X-linked Lymphoproliferative Disease Due To SH2D1A Deficiency

Genetic MONDO:0024551 Pathograph 31 Show in embeddings browser X-linked lymphoproliferative syndrome Primary immunodeficiency Inborn error of immunity

X-linked lymphoproliferative disease type 1 (XLP1, Duncan disease) is a rare inborn error of immunity caused by hemizygous loss-of-function variants in SH2D1A, which encodes SAP (SLAM-associated protein). SAP is a small adaptor built almost entirely from a single SH2 domain that couples the cytoplasmic tails of SLAM-family receptors — SLAM (CD150), 2B4 (CD244), NTB-A (SLAMF6), CD84 and Ly9 — to activating kinases. Without SAP these receptors do not simply fall silent: they recruit SH2-domain-containing phosphatases instead and switch from activating to inhibitory signaling. The consequence is paradoxical, and it is specific to the B-lymphocyte compartment that Epstein-Barr virus (EBV) inhabits, because SLAM-family ligands such as CD48 are densely expressed on EBV-infected B cells. NK cells and EBV-specific CD8+ cytotoxic T cells engage those targets and are inhibited by the encounter, so the virus-driven B-cell expansion is never contained. SAP loss also abolishes invariant NKT (type I NKT) cell development and cripples cognate T-B help and germinal-center formation. The classical triad is fulminant infectious mononucleosis/hemophagocytic lymphohistiocytosis (HLH) on primary EBV exposure, dysgammaglobulinemia, and B-cell lymphoma (historically often ileocecal). Rarer manifestations include hepatitis progressing to liver failure, aplastic anemia, vasculitis, and lymphomatoid granulomatosis. Allogeneic hematopoietic stem cell transplant is the only curative therapy, and outcome depends sharply on whether it is done before or after an HLH episode.

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Inheritance
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Pathophys.
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Phenotypes
31
Pathograph
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Genes
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Medical Actions
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References
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Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC GENETICS ENVIRONMENT DISEASE
IUIS Category
immune dysregulation
👪

Inheritance

1
X-linked recessive HP:0001419
XLP1 is inherited in an X-linked manner. Affected males carry a hemizygous germline SH2D1A pathogenic variant; heterozygous female carriers are typically unaffected, though symptomatic carriers with skewed X-chromosome inactivation have been reported.
X-linked recessive inheritance
Show evidence (2 references)
PMID:20301580 SUPPORT Human Clinical
"XLP is inherited in an X-linked manner."
States the inheritance mode directly.
PMID:48119 SUPPORT Human Clinical
"Approximately half the boys, including the half-brothers, were affected, and girls were spared, implying sex-linked recessive inheritance."
The original Duncan kindred segregation analysis that established X-linked recessive inheritance for the disorder.
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Pathophysiology

