XMEN Disease

XMEN disease (X-linked immunodeficiency with magnesium defect, EBV infection and neoplasia) is an X-linked combined immunodeficiency from loss-of-function variants in MAGT1. Boys have chronic EBV viraemia and a high risk of EBV-driven lymphoma.

Pathophysiology. MAGT1 encodes a magnesium transporter that also supports N-linked glycosylation. Loss lowers surface NKG2D on NK cells and CD8 T cells, which weakens killing of EBV-infected cells, and causes CD4 lymphopenia and poor T cell activation.

It is very rare. Onset is in childhood, and recurrent infections come with EBV problems.

Lymphoma is the main cause of death without transplant.

• Chronic EBV viraemia, often with hepatosplenomegaly and lymphadenopathy
• EBV-driven lymphoproliferation, Hodgkin lymphoma and B cell non-Hodgkin lymphoma
• Recurrent sinopulmonary infection, and herpesvirus infection (herpes simplex, varicella, CMV)
• Warts and molluscum contagiosum
• Autoimmune cytopenias and, in some, enteropathy
• Mild dysmorphism, growth delay or intellectual difficulty in some
• Hypogammaglobulinaemia of variable degree

• NKG2D expression on NK cells and CD8 T cells by flow cytometry (reduced), which is the screening test.
• Genetic testing of MAGT1 (hemizygous variant in males), with carrier testing of the mother.
• EBV load by quantitative PCR in blood.
• Lymphocyte subsets: CD4 lymphopenia, inverted CD4:CD8 ratio, and variable B cell numbers.
• Immunoglobulins and specific antibody responses.
• Imaging: CT or PET for lymphadenopathy, and abdominal ultrasound for spleen and liver.
• Lymph node biopsy of new or asymmetric nodes.
• Serum magnesium, which is often normal.

Differential diagnosis.

• X-linked lymphoproliferative disease (SH2D1A and XIAP deficiency)
• Other EBV-susceptibility immunodeficiencies (CD27, CD70, ITK deficiency)
• Activated PI3K delta syndrome
• Chronic active EBV infection
• Common variable immunodeficiency
• HIV infection

• EBV control: rituximab 375 mg/m2 intravenously weekly for 4 doses for rising EBV load or EBV-driven lymphoproliferation, after hepatitis B screening. Rituximab lowers B cells, so immunoglobulin replacement is continued.
• Immunoglobulin replacement: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Lymphoma treatment by histology and stage under haematology and oncology, with attention to the immunodeficiency.
• Prophylaxis: co-trimoxazole 960 mg orally three times weekly in adults (children trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week) while CD4 counts are low; aciclovir 400 mg orally twice daily in adults for recurrent herpes simplex or zoster (reduce at creatinine clearance under 25 mL/min).
• Magnesium supplementation has been tried to restore NKG2D, but evidence is limited, so it is not a substitute for definitive treatment.
• Haematopoietic stem cell transplantation is the only cure and is offered early, before lymphoma or organ damage.
• Warts and molluscum: cryotherapy or imiquimod 5% cream three times weekly at night for up to 16 weeks.
• Vaccines: inactivated only; avoid live vaccines.

Special groups.

• Female carriers: genetic counselling, with a 50% chance that a son will be affected.

Monitoring. EBV PCR every 3 months. Full blood count, liver enzymes and creatinine every 3 to 6 months. Trough IgG every 3 months. Cross-sectional imaging yearly, or sooner with fever, weight loss or new nodes.

Referral and escalation. Refer to paediatric immunology and a transplant centre. Urgent for lymphadenopathy, B symptoms, rising EBV load or cytopenia.