UNUSUAL PRESENTATION OF HETEROZYGOUS RAG1 DEFICIENCY

Abstract

<h3>Introduction</h3> RAG1 mutations are associated with a broad range of clinical and immunologic phenotypes. We present an adolescent with heterozygous RAG1 mutation identified during work-up for immune dysregulation. <h3>Case Description</h3> A 17-year-old female with a history of sinusitis presents with recurrent episodes of acute hypoxic respiratory failure. Respiratory failure was responsive to oral corticosteroids (OCS). Diagnostic findings were notable for peripheral eosinophilia (AEC of 1,000), ground glass opacities on chest CT, and bronchoscopy with a BAL of 10% eosinophils without evidence of granulomas or vasculitis. Rheumatologic work-up was unrevealing. A unifying diagnosis was not determined but was presumed to be eosinophilic asthma versus chronic eosinophilic pneumonia. Mepolizumab was initiated with significant improvement. Less than two months later, she was admitted for autoimmune hemolytic anemia and immune thrombocytopenia (Evan's Syndrome). Initially unresponsive to OCS, Rituximab proved to be a successful therapy. Immune work-up revealed low IgG, normal IgA, IgM, and IgE, within normal limits T/B/NK cells with slightly decreased CD3+ and CD19+ cells, elevated unswitched memory B cells, protective tetanus and strep pneumonia titers, and normal mitogen proliferation. Genetic testing revealed a heterozygous <i>RAG1</i> mutation (c.2210G>A(p.Arg737His)) associated with severe combined immunodeficiency. The same genetic variant was found in her asymptomatic mother. RAG1 functional testing is pending. <h3>Discussion</h3> Unlike homozygous RAG1 mutations, heterozygous patients have less severe immunodeficiency and can present with autoimmunity. Eosinophilia has been noted in some presentations. This case highlights how genetic testing can be utilized in the work-up and diagnosis of patients presenting with immune dysregulation.