10
SAP Adaptor Deficiency
Hemizygous SH2D1A deletions, frameshifts, nonsense and missense variants abolish or destabilize SAP, a 128-amino-acid protein consisting almost entirely of a single SH2 domain. Affected males typically have absent or markedly reduced intracellular SAP protein by flow cytometry. This is the initiating molecular lesion of XLP1.
Genetic context SH2D1A hgnc:10820 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SH2D1A (hgnc:10820). hgnc:10820 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Hemizygous germline SH2D1A variants in males, including large constitutional deletions, small intragenic deletions, nonsense and missense alleles. Missense alleles such as R55L may retain detectable protein while remaining functionally deficient.
SAP signaling adaptor activity GO:0035591 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves SAP signaling adaptor activity, annotated with signaling adaptor activity (GO:0035591), qualified as loss of function. GO:0035591 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
SLAM-Family Receptor Signaling Failure Loss of the SAP adaptor removes the obligate coupling between SLAM-family receptor cytoplasmic tails and downstream activating signaling.
Show evidence (3 references)
PMID:9771704 SUPPORT Human Clinical
"We have identified a gene, SH2D1A, that is mutated in XLP patients and encodes a novel protein composed of a single SH2 domain."
Identifies SH2D1A as the mutated gene in XLP and its product as a single-SH2-domain protein.
PMID:9811875 SUPPORT Human Clinical
"We describe here the presence of small deletions and intragenic mutations that specifically disrupt a gene named DSHP in 6 of 10 unrelated patients with XLP."
Independent identification of inactivating deletions and intragenic mutations in the same gene (named DSHP in this report) in XLP patients.
PMID:20301580 SUPPORT Human Clinical
"These males typically have low or absent SAP or XIAP protein expression, respectively, by flow cytometry."
Confirms that the genetic lesion translates into absent or reduced SAP protein in affected males.
SLAM-Family Receptor Signaling Failure
SAP binds immunoreceptor tyrosine-based switch motifs in the cytoplasmic tails of SLAM (CD150), 2B4 (CD244), NTB-A (SLAMF6), CD84 and Ly9, and normally recruits the kinase FynT while blocking docking of SH2-containing phosphatases. Without SAP, SHP-1/SHP-2 occupy those docking sites, so the receptors deliver inhibitory rather than activating signals. This inversion — rather than a simple absence of signal — is the defining molecular feature of XLP1 and explains why the immune failure is targeted at SLAM-ligand-bearing B lymphocytes.
SAP SH2-domain binding to SLAM-family receptor tails GO:0042169 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves SAP SH2-domain binding to SLAM-family receptor tails, annotated with SH2 domain binding (GO:0042169), qualified as loss of function. GO:0042169 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
2B4/NTB-A Inhibitory Switch on NK Cells On NK cells, uncoupled 2B4 and NTB-A engage their ligands on EBV-infected B cells and transmit inhibitory signals.
Defective EBV-Specific CD8+ T Cell Cytotoxicity On EBV-specific cytotoxic T cells, the same SLAM-family receptors block recognition of SLAM-ligand-positive B-cell targets.
Absent Invariant NKT Cell Development SAP-dependent SLAM-family homotypic signaling during thymic selection is required for iNKT lineage commitment.
Defective T-B Cell Help and Germinal Center Formation SAP-dependent SLAM-family signaling sustains stable cognate T-B conjugates and follicular helper T-cell function.
Show evidence (3 references)
PMID:9774102 SUPPORT In Vitro
"acts as an inhibitor by blocking recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to a docking site in the SLAM cytoplasmic region"
Defines SAP's molecular role as competitively excluding SHP-2 from the SLAM cytoplasmic tail, the step lost in XLP1.
PMID:9774102 SUPPORT INDIRECT In Vitro
"Absence of the inhibitor SAP in XLP patients affects T/B-cell interactions induced by SLAM, leading to an inability to control B-cell proliferation caused by Epstein-Barr virus infections."
Connects loss of SAP-dependent SLAM signaling to failure of control over EBV-driven B-cell proliferation. Graded IN_VITRO with INDIRECT directness because this is the authors' closing interpretation of their COS-cell and Jurkat transfection experiments, not a clinical observation reported in the paper; it matches the grading of the other quote from this same publication above.
PMID:21219180 SUPPORT Other
"SAP consists almost entirely of a single SH2 protein domain that interacts with the cytoplasmic tail of SLAM and related receptors, including 2B4, Ly108, CD84, Ly9, and potentially CRACC."
Enumerates the SLAM-family receptors whose signaling depends on SAP, defining the breadth of the lesion. Review article, hence OTHER.
2B4/NTB-A Inhibitory Switch on NK Cells
In XLP1 NK cells, 2B4 (CD244) not only fails to transduce a triggering signal but actively inhibits cytolysis, and the same inversion affects NTB-A. Because CD48 — the 2B4 ligand — is densely expressed on EBV-infected B cells, XLP1 NK cells engaging an EBV-positive target receive a dominant inhibitory signal and fail to kill it. Antibody-mediated masking of 2B4 and NTB-A restores lysis, demonstrating that inhibition rather than absent activation is the operative defect. Other NK triggering receptors (CD16, NKp46, NKp44, NKp30) are intrinsically normal but are overridden by 2B4 engagement.
natural killer cell CL:0000623 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves natural killer cell (CL:0000623). CL:0000623 is a cell type from the Cell Ontology.
NK-cell killing of EBV-infected B cells GO:0042267 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased NK-cell killing of EBV-infected B cells, annotated with natural killer cell mediated cytotoxicity (GO:0042267). GO:0042267 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Uncontrolled EBV-Driven B Cell Proliferation Failure of NK-mediated killing leaves the EBV-infected B-cell pool unchecked during primary infection.
Decreased Natural Killer Cell-Induced Killing of Target Cells The inhibitory switch is measured directly as impaired NK killing of EBV-infected B-cell targets — the laboratory readout of this node.
Show evidence (4 references)
PMID:10934222 SUPPORT In Vitro
"We show that, in these patients, 2B4 not only fails to transduce triggering signals, but also mediates a sharp inhibition of the NK-mediated cytolysis."
Direct demonstration that 2B4 signaling is inverted, not merely lost, in XLP1 NK cells.
PMID:10934222 SUPPORT In Vitro
"Remarkably, NK cells from XLP patients could not kill EBV(+) B cell lines."
Establishes the functional consequence: failure of XLP1 NK cells to kill EBV-infected B cells.
PMID:11489943 SUPPORT In Vitro
"Thus, in XLP-NK cells, NTB-A mediates inhibitory rather than activating signals."
Shows the inhibitory switch is not confined to 2B4 but extends to a second SAP-dependent SLAM-family receptor.
+ 1 more reference
Defective EBV-Specific CD8+ T Cell Cytotoxicity
XLP1 patients who survive primary EBV infection mount numerically normal EBV-specific CD8+ T-cell responses, but those T cells are selectively unable to recognize SLAM-ligand-positive targets. CD8+ clones kill EBV-antigen-expressing targets that lack SLAM ligands, yet fail against EBV-transformed lymphoblastoid cell lines; blocking CD244 and NTB-A restores recognition. This selectivity is the best available explanation for why XLP1 confers susceptibility to EBV specifically rather than to viruses in general — EBV's tropism is for the very B lymphocytes that carry the inhibitory ligands.
EBV-specific CD8+ cytotoxic T cell CL:0000625 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves EBV-specific CD8+ cytotoxic T cell, annotated with CD8-positive, alpha-beta T cell (CL:0000625). CL:0000625 is a cell type from the Cell Ontology.
CD8+ T-cell killing of EBV-transformed B cells GO:0001913 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased CD8+ T-cell killing of EBV-transformed B cells, annotated with T cell mediated cytotoxicity (GO:0001913). GO:0001913 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Uncontrolled EBV-Driven B Cell Proliferation Loss of cytotoxic T-cell control over EBV-transformed B cells permits their continued expansion.
Show evidence (2 references)
PMID:20644117 SUPPORT In Vitro
"However, further investigation of in vitro-derived CD8(+) T-cell clones established from 2 of these donors showed they efficiently recognized SLAM ligand-negative target cells expressing EBV antigens, but showed impaired recognition of EBV-transformed, SLAM ligand-positive, lymphoblastoid cell..."
Demonstrates that the CD8+ T-cell defect in XLP1 is target-restricted to SLAM-ligand-positive B cells.
PMID:20644117 SUPPORT In Vitro
"Importantly, LCL recognition was restored when interactions between the SLAM receptors CD244 and natural killer-, T-, and B-cell antigen (NTBA) and their ligands on LCLs were blocked."
Rescue by receptor blockade identifies inhibitory SLAM-family signaling as the operative cause of the CD8+ recognition failure.
Absent Invariant NKT Cell Development
SAP is required for the development of invariant (type I) NKT cells. Sh2d1a-null mice lack NKT cells in thymus and periphery through a hematopoietic-cell-autonomous defect that is rescued by restoring SAP expression in bone marrow, and seventeen genetically confirmed XLP1 patients likewise lacked NKT cells. Absent iNKT cells are a robust, near-universal cellular biomarker of SAP deficiency and are thought to contribute to defective antiviral and antitumor immunity and to hypogammaglobulinemia.
invariant (type I) NKT cell CL:0000921 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves invariant (type I) NKT cell, annotated with type I NK T cell (CL:0000921). CL:0000921 is a cell type from the Cell Ontology.
invariant NKT cell development GO:0001865 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased invariant NKT cell development, annotated with NK T cell differentiation (GO:0001865). GO:0001865 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Immune Surveillance and B Cell Lymphomagenesis Loss of the iNKT compartment removes an antitumor effector arm, contributing to defective surveillance of transformed B cells.
Failed Class Switching and Antibody Production Absent iNKT cells are proposed to contribute to the humoral defect of SAP deficiency alongside the primary T-B help failure.
Show evidence (2 references)
PMID:15711562 SUPPORT Human Clinical
"Seventeen individuals with X-linked lymphoproliferative disease (XLP), who harbored germline mutations in SH2D1A, also lacked NKT cells."
Establishes absent NKT cells in genetically confirmed human XLP1 patients.
PMID:15711562 SUPPORT Model Organism
"The defect in NKT cell ontogeny was hematopoietic cell autonomous and could be rescued by reconstitution of SAP expression within Sh2d1a-/- bone marrow cells."
Mouse genetics establishes that the NKT developmental block is caused by SAP loss within the hematopoietic compartment and is SAP-reversible.
Uncontrolled EBV-Driven B Cell Proliferation
With both NK- and CD8-mediated control of SLAM-ligand-positive targets lost, primary EBV infection produces an uncontained expansion of virus-carrying B cells accompanied by a massive reactive cytotoxic T-cell response. This is the pivotal cellular event of XLP1 and the branch point from which both the acute hyperinflammatory arm and the chronic lymphomagenesis arm descend.
EBV-infected B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves EBV-infected B cell, annotated with B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
EBV-driven B cell proliferation GO:0030890 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased EBV-driven B cell proliferation, annotated with positive regulation of B cell proliferation (GO:0030890). GO:0030890 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Unterminated Hyperinflammatory Response to Primary EBV Infection Persistent antigen load from uncleared EBV-infected B cells drives unterminated lymphocyte and macrophage activation.
Impaired Immune Surveillance and B Cell Lymphomagenesis Sustained polyclonal B-cell proliferation provides the substrate on which monoclonal malignant transformation occurs.
Show evidence (2 references)
PMID:9811875 SUPPORT Human Clinical
"In affected males, primary EBV infection leads to the uncontrolled proliferation of virus-containing B cells and reactive cytotoxic T cells, often culminating in the development of high-grade lymphoma."
States the central pathophysiologic event and its two downstream consequences.
PMID:9811875 SUPPORT Human Clinical
"its inactivation in XLP patients results in a selective immunodeficiency to EBV"
Emphasizes the EBV-selectivity of the immunodeficiency produced by loss of this gene.
Unterminated Hyperinflammatory Response to Primary EBV Infection
The acute arm of XLP1. Because the activating stimulus is never cleared, lymphocyte and macrophage activation continues without a termination signal, producing a hyperinflammatory cytokine state clinically indistinguishable from HLH: prolonged high fever, bi- or trilineage cytopenias, hepatosplenomegaly and hemophagocytosis, with death typically from liver failure or multiorgan dysfunction. This is the most severe feature of XLP1 and the principal determinant of outcome. The general HLH pathophysiology is modeled in the Hemophagocytic_Lymphohistiocytosis entry.
lymphocyte CL:0000542 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lymphocyte (CL:0000542). CL:0000542 is a cell type from the Cell Ontology.
hyperinflammatory cytokine production GO:0002367 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased hyperinflammatory cytokine production, annotated with cytokine production involved in immune response (GO:0002367). GO:0002367 is a biological process from the Gene Ontology. ↑ INCREASED systemic inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased systemic inflammatory response, annotated with inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Fulminant Infectious Mononucleosis with Hemophagocytic Lymphohistiocytosis The unterminated hyperinflammatory state is what presents clinically as fulminant infectious mononucleosis and/or HLH.
Hemophagocytosis Activated macrophages engulf haematopoietic cells, the marrow finding that gives the syndrome its name.
Prolonged high fever Sustained hypercytokinaemia from the unterminated response drives the prolonged high fever that opens the HLH episode.
Bi- or trilineage cytopenias Marrow suppression by the same cytokine excess, compounded by hemophagocytosis of haematopoietic precursors, depresses two or three peripheral lineages during the episode.
Hepatitis Lymphocytic infiltration of the liver during the hyperinflammatory response produces hepatitis.
Hepatosplenomegaly Organ infiltration by activated lymphocytes and macrophages enlarges liver and spleen.
Lymphadenopathy The same uncontrolled lymphoproliferation enlarges lymph nodes.
Aplastic Anemia Marrow failure is a recognized outcome of the acute arm; whether it reflects haemophagocytic consumption, cytokine suppression of haematopoiesis, or a distinct process is not resolved in these cohorts.
Vasculitis Vasculitis is reported among the XLP1 manifestations; the path from the hyperinflammatory state to vessel injury is not established.
Show evidence (4 references)
PMID:20301580 SUPPORT Human Clinical
"HLH is characterized as an acute illness with prolonged and high fever, bi- or trilineage cytopenias, and hepatosplenomegaly, which is often severe or fatal."
Describes the clinical syndrome produced at this node.
PMID:20301580 SUPPORT Human Clinical
"Death is generally secondary to liver failure or multisystem organ dysfunction."
Identifies the organ-level mechanism of death in the acute arm.
PMID:3030174 SUPPORT Human Clinical
"We hypothesized that the defective lymphoproliferative control locus on the X chromosome results in unregulated cytotoxic lymphocytic responses to the Epstein-Barr virus; hence, severe hepatitis and virus-associated hemophagocytic syndrome occur with the infectious mononucleosis phenotype."
The registry-era formulation of this node: unregulated cytotoxic lymphocytic response producing hepatitis and hemophagocytic syndrome.
+ 1 more reference
Defective T-B Cell Help and Germinal Center Formation
SAP-dependent SLAM-family signaling sustains stable cognate interactions between follicular helper T cells and antigen-engaged B cells, and is required for germinal-center development. XLP1 patients have normal B-cell development but markedly reduced memory B cells, and the few present are IgM-positive, indicating failed in vivo isotype switching. The block is B-cell extrinsic: XLP1 B cells proliferate and differentiate normally in vitro, while XLP1 CD4+ T cells fail to differentiate into IL-10-producing effectors, fail to upregulate ICOS, and provide poor B-cell help — a defect partially corrected by exogenous IL-10 or restored SAP expression.
T follicular helper cell CL:0002038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T follicular helper cell (CL:0002038). CL:0002038 is a cell type from the Cell Ontology. memory B cell CL:0000787 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves memory B cell (CL:0000787). CL:0000787 is a cell type from the Cell Ontology.
germinal center formation GO:0002467 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased germinal center formation (GO:0002467). GO:0002467 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failed Class Switching and Antibody Production Failure of germinal-center output and class switching produces the abnormal serum immunoglobulin profile.
Show evidence (4 references)
PMID:15761493 SUPPORT Human Clinical
"Our analysis of 14 XLP patients revealed normal B cell development but a marked reduction in the number of memory B cells."
Localizes the humoral lesion downstream of B-cell development, at memory B-cell generation.
PMID:15761493 SUPPORT Human Clinical
"The few memory cells detected were IgM(+), revealing deficient isotype switching in vivo."
Demonstrates failed in vivo class switching, the hallmark of a defective germinal-center reaction.
PMID:15761493 SUPPORT In Vitro
"XLP CD4(+) T cells did not efficiently differentiate into IL-10(+) effector cells or provide optimal B cell help in vitro"
Identifies the T-cell-intrinsic help defect that makes the B-cell block extrinsic.
+ 1 more reference
Failed Class Switching and Antibody Production
The humoral endpoint of XLP1. Serum immunoglobulins are abnormal, most often as hypogammaglobulinemia but historically spanning agammaglobulinemia to polyclonal hypergammaglobulinemia — hence "dysgammaglobulinemia" rather than a purely quantitative deficit. Untreated, it causes recurrent respiratory infection and bronchiectasis and can itself be fatal. It may be the presenting feature in a boy with no EBV history, and can be indistinguishable from common variable immunodeficiency.
immunoglobulin class switch recombination GO:0045190 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased immunoglobulin class switch recombination, annotated with isotype switching (GO:0045190). GO:0045190 is a biological process from the Gene Ontology. ↓ DECREASED immunoglobulin production GO:0002377 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated immunoglobulin production (GO:0002377). GO:0002377 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Dysgammaglobulinemia The failure of class switching and antibody output is measured as the abnormal serum immunoglobulin profile.
Decreased Circulating Immunoglobulin Concentration Hypogammaglobulinemia is the commonest direction the abnormality takes.
Recurrent Respiratory Infections and Bronchiectasis Untreated antibody deficiency produces recurrent sinopulmonary infection and, over time, bronchiectasis.
Show evidence (2 references)
PMID:20301580 SUPPORT Human Clinical
"In those with XLP1, dys- or hypogammaglobulinemia can lead to varying degrees of humoral immune dysfunction associated with bronchiectasis and recurrent respiratory infections that, if untreated, may result in death."
Establishes dysgammaglobulinemia and its clinical consequences as an XLP1 manifestation.
PMID:48119 SUPPORT Human Clinical
"Fever, pharyngitis, lymphadenomegaly, hepatosplenomegaly, atypical lymphocytosis, and a spectrum ranging from agammaglobulinaemia to polyclonal hyper-gammaglobulinaemia occurred."
The original description of the bidirectional immunoglobulin abnormality that the term dysgammaglobulinemia captures.
Impaired Immune Surveillance and B Cell Lymphomagenesis
The chronic arm of XLP1. Sustained polyclonal B-cell proliferation, combined with loss of NK-, CD8- and iNKT-mediated surveillance of transformed cells, provides both the substrate and the permissive environment for conversion to monoclonal B-cell malignancy. Lymphoma is essentially confined to XLP1 among the X-linked lymphoproliferative syndromes and typically arises in childhood, usually after EBV exposure; extranodal ileocecal/ileal B-cell lymphoma is the classically described site, and the original Duncan kindred included lymphomas of the ileum.
transformed B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves transformed B cell, annotated with B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
immune surveillance of transformed B cells GO:0002418 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased immune surveillance of transformed B cells, annotated with immune response to tumor cell (GO:0002418). GO:0002418 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
B-Cell Lymphoma Failed surveillance of proliferating B cells permits frank lymphoma, characteristically extranodal and often ileocecal.
Show evidence (3 references)
PMID:3030174 SUPPORT Human Clinical
"A sustained polyclonal B-cell proliferation probably converts to a monoclonal B-cell malignancy as a result of molecular alterations."
States the polyclonal-to-monoclonal transition that this node models.
PMID:21119115 SUPPORT Human Clinical
"Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients (17%) had chronic hemorrhagic colitis as documented by histopathology."
Direct comparison establishing that lymphomagenesis is specific to the SAP-deficient (XLP1) form, which supports it being a SAP-dependent surveillance failure rather than a generic XLP feature.
PMID:48119 SUPPORT Human Clinical
"In addition, 2 half-brothers had lymphomas of the ileum and central nervous system."
The original kindred documenting the characteristic extranodal ileal site of XLP lymphoma.
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Pathograph

