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Internal Medicine

X-linked lymphoproliferative disease (XLP)

Rare primary immunodeficiency characterized by the clinical triad of fulminant infectious mononucleosis (FIM), dysgammaglobulinaemia and lymphoma.

Aetiology

Genetic association:

  • SH2D1A gene (M/C, 80%):
    • Encodes the adaptor molecule signalling Lymphocytic Activation Molecule (SLAM)‐associated protein (SAP)
  • XIAP gene:
    • Endcodes X‐linked inhibitor of apoptosis protein (XIAP).
bjh_8442_f1
Protein and gene structures of SAP and XIAP. The human SAP protein is 128 amino acids in length and comprised of a single SH2 domain and a short carboxyl‐terminal tail. SAP is encoded by the SH2D1A gene, which has four coding exons and is located at Xq25. Human XIAP is a protein of 497 amino acids that contains three Baculovirus IAP Repeat (BIR) domains that participate in interactions of XIAP with caspases and a C‐terminal ring domain having potential E3 ubiquitin ligase activity. This protein is encoded by the XIAP (previously BIRC4) gene, also at Xq25. | Rezaei, N., Mahmoudi, E., Aghamohammadi, A., Das, R. and Nichols, K.E. (2011), X‐linked lymphoproliferative syndrome: a genetic condition typified by the triad of infection, immunodeficiency and lymphoma. British Journal of Haematology, 152: 13-30. doi:10.1111/j.1365-2141.2010.08442.x

Pathophysiology

Inability to eliminate Epstein-Barr virus (EBV)
↓
Fulminant infectious mononucleosis
&
Development of B-cell tumours

Clinical features

Unique propensity of affected males to develop progressive lymphoproliferation, hepatosplenomegaly, cytopenias and erythrophagocytosis following Epstein–Barr virus (EBV) infection.

  • Disease onset: 2·5 years

Triad:

  • T and B cell lymphoproliferation → secondary haemophagocytic lymphohistiocytosis (HLH)
  • Dysgammaglobulinaemia
  • Lymphoma

Rare manifestations:

  • Aplastic anaemia
  • Lymphoid vasculitis
  • Pulmonary lymphoid granulomatosis
  • Autoimmune features: Colitis and psoriasis

Differential diagnosis

Common variable immunodeficiency (CVID)

  • Normal B cell countin lymphoid tissues (vs Reduced B cells in XLP)

Management

Myeloablative/reduced-intensity haematopoietic stem cell transplantation (SCT)

Prognosis:

  • Poor: 70% die before 10 years
  • 96% mortality

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