• Clinical features
• Epidemiology
• Gene
• Inborn errors of immunity
• Virus infection

• Humans
• Retrospective Studies
• Male
• Infant
• Female
• Child, Preschool
• Virus Diseases/epidemiology
• Virus Diseases/genetics
• Virus Diseases/virology
• Child
• Genetic Predisposition to Disease
• Infant, Newborn
• Adolescent
• Mutation

• ZD2021CY001 the Shanghai Municipal Science and Technology Major Project
• 23YF1403400 the "Sailing Program" of Shanghai Science and Technology Committee
• the “Sailing Program” of Shanghai Science and Technology Committee

• WASP
• Wiskott-Aldrich
• gene panel
• next-generation sequencing (NGS)
• splice-site mutation

• Humans
• Wiskott-Aldrich Syndrome/genetics
• Wiskott-Aldrich Syndrome/diagnosis
• Wiskott-Aldrich Syndrome Protein/genetics
• Male
• Infant
• RNA Splice Sites/genetics
• Mutation
• RNA Splicing
• High-Throughput Nucleotide Sequencing
• Introns

• Wiskott-Aldrich syndrome protein
• X-linked thrombocytopenia
• lymphocyte
• novel variant

• Bone marrow failure syndrome
• immune thrombocytopenia
• inherited inherited thrombocytopenia
• whole-exome sequencing

• Humans
• Male
• Female
• Thrombocytopenia/genetics
• Child
• Child, Preschool
• Infant
• Adolescent
• Genetic Testing/methods
• Exome Sequencing

• DNA Repair Defects
• Hematologic Cancers
• Inborn Errors of Immunity
• Malignancy
• Primary Immunodeficiency Diseases

• Humans
• Neoplasms/epidemiology
• Neoplasms/genetics
• Neoplasms/immunology
• Prevalence

• 49992 Tehran University of Medical Sciences

• Humans
• Adolescent
• Child
• Male
• Wiskott-Aldrich Syndrome/genetics
• Wiskott-Aldrich Syndrome/diagnosis
• Wiskott-Aldrich Syndrome/therapy
• Female
• Child, Preschool
• Adult
• Retrospective Studies
• Infant
• Young Adult
• Genotype
• Biomarkers
• Hematopoietic Stem Cell Transplantation
• Severity of Illness Index
• Wiskott-Aldrich Syndrome Protein/genetics
• Follow-Up Studies
• Middle Aged
• Prognosis
• Survival Rate

• HSCT
• WAS
• Wiskott-Aldrich syndrome
• adult
• hematopoietic stem cell transplantation

• Wiskott-Aldrich syndrome
• hematopoietic stem cell transplantation
• intracranial hemorrhage
• newborn
• synonymous mutation

• Actin cytoskeleton
• Expression of the intracellular protein
• Hematopoietic malignancies
• Leukaemia and Lymphoma
• Loss and Gain of function mutation
• Wiskott Aldrich syndrome protein

• Humans
• Wiskott-Aldrich Syndrome Protein/genetics
• Wiskott-Aldrich Syndrome Protein/metabolism
• Wiskott-Aldrich Syndrome/genetics
• Wiskott-Aldrich Syndrome/metabolism
• Wiskott-Aldrich Syndrome/therapy
• Hematologic Neoplasms/genetics
• Neoplasms
• Molecular Biology
• Actins/metabolism

• Vietnamese
• WAS gene
• Wiskott–Aldrich syndrome
• hemizygous mutation
• novel variant

• Humans
• Male
• DNA Mutational Analysis
• Mutation
• Vietnam
• Wiskott-Aldrich Syndrome/diagnosis
• Wiskott-Aldrich Syndrome/genetics
• Wiskott-Aldrich Syndrome Protein/genetics

• Humans
• Wiskott-Aldrich Syndrome/genetics
• Wiskott-Aldrich Syndrome/therapy
• Wiskott-Aldrich Syndrome Protein/genetics
• Hematopoietic Stem Cells/metabolism
• Hematopoietic Stem Cell Transplantation/adverse effects
• Genetic Therapy/methods
• Eczema/etiology
• Eczema/metabolism
• Eczema/therapy

• HHSN268201000009C NHLBI NIH HHS
• T32 HL007574 NHLBI NIH HHS
• U01 AI125051 NIAID NIH HHS
• R01 CA241762 NCI NIH HHS
• U19 AI149680 NIAID NIH HHS
• P30 AI045008 NIAID NIH HHS
• R01 HL137848 NHLBI NIH HHS
• R01 HL142791 NHLBI NIH HHS

• Pregnancy
• Humans
• Female
• Blood Platelet Disorders/genetics
• Blood Platelet Disorders/therapy
• Blood Platelets
• Hematopoietic Stem Cells
• Hemophilia A
• Hemostatics