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Pathograph: causal mechanism network for X-linked Lymphoproliferative Disease Due To SH2D1A Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Blood 7
Hemophagocytosis HP:0012156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemophagocytosis (HP:0012156). HP:0012156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:3030174 SUPPORT Human Clinical
"hence, severe hepatitis and virus-associated hemophagocytic syndrome occur with the infectious mononucleosis phenotype"
Documents hemophagocytic syndrome as part of the XLP infectious mononucleosis phenotype.
Bi- or trilineage cytopenias FREQUENT Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bi- or trilineage cytopenias, annotated with Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301580 SUPPORT Human Clinical
"HLH is characterized as an acute illness with prolonged and high fever, bi- or trilineage cytopenias, and hepatosplenomegaly, which is often severe or fatal."
GeneReviews names bi- or trilineage cytopenias as a defining feature of the HLH episode.
PMID:21119115 SUPPORT Human Clinical
"HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups."
The FREQUENT band is inherited from the 55% HLH rate in XLP-1, since GeneReviews defines the episode as including this feature.
Dysgammaglobulinemia FREQUENT Abnormal circulating immunoglobulin concentration HP:0010701 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysgammaglobulinemia, annotated with Abnormal circulating immunoglobulin concentration (HP:0010701). HP:0010701 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21119115 SUPPORT Human Clinical
"HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups."
Quantifies hypogammaglobulinemia at 67% in XLP-1, supporting the FREQUENT band.
PMID:20926771 SUPPORT Human Clinical
"Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection."
Lists dysgammaglobulinemia among the core manifestations in the 91-patient XLP1 cohort.
Decreased Circulating Immunoglobulin Concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:3030174 SUPPORT Human Clinical
"Fifty-seven percent of the males died of infectious mononucleosis, 29% developed acquired hypogammaglobulinemia, and 24% had malignant lymphoma."
Registry data quantifying acquired hypogammaglobulinemia in 29% of affected males.
B-Cell Lymphoma FREQUENT HP:0012191 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is B-cell lymphoma (HP:0012191). HP:0012191 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:21119115 SUPPORT Human Clinical
"Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients (17%) had chronic hemorrhagic colitis as documented by histopathology."
Quantifies lymphoma at 30% in XLP-1 and establishes its specificity to the SAP-deficient subtype.
PMID:20301580 SUPPORT Human Clinical
"Lymphoproliferative disease (malignant lymphoma) and other lymphoproliferative diseases are specific to XLP1 and often develop in childhood, usually following EBV exposure."
Establishes XLP1-specificity, childhood onset and the EBV relationship of the lymphoma.
PMID:48119 SUPPORT Human Clinical
"In addition, 2 half-brothers had lymphomas of the ileum and central nervous system."
Original documentation of the characteristic ileal (ileocecal) lymphoma site in the Duncan kindred.
Aplastic Anemia OCCASIONAL HP:0001915 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplastic anemia (HP:0001915). HP:0001915 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301580 SUPPORT Human Clinical
"Rarer findings in those with XLP1 can include aplastic anemia, vasculitis, and lymphoid granulomatosis."
GeneReviews lists aplastic anemia among the rarer XLP1 findings; the "rarer" wording maps to the OCCASIONAL band.
Decreased Natural Killer Cell-Induced Killing of Target Cells HP:0025808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased natural killer cell-induced killing of target cells (HP:0025808). HP:0025808 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24985396 SUPPORT Human Clinical
"NK cells from all patients showed inhibitory 2B4 function and defective killing of B-EBV cells."
Documents defective NK killing of EBV-transformed targets in every patient of a genetically confirmed XLP1 cohort.
PMID:24985396 SUPPORT Human Clinical
"Study of SAP expression is specific but may have insufficient sensitivity for screening XLP1 as a single tool. Combination with 2B4 functional assay allows identification of all cases."
Establishes the diagnostic value of the NK functional readout alongside SAP protein staining.
Cardiovascular 3
Vasculitis OCCASIONAL HP:0002633 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vasculitis (HP:0002633). HP:0002633 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301580 SUPPORT Human Clinical
"Rarer findings in those with XLP1 can include aplastic anemia, vasculitis, and lymphoid granulomatosis."
GeneReviews lists vasculitis among the rarer XLP1 findings.
Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:48119 SUPPORT Human Clinical
"Fever, pharyngitis, lymphadenomegaly, hepatosplenomegaly, atypical lymphocytosis, and a spectrum ranging from agammaglobulinaemia to polyclonal hyper-gammaglobulinaemia occurred."
Original clinical description documenting lymphadenomegaly in affected males.
Hepatosplenomegaly HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301580 SUPPORT Human Clinical
"HLH is characterized as an acute illness with prolonged and high fever, bi- or trilineage cytopenias, and hepatosplenomegaly, which is often severe or fatal."
Lists hepatosplenomegaly as a defining component of the HLH presentation.
Digestive 2
Hepatitis HP:0012115 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatitis (HP:0012115), qualified as severity severe. HP:0012115 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Sequelae: Hepatic Failure
Show evidence (1 reference)
PMID:3030174 SUPPORT Human Clinical
"hence, severe hepatitis and virus-associated hemophagocytic syndrome occur with the infectious mononucleosis phenotype"
Documents severe hepatitis as a component of the XLP infectious mononucleosis phenotype.
Hepatic Failure HP:0001399 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic failure (HP:0001399). HP:0001399 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301580 SUPPORT Human Clinical
"Death is generally secondary to liver failure or multisystem organ dysfunction."
Identifies liver failure as the leading terminal event.
Immune 1
Fulminant Infectious Mononucleosis with Hemophagocytic Lymphohistiocytosis FREQUENT Severe Epstein Barr virus infection HP:0031693 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe Epstein-Barr virus infection, annotated with Severe Epstein Barr virus infection (HP:0031693), qualified as temporality acute. HP:0031693 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (4 references)
PMID:20301580 SUPPORT Human Clinical
"HLH / fulminant infectious mononucleosis is the most common presentation regardless of subtype."
Establishes fulminant infectious mononucleosis / HLH as the most common presentation.
PMID:21119115 SUPPORT Human Clinical
"HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups."
Quantifies HLH frequency at 55% in a 33-patient XLP-1 cohort, supporting the FREQUENT band.
PMID:21119115 SUPPORT Human Clinical
"Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of HLH (XLP-1, 92%; XLP-2, 83%)."
Quantifies EBV as the trigger in 92% of XLP-1 HLH episodes.
+ 1 more reference
Metabolism 1
Prolonged high fever FREQUENT HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged high fever, annotated with Fever (HP:0001945), qualified as temporality prolonged. HP:0001945 is a phenotype from the Human Phenotype Ontology.
Temporal: PROLONGED
Show evidence (2 references)
PMID:20301580 SUPPORT Human Clinical
"HLH is characterized as an acute illness with prolonged and high fever, bi- or trilineage cytopenias, and hepatosplenomegaly, which is often severe or fatal."
GeneReviews names prolonged high fever as a defining feature of the HLH episode, which the same source reports as the most common presentation of XLP regardless of subtype.
PMID:21119115 SUPPORT Human Clinical
"HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups."
The FREQUENT band is inherited from the 55% HLH rate in XLP-1, since GeneReviews defines the episode as including this feature.
Respiratory 1
Recurrent Respiratory Infections and Bronchiectasis HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301580 SUPPORT Human Clinical
"In those with XLP1, dys- or hypogammaglobulinemia can lead to varying degrees of humoral immune dysfunction associated with bronchiectasis and recurrent respiratory infections that, if untreated, may result in death."
Directly links the humoral defect to bronchiectasis and recurrent respiratory infection.
🧬

Genetic Associations

1
SH2D1A (CAUSATIVE)
Gene: SH2D1A hgnc:10820 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SH2D1A (hgnc:10820). hgnc:10820 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
X-linked recessive
Show evidence (3 references)
PMID:9771704 SUPPORT Human Clinical
"We have identified a gene, SH2D1A, that is mutated in XLP patients and encodes a novel protein composed of a single SH2 domain."
Establishes SH2D1A as the XLP1 disease gene.
PMID:9774102 SUPPORT Human Clinical
"The gene encoding SAP maps to the same area of the X chromosome as the locus for X-linked lymphoproliferative disease (XLP) and we found mutations in the SAP gene in three XLP patients."
Independent identification of SAP gene mutations in XLP patients, with positional concordance at the XLP locus.
PMID:24985396 SUPPORT Human Clinical
"Nine cases were SAP(-), 2 expressed SAP with mean relative fluorescence intensity values below the range of healthy controls (SAP(dull)), and 1, carrying the R55L mutation, was SAP(+)."
Documents allelic heterogeneity: most SH2D1A variants abolish SAP protein, but some (R55L) preserve expression while remaining functionally deficient.
💊

Medical Actions

4
Allogeneic Hematopoietic Stem Cell Transplantation
Action: allogeneic hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is allogeneic hematopoietic stem cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
Allogeneic HSCT is the only known curative therapy for XLP1: it replaces the SAP-deficient hematopoietic compartment, restoring NK, CD8+ T and iNKT function. Outcome depends sharply on timing. In the 91-patient Booth cohort, survival after allogeneic HSCT was 81.4% overall but fell to 50% in patients who had HLH as a feature of disease, while untransplanted patients who had had HLH survived only 18.8% of the time. The evidence therefore supports pre-emptive transplantation in asymptomatic males rather than waiting for an HLH episode.
Mechanism Target:
RESTORES SAP Adaptor Deficiency — Donor-derived hematopoiesis reconstitutes SAP-expressing lymphocytes, correcting the initiating molecular lesion in the hematopoietic compartment.
Show evidence (1 reference)
PMID:20926771 SUPPORT Human Clinical
"Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease."
Good immune reconstitution after HSCT, with resolution of the lymphoproliferative risk, indicates correction of the underlying SAP defect in the hematopoietic compartment.
Show evidence (3 references)
PMID:20301580 SUPPORT Human Clinical
"The only known curative therapy for XLP1 is allogeneic hematopoietic stem cell transplant (HSCT), which should be strongly considered in all males as early in life as is feasible, particularly in those who have not developed symptoms"
Establishes HSCT as the only curative therapy and supports pre-emptive timing.
PMID:20926771 SUPPORT Human Clinical
"However, survival falls to 50% in patients with HLH as a feature of disease."
Quantifies the outcome penalty of transplanting after HLH rather than preemptively.
PMID:20926771 SUPPORT Human Clinical
"HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor."
The cohort's management conclusion: HSCT is mandatory once HLH has occurred.
Rituximab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus. monoclonal antibody NCIT:C20401 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses monoclonal antibody (NCIT:C20401). NCIT:C20401 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Anti-CD20 monoclonal antibody depletion of B cells removes the EBV-infected B-cell reservoir that XLP1 NK and CD8+ T cells cannot clear, addressing the antigen source that sustains the hyperinflammatory state. It is used as part of the management of fulminant EBV infection / HLH in XLP.
Mechanism Target:
INHIBITS Uncontrolled EBV-Driven B Cell Proliferation — CD20-directed depletion removes the expanding EBV-infected B-cell population directly, bypassing the SAP-dependent cytotoxic pathways that cannot act on it.
Show evidence (1 reference)
PMID:20301580 SUPPORT INDIRECT Human Clinical
"Standard treatment for liver dysfunction/failure, hypogammaglobulinemia (IVIG or IgG), fulminant EBV infection / HLH (including etoposide and steroids and consideration of rituximab), lymphoma, colitis, aplastic anemia, and vasculitis."
Places rituximab in the management of fulminant EBV infection / HLH, which is where the EBV-driven B-cell expansion is the therapeutic target.
Show evidence (1 reference)
PMID:20301580 SUPPORT Human Clinical
"Standard treatment for liver dysfunction/failure, hypogammaglobulinemia (IVIG or IgG), fulminant EBV infection / HLH (including etoposide and steroids and consideration of rituximab), lymphoma, colitis, aplastic anemia, and vasculitis."
GeneReviews management guidance naming rituximab as a consideration in fulminant EBV infection / HLH.
Immunoglobulin Replacement Therapy
Action: immunoglobulin replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunoglobulin replacement therapy, annotated with Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunoglobulin Therapy NCIT:C62710
Platform: Protein replacement
Intravenous or subcutaneous immunoglobulin replaces the antibody the failed germinal-center reaction cannot generate, preventing the recurrent respiratory infection and bronchiectasis that untreated dysgammaglobulinemia causes. It is supportive rather than curative: in the Booth cohort the majority of untransplanted survivors were maintained on immunoglobulin replacement.
Mechanism Target:
BYPASSES Failed Class Switching and Antibody Production — Exogenous polyclonal IgG substitutes for the class-switched antibody that SAP-deficient T-B collaboration fails to produce; it does not repair the germinal-center defect.
Show evidence (1 reference)
PMID:20301580 SUPPORT Human Clinical
"Standard treatment for liver dysfunction/failure, hypogammaglobulinemia (IVIG or IgG), fulminant EBV infection / HLH (including etoposide and steroids and consideration of rituximab), lymphoma, colitis, aplastic anemia, and vasculitis."
Names IVIG/IgG as the standard treatment for the hypogammaglobulinemia arm of XLP.
Show evidence (1 reference)
PMID:20926771 SUPPORT Human Clinical
"Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%)."
Documents immunoglobulin replacement as the mainstay for untransplanted XLP1 patients, and its limits once HLH has occurred.
HLH-Directed Etoposide-Based Therapy
Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632
Agent: etoposide CHEBI:4911 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses etoposide (CHEBI:4911). CHEBI:4911 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Etoposide plus corticosteroids (the HLH-94/HLH-2004 backbone) suppresses the activated lymphocyte and macrophage compartment driving the hyperinflammatory state. In XLP1 this is a bridge, not a cure: it controls the acute episode so that curative HSCT can be performed. The detailed HLH protocol is modeled in the Hemophagocytic_Lymphohistiocytosis entry.
Mechanism Target:
INHIBITS Unterminated Hyperinflammatory Response to Primary EBV Infection — Etoposide-based cytoreduction deletes the activated lymphocytes and macrophages sustaining the cytokine state, interrupting the hyperinflammatory arm without correcting the SAP defect.
Show evidence (1 reference)
PMID:20301580 SUPPORT Human Clinical
"Standard treatment for liver dysfunction/failure, hypogammaglobulinemia (IVIG or IgG), fulminant EBV infection / HLH (including etoposide and steroids and consideration of rituximab), lymphoma, colitis, aplastic anemia, and vasculitis."
Names etoposide and steroids as the standard treatment for the fulminant EBV infection / HLH manifestation this node represents.
Show evidence (1 reference)
PMID:20926771 SUPPORT Human Clinical
"The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1."
Attributes the modern mortality reduction to improved HLH-directed treatment, while noting it does not eliminate HLH as the dominant risk.
🌍

