell deficiency with varying clinical presentations. This study aimed to define the...
Recombination activating genes (RAG)1 and RAG2 deficiency leads to combined T/B-cell deficiency with varying clinical presentations. This study aimed to define the clinical/laboratory spectrum of RAG1 and RAG2 deficiency. We retrospectively reviewed the clinical/laboratory data of 35 patients, grouped them as severe combined immunodeficiency (SCID), Omenn syndrome (OS), and delayed-onset combined immunodeficiency (CID) and reported nine novel mutations. The male/female ratio was 23/12. Median age of clinical manifestations was 1 months (mo) (0.5-2), 2 mo (1.25-5), and 14 mo (3.63-27), age at diagnosis was 4 mo (3-6), 4.5 mo (2.5-9.75), and 27 mo (14.5-70) in SCID (n = 25; 71.4%), OS (n = 5; 14.3%), and CID (n = 5; 14.3%) patients, respectively. Common clinical manifestations were recurrent sinopulmonary infections 82.9%, oral moniliasis 62.9%, diarrhea 51.4%, and eczema/dermatitis 42.9%. Autoimmune features were present in 31.4% of the patients; 80% were in CID patients. Lymphopenia was present in 92% of SCID, 80% of OS, and 80% of CID patients. All SCID and CID patients had low T (CD3, CD4, and CD8), low B, and increased NK cell numbers. Twenty-eight patients underwent hematopoietic stem cell transplantation (HSCT), whereas seven patients died before HSCT. Median age at HSCT was 7 mo (4-13.5). Survival differed in groups; maximum in SCID patients who had an HLA-matched family donor, minimum in OS. Totally 19 (54.3%) patients survived. Early molecular genetic studies will give both individualized therapy options, and a survival advantage because of timely diagnosis and treatment. Further improvement in therapeutic outcomes will be possible if clinicians gain time for HSCT.
Topics: Humans; Male; Female; Infant; Homeodomain Proteins; Retrospective Studies; Severe Combined Immunodeficiency; Lymphopenia; Primary Immunodeficiency Diseases; Mutation; DNA-Binding Proteins; Nuclear Proteins
PubMed: 37724703
DOI: 10.1093/cei/uxad110 -
Journal of Clinical Immunology Apr 2021T cell receptor excision circle (TREC) quantification is a recent addition to newborn screening (NBS) programs and is intended to identify infants with severe combined...
PURPOSE
T cell receptor excision circle (TREC) quantification is a recent addition to newborn screening (NBS) programs and is intended to identify infants with severe combined immunodeficiencies (SCID). However, other primary immunodeficiency diseases (PID) have also been identified as the result of TREC screening. We recently reported a newborn with a low TREC level on day 1 of life who was diagnosed with WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome, a non-SCID primary immunodeficiency caused by mutations in the chemokine receptor CXCR4.
METHODS
We have now retrospectively reviewed the birth and clinical histories of all known WHIM infants born after the implementation of NBS for SCID.
RESULTS
We identified six infants with confirmed WHIM syndrome who also had TREC quantification on NBS. Three of the six WHIM infants had low TREC levels on NBS. All six patients were lymphopenic but only one infant had a T cell count below 1,500 cells/μL. The most common clinical manifestation was viral bronchiolitis requiring hospitalization. One infant died of complications related to Tetralogy of Fallot, a known WHIM phenotype.
CONCLUSION
The results suggest that WHIM syndrome should be considered in the differential diagnosis of newborns with low NBS TREC levels.
TRIAL REGISTRATION
Not applicable.
Topics: Biomarkers; DNA Mutational Analysis; Diagnosis, Differential; Disease Susceptibility; Female; Humans; Infant, Newborn; Male; Mutation; Neonatal Screening; Phenotype; Primary Immunodeficiency Diseases; Receptors, Antigen, T-Cell; Receptors, CXCR4; Severe Combined Immunodeficiency; Warts
PubMed: 33415666
DOI: 10.1007/s10875-020-00921-4 -
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... Feb 2023Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune...
BACKGROUND
Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID.
OBJECTIVE
Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed.
METHODS
We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes.
RESULTS
According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 10/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 10/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001).
CONCLUSIONS
The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.
