Loss-of-function variants in magnesium transporter 1 (MAGT1) cause X-linked Immunodeficiency with Magnesium defect, Epstein-Barr virus infection, and Neoplasia (XMEN) disease through impaired glycosylation. The impaired glycosylation impacts several lymphocytic proteins, resulting in immune dysregulation (e.g., autoimmune cytopenias, hypogammaglobulinemia, recurrent infections, etc.) as well as platelet receptors leading to platelet function defects. Given the risk of both immune thrombocytopenia (ITP) and platelet dysfunction, successful treatment for ITP is critical to limiting bleeding risk. American Society of Hematology (ASH) ITP guidelines rely on thrombopoietin receptor (TPO) agonists if there is not an adequate response to first-line therapy. However, there are limited reports of the utility of standard ITP-directed therapies, particularly TPO agonists, in XMEN disease. Literature review identifies 7 cases of ITP in XMEN with variable response to TPO agonists and limited clinical details.
Following a COVID-19 infection, a 10-year-old male presented with epistaxis and severe thrombocytopenia (platelets 8,000/µL), hypogammaglobulinemia (IgG 370 mg/dL, IgA <7 mg/dL, and IgM 18 mg/dL), and a normal bone marrow biopsy. He was diagnosed with ITP and treated with prednisolone and intravenous immunoglobulin (IVIG) with an adequate platelet rise. He required multiple courses of corticosteroids and IVIG and suffered a subgaleal hemorrhage after head trauma. Genetic testing via a commercial next generation sequencing (NGS) immune and cytopenia panel (642 genes) revealed a hemizygous variant of uncertain significance in MAGT1, denoted as c.628-2A>G. This variant was found to be maternally inherited, and ultimately reclassified as likely pathogenic, consistent with a diagnosis of XMEN disease. Due to persistence of thrombocytopenia and bleeding symptoms, he was started on a TPO agonist, eltrombopag, at age 11 years with a variable response. At age 14 years, he redeveloped severe thrombocytopenia refractory to escalated doses of eltrombopag. Of note, he remains EBV-naïve.
The optimal treatment for severe ITP associated with XMEN disease remains unclear. Urgency remains to determine efficacious treatment modalities given the compounding platelet dysfunction in XMEN disease exacerbates the bleeding risk.