Environmental Factors

1
Primary Epstein-Barr Virus Infection
exposure to Epstein-Barr virus ECTO:3000001 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to Epstein-Barr virus, annotated with exposure to virus (ECTO:3000001). ECTO:3000001 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Primary EBV infection is the disease-defining environmental trigger of XLP1. The genetic lesion is present from birth, but the fulminant infectious mononucleosis/HLH phenotype is precipitated by the first encounter with the virus, which was the trigger in 92% of XLP-1 HLH episodes in the Pachlopnik Schmid cohort. GeneReviews accordingly lists EBV contact as an agent/circumstance to avoid. Note that EBV is not required for every manifestation — dysgammaglobulinemia may precede or occur without documented EBV infection — so this is modeled as a trigger of the acute arm rather than of the disease as a whole.
Show evidence (2 references)
PMID:9771704 SUPPORT Human Clinical
"X-linked lymphoproliferative syndrome (XLP or Duncan disease) is characterized by extreme sensitivity to Epstein-Barr virus (EBV), resulting in a complex phenotype manifested by severe or fatal infectious mononucleosis, acquired hypogammaglobulinemia and malignant lymphoma."
Establishes EBV sensitivity as the defining environmental dimension of the disease.
PMID:48119 SUPPORT Human Clinical
"This study suggests that the Epstein-Barr virus or other viruses triggered the fatal proliferation of lymphocytes"
The original hypothesis that a viral exposure triggers the fatal lymphoproliferation, later confirmed as EBV.
Mechanism Target:
TRIGGERS Unterminated Hyperinflammatory Response to Primary EBV Infection — Primary EBV infection supplies the SLAM-ligand-bearing B-cell target population that SAP-deficient NK and CD8+ T cells cannot clear, and is the documented precipitant of the great majority of XLP1 HLH episodes.
Show evidence (2 references)
PMID:21119115 SUPPORT Human Clinical
"Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of HLH (XLP-1, 92%; XLP-2, 83%)."
Quantifies EBV infection as the precipitant of 92% of HLH episodes in XLP-1, supporting a TRIGGERS edge onto the HLH node.
PMID:20301580 SUPPORT Human Clinical
"Individuals with XLP who come into contact with EBV are at risk of developing HLH and/or lymphoproliferation."
States the exposure-outcome relationship directly, as an agent/circumstance to avoid.
📊

Prevalence

1
Worldwide (males)
Unknown 0.1 per 100,000 1–9 per 1,000,000
Approximately one affected male per million. Two caveats: the source figure is for X-linked lymphoproliferative syndrome as a whole (XLP1 plus XLP2), not XLP1 alone, and the source does not state whether the estimate is a point prevalence or a birth incidence, so measure_type is UNKNOWN. The same source notes the condition is probably underdiagnosed. An Orphanet-backed record keyed on ORPHA:538931 would give a second, independently derived estimate and split XLP1 from XLP2, and is worth adding.
Show evidence (1 reference)
PMID:31754776 SUPPORT Human Clinical
"XLP is estimated to affect approximately one per million males"
Source for the approximately one-per-million-males estimate underlying the 1-9 per 1,000,000 band.
{ }

Source YAML

click to show 
name: X-linked Lymphoproliferative Disease Due To SH2D1A Deficiency
creation_date: '2026-09-01T00:00:00Z'
category: Genetic
synonyms:
- XLP1
- XLP type 1
- Duncan disease
- Purtilo syndrome
- SAP deficiency
- X-linked lymphoproliferative syndrome type 1
description: >-
  X-linked lymphoproliferative disease type 1 (XLP1, Duncan disease) is a rare
  inborn error of immunity caused by hemizygous loss-of-function variants in
  SH2D1A, which encodes SAP (SLAM-associated protein). SAP is a small adaptor
  built almost entirely from a single SH2 domain that couples the cytoplasmic
  tails of SLAM-family receptors — SLAM (CD150), 2B4 (CD244), NTB-A (SLAMF6),
  CD84 and Ly9 — to activating kinases. Without SAP these receptors do not
  simply fall silent: they recruit SH2-domain-containing phosphatases instead
  and switch from activating to inhibitory signaling. The consequence is
  paradoxical, and it is specific to the B-lymphocyte compartment that
  Epstein-Barr virus (EBV) inhabits, because SLAM-family ligands such as CD48
  are densely expressed on EBV-infected B cells. NK cells and EBV-specific CD8+
  cytotoxic T cells engage those targets and are inhibited by the encounter,
  so the virus-driven B-cell expansion is never contained. SAP loss also
  abolishes invariant NKT (type I NKT) cell development and cripples cognate
  T-B help and germinal-center formation.