Topics: Infant, Newborn; Humans; Infant; Severe Combined Immunodeficiency; Retrospective Studies; Prospective Studies; Homeodomain Proteins
PubMed: 36456360
DOI: 10.1016/j.jaci.2022.10.021 -
Human Gene Therapy Apr 2015Primary immunodeficiencies (PIDs) have represented a paradigmatic model for successes and pitfalls of hematopoietic stem cells gene therapy. First clinical trials... (Review)
Review
Primary immunodeficiencies (PIDs) have represented a paradigmatic model for successes and pitfalls of hematopoietic stem cells gene therapy. First clinical trials performed with gamma retroviral vectors (γ-RV) for adenosine deaminase severe combined immunodeficiency (ADA-SCID), X-linked SCID (SCID-X1), and Wiskott-Aldrich syndrome (WAS) showed that gene therapy is a valid therapeutic option in patients lacking an HLA-identical donor. No insertional mutagenesis events have been observed in more than 40 ADA-SCID patients treated so far in the context of different clinical trials worldwide, suggesting a favorable risk-benefit ratio for this disease. On the other hand, the occurrence of insertional oncogenesis in SCID-X1, WAS, and chronic granulomatous disease (CGD) RV clinical trials prompted the development of safer vector construct based on self-inactivating (SIN) retroviral or lentiviral vectors (LVs). Here we present the recent results of LV-mediated gene therapy for WAS showing stable multilineage engraftment leading to hematological and immunological improvement, and discuss the differences with respect to the WAS RV trial. We also describe recent clinical results of SCID-X1 gene therapy with SIN γ-RV and the perspectives of targeted genome editing techniques, following early preclinical studies showing promising results in terms of specificity of gene correction. Finally, we provide an overview of the gene therapy approaches for other PIDs and discuss its prospects in relation to the evolving arena of allogeneic transplant.
Topics: Animals; Clinical Trials as Topic; Genetic Therapy; Humans; Severe Combined Immunodeficiency
PubMed: 25860576
DOI: 10.1089/hum.2015.047 -
Revista Colombiana de Obstetricia Y... Sep 2021To report the case of a pregnant woman with ultrasound diagnosis of altered fetal tegumental system and postnatal diagnosis of Omenn syndrome.
OBJECTIVE
To report the case of a pregnant woman with ultrasound diagnosis of altered fetal tegumental system and postnatal diagnosis of Omenn syndrome.
CASE PRESENTATION
A 27-year-old patient who presented at 31 weeks of gestation with prenatal ultrasound evidence of a fetus with significant scalp edema, echogenic amniotic fluid and scaly abdominal skin, with ichtyosis variant impression on diagnostic ultrasound. The baby was born with congenital erythroderma complicated with skin infection, and later developed septic shock and died. The genetic and pathologic workup led to the conclusion of Omenn syndrome.
CONCLUSION
Omenn syndrome must be considered as part of the differential diagnoses when prenatal ultrasound shows findings of altered tegument system. Studies are required to assess the accuracy of ultrasound for prenatal diagnosis of erythroderma.
Topics: Adult; Amniotic Fluid; Dermatitis, Exfoliative; Female; Humans; Infant; Pregnancy; Prenatal Diagnosis; Severe Combined Immunodeficiency; Ultrasonography, Prenatal
PubMed: 34851571
DOI: 10.18597/rcog.3670 -
Acta Biochimica Polonica Aug 2021Seminal demonstration of the possibility of stable genetic modification of mammalian cells performed by Wacław and Elisabeth Szybalski opened the doors for gene... (Review)
Review
Seminal demonstration of the possibility of stable genetic modification of mammalian cells performed by Wacław and Elisabeth Szybalski opened the doors for gene therapy, the term coined by Wacław Szybalski already in 1962. In the next 60 years, numerous tools for gene delivery have been developed and applied for clinical research, culminating in the registration of several genetic therapies in Europe and the USA. Some of these strategies, aimed to treat severe combined immunodeficiencies, inherited forms of blindness, spinal muscular atrophy, some cancers, and genetic anemias, are the real hope for patients suffering from previously incurable diseases or the ones whose treatment was not effective. On the approaching 60th anniversary of gene therapy, combined with the 100th anniversary of the birth of Professor Wacław Szybalski (September 9th, 1921), who passed away on December 16, 2020, here I present the summary of the most important aspects of clinical applications of genetic therapies.
