Ctla4 Variant of Uncertain Significance in a Patient with a History of Cytopenias

ABSTRACT

Introduction: CTLA-4 haploinsufficiency is caused by heterozygous mutations in CTLA4, a negative regulator of immune responses. Hypogammaglobulinemia, infections, and autoimmune cytopenias can be seen. Here, we describe a patient with history of ITP who presented with neutropenic fever, lymphopenia, and hypogammaglobulinemia in the setting of COVID-19 with a VUS in CTLA4. Case Description The patient is a 24-year-old female diagnosed with ITP at 10-years-old, initially treated with IVIG/steroids, then on mycophenolate for 6-years. 5-years later, she had a relapse of ITP in the setting of viral illness, requiring steroids/IVIG/rituximab. She developed neutropenic fever, unresponsive to GCSF, but responsive to cyclosporine and was noted to have a LGL clone. At 24-years-old, she was admitted with neutropenic fever (ANC 0);adenovirus, parainfluenza-virus, and SARS-CoV-2 were positive. Immunology was consulted due to hypogammaglobulinemia (IgG 140, IgA 7, IgM <5 mg/dL). Prior genetic testing identified a missense VUS in CTLA4 c.370A>C (P.Thr124Pro), shown to affect CTLA4 function and observed in individuals with clinical features of CTLA-4 haploinsufficiency. Lymphopenia, absent lymphocyte antigen responses, and impaired vaccine immunity were noted. ANC improved with GCSF. The patient was discharged with immunology follow-up for consideration of abatacept. Discussion(s) This case highlights the importance of considering VUS in the diagnosis and treatment of primary immunodeficiency. Our patient had a history of recurrent ITP, neutropenia, and LGL clone, all likely manifestations of CTLA-4 haploinsufficiency. Subsequent recognition of hypogammaglobulinemia and lymphopenia in the setting of neutropenia supported the diagnosis. Abatacept replaces the missing CTLA4-protein and should be considered in patients with CTLA-4 haploinsufficiency presenting with cytopenias. Copyright © 2022