  The classical triad is fulminant infectious mononucleosis/hemophagocytic
  lymphohistiocytosis (HLH) on primary EBV exposure, dysgammaglobulinemia, and
  B-cell lymphoma (historically often ileocecal). Rarer manifestations include
  hepatitis progressing to liver failure, aplastic anemia, vasculitis, and
  lymphomatoid granulomatosis. Allogeneic hematopoietic stem cell transplant is
  the only curative therapy, and outcome depends sharply on whether it is done
  before or after an HLH episode.
notes: >-
  Scope note: this entry is the dedicated XLP1 (SH2D1A/SAP) disease entry. The
  Hemophagocytic_Lymphohistiocytosis entry covers HLH as a syndrome and carries
  XLP1 and XLP2 as HLH-predisposing subtypes; it is the place to look for the
  general HLH pathophysiology, diagnostic criteria and HLH-94/HLH-2004
  treatment protocols. This entry covers the SAP-specific mechanism and the
  non-HLH arms of XLP1 (dysgammaglobulinemia, lymphoma, absent iNKT cells) that
  the HLH entry does not model. XLP2 (XIAP/BIRC4 deficiency, MONDO:0010385) is a
  separate disease and is not covered here.
disease_term:
  preferred_term: X-linked lymphoproliferative disease type 1 (SAP deficiency)
  term:
    id: MONDO:0024551
    label: X-linked lymphoproliferative disease due to SH2D1A deficiency
parents:
- X-linked lymphoproliferative syndrome
- Primary immunodeficiency
- Inborn error of immunity
references:
- reference: PMID:20301580
  title: X-Linked Lymphoproliferative Disease.
  tags:
  - GeneReviews
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      XLP1 is an inborn error of immunity (primary immunodeficiency) presenting
      as severe immune dysregulation, placing it in the immunology grouping.
    evidence:
    - reference: PMID:20926771
      reference_title: "X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency
        characterized by severe immune dysregulation and caused by mutations in
        the SH2D1A/SAP gene.
      explanation: >-
        Characterizes XLP1 as an immunodeficiency with severe immune
        dysregulation, supporting placement in the immunologic Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      XLP1 is a monogenic X-linked disorder whose clinical expression is gated
      by an environmental exposure (primary EBV infection), so it also belongs
      in the genetics/gene-environment Part.
    evidence:
    - reference: PMID:20301580
      reference_title: X-Linked Lymphoproliferative Disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The diagnosis of XLP1 or XLP2 can be established in a male proband who
        has a hemizygous germline pathogenic variant in SH2D1A (XLP1) or XIAP
        (XLP2) identified on molecular genetic testing.
      explanation: >-
        Establishes XLP1 as a single-gene germline disorder diagnosed by
        molecular genetic testing.
  iuis_category:
    classification_value: immune dysregulation
    notes: >-
      IUIS 2022 (Tangye et al.) places SAP deficiency (XLP1) in Table 4,
      Diseases of immune dysregulation, subsection 7 "Susceptibility to EBV and
      Lymphoproliferative Conditions".
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SAP deficiency (XLP1) SH2D1A XL 300490"
      explanation: >-
        The IUIS Table 4 (Diseases of immune dysregulation) row for SAP
        deficiency (XLP1), giving the gene SH2D1A, X-linked inheritance and OMIM
        300490.
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "7. Susceptibility to EBV and Lymphoproliferative Conditions"
      explanation: >-
        Names the Table 4 subsection under which the SAP deficiency row is
        listed, fixing the IUIS placement within immune dysregulation.
inheritance:
- name: X-linked recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    XLP1 is inherited in an X-linked manner. Affected males carry a hemizygous
    germline SH2D1A pathogenic variant; heterozygous female carriers are
    typically unaffected, though symptomatic carriers with skewed X-chromosome
    inactivation have been reported.
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "XLP is inherited in an X-linked manner."
    explanation: States the inheritance mode directly.
  - reference: PMID:48119
    reference_title: "X-linked recessive progressive combined variable immunodeficiency (Duncan's disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately half the boys, including the half-brothers, were affected,
      and girls were spared, implying sex-linked recessive inheritance.
    explanation: >-
      The original Duncan kindred segregation analysis that established X-linked
      recessive inheritance for the disorder.
pathophysiology:
- name: SAP Adaptor Deficiency
  biological_scale: MOLECULAR
  description: >-
    Hemizygous SH2D1A deletions, frameshifts, nonsense and missense variants
    abolish or destabilize SAP, a 128-amino-acid protein consisting almost
    entirely of a single SH2 domain. Affected males typically have absent or
    markedly reduced intracellular SAP protein by flow cytometry. This is the
    initiating molecular lesion of XLP1.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    genes:
    - preferred_term: SH2D1A
      term:
        id: hgnc:10820
        label: SH2D1A
    description: >-
      Hemizygous germline SH2D1A variants in males, including large constitutional
      deletions, small intragenic deletions, nonsense and missense alleles.
      Missense alleles such as R55L may retain detectable protein while remaining
      functionally deficient.
  molecular_functions:
  - preferred_term: SAP signaling adaptor activity
    term:
      id: GO:0035591
      label: signaling adaptor activity
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:9771704
    reference_title: Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified a gene, SH2D1A, that is mutated in XLP patients and
      encodes a novel protein composed of a single SH2 domain.
    explanation: >-
      Identifies SH2D1A as the mutated gene in XLP and its product as a
      single-SH2-domain protein.
  - reference: PMID:9811875
    reference_title: Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe here the presence of small deletions and intragenic mutations
      that specifically disrupt a gene named DSHP in 6 of 10 unrelated patients
      with XLP.
    explanation: >-
      Independent identification of inactivating deletions and intragenic
      mutations in the same gene (named DSHP in this report) in XLP patients.
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These males typically have low or absent SAP or XIAP protein expression,
      respectively, by flow cytometry.
    explanation: >-
      Confirms that the genetic lesion translates into absent or reduced SAP
      protein in affected males.
  downstream:
  - target: SLAM-Family Receptor Signaling Failure
    description: >-
      Loss of the SAP adaptor removes the obligate coupling between SLAM-family
      receptor cytoplasmic tails and downstream activating signaling.
    causal_link_type: DIRECT
- name: SLAM-Family Receptor Signaling Failure
  biological_scale: MOLECULAR
  description: >-
    SAP binds immunoreceptor tyrosine-based switch motifs in the cytoplasmic
    tails of SLAM (CD150), 2B4 (CD244), NTB-A (SLAMF6), CD84 and Ly9, and
    normally recruits the kinase FynT while blocking docking of SH2-containing
    phosphatases. Without SAP, SHP-1/SHP-2 occupy those docking sites, so the
    receptors deliver inhibitory rather than activating signals. This inversion —
    rather than a simple absence of signal — is the defining molecular feature
    of XLP1 and explains why the immune failure is targeted at SLAM-ligand-bearing
    B lymphocytes.
  molecular_functions:
  - preferred_term: SAP SH2-domain binding to SLAM-family receptor tails
    term:
      id: GO:0042169
      label: SH2 domain binding
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:9774102
    reference_title: The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      acts as an inhibitor by blocking recruitment of the SH2-domain-containing
      signal-transduction molecule SHP-2 to a docking site in the SLAM
      cytoplasmic region
    explanation: >-
      Defines SAP's molecular role as competitively excluding SHP-2 from the
      SLAM cytoplasmic tail, the step lost in XLP1.
  - reference: PMID:9774102
    reference_title: The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      Absence of the inhibitor SAP in XLP patients affects T/B-cell interactions
      induced by SLAM, leading to an inability to control B-cell proliferation
      caused by Epstein-Barr virus infections.
    explanation: >-
      Connects loss of SAP-dependent SLAM signaling to failure of control over
      EBV-driven B-cell proliferation. Graded IN_VITRO with INDIRECT
      directness because this is the authors' closing interpretation of their
      COS-cell and Jurkat transfection experiments, not a clinical observation
      reported in the paper; it matches the grading of the other quote from
      this same publication above.
  - reference: PMID:21219180
    reference_title: SLAM family receptors and SAP adaptors in immunity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SAP consists almost entirely of a single SH2 protein domain that interacts
      with the cytoplasmic tail of SLAM and related receptors, including 2B4,
      Ly108, CD84, Ly9, and potentially CRACC.
    explanation: >-
      Enumerates the SLAM-family receptors whose signaling depends on SAP,
      defining the breadth of the lesion. Review article, hence OTHER.
  downstream:
  - target: 2B4/NTB-A Inhibitory Switch on NK Cells
    description: >-
      On NK cells, uncoupled 2B4 and NTB-A engage their ligands on EBV-infected
      B cells and transmit inhibitory signals.
    causal_link_type: DIRECT
  - target: Defective EBV-Specific CD8+ T Cell Cytotoxicity
    description: >-
      On EBV-specific cytotoxic T cells, the same SLAM-family receptors block
      recognition of SLAM-ligand-positive B-cell targets.
    causal_link_type: DIRECT
  - target: Absent Invariant NKT Cell Development
    description: >-
      SAP-dependent SLAM-family homotypic signaling during thymic selection is
      required for iNKT lineage commitment.
    causal_link_type: DIRECT
  - target: Defective T-B Cell Help and Germinal Center Formation
    description: >-
      SAP-dependent SLAM-family signaling sustains stable cognate T-B conjugates
      and follicular helper T-cell function.
    causal_link_type: DIRECT
- name: 2B4/NTB-A Inhibitory Switch on NK Cells
  biological_scale: CELLULAR
  description: >-
    In XLP1 NK cells, 2B4 (CD244) not only fails to transduce a triggering
    signal but actively inhibits cytolysis, and the same inversion affects
    NTB-A. Because CD48 — the 2B4 ligand — is densely expressed on EBV-infected
    B cells, XLP1 NK cells engaging an EBV-positive target receive a dominant
    inhibitory signal and fail to kill it. Antibody-mediated masking of 2B4 and
    NTB-A restores lysis, demonstrating that inhibition rather than absent
    activation is the operative defect. Other NK triggering receptors (CD16,
    NKp46, NKp44, NKp30) are intrinsically normal but are overridden by 2B4
    engagement.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: NK-cell killing of EBV-infected B cells
    term:
      id: GO:0042267
      label: natural killer cell mediated cytotoxicity
    modifier: DECREASED
  evidence:
  - reference: PMID:10934222
    reference_title: X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that, in these patients, 2B4 not only fails to transduce
      triggering signals, but also mediates a sharp inhibition of the NK-mediated
      cytolysis.
    explanation: >-
      Direct demonstration that 2B4 signaling is inverted, not merely lost, in
      XLP1 NK cells.
  - reference: PMID:10934222
    reference_title: X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Remarkably, NK cells from XLP patients could not kill EBV(+) B cell lines."
    explanation: >-
      Establishes the functional consequence: failure of XLP1 NK cells to kill
      EBV-infected B cells.
  - reference: PMID:11489943
    reference_title: "NTB-A [correction of GNTB-A], a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Thus, in XLP-NK cells, NTB-A mediates inhibitory rather than activating signals."
    explanation: >-
      Shows the inhibitory switch is not confined to 2B4 but extends to a second
      SAP-dependent SLAM-family receptor.
  - reference: PMID:24985396
    reference_title: Diagnosing XLP1 in patients with hemophagocytic lymphohistiocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NK cells from all patients showed inhibitory 2B4 function and defective
      killing of B-EBV cells.
    explanation: >-
      Confirms the inhibitory 2B4 phenotype in every patient of a genetically
      confirmed XLP1 cohort, establishing it as a consistent disease feature.
  downstream:
  - target: Uncontrolled EBV-Driven B Cell Proliferation
    description: >-
      Failure of NK-mediated killing leaves the EBV-infected B-cell pool
      unchecked during primary infection.
    causal_link_type: DIRECT
  - target: Decreased Natural Killer Cell-Induced Killing of Target Cells
    causal_link_type: DIRECT
    description: >-
      The inhibitory switch is measured directly as impaired NK killing of
      EBV-infected B-cell targets — the laboratory readout of this node.
- name: Defective EBV-Specific CD8+ T Cell Cytotoxicity
  biological_scale: CELLULAR
  description: >-
    XLP1 patients who survive primary EBV infection mount numerically normal
    EBV-specific CD8+ T-cell responses, but those T cells are selectively unable
    to recognize SLAM-ligand-positive targets. CD8+ clones kill EBV-antigen-expressing
    targets that lack SLAM ligands, yet fail against EBV-transformed lymphoblastoid
    cell lines; blocking CD244 and NTB-A restores recognition. This selectivity
    is the best available explanation for why XLP1 confers susceptibility to EBV
    specifically rather than to viruses in general — EBV's tropism is for the
    very B lymphocytes that carry the inhibitory ligands.
  cell_types:
  - preferred_term: EBV-specific CD8+ cytotoxic T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: CD8+ T-cell killing of EBV-transformed B cells
    term:
      id: GO:0001913
      label: T cell mediated cytotoxicity
    modifier: DECREASED
  evidence:
  - reference: PMID:20644117
    reference_title: Impaired Epstein-Barr virus-specific CD8+ T-cell function in X-linked lymphoproliferative disease is restricted to SLAM family-positive B-cell targets.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, further investigation of in vitro-derived CD8(+) T-cell clones
      established from 2 of these donors showed they efficiently recognized SLAM
      ligand-negative target cells expressing EBV antigens, but showed impaired
      recognition of EBV-transformed, SLAM ligand-positive, lymphoblastoid cell
      lines (LCLs).
    explanation: >-
      Demonstrates that the CD8+ T-cell defect in XLP1 is target-restricted to
      SLAM-ligand-positive B cells.
  - reference: PMID:20644117
    reference_title: Impaired Epstein-Barr virus-specific CD8+ T-cell function in X-linked lymphoproliferative disease is restricted to SLAM family-positive B-cell targets.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Importantly, LCL recognition was restored when interactions between the
