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Conditions

X-linked lymphoproliferative syndrome

X-linked lymphoproliferative syndrome is a rare genetic condition that affects the immune system, causing susceptibility to infections and haemophagocytic lymphohistiocytosis.

Overview

X-linked lymphoproliferative (XLP) syndrome is a rare primary immunodeficiency condition with two main subtypes:

  • XLP1: a deficiency of signalling lymphocyte activation molecule (SLAM)-associated protein (SAP); and
  • XLP2: a deficiency of X-linked inhibitor of apoptosis (XIAP).

Affected males may present acutely with haemophagocytic lymphohistiocytosis (HLH) or features of lymphoproliferation.

Clinical features

The main clinical features of XLP are:

  • increased susceptibility to HLH, which may be triggered by Epstein-Barr virus (EBV) infection;
  • lymphoproliferative features, such as splenomegaly; and
  • hypogammaglobulinaemia with susceptibility to recurrent bacterial infections.

Key distinguishing features between the subtypes include increased frequency in XLP1 of:

  • severe EBV susceptibility and transformation to EBV-associated lymphoma;
  • infections due to hypogammaglobulinaemia; and
  • an asymptomatic period prior to EBV infection.

Patients with XLP2 are more likely to present with:

  • inflammatory bowel disease;
  • recurrent HLH; and
  • splenomegaly.

Genomics

XLP1 is caused by pathogenic genetic variants in the SH2D1A gene, which encodes SAP. The protein acts as a signal transducer, with deficiency causing failure of activation of cytotoxic T cells and NK cells that prevent invasive pathogens, particularly EBV.

Pathogenic variants observed with SH2D1A include missense, nonsense, frameshift and splice-site variants, as well as small insertions and deletions. Missense variants are common and often affect residues critical for phosphotyrosine ligand binding or protein stability.

XLP2 is caused by pathogenic genetic variants in the XIAP gene, which encodes X-linked inhibitor of apoptosis. Deficiency of the gene causes excessive activation of controlled cell death processes, resulting in reduced NK and T cells.

The presence of pathogenic variants in XIAP typically results in absent or severely reduced XIAP protein expression. Variants include missense, nonsense, frameshift, splice-site, in-frame deletions, large deletions of coding exons and non-coding regulatory region deletions. Non-coding deletions affecting promoter or regulatory regions have also been identified and can lead to complete loss of XIAP expression, despite the absence of coding sequence variants.

No genotype-phenotype correlation has been established for either condition, though it is recognised that ‘hypomorphic’ variants give rise to a milder presentation.

Diagnosis

XLP may be diagnosed following clinical evaluation, laboratory evaluation and molecular analysis. Patients may have a family history of immunodeficiency or inflammatory bowel disease, particularly XLP2. Genomic testing confirms the diagnosis and differentiates XLP subtypes.

The European Society for Immunodeficiencies diagnostic criteria for both conditions is laid out below.

  • Male individual (or female with severely skewed X-chromosome inactivation) and two of the following:
    • at least one episode of HLH (according to the Histiocyte Society criteria);
    • affected family member/s;
    • atypical EBV response;
    • hypogammaglobulinaemia;
    • inflammatory bowel disease;
    • vasculitis; and/or
    • lymphoid neoplasm, especially if EBV-associated;
  • and at least one of the following minor criteria:
    • decreased or absent SAP (for XLP1) or XIAP (for XLP2) expression assessed by flow cytometry;
    • reduced frequency of iNKT cells (<0.02% of T cells);
    • normal perforin expression in flow cytometry; and/or
    • normal degranulation assays or normal NK cell cytotoxicity assays;
  • and
    • no partial albinism;
  • and
    • normal work-up for metabolic diseases.

XLP 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.

For information about testing in those with a clinical diagnosis of XLP1, see ‘Child with suspected lymphoproliferative syndrome with absent SAP expression (X-linked lymphoproliferative disease type 1)‘.

For information about testing in those with a clinical diagnosis of XLP2, see ‘Child presenting with suspected haemophagocytic syndrome with absent XIAP expression‘.

For information about testing in those with early-onset inflammatory bowel disease where the differential is broader than XLP, see ‘Infant with features of very early-onset inflammatory bowel disease‘.

Inheritance and genetic counselling

XLP is caused by pathogenic genetic variants in the SH2D1A (XLP1) and XIAP (XLP2) genes, both of which lie on the X chromosome. The inheritance pattern is X-linked recessive. The condition has a prevalence of 1–2 per million and may account for 5% or more of patients with inflammatory bowel disease, particularly XLP2.

  • 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. Note that mothers are typically asymptomatic carriers, and that de novo variants 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

XLP can present variably and this will determine management options.

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.

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. Reduced intensity conditioning regimens have proven beneficial in patients with XLP, particularly with coexisting inflammatory bowel disease.

Patients should receive multidisciplinary care with:

  • immunoglobulin replacement therapy;
  • infection prophylaxis; and
  • regular monitoring for HLH/EBV infections, including lymphoma surveillance as appropriate.

XLP 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: 06/09/2025
  • Next review due: 06/09/2027
  • Authors: Dr Jesmeen Maimaris
  • Reviewers: Dr Eleanor Hay