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Conditions

XMEN syndrome (MAGT1 deficiency)

XMEN syndrome, also known as MAGT1 deficiency, is a rare genetic condition associated with magnesium deficiency with severe Epstein-Barr virus infection and neoplasia.

Overview

X-linked magnesium deficiency with Epstein-Barr virus (EBV) infection and neoplasia (XMEN) syndrome is a rare immunodeficiency condition caused by loss-of-function variants in the MAGT1 gene. Affected patients present with viral infections, particularly chronic EBV infection, with increased susceptibility to EBV-driven lymphoma. MAGT1 defects lead to cellular magnesium transport defects and reduced expression of natural killer (NK) group 2 member D (NKG2D) protein, leading to NK cell dysfunction.

Clinical features

XMEN syndrome typically presents in early childhood and clinical features can be variable.

The main clinical features are:

  • chronic EBV infection with high viral load and persistent EBV-associated lymphoproliferative disease;
  • heightened susceptibility to EBV-associated lymphoma;
  • recurrent, chronic viral infections, particularly in the upper and lower respiratory tracts;
  • chronic or persistent molluscum contagiosum;
  • chronic, persistent or severe warts;
  • autoimmune manifestations, such as autoimmune cytopenias;
  • increased susceptibility to haemophagocytic lymphohistiocytosis (HLH); and
  • neurological complications, such as confusion and seizures.

Genomics

XMEN syndrome is caused by hemizygous pathogenic genetic variants in the MAGT1 gene, located on the X chromosome. The gene encodes magnesium transporter 1, which is responsible for glycosylation in cells, particularly affecting T and NK cell activation.

Causative variants are loss-of-function effect and are typically nonsense, frameshift and splice-site variants. Large deletions of the gene are also reported.

Diagnosis

XMEN syndrome may be diagnosed following clinical evaluation of EBV viraemia and/or EBV-related lymphoproliferation. Patients may have a family history of immunodeficiency in male family members.

In laboratory test results:

  • immunoglobulin levels may be low;
  • lymphocyte subsets show CD4 T lymphopenia;
  • there may be a persistent elevation of EBV viral load; and
  • there may be low or absent NKG2D expression.

Genomic testing confirms the diagnosis and differentiates XMEN syndrome from other forms of EBV-related lymphoproliferation syndromes.

For information about testing, see ‘Infant or child with severe, recurrent, persistent and/or unusual infections‘.

XMEN syndrome may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services. Please refer to the local pathway for your region for this condition.

Inheritance and genetic counselling

XMEN syndrome is caused by pathogenic genetic variants in the MAGT1 gene, located on the X chromosome. It is inherited in an X-linked recessive pattern.

  • X-linked recessive conditions are usually only present in males.
  • Males with X-linked conditions cannot pass the variant on to their sons, but they always pass their affected X chromosome to their daughters. If the condition is recessive, their daughters will be carriers for the condition.
  • Female carriers of X-linked recessive conditions have a second, working copy of the gene and are therefore usually unaffected, or affected only mildly.
  • Sons of female carriers of X-linked recessive conditions have a 1-in-2 (50%) chance of being affected by the condition, and their daughters have a 1-in-2 (50%) chance of being carriers.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. Mothers are asymptomatic carriers. Note that de novo variants also commonly arise.

Reproductive options are available and genetic counselling, ideally prior to conception, is recommended. Options are likely to include testing in early pregnancy or preimplantation genetic testing.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management

XMEN syndrome can present variably, and this will determine management options.

Chronic EBV infection may initially be treated with anti-viral agents such as ganciclovir and cidofovir. Rituximab (anti-CD20) may also be used to deplete EBV-infected B cells.

Regular screening for EBV-driven lymphoma should be undertaken. Treatment of lymphoma follows standard treatment protocols, depending on the histological subtype.

The primary curative treatment is haematopoietic stem cell transplantation (HSCT). This involves replacing stem cells from the patient’s bone marrow with that of a compatible donor. Patients who receive allogeneic HSCT soon after birth tend to have the best outcomes with fewer complications.

Patients with HLH should be managed using standard treatment based on current HLH diagnostic and therapeutic protocols. Initial therapy consists of etoposide and dexamethasone for eight weeks in varying doses. Patients with central nervous system involvement may require intrathecal methotrexate. In some cases, emapalumab targeting interferon-γ has been used successfully.

Patients should receive multidisciplinary care with:

  • immunoglobulin replacement therapy;
  • infection prophylaxis; and
  • regular monitoring for HLH/lymphoma.

XMEN syndrome may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 01/08/2025
  • Next review due: 01/08/2027
  • Authors: Dr Jesmeen Maimaris
  • Reviewers: Dr Eleanor Hay