      SLAM receptors CD244 and natural killer-, T-, and B-cell antigen (NTBA) and
      their ligands on LCLs were blocked.
    explanation: >-
      Rescue by receptor blockade identifies inhibitory SLAM-family signaling as
      the operative cause of the CD8+ recognition failure.
  downstream:
  - target: Uncontrolled EBV-Driven B Cell Proliferation
    description: >-
      Loss of cytotoxic T-cell control over EBV-transformed B cells permits their
      continued expansion.
    causal_link_type: DIRECT
- name: Absent Invariant NKT Cell Development
  biological_scale: CELLULAR
  description: >-
    SAP is required for the development of invariant (type I) NKT cells. Sh2d1a-null
    mice lack NKT cells in thymus and periphery through a hematopoietic-cell-autonomous
    defect that is rescued by restoring SAP expression in bone marrow, and seventeen
    genetically confirmed XLP1 patients likewise lacked NKT cells. Absent iNKT cells
    are a robust, near-universal cellular biomarker of SAP deficiency and are thought
    to contribute to defective antiviral and antitumor immunity and to
    hypogammaglobulinemia.
  cell_types:
  - preferred_term: invariant (type I) NKT cell
    term:
      id: CL:0000921
      label: type I NK T cell
  biological_processes:
  - preferred_term: invariant NKT cell development
    term:
      id: GO:0001865
      label: NK T cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:15711562
    reference_title: "Regulation of NKT cell development by SAP, the protein defective in XLP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventeen individuals with X-linked lymphoproliferative disease (XLP), who
      harbored germline mutations in SH2D1A, also lacked NKT cells.
    explanation: >-
      Establishes absent NKT cells in genetically confirmed human XLP1 patients.
  - reference: PMID:15711562
    reference_title: "Regulation of NKT cell development by SAP, the protein defective in XLP."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The defect in NKT cell ontogeny was hematopoietic cell autonomous and could
      be rescued by reconstitution of SAP expression within Sh2d1a-/- bone marrow
      cells.
    explanation: >-
      Mouse genetics establishes that the NKT developmental block is caused by
      SAP loss within the hematopoietic compartment and is SAP-reversible.
  downstream:
  - target: Impaired Immune Surveillance and B Cell Lymphomagenesis
    description: >-
      Loss of the iNKT compartment removes an antitumor effector arm, contributing
      to defective surveillance of transformed B cells.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Failed Class Switching and Antibody Production
    description: >-
      Absent iNKT cells are proposed to contribute to the humoral defect of SAP
      deficiency alongside the primary T-B help failure.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Uncontrolled EBV-Driven B Cell Proliferation
  biological_scale: CELLULAR
  description: >-
    With both NK- and CD8-mediated control of SLAM-ligand-positive targets lost,
    primary EBV infection produces an uncontained expansion of virus-carrying B
    cells accompanied by a massive reactive cytotoxic T-cell response. This is
    the pivotal cellular event of XLP1 and the branch point from which both the
    acute hyperinflammatory arm and the chronic lymphomagenesis arm descend.
  cell_types:
  - preferred_term: EBV-infected B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: EBV-driven B cell proliferation
    term:
      id: GO:0030890
      label: positive regulation of B cell proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:9811875
    reference_title: Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In affected males, primary EBV infection leads to the uncontrolled
      proliferation of virus-containing B cells and reactive cytotoxic T cells,
      often culminating in the development of high-grade lymphoma.
    explanation: >-
      States the central pathophysiologic event and its two downstream
      consequences.
  - reference: PMID:9811875
    reference_title: Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      its inactivation in XLP patients results in a selective immunodeficiency to
      EBV
    explanation: >-
      Emphasizes the EBV-selectivity of the immunodeficiency produced by loss of
      this gene.
  downstream:
  - target: Unterminated Hyperinflammatory Response to Primary EBV Infection
    description: >-
      Persistent antigen load from uncleared EBV-infected B cells drives
      unterminated lymphocyte and macrophage activation.
    causal_link_type: DIRECT
  - target: Impaired Immune Surveillance and B Cell Lymphomagenesis
    description: >-
      Sustained polyclonal B-cell proliferation provides the substrate on which
      monoclonal malignant transformation occurs.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Unterminated Hyperinflammatory Response to Primary EBV Infection
  biological_scale: ORGANISM
  description: >-
    The acute arm of XLP1. Because the activating stimulus is never cleared,
    lymphocyte and macrophage activation continues without a termination signal,
    producing a hyperinflammatory cytokine state clinically indistinguishable
    from HLH: prolonged high fever, bi- or trilineage cytopenias,
    hepatosplenomegaly and hemophagocytosis, with death typically from liver
    failure or multiorgan dysfunction. This is the most severe feature of XLP1
    and the principal determinant of outcome. The general HLH pathophysiology is
    modeled in the Hemophagocytic_Lymphohistiocytosis entry.
  cell_types:
  - preferred_term: lymphocyte
    term:
      id: CL:0000542
      label: lymphocyte
  biological_processes:
  - preferred_term: hyperinflammatory cytokine production
    term:
      id: GO:0002367
      label: cytokine production involved in immune response
    modifier: INCREASED
  - preferred_term: systemic inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HLH is characterized as an acute illness with prolonged and high fever,
      bi- or trilineage cytopenias, and hepatosplenomegaly, which is often severe
      or fatal.
    explanation: Describes the clinical syndrome produced at this node.
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Death is generally secondary to liver failure or multisystem organ
      dysfunction.
    explanation: >-
      Identifies the organ-level mechanism of death in the acute arm.
  - reference: PMID:3030174
    reference_title: Epstein-Barr virus infections in males with the X-linked lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We hypothesized that the defective lymphoproliferative control locus on the
      X chromosome results in unregulated cytotoxic lymphocytic responses to the
      Epstein-Barr virus; hence, severe hepatitis and virus-associated
      hemophagocytic syndrome occur with the infectious mononucleosis phenotype.
    explanation: >-
      The registry-era formulation of this node: unregulated cytotoxic
      lymphocytic response producing hepatitis and hemophagocytic syndrome.
  - reference: PMID:20926771
    reference_title: "X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The advent of better treatment strategies for HLH and malignancy has
      greatly reduced mortality for these patients, but HLH still remains the
      most severe feature of XLP1.
    explanation: >-
      Establishes HLH as the dominant severity determinant in a modern
      91-patient XLP1 cohort.
  downstream:
  - target: Fulminant Infectious Mononucleosis with Hemophagocytic Lymphohistiocytosis
    causal_link_type: DIRECT
    description: >-
      The unterminated hyperinflammatory state is what presents clinically as
      fulminant infectious mononucleosis and/or HLH.
  - target: Hemophagocytosis
    causal_link_type: DIRECT
    description: >-
      Activated macrophages engulf haematopoietic cells, the marrow finding that
      gives the syndrome its name.
  - target: Prolonged high fever
    causal_link_type: DIRECT
    description: >-
      Sustained hypercytokinaemia from the unterminated response drives the
      prolonged high fever that opens the HLH episode.
  - target: Bi- or trilineage cytopenias
    causal_link_type: DIRECT
    description: >-
      Marrow suppression by the same cytokine excess, compounded by
      hemophagocytosis of haematopoietic precursors, depresses two or three
      peripheral lineages during the episode.
  - target: Hepatitis
    causal_link_type: DIRECT
    description: >-
      Lymphocytic infiltration of the liver during the hyperinflammatory
      response produces hepatitis.
  - target: Hepatosplenomegaly
    causal_link_type: DIRECT
    description: >-
      Organ infiltration by activated lymphocytes and macrophages enlarges liver
      and spleen.
  - target: Lymphadenopathy
    causal_link_type: DIRECT
    description: >-
      The same uncontrolled lymphoproliferation enlarges lymph nodes.
  - target: Aplastic Anemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Marrow failure is a recognized outcome of the acute arm; whether it
      reflects haemophagocytic consumption, cytokine suppression of
      haematopoiesis, or a distinct process is not resolved in these cohorts.
  - target: Vasculitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Vasculitis is reported among the XLP1 manifestations; the path from the
      hyperinflammatory state to vessel injury is not established.
- name: Defective T-B Cell Help and Germinal Center Formation
  biological_scale: CELLULAR
  description: >-
    SAP-dependent SLAM-family signaling sustains stable cognate interactions
    between follicular helper T cells and antigen-engaged B cells, and is
    required for germinal-center development. XLP1 patients have normal B-cell
    development but markedly reduced memory B cells, and the few present are
    IgM-positive, indicating failed in vivo isotype switching. The block is
    B-cell extrinsic: XLP1 B cells proliferate and differentiate normally in
    vitro, while XLP1 CD4+ T cells fail to differentiate into IL-10-producing
    effectors, fail to upregulate ICOS, and provide poor B-cell help — a defect
    partially corrected by exogenous IL-10 or restored SAP expression.
  cell_types:
  - preferred_term: T follicular helper cell
    term:
      id: CL:0002038
      label: T follicular helper cell
  - preferred_term: memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  biological_processes:
  - preferred_term: germinal center formation
    term:
      id: GO:0002467
      label: germinal center formation
    modifier: DECREASED
  evidence:
  - reference: PMID:15761493
    reference_title: Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our analysis of 14 XLP patients revealed normal B cell development but a
      marked reduction in the number of memory B cells.
    explanation: >-
      Localizes the humoral lesion downstream of B-cell development, at memory
      B-cell generation.
  - reference: PMID:15761493
    reference_title: Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The few memory cells detected were IgM(+), revealing deficient isotype
      switching in vivo.
    explanation: >-
      Demonstrates failed in vivo class switching, the hallmark of a defective
      germinal-center reaction.
  - reference: PMID:15761493
    reference_title: Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      XLP CD4(+) T cells did not efficiently differentiate into IL-10(+) effector
      cells or provide optimal B cell help in vitro
    explanation: >-
      Identifies the T-cell-intrinsic help defect that makes the B-cell block
      extrinsic.
  - reference: PMID:22500829
    reference_title: "From SAP-less T cells to helpless B cells and back: dynamic T-B cell interactions underlie germinal center development and function."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP)
      has recently been defined as a pivotal molecule that controls cognate T-B
      interactions and GC formation.
    explanation: >-
      Review establishing SAP as the controller of cognate T-B interaction and
      germinal-center formation. Review article, hence OTHER.
  downstream:
  - target: Failed Class Switching and Antibody Production
    description: >-
      Failure of germinal-center output and class switching produces the
      abnormal serum immunoglobulin profile.
    causal_link_type: DIRECT
- name: Failed Class Switching and Antibody Production
  biological_scale: ORGANISM
  description: >-
    The humoral endpoint of XLP1. Serum immunoglobulins are abnormal, most often
    as hypogammaglobulinemia but historically spanning agammaglobulinemia to
    polyclonal hypergammaglobulinemia — hence "dysgammaglobulinemia" rather than
    a purely quantitative deficit. Untreated, it causes recurrent respiratory
    infection and bronchiectasis and can itself be fatal. It may be the presenting
    feature in a boy with no EBV history, and can be indistinguishable from common
    variable immunodeficiency.
  biological_processes:
  - preferred_term: immunoglobulin class switch recombination
    term:
      id: GO:0045190
      label: isotype switching
    modifier: DECREASED
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In those with XLP1, dys- or hypogammaglobulinemia can lead to varying
      degrees of humoral immune dysfunction associated with bronchiectasis and
      recurrent respiratory infections that, if untreated, may result in death.
    explanation: >-
      Establishes dysgammaglobulinemia and its clinical consequences as an XLP1
      manifestation.
  - reference: PMID:48119
    reference_title: "X-linked recessive progressive combined variable immunodeficiency (Duncan's disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fever, pharyngitis, lymphadenomegaly, hepatosplenomegaly, atypical
      lymphocytosis, and a spectrum ranging from agammaglobulinaemia to
      polyclonal hyper-gammaglobulinaemia occurred.
    explanation: >-
      The original description of the bidirectional immunoglobulin abnormality
      that the term dysgammaglobulinemia captures.
  downstream:
  - target: Dysgammaglobulinemia
    causal_link_type: DIRECT
    description: >-
      The failure of class switching and antibody output is measured as the
      abnormal serum immunoglobulin profile.
  - target: Decreased Circulating Immunoglobulin Concentration
    causal_link_type: DIRECT
    description: >-
      Hypogammaglobulinemia is the commonest direction the abnormality takes.
  - target: Recurrent Respiratory Infections and Bronchiectasis
    causal_link_type: DIRECT
    description: >-
      Untreated antibody deficiency produces recurrent sinopulmonary infection
      and, over time, bronchiectasis.
- name: Impaired Immune Surveillance and B Cell Lymphomagenesis
  biological_scale: TISSUE
  description: >-
    The chronic arm of XLP1. Sustained polyclonal B-cell proliferation, combined
    with loss of NK-, CD8- and iNKT-mediated surveillance of transformed cells,
    provides both the substrate and the permissive environment for conversion to
    monoclonal B-cell malignancy. Lymphoma is essentially confined to XLP1 among
    the X-linked lymphoproliferative syndromes and typically arises in childhood,
    usually after EBV exposure; extranodal ileocecal/ileal B-cell lymphoma is the
    classically described site, and the original Duncan kindred included