• España
• Síndrome de Wiskott-Aldrich
• epidemiología
• incidencia
• mortalidad
• mujeres

• P01 AI127335 NIAID NIH HHS
• P20 GM134974 NIGMS NIH HHS

• Aldrich syndrome
• RAC2
• Wiskott
• genotype–phenotype
• mutation

• Humans
• Mutation/genetics
• Phenotype
• Thrombocytopenia/genetics
• Wiskott-Aldrich Syndrome/genetics
• Wiskott-Aldrich Syndrome/metabolism
• Wiskott-Aldrich Syndrome Protein/genetics
• RAC2 GTP-Binding Protein

• National Institutes of Health
• National Institute of Allergy and Infectious Diseases

• combined immune deficiency
• inborn errors of immunity
• infections

• In vitro models
• Microthrombocytopenia
• Novel mutation
• Splicing effect
• Wiskott–Aldrich syndrome

Inflammatory bowel diseases are considered immune disorders with a complex genetic architecture involving constantly changing endogenous and exogenous factors. The rapid evolution of genomic technologies and the emergence of newly discovered molecular actors are compelling the research community to reevaluate the knowledge and molecular processes. The human intestinal tract contains intestinal human microbiota consisting of commensal, pathogenic, and symbiotic strains leading to immune responses that can contribute and lead to both systemic and intestinal disorders including IBD. In this review, we attempted to highlight some updates of the new IBD features related to genomics, microbiota, new emerging therapies and some major established IBD risk factors.

• study received no specific funding

Primary immunodeficiency diseases (PIDs) are a group of rare inherited disorders affecting the immune system that can be conventionally treated with allogeneic hematopoietic stem cell transplantation and with experimental autologous gene therapy. With both approaches still facing important challenges, gene editing has recently emerged as a potential valuable alternative for the treatment of genetic disorders and within a relatively short period from its initial development, has already entered some landmark clinical trials aimed at tackling several life-threatening diseases. In this review, we discuss the progress made towards the development of gene editing-based therapeutic strategies for PIDs with a special focus on Wiskott - Aldrich syndrome and outline their main challenges as well as future directions with respect to already established treatments.

• Gene Editing/methods
• Genetic Therapy/methods
• Hematopoietic Stem Cell Transplantation/methods
• Humans
• Wiskott-Aldrich Syndrome/genetics
• Wiskott-Aldrich Syndrome/therapy
• Wiskott-Aldrich Syndrome Protein/genetics

• MR/W001314/1 Medical Research Council

• Conditioning regimen
• Hematopoietic cell transplantation
• Inborn errors of immunity
• Primary immunodeficiency

Perturbation in the replication-stress response (RSR) and DNA-damage response (DDR) causes genomic instability. Genomic instability occurs in Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency disorder, yet the mechanism remains largely uncharacterized. Replication protein A (RPA), a single-strand DNA (ssDNA) binding protein, has key roles in the RSR and DDR. Here we show that human WAS-protein (WASp) modulates RPA functions at perturbed replication forks (RFs). Following genotoxic insult, WASp accumulates at RFs, associates with RPA, and promotes RPA:ssDNA complexation. WASp deficiency in human lymphocytes destabilizes RPA:ssDNA-complexes, impairs accumulation of RPA, ATR, ETAA1, and TOPBP1 at genotoxin-perturbed RFs, decreases CHK1 activation, and provokes global RF dysfunction. las17 (yeast WAS-homolog)-deficient S. cerevisiae also show decreased ScRPA accumulation at perturbed RFs, impaired DNA recombination, and increased frequency of DNA double-strand break (DSB)-induced single-strand annealing (SSA). Consequently, WASp (or Las17)-deficient cells show increased frequency of DSBs upon genotoxic insult. Our study reveals an evolutionarily conserved, essential role of WASp in the DNA stress-resolution pathway, such that WASp deficiency provokes RPA dysfunction-coupled genomic instability.

Cancer develops in Wiskott-Aldrich syndrome (WAS). Here the authors identify a role for WAS-protein (WASp) in the DNA stress-resolution pathway by promoting the function of Replication Protein A at replication forks after DNA damage.

The new techniques of genetic analysis have made it possible to identify many new forms of inherited thrombocytopenias (IT) and study large series of patients. In recent years, this has changed the view of IT, highlighting the fact that, in contrast to previous belief, most patients have a modest bleeding diathesis. On the other hand, it has become evident that some of the mutations responsible for platelet deficiency predispose the patient to serious, potentially life-threatening diseases. Today's vision of IT is, therefore, very different from that of the past and the therapeutic approach must take these changes into account while also making use of the new therapies that have become available in the meantime. This review, the first devoted entirely to IT therapy, discusses how to prevent bleeding in those patients who are exposed to this risk, how to treat it if it occurs, and how to manage the serious illnesses to which patients with IT may be predisposed.

