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Major histocompatibility complex (MHC) Class II deficiency is a rare primary immunodeficiency resulting in severely impaired cellular and humoral immunity [1]. Here, we report the case of a 14-year old Hispanic female with a novel mutation in the CIITA gene. She presented at 6 months of age with pneumonia due to Pneumocystis jiroveci. She had a notable family history of consanguinity and an older sibling that died in infancy from pneumonia. Her immunologic evaluation at initial admission revealed low CD4+ T cell number, absent NK cells and elevated B cells. She also had absent serum concentrations of IgA and IgG, but detectable IgM. The patient was initially misclassified as combined immunodeficiency without a known genetic cause. The relevant immunological investigations at ages 6 months, 9 and 14 years are summarized in Table 1. At 9 years of age, the patient’s care was transferred to a new provider who explored the possibility of MHCII deficiency for the unexplained CD4 lymphopenia. Peripheral blood flow cytometry revealed monocytes that were completely negative for HLA-DR (normal 80 % HLA-DR). MHC Class II deficiency was confirmed by Sanger sequencing which revealed a CIITA homozygous c.682 C>T nonsense mutation pGlu228X. This patient’s clinical course has included severe, recurrent infections, chronic lung disease, failure to thrive, profound neutropenia (despite several normal bone marrow biopsies and no diagnostic evidence of chronic viral infection). Specific PCR and cell culture based viral testing included serum testing for CMV, EBV, HSV and respiratory testing for Adenovirus, Influenza A&B, Parainfluenza 1, 2 &3, Metapneumovirus and Adenovirus. Only Rhinovirus and RSV have ever been isolated. In addition, she has renal tubular acidosis and antithyroid antibodies, suggesting a potential role for autoimmunity in this condition. Her treatment regimen includes IVIG, antimicrobial prophylaxis, and granulocyte colony stimulating factor. Her lack of a matched donor combined with her multi-organ disease presented an unacceptably high risk to undergo hematopoietic stem cell transplantation. Early recognition and gene diagnosis could offer the possibility of better outcomes for this rare condition [2]. This case provides important clinical pearls for providers who care for patients with primary immunodeficiencies. We recommend exploring HLA-DR expression in any case of isolated CD4 lymphopenia [3]. Novel options for transplant, including a haplo-identical transplant using TCRαβ depleted cells, could be considered if there is no suitable HLA match. In addition, this case highlights the potential role of autoimmunity in contributing towards non-infectious complications including cytopenias [4]. Lastly, a delayed diagnosis may preclude curative options due to progressive disease complications. This is particularly important in the era of newborn screening because MHCII deficiency is unlikely to be detected by TREC-based assays [5]. Knowledge of this novel mutation may promote * Laurence E. Cheng laurence.cheng@ucsf.edu

Novel Mutation in the Class II Transactivator Associated with Immunodeficiency and Autoimmunity