Introduction: Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Delta (PIK3CD) is one part of a heterodimer forming the enzyme phosphoinositide 3-kinase (PI3K), found primarily in leukocytes. PIK3CD generates phosphatidyl-inositol 3,4,5-trisphosphate (PIP3), and is involved in cell growth, survival, proliferation, motility, and morphology. An increasing number of patients have been described with heterozygous PIK3CD gain-of-function (GOF) mutations, leading to combined immunodeficiency with both B- and T-cell dysfunction. Patients suffer recurrent respiratory infections, often associated with bronchiectasis and ear and sinus damage, as well as severe recurrent or persistent infections by herpesviruses, including EBV-induced lymphoproliferation.Aim: To present the clinical phenotypic variability of a novel PI3KCD mutation within a family.Methods: Patient information was collected prospectively and retrospectively from medical records. Comprehensive immune work up, genetic, and signaling evaluation was performed.Results: We describe here 2 patients, daughter and mother, with heterozygous PIK3CD mutation identified by whole exome sequencing and Sanger confirmation. The child was screen-positive by newborn screening for severe combined immunodeficiency (SCID). Cellular assays revealed an increase in the baseline phosphorylation of T cells in the patient. Furthermore, both patients had hyper-activation of the catalytic domain, resulting in increased phosphorylation of AKT upon activation.Discussion: GOF mutations affecting the PIK3CD gene are associated with an increased risk for lymphoproliferation leading to Activated PIK3-delta syndrome (APDS). The clinical course of APDS is highly variable, ranging from combined immunodeficiency with recurrent infections, autoimmune complications, and requiring stem cell transplantation, through isolated antibody deficiency, to asymptomatic adults. Our patient is the first to be identified by newborn screening for SCID. Surprisingly, the clinical course has so far been unremarkable, as well, the mother appears to be completely asymptomatic. Nevertheless, the persistent lymphopenia indicates PIK3CD dysfunction. Because of the wide gap between laboratory findings and clinical manifestations, this kindred poses both a diagnostic as well treatment challenge.Statement of novelty: We report here a novel PIK3CD mutation diagnosed due to abnormal newborn screen for SCID.

Introduction: Chronic granulomatous disease (CGD) is one of the most common primary immunodeficiencies of childhood, and is caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Alongside neutrophil dysfunction, dysregulation of the immune system predisposes patients to recurrent life-threatening infections as well as granuloma formation, hyperinflammation, and autoimmunity. Examination by imaging (radiography, ultrasound, computed tomography, magnetic resonance) in conjunction with biopsy and tissue or fluid cultures are essential to identify the extent and severity of infections as well as the microorganisms responsible. These modalities also help to guide the management of inflammatory complications.Aim: We highlight the common radiographic findings in 10 pediatric CGD patients followed at our centre over a period of 10 years.Methods: Medical records of patients with confirmed CGD diagnosis were reviewed retrospectively. All had low neutrophil oxidative burst index (NOBI) and pathogenic mutation in 1 of the 5 subunits of the NADPH oxidase. Three patients had autosomal recessive CGD and 7 had X-linked recessive CGD. All but 1 are male.Results: The most common radiographic presentation was hilar lymphadenopathy and pulmonary nodules. Other lung complications include cavitating lesions, lung abscess, pulmonary nodule, and pleuritic nodules. Lymphatic tissue and lymph nodes were involved in 50% of our cohort of patients, while gastrointestinal manifestations were noted in approximately 35% of our patients. These include the presence of pigmented macrophages, multiple granulomas, liver abscess, or detection of Aspergillus in tissue or fluid culture.Discussion: It is essential for clinicians to keep primary immunodeficiency as one of the differential diagnoses in patients who present with severe infection or inflammation. We encourage physicians to consider CGD in patients with above described findings and consider measuring NOBI in patients with early onset infection, inflammation, or granuloma formation.Statement of novelty: We describe the radiographic findings of a pediatric cohort of patients with CGD.