Chronic granulomatous disease with an initial presentation of arthritis and oral ulcers

Chronic granulomatous disease (CGD) is an inherited defect of leukocyte phagocytic function leading to recurrent infections. Autoimmune manifestations are reported in up to 6% of patients with CGD. We report a case of CGD presenting with arthritis as the first manifestation of disease. A 12-year-old Pakistani male of consanguineous parents presented with migratory arthritis and painless oral ulcerations of 6 months duration that were minimally responsive to nonsteroidal anti-inflammatory treatment. Initial assessment demonstrated elevated inflammatory markers (ESR 62), weakly positive ANA (titer 1:40), negative anti-DsDNA, and negative RF. He presented to the emergency department with fevers and arthritis. Repeat work-up suggested early Macrophage Activation Syndrome: normocytic anemia (Hgb 95 g/L), thrombocytopenia (Plt 141 × 109/L), elevated LDH 1603, ferritin 1230 mcg/L, ESR 127, CRP 9.3, hypertiglycerdemia (3.2 mmoL/L) and mild transaminitis (ALT 63, AST 87), normal bone marrow (no hemophagocytosis), but mildly elevated Soluble CD 136 (1086 ng/mL) and Soluble IL-2 receptor (CD25) (1698 U/mL). He was treated with oral prednisone with symptom resolution. The arthritis relapsed after 1 month and the patient developed fever, productive cough, and pleuritic chest pain. Chest imaging revealed multiple nodular opacities and enlarged mediastinal lymph nodes. Aspergillus fumigatus complex was isolated from induced sputum prompting screening for primary immunodeficiency. Neutrophil oxidative burst function, as assessed by a dihydrorhodamine flow cytometry based assay, was low at 1.26 and 1.48 (normal range 32–300). Genetic analysis showed a previously described mutation in the NCF1 gene confirming the diagnosis of autosomal-recessive CGD. CGD can present with an exclusively rheumatologic presentation including arthritis and oral ulceration. Statement of Novelty: This case demonstrates that CGD can present with rheumatological symptoms prior to any infectious features.

Essential role of nuclear factor-κB for NADPH oxidase activity in normal and anhidrotic ectodermal dysplasia leukocytes

This work investigated the functional role of nuclear factor–κB (NF-κB) in respiratory burst activity and in expression of the human phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase genes CYBB, CYBA, NCF1, and NCF2. U937 cells with a stably transfected repressor of NF-κB (IκBα-S32A/S36A) demonstrated significantly lower superoxide release and lower CYBB and NCF1 gene expression compared with control U937 cells. We further tested Epstein-Barr virus (EBV)-transformed B cells from patients with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), an inherited disorder of NF-κB function. Superoxide release and CYBB gene expression by EDA-ID cells were significantly decreased compared with healthy cells and similar to cells from patients with X-linked chronic granulomatous disease (X910 CGD). NCF1 gene expression in EDA-ID S32I cells was decreased compared with healthy control cells and similar to that in autosomal recessive (A470) CGD cells. Gel shift assays demonstrated loss of recombinant human p50 binding to a NF-κB site 5′ to the CYBB gene in U937 cells treated with NF-κB inhibitors, repressor-transfected U937 cells, and EDA-ID patients' cells. Zymosan phagocytosis was not affected by transfection of U937 cells with the NF-κB repressor. These studies show that NF-κB is necessary for CYBB and NCF1 gene expression and activation of the phagocyte NADPH oxidase in this model system.