Successful Haematopoietic Stem Cell Transplantation for LRBA Deficiency with Fludarabine, Treosulfan, and Thiotepa-Based Conditioning.

LRBA deficiency is an inborn error of immunity defined by autoimmunity, lymphoproliferation, recurrent infections, cytopenia, and inflammatory bowel disease. Despite recent advances in managing this disease with targeted biologic therapy, haematopoietic stem cell transplant (HSCT) remains the only cure. However, great variability exists between protocols used to transplant patients with LRBA deficiency.

Risk and promise: an 11-year, single-center retrospective study of severe acute GVHD in pediatric patients undergoing allogeneic HSCT for nonmalignant diseases.

Background: Hematopoietic stem cell transplantation (HSCT) is the only curative option for many nonmalignant hematopoietic-derived diseases in pediatric patients. Survival after HSCT has improved in recent years and resulted in a 90% survival rate and cure in some nonmalignant diseases. Graft-vs.

Neurological complications following pediatric allogeneic hematopoietic stem cell transplantation: Risk factors and outcome.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is an efficient treatment for numerous malignant and nonmalignant conditions affecting children. This procedure can result in infectious and noninfectious neurological complications (NCs).

Objective: The objective of the study is to examine the incidence, risk factors, and outcomes of NCs in pediatric patients following allogeneic HSCT.

Autoimmune Cytopenias Post Hematopoietic Stem Cell Transplantation in Pediatric Patients With Osteopetrosis and Other Nonmalignant Diseases.

Autoimmune cytopenia (AIC) is a rare complication post hematopoietic stem cell transplantation (HSCT), with a higher incidence in nonmalignant diseases. The etiology of post-HSCT AIC is poorly understood, and in many cases, the cytopenia is prolonged and refractory to treatment. Diagnosis of post-HSCT AIC may be challenging, and there is no consensus for a standard of care.

GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans.

Inborn errors of immunity (IEIs) unveil regulatory pathways of human immunity. We describe a new IEI caused by mutations in the GTPase of the immune-associated protein 6 (GIMAP6) gene in patients with infections, lymphoproliferation, autoimmunity, and multiorgan vasculitis. Patients and Gimap6-/- mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)-containing lipids.

The expansion of human T-betCD21 B cells is T cell dependent.

Accumulation of human CD21 B cells in peripheral blood is a hallmark of chronic activation of the adaptive immune system in certain infections and autoimmune disorders. The molecular pathways underpinning the development, function, and fate of these CD21 B cells remain incompletely characterized. Here, combined transcriptomic and chromatin accessibility analyses supported a prominent role for the transcription factor T-bet in the transcriptional regulation of these T-betCD21 B cells.

Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III.

Type I and III leukocyte adhesion deficiencies (LADs) are primary immunodeficiency disorders resulting in early death due to infections and additional bleeding tendency in LAD-III. The curative treatment of LAD-I and LAD-III is allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this retrospective multicenter study, data were collected using the European Society for Blood and Marrow Transplantation registry; we analyzed data from 84 LAD patients from 33 centers, all receiving an allo-HSCT from 2007 to 2017.

A human case of GIMAP6 deficiency: a novel primary immune deficiency.

The GTPase of immunity-associated proteins (GIMAPs) are a family of genes believed to contribute to lymphocyte development, signaling, and apoptosis, thus playing an important role in immune system homeostasis. While models of gene derangement have been described in both mice and immortalized cell lines, human examples of these diseases remain exceptionally rare. In this manuscript we describe the first documented human cases of a homozygous deleterious GIMAP6 variant in the GIMAP6 gene and their subsequent clinical and immunological phenotype.

Bacillus Calmette-Guerin (BCG) Vaccine-associated Complications in Immunodeficient Patients Following Stem Cell Transplantation.

Purpose: Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine with the potential of causing severe iatrogenic complications in patients with primary immunodeficiency diseases (PID) before and after hematopoietic stem cell transplantation (HSCT). We aim to investigate risk factors of post-HSCT BCG-related complications in PID patients.

Methods: A retrospective analysis of pediatric PID patients who had received the BCG vaccine and underwent HSCT at Hadassah-Hebrew University Medical Center, between 2007 and 2019.

Haploidentical stem cell transplantation with post-transplant cyclophosphamide for osteopetrosis and other nonmalignant diseases.

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for a variety of nonmalignant disorders including osteopetrosis, bone marrow failures, and immune deficiencies. Haploidentical HSCT is a readily available option in the absence of a matched donor, but engraftment failure and other post-transplant complications are a concern. Post-transplant cyclophosphamide (PT-Cy) regimens are gaining popularity and recent reports show promising results.

Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score.

Background: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant.

Objective: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant.

Method: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices.

Skin testing with ultra-heat-treated (UHT) cow's milk in children with cow's milk allergy.

Background: A large proportion of cow's milk (CM)-allergic children are able to tolerate extensively heated forms of CM such as baked goods. Little is known about whether ultra-heat-treated (UHT) forms of cow's milk are immunologically similar to extensively heated cow's milk and therefore may be tolerated by these children.

Objective: To determine whether skin test wheal size using UHT CM was significantly different from other forms of CM and CM extracts.