    lymphomas of the ileum.
  cell_types:
  - preferred_term: transformed B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: immune surveillance of transformed B cells
    term:
      id: GO:0002418
      label: immune response to tumor cell
    modifier: DECREASED
  evidence:
  - reference: PMID:3030174
    reference_title: Epstein-Barr virus infections in males with the X-linked lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A sustained polyclonal B-cell proliferation probably converts to a
      monoclonal B-cell malignancy as a result of molecular alterations.
    explanation: >-
      States the polyclonal-to-monoclonal transition that this node models.
  - reference: PMID:21119115
    reference_title: Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients
      (17%) had chronic hemorrhagic colitis as documented by histopathology.
    explanation: >-
      Direct comparison establishing that lymphomagenesis is specific to the
      SAP-deficient (XLP1) form, which supports it being a SAP-dependent
      surveillance failure rather than a generic XLP feature.
  - reference: PMID:48119
    reference_title: "X-linked recessive progressive combined variable immunodeficiency (Duncan's disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, 2 half-brothers had lymphomas of the ileum and central nervous
      system.
    explanation: >-
      The original kindred documenting the characteristic extranodal ileal site
      of XLP lymphoma.
  downstream:
  - target: B-Cell Lymphoma
    causal_link_type: DIRECT
    description: >-
      Failed surveillance of proliferating B cells permits frank lymphoma,
      characteristically extranodal and often ileocecal.
phenotypes:
- category: Immunologic
  name: Fulminant Infectious Mononucleosis with Hemophagocytic Lymphohistiocytosis
  description: >-
    The defining acute presentation: an overwhelming response to primary EBV
    infection producing severe or fatal mononucleosis and/or HLH with prolonged
    high fever, cytopenias, hepatosplenomegaly and hemophagocytosis. It is the
    most common presentation of XLP and the leading cause of death. In the
    modern Pachlopnik Schmid cohort HLH occurred in 55% of XLP-1 patients and
    was EBV-triggered in 92%; in the historical Purtilo registry 57% of affected
    males died of infectious mononucleosis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Severe Epstein-Barr virus infection
    term:
      id: HP:0031693
      label: Severe Epstein Barr virus infection
    temporality: ACUTE
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HLH / fulminant infectious mononucleosis is the most common presentation
      regardless of subtype.
    explanation: >-
      Establishes fulminant infectious mononucleosis / HLH as the most common
      presentation.
  - reference: PMID:21119115
    reference_title: Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2,
      33%) occurred in both groups.
    explanation: >-
      Quantifies HLH frequency at 55% in a 33-patient XLP-1 cohort, supporting
      the FREQUENT band.
  - reference: PMID:21119115
    reference_title: Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of
      HLH (XLP-1, 92%; XLP-2, 83%).
    explanation: >-
      Quantifies EBV as the trigger in 92% of XLP-1 HLH episodes.
  - reference: PMID:21119115
    reference_title: Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Survival rates and mean ages at the first HLH episode did not differ for
      both groups, but HLH was more severe with lethal outcome in XLP-1 (XLP-1,
      61%; XLP-2, 23%).
    explanation: >-
      Documents the high lethality of HLH specifically in the SAP-deficient form.
- category: Hematologic
  name: Hemophagocytosis
  description: >-
    Histologic hemophagocytosis in bone marrow, liver, spleen or lymph node is
    the pathologic correlate of the HLH episode in XLP1.
  phenotype_term:
    preferred_term: Hemophagocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
  evidence:
  - reference: PMID:3030174
    reference_title: Epstein-Barr virus infections in males with the X-linked lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hence, severe hepatitis and virus-associated hemophagocytic syndrome occur
      with the infectious mononucleosis phenotype
    explanation: >-
      Documents hemophagocytic syndrome as part of the XLP infectious
      mononucleosis phenotype.
- category: Clinical
  name: Prolonged high fever
  description: >-
    Prolonged, high fever is one of the three cardinal features of the HLH
    episode, alongside cytopenias and hepatosplenomegaly. It is curated as its
    own phenotype rather than left inside the HLH narrative because it is the
    presenting sign that brings these patients to attention, and because the
    sibling XLP2 entry binds it from the same GeneReviews sentence.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Prolonged high fever
    term:
      id: HP:0001945
      label: Fever
    temporality: PROLONGED
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HLH is characterized as an acute illness with prolonged and high fever,
      bi- or trilineage cytopenias, and hepatosplenomegaly, which is often
      severe or fatal.
    explanation: >-
      GeneReviews names prolonged high fever as a defining feature of the HLH
      episode, which the same source reports as the most common presentation of
      XLP regardless of subtype.
  - reference: PMID:21119115
    reference_title: Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2,
      33%) occurred in both groups.
    explanation: >-
      The FREQUENT band is inherited from the 55% HLH rate in XLP-1, since
      GeneReviews defines the episode as including this feature.
- category: Laboratory
  name: Bi- or trilineage cytopenias
  description: >-
    Anemia, thrombocytopenia and/or neutropenia accompanying the acute
    hyperinflammatory episode. Distinct from the separately curated Aplastic
    Anemia phenotype, which is a marrow-failure entity rather than the transient
    cytopenia of an HLH episode.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bi- or trilineage cytopenias
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HLH is characterized as an acute illness with prolonged and high fever,
      bi- or trilineage cytopenias, and hepatosplenomegaly, which is often
      severe or fatal.
    explanation: >-
      GeneReviews names bi- or trilineage cytopenias as a defining feature of
      the HLH episode.
  - reference: PMID:21119115
    reference_title: Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2,
      33%) occurred in both groups.
    explanation: >-
      The FREQUENT band is inherited from the 55% HLH rate in XLP-1, since
      GeneReviews defines the episode as including this feature.
- category: Immunologic
  name: Dysgammaglobulinemia
  description: >-
    Abnormal serum immunoglobulin concentrations, most commonly
    hypogammaglobulinemia. Reported in 67% of XLP-1 patients in the Pachlopnik
    Schmid cohort and in 29% of the historical Purtilo registry as acquired
    hypogammaglobulinemia. May be the presenting feature and mimics common
    variable immunodeficiency.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dysgammaglobulinemia
    term:
      id: HP:0010701
      label: Abnormal circulating immunoglobulin concentration
  evidence:
  - reference: PMID:21119115
    reference_title: Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2,
      33%) occurred in both groups.
    explanation: >-
      Quantifies hypogammaglobulinemia at 67% in XLP-1, supporting the FREQUENT
      band.
  - reference: PMID:20926771
    reference_title: "X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical manifestations are varied and include hemophagocytic
      lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often
      triggered by Epstein-Barr virus infection.
    explanation: >-
      Lists dysgammaglobulinemia among the core manifestations in the 91-patient
      XLP1 cohort.
- category: Immunologic
  name: Decreased Circulating Immunoglobulin Concentration
  description: >-
    Hypogammaglobulinemia specifically, the most common direction of the
    dysgammaglobulinemia, and the manifestation that drives immunoglobulin
    replacement therapy.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:3030174
    reference_title: Epstein-Barr virus infections in males with the X-linked lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fifty-seven percent of the males died of infectious mononucleosis, 29%
      developed acquired hypogammaglobulinemia, and 24% had malignant lymphoma.
    explanation: >-
      Registry data quantifying acquired hypogammaglobulinemia in 29% of affected
      males.
- category: Oncologic
  name: B-Cell Lymphoma
  description: >-
    Malignant lymphoma, characteristically B-lineage and often extranodal with a
    predilection for the ileocecal region. Occurred in 30% of XLP-1 patients in
    the Pachlopnik Schmid cohort and 24% of the Purtilo registry, and is specific
    to XLP1 among the XLP subtypes. Usually develops in childhood following EBV
    exposure.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: B-cell lymphoma
    term:
      id: HP:0012191
      label: B-cell lymphoma
  evidence:
  - reference: PMID:21119115
    reference_title: Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients
      (17%) had chronic hemorrhagic colitis as documented by histopathology.
    explanation: >-
      Quantifies lymphoma at 30% in XLP-1 and establishes its specificity to the
      SAP-deficient subtype.
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphoproliferative disease (malignant lymphoma) and other
      lymphoproliferative diseases are specific to XLP1 and often develop in
      childhood, usually following EBV exposure.
    explanation: >-
      Establishes XLP1-specificity, childhood onset and the EBV relationship of
      the lymphoma.
  - reference: PMID:48119
    reference_title: "X-linked recessive progressive combined variable immunodeficiency (Duncan's disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, 2 half-brothers had lymphomas of the ileum and central nervous
      system.
    explanation: >-
      Original documentation of the characteristic ileal (ileocecal) lymphoma
      site in the Duncan kindred.
- category: Hepatic
  name: Hepatitis
  description: >-
    Severe hepatitis accompanies the fulminant infectious mononucleosis
    phenotype and reflects lymphocytic infiltration and hemophagocytosis in the
    liver.
  phenotype_term:
    preferred_term: Hepatitis
    term:
      id: HP:0012115
      label: Hepatitis
    severity: SEVERE
  evidence:
  - reference: PMID:3030174
    reference_title: Epstein-Barr virus infections in males with the X-linked lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hence, severe hepatitis and virus-associated hemophagocytic syndrome occur
      with the infectious mononucleosis phenotype
    explanation: >-
      Documents severe hepatitis as a component of the XLP infectious
      mononucleosis phenotype.
  sequelae:
  - target: Hepatic Failure
    causal_link_type: DIRECT
    description: >-
      Progressive hepatic necrosis during fulminant disease culminates in liver
      failure, the usual proximate cause of death.
- category: Hepatic
  name: Hepatic Failure
  description: >-
    Liver failure is the usual proximate cause of death in fulminant XLP1
    disease, alongside multisystem organ dysfunction.
  phenotype_term:
    preferred_term: Hepatic failure
    term:
      id: HP:0001399
      label: Hepatic failure
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Death is generally secondary to liver failure or multisystem organ
      dysfunction.
    explanation: >-
      Identifies liver failure as the leading terminal event.
- category: Hematologic
  name: Aplastic Anemia
  description: >-
    A rarer manifestation of XLP1, reflecting marrow failure in the setting of
    severe immune dysregulation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Aplastic anemia
    term:
      id: HP:0001915
      label: Aplastic anemia
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rarer findings in those with XLP1 can include aplastic anemia, vasculitis,
      and lymphoid granulomatosis.
    explanation: >-
      GeneReviews lists aplastic anemia among the rarer XLP1 findings; the
      "rarer" wording maps to the OCCASIONAL band.
- category: Vascular
  name: Vasculitis
  description: >-
    Vasculitis, including lymphomatoid granulomatosis, is an uncommon
    manifestation of XLP1 reflecting the underlying lymphoproliferative and
    immune-dysregulatory process.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Vasculitis
    term:
      id: HP:0002633
      label: Vasculitis
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rarer findings in those with XLP1 can include aplastic anemia, vasculitis,
      and lymphoid granulomatosis.
    explanation: >-
      GeneReviews lists vasculitis among the rarer XLP1 findings.
- category: Respiratory
  name: Recurrent Respiratory Infections and Bronchiectasis
  description: >-
    Untreated dysgammaglobulinemia produces recurrent respiratory infection and
    bronchiectasis, which can itself be fatal. This is the manifestation that
    immunoglobulin replacement is intended to prevent.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In those with XLP1, dys- or hypogammaglobulinemia can lead to varying
      degrees of humoral immune dysfunction associated with bronchiectasis and
      recurrent respiratory infections that, if untreated, may result in death.
    explanation: >-
      Directly links the humoral defect to bronchiectasis and recurrent
      respiratory infection.
- category: Immunologic
  name: Decreased Natural Killer Cell-Induced Killing of Target Cells
  description: >-
    A cellular phenotype and diagnostic assay readout: XLP1 NK cells show
    inhibitory 2B4 function and fail to kill EBV-transformed B-cell targets. The
    combination of SAP expression by flow cytometry and a 2B4 functional assay
    identifies XLP1 patients whom SAP staining alone would miss.
  phenotype_term:
    preferred_term: Decreased natural killer cell-induced killing of target cells
    term:
      id: HP:0025808
      label: Decreased natural killer cell-induced killing of target cells
  evidence:
  - reference: PMID:24985396
    reference_title: Diagnosing XLP1 in patients with hemophagocytic lymphohistiocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NK cells from all patients showed inhibitory 2B4 function and defective
      killing of B-EBV cells.
    explanation: >-
      Documents defective NK killing of EBV-transformed targets in every patient
      of a genetically confirmed XLP1 cohort.
  - reference: PMID:24985396
    reference_title: Diagnosing XLP1 in patients with hemophagocytic lymphohistiocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Study of SAP expression is specific but may have insufficient sensitivity
      for screening XLP1 as a single tool. Combination with 2B4 functional assay
      allows identification of all cases.
    explanation: >-
      Establishes the diagnostic value of the NK functional readout alongside SAP
      protein staining.
- category: Lymphatic
  name: Lymphadenopathy
  description: >-
    Lymphadenomegaly accompanies both the acute mononucleosis-like illness and