• Actin
• combined immunodeficiency
• gene therapy
• hematopoietic stem cell transplantation
• inborn errors of immunity
• primary immunodeficiency

• Follicular dendritic cell-only lymphoid follicles
• Wiskott-Aldrich syndrome
• histopathology
• immune synapse
• intracerebral hemorrhage
• lymphoid tissue

The gain-of-function p.I294T variant in WASp causes a disease combining neutropenia, macrothrombocytopenia, proteinuria, and renal failure.

While loss-of-function variants in the WAS gene are associated with Wiskott-Aldrich syndrome and lead to microthrombocytopenia, gain-of-function variants of WAS are associated with X-linked neutropenia (XLN) and the absence of microthrombocytopenia. Only a few XLN families have been reported so far, and their platelet phenotype was not described in detail. To date, no renal involvement was described in XLN. In the present study, we report exome sequencing of individuals from 3 generations of a family with a dominant disease combining neutropenia, macrothrombocytopenia, and renal failure. We identified a heterozygous missense gain-of-function variant in the WAS gene (c.881T>C, p.I294T) that segregates with the disease and is already known to cause XLN. There was no pathogenic variant in MYH9, TUBB1, or ACTN1. This is the first report of a WAS gain-of-function variant associated with both the hematological phenotype of XLN (neutropenia, macrothrombocytopenia) and renal disease (proteinuria, renal failure) with glomerular tip lesion hyalinosis and actin condensations in effaced podocytes foot processes.

• Wiskott-Aldrich syndrome
• autoimmune
• dermatitis herpetiformis

Patients with Wiskott–Aldrich syndrome (WAS) lacking a human leukocyte antigen-matched donor may benefit from gene therapy through the provision of gene-corrected, autologous hematopoietic stem/progenitor cells. Here, we present comprehensive, long-term follow-up results (median follow-up, 7.6 years) (phase I/II trial no. NCT02333760) for eight patients with WAS having undergone phase I/II lentiviral vector-based gene therapy trials (nos. NCT01347346 and NCT01347242), with a focus on thrombocytopenia and autoimmunity. Primary outcomes of the long-term study were to establish clinical and biological safety, efficacy and tolerability by evaluating the incidence and type of serious adverse events and clinical status and biological parameters including lentiviral genomic integration sites in different cell subpopulations from 3 years to 15 years after gene therapy. Secondary outcomes included monitoring the need for additional treatment and T cell repertoire diversity. An interim analysis shows that the study meets the primary outcome criteria tested given that the gene-corrected cells engrafted stably, and no serious treatment-associated adverse events occurred. Overall, severe infections and eczema resolved. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. The results suggest that lentiviral gene therapy provides sustained clinical benefits for patients with WAS.

Long-term monitoring of patients with Wiskott–Aldrich syndrome following lentiviral gene therapy shows a safe profile and a reduction in the frequency of autoimmune manifestations and bleeding events, despite incomplete platelet reconstitution.

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive inborn error of immunity (IEI) first described in 1937. Classic WAS is characterized by the triad of thrombocytopenia with small platelets, recurrent infections due to combined immunodeficiency, and eczema. Hematopoietic stem cell transplantation (HSCT) was the only curative option available for five decades, with excellent outcomes reported for matched sibling donors (MSD) and matched unrelated donors (MUD). More recently, alternative donor transplants such as umbilical cord blood (UCB) and haploidentical transplant have emerged as viable options due to improvements in better graft selection, cell dosing, and effective allograft manipulation measures. Gene therapy is another potential curative option with promising results, yet currently is offered only as part of a clinical trial.

• Wiskott–Aldrich syndrome
• X-linked thrombocytopenia
• gene therapy
• hematopoietic stem cell transplantation
• supportive care

• Wiskott-Aldrich syndrome
• Wiskott-Aldrich syndrome protein
• primary immunodeficiency

• Atopic disease
• Eosinophilia
• Inborn errors of immunity
• Primary immunodeficiency
• Type 2 immunity

• Actins/immunology
• Animals
• Cytokines/immunology
• Eosinophilia/immunology
• Genetic Diseases, Inborn/immunology
• Humans
• Immune System Diseases/immunology
• Immune Tolerance
• Receptors, Antigen, T-Cell/immunology
• T-Box Domain Proteins/deficiency
• T-Box Domain Proteins/immunology
• T-Lymphocytes/immunology

