The nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) family of transcription factors plays an instrumental role in human immunity and lymphoid organ development. Inherited defects affecting these factors or their regulation are associated with increased susceptibility to infections, as well as non-immune abnormalities. Hematopoietic stem cell transplantations (HSCT) have been shown to correct the immune abnormalities in a few patients with NFκB pathway defects. Here we review the pre-HSCT characteristics, as well as the HSCT and outcome of 35 patients who received HSCT for NFκB defects. Twenty-three patients (65.7%) were reported to have survived HSCT. Survival was higher among patients with X-linked ectodermal dysplasia and immunodeficiency (XL-EDA-ID), and those with CARD11-BCL10-MALT1 (CBM) complex defects, in comparison to patients with autosomal dominant ectodermal dysplasia and immunodeficiency (AD-EDA-ID) and IKBKB defects. Survival following myeloablative conditioning was similar to that after reduced intensity conditioning, although donor cells engraftment and immune reconstitution after HSCT was not complete in some patients. The effects of HSCT on organ dysfunction associated with NFκB defects, such as liver toxicity or bowel inflammation, are still not clear. Earlier identification and transplantation of affected patients, as well as better understanding of the pathogenesis and complications of the different NFκB mutations, might improve outcome of HSCT for specific patient populations.Statement of novelty: This review highlights the current indications, regimens, and outcome of HSCT for inherited defects involving various components of the canonical and non-canonical NFκB pathways.

Introduction: Childhood interstitial lung disease (chILD) syndrome describes findings of respiratory symptoms and diffuse abnormalities on lung imaging. Immunodeficiency and immune dysregulation are increasingly recognized as potential causes of these clinical findings. Patients with CD40 ligand (CD40L) deficiency typically present with sinopulmonary and opportunistic infections secondary to impairments in both humoral and cellular immunity. chILD syndrome has not previously been reported as a presenting feature of this disease.Objectives: We describe a patient with CD40L deficiency, caused by a novel mutation in CD40LG (c.464 T>A, p.Leu155Gln), who presented in infancy with chILD syndrome and lung biopsy findings of chronic interstitial pneumonitis and patchy pulmonary glycogenosis.Methods: A left lingula wedge lung biopsy was fixed with formalin and stained for analysis. Whole blood samples from the patient and parents were sent for whole exome sequencing. Flow cytometry to assess CD40L expression on activated CD3⁺CD8⁻ T cells was performed.Results: Lung biopsy demonstrated lymphoid aggregates and patchy pulmonary interstitial glycogenosis. Whole exome sequencing revealed maternal inheritance of a novel mutation in CD40LG (c.464 T>A, p.Leu155Gln). Functional studies demonstrated absent CD40L expression on activated CD3⁺CD8⁻ T cells.Conclusion: This novel mutation in CD40LG, c.464 T>A, is disease-causing based on the patient’s clinical features and absent CD40L expression. This is the first report of CD40L deficiency presenting as chILD syndrome.Statement of novelty: The missense mutation observed in our patient (c.464 T>A, p.Leu155Gln), is novel; CD40L deficiency secondary to a different missense variant at the same amino acid position has been described (c.464 T>P, p.Leu155Pro). To our knowledge, this is the first report of CD40L deficiency with an initial clinical picture consistent with interstitial lung disease.

Newborn screening for severe combined immunodeficiency was implemented in Ontario in August 2013. Infants identified by a positive newborn screen are referred in an orderly fashion for evaluation by an expert immunologist and, when appropriate, for immune function studies and treatment.Statement of novelty: We demonstrate a novel flow chart for assessing and referring newborn screen-positive cases.

Defects in interleukin (IL)-10 cytokine and receptors are associated with severe immune dysregulation, with affected patients presenting mainly with very early onset inflammatory bowel disease (VEO-IBD), arthritis, and skin manifestations such as dermatitis and folliculitis. We have created a database of published mutations in the genes encoding for IL-10, IL-10 receptor A (IL-10RA), and IL-10 receptor B (IL-10RB). All published mutations were reviewed and clinical as well as laboratory phenotypes recorded. Many variants in these genes are reported to be associated with IBD, as well as other diseases and pathologies. However, in this review we have focused on mutations considered harmful to the gene product and which lead to the classic presentation of VEO-IBD. This database can assist clinicians in the diagnosis of patients with specific features of immunodeficiency. A yearly update of new mutations and phenotypes will be performed.Statement of novelty: The presented database and short review is the first extensive collection of reported mutations and the clinical features of Very Early Onset IBD due to IL10 related genes.