    the lymphoproliferative manifestations of XLP1.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:48119
    reference_title: "X-linked recessive progressive combined variable immunodeficiency (Duncan's disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fever, pharyngitis, lymphadenomegaly, hepatosplenomegaly, atypical
      lymphocytosis, and a spectrum ranging from agammaglobulinaemia to
      polyclonal hyper-gammaglobulinaemia occurred.
    explanation: >-
      Original clinical description documenting lymphadenomegaly in affected
      males.
- category: Gastrointestinal
  name: Hepatosplenomegaly
  description: >-
    Hepatosplenomegaly is a core feature of the HLH episode and was present in
    the original Duncan kindred description.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HLH is characterized as an acute illness with prolonged and high fever,
      bi- or trilineage cytopenias, and hepatosplenomegaly, which is often severe
      or fatal.
    explanation: >-
      Lists hepatosplenomegaly as a defining component of the HLH presentation.
genetic:
- name: SH2D1A
  gene_term:
    preferred_term: SH2D1A
    term:
      id: hgnc:10820
      label: SH2D1A
  association: CAUSATIVE
  relationship_type: CAUSATIVE
  inheritance:
  - name: X-linked recessive
    inheritance_term:
      preferred_term: X-linked recessive inheritance
      term:
        id: HP:0001419
        label: X-linked recessive inheritance
  notes: >-
    XLP1 is caused by hemizygous germline loss-of-function variants in SH2D1A
    (Xq25), encoding SAP. Reported alleles include large constitutional genomic
    deletions, small intragenic deletions, frameshift, nonsense, splice-site and
    missense changes. Most abolish SAP protein expression; a minority (e.g.
    R55L) retain detectable protein but are functionally deficient.
  evidence:
  - reference: PMID:9771704
    reference_title: Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified a gene, SH2D1A, that is mutated in XLP patients and
      encodes a novel protein composed of a single SH2 domain.
    explanation: Establishes SH2D1A as the XLP1 disease gene.
  - reference: PMID:9774102
    reference_title: The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The gene encoding SAP maps to the same area of the X chromosome as the
      locus for X-linked lymphoproliferative disease (XLP) and we found mutations
      in the SAP gene in three XLP patients.
    explanation: >-
      Independent identification of SAP gene mutations in XLP patients, with
      positional concordance at the XLP locus.
  - reference: PMID:24985396
    reference_title: Diagnosing XLP1 in patients with hemophagocytic lymphohistiocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nine cases were SAP(-), 2 expressed SAP with mean relative fluorescence
      intensity values below the range of healthy controls (SAP(dull)), and 1,
      carrying the R55L mutation, was SAP(+).
    explanation: >-
      Documents allelic heterogeneity: most SH2D1A variants abolish SAP protein,
      but some (R55L) preserve expression while remaining functionally
      deficient.
environmental:
- name: Primary Epstein-Barr Virus Infection
  description: >-
    Primary EBV infection is the disease-defining environmental trigger of XLP1.
    The genetic lesion is present from birth, but the fulminant infectious
    mononucleosis/HLH phenotype is precipitated by the first encounter with the
    virus, which was the trigger in 92% of XLP-1 HLH episodes in the Pachlopnik
    Schmid cohort. GeneReviews accordingly lists EBV contact as an
    agent/circumstance to avoid. Note that EBV is not required for every
    manifestation — dysgammaglobulinemia may precede or occur without documented
    EBV infection — so this is modeled as a trigger of the acute arm rather than
    of the disease as a whole.
  exposure_term:
    preferred_term: exposure to Epstein-Barr virus
    term:
      id: ECTO:3000001
      label: exposure to virus
  effect: Precipitates fulminant infectious mononucleosis and HLH in SAP-deficient males.
  influences_mechanisms:
  - target: Unterminated Hyperinflammatory Response to Primary EBV Infection
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Primary EBV infection supplies the SLAM-ligand-bearing B-cell target
      population that SAP-deficient NK and CD8+ T cells cannot clear, and is the
      documented precipitant of the great majority of XLP1 HLH episodes.
    evidence:
    - reference: PMID:21119115
      reference_title: Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of
        HLH (XLP-1, 92%; XLP-2, 83%).
      explanation: >-
        Quantifies EBV infection as the precipitant of 92% of HLH episodes in
        XLP-1, supporting a TRIGGERS edge onto the HLH node.
    - reference: PMID:20301580
      reference_title: X-Linked Lymphoproliferative Disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Individuals with XLP who come into contact with EBV are at risk of
        developing HLH and/or lymphoproliferation.
      explanation: >-
        States the exposure-outcome relationship directly, as an
        agent/circumstance to avoid.
  evidence:
  - reference: PMID:9771704
    reference_title: Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-linked lymphoproliferative syndrome (XLP or Duncan disease) is
      characterized by extreme sensitivity to Epstein-Barr virus (EBV), resulting
      in a complex phenotype manifested by severe or fatal infectious
      mononucleosis, acquired hypogammaglobulinemia and malignant lymphoma.
    explanation: >-
      Establishes EBV sensitivity as the defining environmental dimension of the
      disease.
  - reference: PMID:48119
    reference_title: "X-linked recessive progressive combined variable immunodeficiency (Duncan's disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study suggests that the Epstein-Barr virus or other viruses triggered
      the fatal proliferation of lymphocytes
    explanation: >-
      The original hypothesis that a viral exposure triggers the fatal
      lymphoproliferation, later confirmed as EBV.
prevalence:
- population: Worldwide (males)
  measure_type: UNKNOWN
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.1
  notes: >-
    Approximately one affected male per million. Two caveats: the source figure
    is for X-linked lymphoproliferative syndrome as a whole (XLP1 plus XLP2),
    not XLP1 alone, and the source does not state whether the estimate is a
    point prevalence or a birth incidence, so measure_type is UNKNOWN. The same
    source notes the condition is probably underdiagnosed. An Orphanet-backed
    record keyed on ORPHA:538931 would give a second, independently derived
    estimate and split XLP1 from XLP2, and is worth adding.
  evidence:
  - reference: PMID:31754776
    reference_title: "X-linked lymphoproliferative syndrome in mainland China: review of clinical, genetic, and immunological characteristic."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XLP is estimated to affect approximately one per million males
    explanation: >-
      Source for the approximately one-per-million-males estimate underlying the
      1-9 per 1,000,000 band.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Allogeneic HSCT is the only known curative therapy for XLP1: it replaces the
    SAP-deficient hematopoietic compartment, restoring NK, CD8+ T and iNKT
    function. Outcome depends sharply on timing. In the 91-patient Booth cohort,
    survival after allogeneic HSCT was 81.4% overall but fell to 50% in patients
    who had HLH as a feature of disease, while untransplanted patients who had
    had HLH survived only 18.8% of the time. The evidence therefore supports
    pre-emptive transplantation in asymptomatic males rather than waiting for an
    HLH episode.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: SAP Adaptor Deficiency
    treatment_effect: RESTORES
    description: >-
      Donor-derived hematopoiesis reconstitutes SAP-expressing lymphocytes,
      correcting the initiating molecular lesion in the hematopoietic
      compartment.
    evidence:
    - reference: PMID:20926771
      reference_title: "X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Survival after allogeneic HSCT is 81.4% with good immune reconstitution
        in the large majority of patients and little evidence of posttransplant
        lymphoproliferative disease.
      explanation: >-
        Good immune reconstitution after HSCT, with resolution of the
        lymphoproliferative risk, indicates correction of the underlying SAP
        defect in the hematopoietic compartment.
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The only known curative therapy for XLP1 is allogeneic hematopoietic stem
      cell transplant (HSCT), which should be strongly considered in all males as
      early in life as is feasible, particularly in those who have not developed
      symptoms
    explanation: >-
      Establishes HSCT as the only curative therapy and supports pre-emptive
      timing.
  - reference: PMID:20926771
    reference_title: "X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, survival falls to 50% in patients with HLH as a feature of
      disease.
    explanation: >-
      Quantifies the outcome penalty of transplanting after HLH rather than
      preemptively.
  - reference: PMID:20926771
    reference_title: "X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HSCT should be undertaken in all patients with HLH, because outcome without
      transplant is extremely poor.
    explanation: >-
      The cohort's management conclusion: HSCT is mandatory once HLH has
      occurred.
- name: Rituximab
  description: >-
    Anti-CD20 monoclonal antibody depletion of B cells removes the EBV-infected
    B-cell reservoir that XLP1 NK and CD8+ T cells cannot clear, addressing the
    antigen source that sustains the hyperinflammatory state. It is used as part
    of the management of fulminant EBV infection / HLH in XLP.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
    - preferred_term: monoclonal antibody
      term:
        id: NCIT:C20401
        label: Monoclonal Antibody
  target_mechanisms:
  - target: Uncontrolled EBV-Driven B Cell Proliferation
    treatment_effect: INHIBITS
    description: >-
      CD20-directed depletion removes the expanding EBV-infected B-cell
      population directly, bypassing the SAP-dependent cytotoxic pathways that
      cannot act on it.
    evidence:
    - reference: PMID:20301580
      reference_title: X-Linked Lymphoproliferative Disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Standard treatment for liver dysfunction/failure, hypogammaglobulinemia
        (IVIG or IgG), fulminant EBV infection / HLH (including etoposide and
        steroids and consideration of rituximab), lymphoma, colitis, aplastic
        anemia, and vasculitis.
      explanation: >-
        Places rituximab in the management of fulminant EBV infection / HLH,
        which is where the EBV-driven B-cell expansion is the therapeutic target.
      directness: INDIRECT
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Standard treatment for liver dysfunction/failure, hypogammaglobulinemia
      (IVIG or IgG), fulminant EBV infection / HLH (including etoposide and
      steroids and consideration of rituximab), lymphoma, colitis, aplastic
      anemia, and vasculitis.
    explanation: >-
      GeneReviews management guidance naming rituximab as a consideration in
      fulminant EBV infection / HLH.
- name: Immunoglobulin Replacement Therapy
  description: >-
    Intravenous or subcutaneous immunoglobulin replaces the antibody the failed
    germinal-center reaction cannot generate, preventing the recurrent
    respiratory infection and bronchiectasis that untreated dysgammaglobulinemia
    causes. It is supportive rather than curative: in the Booth cohort the
    majority of untransplanted survivors were maintained on immunoglobulin
    replacement.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Failed Class Switching and Antibody Production
    treatment_effect: BYPASSES
    description: >-
      Exogenous polyclonal IgG substitutes for the class-switched antibody that
      SAP-deficient T-B collaboration fails to produce; it does not repair the
      germinal-center defect.
    evidence:
    - reference: PMID:20301580
      reference_title: X-Linked Lymphoproliferative Disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Standard treatment for liver dysfunction/failure, hypogammaglobulinemia
        (IVIG or IgG), fulminant EBV infection / HLH (including etoposide and
        steroids and consideration of rituximab), lymphoma, colitis, aplastic
        anemia, and vasculitis.
      explanation: >-
        Names IVIG/IgG as the standard treatment for the hypogammaglobulinemia
        arm of XLP.
  evidence:
  - reference: PMID:20926771
    reference_title: "X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Untransplanted patients have an overall survival of 62.5% with the majority
      on immunoglobulin replacement therapy, but the outcome for those
      untransplanted after HLH is extremely poor (18.8%).
    explanation: >-
      Documents immunoglobulin replacement as the mainstay for untransplanted
      XLP1 patients, and its limits once HLH has occurred.
- name: HLH-Directed Etoposide-Based Therapy
  description: >-
    Etoposide plus corticosteroids (the HLH-94/HLH-2004 backbone) suppresses the
    activated lymphocyte and macrophage compartment driving the hyperinflammatory
    state. In XLP1 this is a bridge, not a cure: it controls the acute episode so
    that curative HSCT can be performed. The detailed HLH protocol is modeled in
    the Hemophagocytic_Lymphohistiocytosis entry.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: etoposide
      term:
        id: CHEBI:4911
        label: etoposide
  target_mechanisms:
  - target: Unterminated Hyperinflammatory Response to Primary EBV Infection
    treatment_effect: INHIBITS
    description: >-
      Etoposide-based cytoreduction deletes the activated lymphocytes and
      macrophages sustaining the cytokine state, interrupting the
      hyperinflammatory arm without correcting the SAP defect.
    evidence:
    - reference: PMID:20301580
      reference_title: X-Linked Lymphoproliferative Disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Standard treatment for liver dysfunction/failure, hypogammaglobulinemia
        (IVIG or IgG), fulminant EBV infection / HLH (including etoposide and
        steroids and consideration of rituximab), lymphoma, colitis, aplastic
        anemia, and vasculitis.
      explanation: >-
        Names etoposide and steroids as the standard treatment for the fulminant
        EBV infection / HLH manifestation this node represents.
  evidence:
  - reference: PMID:20926771
    reference_title: "X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The advent of better treatment strategies for HLH and malignancy has
      greatly reduced mortality for these patients, but HLH still remains the
      most severe feature of XLP1.
    explanation: >-
      Attributes the modern mortality reduction to improved HLH-directed
      treatment, while noting it does not eliminate HLH as the dominant risk.
📚

References & Deep Research

References

1
PMID:20301580
X-Linked Lymphoproliferative Disease.
No top-level findings curated for this source.