Cancer cells depend on actin cytoskeleton rearrangement to carry out hallmark malignant functions including activation, proliferation, migration and invasiveness. Wiskott–Aldrich Syndrome protein (WASp) is an actin nucleation-promoting factor and is a key regulator of actin polymerization in hematopoietic cells. The involvement of WASp in malignancies is incompletely understood. Since WASp is exclusively expressed in hematopoietic cells, we performed in silico screening to identify small molecule compounds (SMCs) that bind WASp and promote its degradation. We describe here one such identified molecule; this WASp-targeting SMC inhibits key WASp-dependent actin processes in several types of hematopoietic malignancies in vitro and in vivo without affecting naïve healthy cells. This small molecule demonstrates limited toxicity and immunogenic effects, and thus, might serve as an effective strategy to treat specific hematopoietic malignancies in a safe and precisely targeted manner.

Cancer cells proliferate and invade via cytoskeletal proteins such as WASp, exclusively expressed in hematopoietic cells. Here the authors show a specific small molecule compound inhibiting cancer cell activity by WASp degradation and demonstrating its therapeutic potential in vitro and in vivo.

• bleeding
• genetics
• hematopoietic stem–cell transplant
• malignancy
• thrombocytopenia
• vasculitis

• Bleeding
• Inherited platelet disorders
• Platelets

• Blood Coagulation Disorders
• Blood Platelet Disorders/diagnosis
• Blood Platelet Disorders/genetics
• Blood Platelet Disorders/therapy
• Blood Platelets
• Hemorrhage/genetics
• Humans
• Platelet Activation

• T32 CA009172 NCI NIH HHS

• GT
• HSCT
• WAS
• Wiskott–Aldrich syndrome
• X-linked neutropenia
• X-linked thrombocytopenia
• XLN
• XLT
• gene therapy
• hematopoietic stem cell transplantation
• lentiviral vectors
• reduced intensity conditioning

• haematopoietic stem cell transplantation
• inborn errors of immunity
• treosulfan

• cancer
• cancer predisposition
• genetic models
• model organism
• p53
• zebrafish

• WASP
• X-linked thrombocytopenia
• autoimmunity
• bleeding
• hematopoetic stem cell transplant
• malignancy
• microplatelets
• thrombocytopenia

• Age Factors
• Child, Preschool
• Developing Countries
• Disease-Free Survival
• Female
• Genetic Predisposition to Disease
• Hematopoietic Stem Cell Transplantation
• Humans
• Immunoglobulins, Intravenous/administration & dosage
• India
• Infant
• Male
• Mutation
• Phenotype
• Risk Assessment
• Risk Factors
• Time Factors
• Wiskott-Aldrich Syndrome/diagnosis
• Wiskott-Aldrich Syndrome/genetics
• Wiskott-Aldrich Syndrome/immunology
• Wiskott-Aldrich Syndrome/therapy
• Wiskott-Aldrich Syndrome Protein/genetics

Inborn Errors of Immunity (IEI) are a heterogeneous group of disorders characterized by a defect in the function of at least one, and often more, components of the immune system. The overall risk for cancer in children with IEI ranges from 4 to 25%. Several factors, namely, age of the patient, viral infection status and IEI type can influence the development of different cancer types. Immunologists and oncologists should interact to monitor and promptly diagnose the potential development of cancer in known IEI patients, as well as an underlying IEI in newly diagnosed cancers with suggestive medical history or high rate of therapy-related toxicity. The creation of an international registry of IEI cases with detailed information on the occurrence of cancer is fundamental to optimizing the diagnostic process and to evaluating the outcomes of new therapeutic options, with the aim of improving prognosis and reducing comorbidities.

Inborn Errors of Immunity (IEI) are a heterogeneous group of disorders characterized by a defect in the function of at least one, and often more, components of the immune system. The aim of this narrative review is to discuss the epidemiology, the pathogenesis and the correct management of tumours in patients with IEI. PubMed was used to search for all of the studies published over the last 20 years using the keywords: “inborn errors of immunity” or “primary immunodeficiency” and “cancer” or “tumour” or “malignancy”. Literature analysis showed that the overall risk for cancer in children with IEI ranges from 4 to 25%. Several factors, namely, age of the patient, viral infection status and IEI type can influence the development of different cancer types. The knowledge of a specific tumour risk in the presence of IEI highlights the importance of a synergistic effort by immunologists and oncologists in tracking down the potential development of cancer in known IEI patients, as well as an underlying IEI in patients with newly diagnosed cancers. In the current genomic era, the creation of an international registry of IEI cases integrated with malignancies occurrence information is fundamental to optimizing the diagnostic process and to evaluating the outcomes of new therapeutic options, with the hope to obtain a better prognosis for these patients.

• cancer
• children
• inborn errors of immunity