This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting appropriate clinical management.

Autoimmune lymphoproliferative syndrome (ALPS) is classically defined as a disease with defective FAS-mediated apoptosis (type I-III). Germline NRAS mutation was recently identified in type IV ALPS. We report 2 cases with ALPS-like disease with somatic KRAS mutation. Both cases were characterized by prominent autoimmune cytopenia and lymphoadenopathy/splenomegaly. These patients did not satisfy the diagnostic criteria for ALPS or juvenile myelomonocytic leukemia and are probably defined as a new disease entity of RAS-associated ALPS-like disease (RALD).

PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.

Summary Cytotoxic‐T‐lymphocyte‐antigen‐4 (CTLA‐4) is a negative immune regulator constitutively expressed on regulatory T (Treg) cells and upregulated on activated T cells. CTLA‐4 inhibits T cell activation by various suppressive functions including competition with CD28, regulation of the inhibitory function of Treg cells, such as transendocytosis, and the control of adhesion and motility. Intrinsic CTLA‐4 signaling has been controversially discussed, but so far no distinct signaling pathway has been identified. The CTLA‐4‐mediated Treg suppression plays an important role in the maintenance of peripheral tolerance and the prevention of autoimmune diseases. Human CTLA‐4 insufficiency is caused by heterozygous germline mutations in CTLA4 and characterized by a complex immune dysregulation syndrome. Clinical studies on CTLA4 mutation carriers showed a reduced penetrance and variable expressivity, suggesting modifying factor(s). One hundred and forty‐eight CTLA4 mutation carriers have been reported; patients showed hypogammaglobulinemia, recurrent infectious diseases, various autoimmune diseases, and lymphocytic infiltration into multiple organs. The CTLA‐4 expression level in Treg cells was reduced, while the frequency of Treg cells was increased in CTLA‐4‐insufficient patients. The transendocytosis assay is a specific functional test for the assessment of newly identified CTLA4 gene variants. Immunoglobulin substitution, corticosteroids, immunosuppressive therapy, and targeted therapy such as with CTLA‐4 fusion proteins and mechanistic target of rapamycin (mTOR) inhibitors were applied; patients with life‐threatening, treatment‐resistant symptoms underwent hematopoietic stem cell transplantation. The fact that in humans CTLA‐4 insufficiency causes severe disease taught us that the amount of CTLA‐4 molecules present in/on T cells matters for immune homeostasis. However, whether the pathology‐causing activated T lymphocytes in CTLA‐4‐insufficient patients are antigen‐specific is an unsolved question. CTLA‐4, in addition, has a role in autoimmune diseases and cancer. Anti‐CTLA‐4 drugs are employed as checkpoint inhibitors to target various forms of cancer. Thus, clinical research on human CTLA‐4 insufficiency might provide us a deeper understanding of the mechanism(s) of the CTLA‐4 molecule and immune dysregulation disorders.

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Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning-HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.

Chronic granulomatous disease (CGD) results from an inherited defect in the phagocytic cells of the immune system. It is a genetically heterogenous disease caused by defects in one of the five major subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. There is a paucity of data from India on CGD. We herein describe the clinical features in 17 children with CGD from a single tertiary referral center in India. A detailed analysis of the clinical features, laboratory investigations and outcome of 17 children 7 with X-linked (XL) and 10 with autosomal recessive (AR) form was performed. Diagnosis of CGD was based on an abnormal granulocyte oxidative burst evaluated by either Nitroblue Tetrazolium (NBT) test or flow cytometry based Dihyrorhodamine 123 assay or both. The molecular diagnosis was confirmed by genetic mutation analysis in 13 cases. The mean age at diagnosis and the age at onset of symptoms was significantly lower in children diagnosed with XL- CGD compared those with AR disease. Mutations were detected in CYBB gene in 6 patients with XL-CGD and NCF-1 gene mutations were observed in 7 cases of AR- CGD. The course and outcome of the disease was much worse in children diagnosed with X-linked form of disease compared to AR forms of the disease; 4/7 (57%) children with X-CGD were dead at the time of data analysis. This is one of the largest series on chronic granulomatous disease from any developing country.