The Evidence for Allogeneic Hematopoietic Stem Cell Transplantation for Congenital Neutrophil Disorders: A Comprehensive Review by the Inborn Errors Working Party Group of the EBMT.

Congenital disorders of the immune system affecting maturation and/or function of phagocytic leucocytes can result in severe infectious and inflammatory complications with high mortality and morbidity. Further complications include progression to MDS/AML in some cases. Allogeneic stem cell transplantation is the only curative treatment for most patients with these diseases.

The Broad Clinical Spectrum and Transplant Results of PNP Deficiency.

Purpose: Purine nucleoside phosphorylase (PNP) is a known yet rare cause of combined immunodeficiency with a heterogeneous clinical presentation. We aim to add to the expanding clinical spectrum of disease, and to summarize the available data on bone marrow transplant for this condition.

Methods: Data was collected from patient files retrospectively.

Successful treatment with daratumumab for post-HSCT refractory hemolytic anemia.

Autoimmune cytopenias (AIC) following allogeneic hematopoietic stem cell transplantation (HSCT) may cause significant morbidity and mortality and are often challenging to treat. We present a case of a pediatric patient with primary myelofibrosis of infancy caused by VPS45 protein deficiency, who developed severe refractory hemolytic anemia and immune-mediated thrombocytopenia 3.5 months following HSCT.

Stem cell transplantation for osteopetrosis in patients beyond the age of 5 years.

Osteopetrosis (OP) is a rare disease caused by defective osteoclast differentiation or function. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment available in the infantile "malignant" form of OP. Improved clinical and genetic diagnosis of OP has seen the emergence of a cohort of patients with less severe and heterogeneous clinical presentations.

Management of XLP-1 and ITK deficiency: The challenges posed by PID with an unpredictable spectrum of disease manifestations.

The incorporation of next generation sequencing into routine immunological practice has enabled the identification of novel inborn errors of disease, helped define new categories of immune deficiency and extended the clinical spectrum associated with many long-recognised diseases. The family of EBV (Epstein Barr Virus)-sensitive primary immune deficiencies is one such group and in this paper we describe three families: two with X-linked lymphoproliferative disease type-1 (XLP-1) and one with deficiency of Interleukin-2 Inducible T-cell Kinase (ITK). Both diseases have a wide range of clinical manifestations and are united by an exquisite predisposition to EBV, dysgammaglobulinemia, hemophagocytic lymphohistiocytosis, and lymphoma.

How we approach: Severe congenital neutropenia and myelofibrosis due to mutations in VPS45.

Mutations in the VPS45 gene lead to a severe primary immune deficiency characterized by severe congenital neutropenia and primary myelofibrosis, leading to overwhelming infection and early death. This condition is exceedingly rare with only 16 patients previously reported, including four with successful hematopoietic stem cell transplantation. We review the pathophysiology underlying this condition and detail our approach to treatment, particularly vis-à-vis bone marrow transplantation and the challenges of transplanting into a diseased bone marrow niche.

T NK IL-2 Receptor γ Chain Mutation: a Challenging Diagnosis of Atypical Severe Combined Immunodeficiency.

Purpose: All reported patients with hypomorphic X-linked severe combined immunodeficiency (X-SCID) due to c.664C>T (p.R222C) mutations in the gene (IL2RG) encoding the common γ chain (γc) have presented with opportunistic infections within the first year of life, despite the presence of nearly normal NK and T cell numbers.

Respiratory manifestations in LPS-responsive beige-like anchor (LRBA) protein-deficient patients.

Unlabelled: Lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) protein deficiency is a rare syndrome of primary immune deficiency and immune dysregulation. In this study, we sought to summarize our experience with respiratory manifestations in LRBA-deficient patients. We conducted a retrospective analysis of the medical records of LRBA-deficient patients treated at Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Successful hematopoietic stem cell transplantation for osteopetrosis using reduced intensity conditioning.

Background: Infantile malignant osteopetrosis (IMO) is an autosomal recessive condition characterized by defective osteoclast activity, with hematopoietic bone marrow transplant being the only available cure. Over the past several years, new conditioning regimes and donor options have emerged, thus extending the possibility of cure to a greater number of patients and improving the outcomes of bone marrow transplant. Here we detail the outcomes of bone marrow transplant in a cohort of 31 patients treated with a combination of fludarabine, treosulphan, thiotepa, and antithymocyte globulin.

Neonatal Cytomegalovirus Palatal Ulceration and Bocavirus Pneumonitis Associated With a Defect of Lymphocyte Cytotoxicity Caused by Mutations in UNC13D.

Single gene defects that impair lymphocyte cytotoxicity can predispose to severe viral infection that normally remains subclinical. The classic severe presentation is hemophagocytic lymphohistiocytosis. Here, we report the case of a neonate who presented with cytomegalovirus palatal ulceration and bocavirus pneumonitis secondary to impaired cytotoxicity caused by biallelic mutations in the UNC13D gene.

Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in .

Bi-allelic null mutations affecting , or result in defects of lymphocyte cytotoxic degranulation and commonly cause familial hemophagocytic lymphohistiocytosis (FHL) in early life. Patients with partial loss of function are increasingly being diagnosed after presenting with alternative features of this disease, or with HLH later in life. Here, we studied two sisters with lymphocyte degranulation defects secondary to compound heterozygote missense variants in .