476 Severe Autoimmunity with Polyarticular Joint Disease Requiring Anti-TNF Therapy and T+B-NK+ Immunodeficiency in a Family with Small Stature and Intermediate Radiation Sensitivity

BACKGROUND: We have identified a family in which 3 of 4 children are affected with significant autoimmunity and immunodeficiency that does not fit any of the known disorders. We have embarked to characterize their defect and describe a completely new disorder. METHODS: Whole Exome Sequencing, T and B Cell Immunophenotyping, Radiation Sensitivity, Bacteriophage. RESULTS: The oldest affected child is female with severe polyarticular arthritis (treated with etanercept), eczema, diarrhea, short stature and numerous infections including pneumonia. She is s/p bone marrow transplant using a matched sibling donor, is fully engrafted and doing well. The second affected child was also female and had numerous episodes of pneumonia, bronchiolitis, otitis media and conjunctivitis. She died at 11 months from presumed fulminant CMV hepatitis. The third affected child is male with hypothyroidism, chronic diarrhea, alopecia totalis, eczema, multiple food allergies, reactive airway disease and short stature. All had normal CD4+ and CD8+ T cell and NK cell numbers but marked B cell lymphopenia. T cell immunophenotyping demonstrated a modest decrease in effector memory T cells. Mitogens were normal. B cell immunophenotyping demonstrated a dramatic block in B cell development at the transition from immature to mature B cells suggesting a defect in immunoglobulin gene rearrangement. All affected patients were hypogammaglobulinemic. Immunization with bacteriophage ΦX174 to more thoroughly evaluate humoral immune responses demonstrated a poor immunoglobulin response with only modest amplification and markedly decreased immunoglobulin class switching. Radiation sensitivity testing using skin fibroblasts was performed and demonstrated an intermediate radiation sensitivity. Sequencing of the RAG1, RAG2, and Artemis genes was normal. Evaluation via western blotting of other components of the DNA repair machinery that lead to defective immunoglobulin gene rearrangement and radiation sensitivity was normal. CONCLUSIONS: The overall clinical and laboratory picture of severe autoimmunity with a T+B-NK+ phenotype is unusual and does not fit any known immune defect. The CMV susceptibility suggests that even though T cell numbers and proliferation are normal, there may be a subtle defect in T cell function. We are currently in the process of whole exome sequencing and optimistic we will find a novel defect in DNA repair.