Pioneered in 1968, hematopoietic stem cell transplantation (HSCT) first cured a patient with severe combined immune deficiency (SCID) transplanted from a matched sibling, bringing hope for this previously fatal disease. Since then, HSCT has become the standard of care treatment for SCID with thousands of patients transplanted successfully worldwide. Initially successful mainly in patients with a matched sibling donor and in specific easier to transplant types of SCID, nowadays, most patients with SCID undergo successful transplantation due to HSCT technique advances. These include refined human leukocyte antigen (HLA)-tissue typing, use of alternative donors, availability of new stem cell sources such as umbilical cord blood, less toxic chemotherapeutic conditioning, as well as improved graft-versus-host disease (GvHD) prophylaxis. Other factors contributing to the success of transplantation include the improvement of supportive care by molecular detection of viral infections, enabling preemptive antiviral treatment before organ damage occurs. Increased awareness for primary immunodeficiency disorders (PID), leading to earlier diagnosis and referral to specialist centers, has been another important factor in successfully transplanting SCID patients. A major game changer in the last decade has been the implementation of neonatal screening for SCID. This increased early diagnosis, allowing for this disease to be almost universally diagnosed soon after birth in countries which included this test in their newborn screening program. As a result, early and optimal transplant timing and conditions could be achieved. However, very early diagnosis also raised new questions regarding SCID patients with a “leaky” phenotype, as well as dilemmas regarding transplant and conditioning regimens in very young infants. With improved diagnosis and treatment options, overall survival has increased to over 90% for SCID babies with a genoidentical donor and similar results are emerging for matched unrelated donor HSCT. Due to new advances, we hope to achieve similar results for those given HSCT from haploidentical donors as well. This review will focus on the new considerations in HSCT seen in recent years, and examines the effect they have had on treatment options and outcomes for SCID patients.Statement of novelty: The field of HSCT has advanced considerably since the first successful SCID bone marrow transplant in 1968. However, success rates have been limited due to delayed diagnosis and poor outcome of patients for which a HLA-matched donor could not be found. This review will discuss recent advances occurring in the last decade in HSCT for SCID, and our hopes to bring cure to this once fatal disease.

Background: Common variable immunodeficiency (CVID) is a term used to define a heterogeneous group of patients who commonly have hypogammaglobulinemia and variable degrees of modest T cell dysfunction. Recent advances made in next generation sequencing technologies have accelerated the identification of CVID disease-causing genes, including NFKB1, a component of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway.Objective: We sought to identify the genetic defect in a 3-generation family of patients with CVID who presented with cytopenias, eczema, and recurrent sinopulmonary infections.Methods: Whole exome sequencing and Sanger confirmation was performed, and a combination of molecular and cellular techniques used to assess the variant impact on B and T cell function.Results: A novel heterozygous frameshift mutation in NFKB1, encoding the transcriptional regulator protein p50/p105, was identified. This resulted in c.1584dupG (p.M528fs). We demonstrate that c.1584dupG is a loss-of-function variant, responsible for reduced p105/p50 protein expression in affected individuals as well as variable increased CD21^low B cell numbers.Conclusion: This novel mutation affecting NFKB1 causes a CVID phenotype with variable clinical manifestations. Given the wide spectrum of age in this kindred, this may reflect diversity of phenotype expression, or more probably, age-related expression of typical features.Statement of novelty: We report here a novel loss-of-function frameshift mutation in NFKB1.

Introduction: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Affected patients suffer recurrent life-threatening infections due to phagocyte dysfunction and dysregulation of the immune system. Histopathological assessment is important to help identify the extent and severity of infection and tissue injury.Aim: We present pathological findings in 5 patients with CGD who were followed at our centre.Methods: Patient information was reviewed retrospectively in accordance with local institutional guidelines. All patients had confirmed diagnosis of CGD with mutation in one of the 5 subunits of the NADPH oxidase.Results: Histopathological features of the gastrointestinal tract, liver, and spleen are noted, and include the presence of granulomatous inflammation and pigmented macrophages.Discussion: It is essential for clinicians to keep primary immunodeficiency as one of the differential diagnoses in patients with severe infection or inflammation, whether in the absence or presence of granuloma formation. The detection of PAS-positive macrophages, diffuse granulomatous inflammation, and hepatic abscesses should raise strong suspicion of CGD.Statement of novelty: We describe the histopathological findings of a paediatric cohort of patients with CGD.

The continued demand for immunoglobulin treatment for multiple indications has placed considerable strain on the supply of immunoglobulin product. Reliance on a few manufacturers can significantly impact the availability of product. In addition, patient tolerability may vary from one product to another necessitating a choice of products to find the best treatment for an individual patient. Therefore, it is important to conduct clinical trials with new immunoglobulin products to ensure that there is adequate supply and choice of products available on the market. This is particularly important for immunodeficient patients who require treatment with immunoglobulins for life. A requirement for licensing by the Federal Food and Drug Administration and Health Canada is that every immunoglobulin licensing study includes some paediatric patients. Enrolling paediatric subjects in immunoglobulin clinical trials can be challenging due to the need for both consent and assent for enrolment, as well as the increased demands that the study protocol places on the child and family over their usual clinical care. Therefore, it is necessary to utilize strategies that make the demands of the protocol more tolerable for children, and to ensure that the study documentation reflects the unique needs of paediatric patients (Denhoff et al. 2015).Statement of novelty: This paper discusses strategies to facilitate enrolment and adherence to immunoglobulin study protocols that are unique to paediatric patients.