X-linked lymphoproliferative syndrome type 1 (XLP1)

XLP1 primarily affects males and presents most often in childhood after primary EBV infection. Before EBV exposure, most affected males appear healthy; clinical findings are highly variable, even within the same family, and rarely a male remains asymptomatic across life.

Haemophagocytic lymphohistiocytosis (HLH), often as fulminant infectious mononucleosis, is the most common presentation and is typically characterised by prolonged high fever, bi- or trilineage cytopenias, and hepatosplenomegaly; it is frequently severe or fatal in individuals with XLP1.  Across published series, HLH or fulminant infectious mononucleosis occurs in 45-58%, dysgammaglobulinaemia in approximately 50.5%, and lymphoma in approximately 24.2% of affected males. Lymphomas are typically high-grade, non-Hodgkin B-cell lymphomas, often extranodal and predominantly ileocaecal, with Burkitt lymphoma the commonest histology.

Dysgammaglobulinaemia is usually progressive and may cause bronchiectasis and recurrent respiratory infections; aplastic anaemia and vasculitis (most often of the central nervous system) are additional recognised manifestations.

The estimated prevalence is 1/1,000,000-1/2,000,000 in males.

XLP1 is caused by hemizygous germline pathogenic variants in SH2D1A (locus Xq25), which accounts for 83-97% of all X-linked lymphoproliferative disease. SH2D1A encodes SH2 domain-containing protein 1A, also known as SLAM-associated protein (SAP), an adaptor that binds members of the SLAM family of receptors. Loss-of-function variants – including large deletions – disrupt SAP binding to SLAM receptors, producing intrinsic defects in lymphocyte cytotoxicity, T-cell cytokine production, T-cell-dependent humoral immune responses, and natural killer T cell development.

XLP1 is inherited in an X-linked recessive manner. Affected males transmit the pathogenic SH2D1A variant to all daughters (obligate heterozygotes) and to none of their sons; heterozygous females have a 50% chance of transmitting the variant with each pregnancy, and male offspring inheriting the variant are expected to be affected. Heterozygous females are usually asymptomatic but may rarely show clinical features. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis of XLP1 is established in a male proband with suggestive immunological findings by identification of a hemizygous germline pathogenic variant in SH2D1A. Low or absent SAP protein expression on flow cytometry is highly suggestive; supportive findings include absent or markedly reduced invariant natural killer T (iNKT) cells, impaired 2B4-mediated cytotoxicity of CD8+ T and NK cells, and reduced CD27+ memory B cells. Established consensus clinical diagnostic criteria do not exist; molecular confirmation of a pathogenic SH2D1A variant remains definitive.

Main differential diagnoses include:

• Familial haemophagocytic lymphohistiocytosis: excessive immune activation with uncontrolled T lymphocyte and macrophage activation, often presenting in infancy and not consistently EBV-triggered; PRF1, STX11, STXBP2, UNC13D and others
• EBV-associated lymphoproliferative disorders without SAP deficiency: strong susceptibility to EBV and EBV-associated lymphomas without the SAP-deficiency biochemical signature; CD27, CD70, MAGT1 and others
• : humoral deficiency with onset typically between 16 and 20 years and sinopulmonary infection, occurring in both sexes; LRBA, NFKB1, TNFRSF13B and others

• Genetic testing establishes the diagnosis at the molecular level and provides the basis for genetic counselling of the affected individual and the family.
• Identification of the underlying pathogenic variant enables specific and individualised surveillance and is a prerequisite for targeted medical care, which is determined by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is known, predictive testing of at-risk relatives can be offered within the framework of genetic counselling.

• Meyer L, Hines M, Zhang K, Nichols KE. X-linked lymphoproliferative disease. 2024 May 16. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301580.
• Booth C, Gilmour KC, Veys P, Gennery AR, Slatter MA, Chapel H, et al. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood. 2011;117(1):53-62. doi:10.1182/blood-2010-06-284935. PMID:.
• Tangye SG. XLP: clinical features and molecular etiology due to mutations in SH2D1A encoding SAP. J Clin Immunol. 2014;34(7):772-9. doi:10.1007/s10875-014-0083-7. PMID:.
• Panchal N, Booth C, Cannons JL, Schwartzberg PL. X-linked lymphoproliferative disease type 1: a clinical and molecular perspective. Front Immunol. 2018;9:666. doi:10.3389/fimmu.2018.00666. PMID:.