Abstract
BACKGROUND: Patients with recurrent, chronic, or refractory cytopenias represent a challenging subgroup that may harbor an underlying diagnosis, such as an inborn error of immunity (IEI). Patients with IEIs such as activated phosphoinositide 3-kinase delta syndrome (APDS), frequently have hematologic manifestations, but these are not often reported as presenting symptoms. As a result, IEIs may be overlooked in patients presenting with early and/or recalcitrant cytopenias. Here, we describe the diagnostic journey and management of three patients who presented to a pediatric hematologist/oncologist with early-onset or recalcitrant cytopenias and were ultimately diagnosed with APDS. CASE PRESENTATIONS: Patients presented with early-onset and/or refractory cytopenias, with two of the three developing multilineage cytopenias. Prior to an APDS diagnosis, two patients underwent a total of approximately 20 procedures, including biopsies, invasive endoscopies, and imaging, with one undergoing eight differential diagnoses that were ruled out through additional testing. Recalcitrant cytopenias, a history of infection, and a family history of lymphoproliferation, infection, or autoimmunity raised suspicion of an underlying IEI, leading to genetic testing. Genetic testing identified a pathogenic variant of PIK3CD in each patient, resulting in the diagnosis of APDS. Following these diagnoses, two patients underwent modifications in the management of care with the administration of intravenous immunoglobulin therapy (IVIG), the mTOR inhibitor sirolimus, or surgical procedures. These treatment modifications either improved or resolved the cytopenias. The third patient showed improvement in immune thrombocytopenia with IVIG 1 month prior to receiving a definitive diagnosis. Following diagnosis, follow-up genetic testing of family members led to the identification of additional cases of APDS. CONCLUSIONS: These cases highlight the importance of early genetic evaluation in patients with early-onset or recalcitrant cytopenias and demonstrate the challenges of differential diagnosis. In addition, these cases demonstrate beneficial changes in management and outcomes that can follow a definitive diagnosis, including the identification of targeted treatment options. Collectively, this case series supports the notion that underlying IEIs should be considered in the workup of early-onset or recalcitrant cytopenias, particularly in patients who present with a combination of hematologic and immunologic manifestations that are refractory to treatment, manifest at an unusually young age, or can be tied to family history.