Chronic granulomatous disease (CGD) is a rare immunodeficiency disorder of phagocytic cells resulting in failure to kill a characteristic spectrum of bacteria and fungi and to resolve inflammation. The last few years have witnessed major advances in pathogenesis and clinical management of the disease:Better understanding of 3 physiologic anti-inflammatory functions of NADPH oxidase-derived reactive oxygen species: Promotion of the clearance of dying host cells, suppression of inflammasomes, and regulation of type I interferon signalling. This insight is opening new avenues for targeted drug interventions.Advances in reduced intensity conditioning (RIC) for allogeneic hematopoietic stem cell transplantation (HSCT) make it a promising and safe procedure even for fragile patients with ongoing severe infection or hyperinflammation.Encouraging early data of a multicenter trial of gene-replacement therapy using a self-inactivated lentiviral vector.Combining targeted anti-infectious/anti-inflammatory measures and considering extended indications for curative HSCT are key to improving patient outcome further. Gene therapy will likely become a viable option for disease correction, but long-term assessment is not yet possible.Statement of novelty: We discuss important advances in pathogenesis and treatment of CGD that will change our approach to clinical management.

Introduction: Coronin 1A belongs to a large family of actin regulatory proteins with a role in T cell homeostasis. A role for coronin 1A was also observed in macrophages, NK, and neuronal cells. To date, coronin 1A deficiency has been described in relatively few patients with combined immunodeficiency.Aim: We studied here the molecular and genetic basis of immunodeficiency detected by newborn screening for severe combined immunodeficiency.Methods: Patient data was collected in accordance with REB approved protocols. Immune work up, including T and B cell proliferative responses and serum concentrations of immunoglobulins, was performed. Next generation sequencing techniques and cellular analyses were also utilized.Results: The patient presented with T cell lymphopenia, reduction in CD4⁺CD45Ra⁺ cells and hypogammaglobulinemia. Uniquely, she also had persistent severe neutropenia. Whole exome sequencing and Sanger confirmation revealed a novel homozygous mutation in coronin 1A.Conclusion: Coronin 1A deficiency can be detected after birth by T cell receptor excision circle-based newborn screening.Statement of novelty: We report here a patient with a novel mutation in coronin 1A, identified during newborn screening with low T cell receptor excision circle levels and neutropenia, which is a unique finding in this condition.

Introduction: The evaluation of lymphocyte proliferation responses is a critical component of the clinical work up for patients with suspected immunodeficiencies. Those with severe combined immunodeficiency (SCID) have consistently low to absent responses (stimulation index, SI) to the mitogen phytohemagglutinin (PHA). However, patients with combined immunodeficiency (CID) have more varied proliferative responses, and are open to a wide range of interpretations.Aims: To establish lymphocyte proliferation response reference ranges for patients with T cell defects, especially those with CID as well as healthy controls.Methods: Data was collected retrospectively from charts of patients with a diagnosis of SCID (n = 39), CID (n = 52), or from healthy controls (n = 440). Reference percentiles were calculated using the 95% of the distribution of the test results.Results: The reference ranges for the control group ranged from 134 to 2220.5, whereas those with CID were distributed between 0.81 and 169.1. Patients with typical SCID had profound low proliferative responses, with SI <5.Conclusion: Our results highlight the variability of lymphocyte proliferation responses to PHA in patients with CID as well as healthy controls. These reference ranges will assist with the critical interpretation of assay results, particularly when values fall on the extreme end of the range.Statement of novelty: We provide reference ranges for lymphocyte proliferation responses to PHA from patients with CID and healthy controls.