Topics: Animals; Europe; Genetic Therapy; History, 20th Century; History, 21st Century; Humans; Mice; Muscular Atrophy, Spinal; Severe Combined Immunodeficiency; United States; beta-Thalassemia
PubMed: 34464044
DOI: 10.18388/abp.2020_5805 -
Blood Aug 2022Adenosine deaminase (ADA) deficiency causes ∼13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT),... (Clinical Trial)
Clinical Trial
Adenosine deaminase (ADA) deficiency causes ∼13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium SCID studies. Baseline clinical, immunologic, genetic characteristics, and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event-free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT; P < .01). Overall survival (OS) at 5 years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT; P = .01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs 68% if ≥3.5 months, P = .02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs 68.2%, P < .01) and OS (64.7% vs 82.3%, P = .02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies patients with ADA-SCID soon after birth and before the onset of infections. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.
Topics: Adenosine Deaminase; Agammaglobulinemia; Child, Preschool; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Severe Combined Immunodeficiency
PubMed: 35671392
DOI: 10.1182/blood.2022016196 -
European Journal of Immunology May 2021The RAG1 and RAG2 proteins initiate the process of V(D)J recombination and therefore play an essential role in adaptive immunity. While null mutations in the RAG genes... (Review)
Review
The RAG1 and RAG2 proteins initiate the process of V(D)J recombination and therefore play an essential role in adaptive immunity. While null mutations in the RAG genes cause severe combined immune deficiency with lack of T and B cells (T B SCID) and susceptibility to life-threatening, early-onset infections, studies in humans and mice have demonstrated that hypomorphic RAG mutations are associated with defects of central and peripheral tolerance resulting in immune dysregulation. In this review, we provide an overview of the extended spectrum of RAG deficiencies and their associated clinical and immunological phenotypes in humans. We discuss recent advances in the mechanisms that control RAG expression and function, the effects of perturbed RAG activity on lymphoid development and immune homeostasis, and propose novel approaches to correct this group of disorders.
Topics: Animals; DNA-Binding Proteins; Diagnosis, Differential; Disease Management; Disease Models, Animal; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Therapy; Genotype; Homeodomain Proteins; Humans; Mutation; Nuclear Proteins; Phenotype; Severe Combined Immunodeficiency; V(D)J Recombination
PubMed: 33682138
DOI: 10.1002/eji.202048880 -
Expert Review of Clinical Immunology Nov 2017Newborn screening has led to a better understanding of the prevalence of Severe Combined Immunodeficiency (SCID) overall and in terms of specific genotypes. Survival has... (Review)
Review
Newborn screening has led to a better understanding of the prevalence of Severe Combined Immunodeficiency (SCID) overall and in terms of specific genotypes. Survival has improved following hematopoietic stem cell transplantation (HCT) with the best outcomes seen following use of a matched sibling donor. However, questions remain regarding the optimal alternative donor source, appropriate use of conditioning and the impact of these decisions on immune reconstitution and other late morbidities. Areas covered: The currently available literature reporting late effects after HCT for SCID and use of alternative therapies including enzyme replacement, alternative donors and gene therapy are reviewed. A literature search was performed on Pubmed and ClinicalTrials.gov using key words 'Severe Combined Immunodeficiency', 'SCID', 'hematopoietic stem cell transplant', 'conditioning', 'gene therapy', 'SCID newborn screening', 'TREC' and 'late effects'. Expert commentary: Newborn screening has dramatically changed the clinical presentation of newborn SCID. While the majority of patients with SCID survive HCT, data regarding late effects in these patients is limited and additional studies focused on genotype specific late effects are needed. Prospective studies aimed at minimizing the use of alkylating agents and reducing late effects beyond survival are needed. Gene therapy is being developed and will likely become a more commonly used treatment that will require separate consideration of survival and late effects.
Topics: Expert Testimony; Genetic Therapy; Genotype; Hematopoietic Stem Cell Transplantation; Humans; Infant, Newborn; Neonatal Screening; Severe Combined Immunodeficiency; Transplantation Conditioning; Treatment Outcome
PubMed: 28918671
DOI: 10.1080/1744666X.2017.1381558