X-linked Lymphoproliferative Disease Due To XIAP Deficiency

Genetic MONDO:0010385 Pathograph 20 Show in embeddings browser X-linked lymphoproliferative syndrome Inborn error of immunity

X-linked lymphoproliferative disease type 2 (XLP2) is caused by hemizygous loss-of-function variants in XIAP (also called BIRC4), which encodes the X-linked inhibitor of apoptosis protein. Despite sharing the XLP name and the susceptibility to Epstein-Barr virus with SAP/SH2D1A deficiency (XLP1), XIAP deficiency is a clinically distinct disease. Its core triad is recurrent hemophagocytic lymphohistiocytosis (HLH) - often EBV-triggered but frequently occurring without any demonstrable EBV infection - recurrent splenomegaly with cytopenias and fever, and a severe, treatment-refractory Crohn-like inflammatory bowel disease. The single most useful discriminator from XLP1 is a negative one: lymphoma, which affects roughly a third of XLP1 patients, has not been reported in males with XLP2, and common variable immunodeficiency has likewise not been described in them. XIAP has two largely separable functions that map onto the two clinical arms of the disease. Through its BIR domains it inhibits apoptotic caspases, so its loss makes lymphocytes hypersensitive to CD95-, TRAIL-R- and TCR-driven activation-induced cell death and depletes invariant NKT cells, degrading control of EBV and predisposing to HLH. Through its RING domain it is the essential ubiquitin ligase that ubiquitylates RIPK2 and recruits LUBAC to NOD2, so its loss cripples NOD2/NOD1-dependent NF-kappaB signaling in monocytes and intestinal epithelium and produces the Crohn-like colitis. A third strand, inflammasome dysregulation with strikingly and persistently elevated serum IL-18, accompanies and probably amplifies the hyperinflammatory episodes.

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1
Inheritance
7
Pathophys.
8
Phenotypes
20
Pathograph
1
Genes
4
Medical Actions
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References
🏷

Classifications

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

Inheritance

1
X-linked recessive HP:0001419
XLP2 is inherited in an X-linked manner and is caused by hemizygous germline loss-of-function variants in XIAP. Heterozygous female carriers are usually asymptomatic, but carriers with skewed X-chromosome inactivation favouring the mutant allele can develop HLH and inflammatory bowel disease.
X-linked recessive inheritance
Show evidence (3 references)
PMID:20301580 SUPPORT Human Clinical
"XLP is inherited in an X-linked manner."
States the X-linked mode of inheritance for XLP, including XLP2.
PMID:20301580 SUPPORT Human Clinical
"There are, however, increasing numbers of reports of affected females with unfavorable (skewed) X-chromosome inactivation favoring the X chromosome with the pathogenic variant who develop HLH, inflammatory bowel disease, and erythema nodosum."
Documents symptomatic heterozygous females with skewed X-inactivation, the qualification to the X-linked recessive pattern.
PMID:24942515 SUPPORT Human Clinical
"Importantly, we report that it is not restricted to male patients because we identified 2 symptomatic female heterozygous carriers of XIAP mutations."
Independent documentation that heterozygous female carriers can be symptomatic, qualifying the recessive X-linked pattern.
⚙

Pathophysiology

7
XIAP Loss of Function
Mechanism confidence: Established
Hemizygous germline XIAP/BIRC4 variants - most often nonsense, frameshift or splice alleles that abolish protein expression, and a smaller set of missense alleles clustered in the BIR2 and RING domains - eliminate or cripple XIAP protein. XIAP has two separable activities that both fail: its N-terminal BIR domains inhibit the apoptotic caspases, and its C-terminal RING domain provides the ubiquitin ligase activity required for NOD1/NOD2 signaling. Loss of the first drives the lymphocyte-apoptosis arm of the disease; loss of the second drives the intestinal-inflammation arm.
Genetic context XIAP hgnc:592 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns XIAP (hgnc:592). hgnc:592 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION
XIAP-mediated ubiquitylation of RIPK2 GO:0016567 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased XIAP-mediated ubiquitylation of RIPK2, annotated with protein ubiquitination (GO:0016567). GO:0016567 is a biological process from the Gene Ontology. ↓ DECREASED
caspase inhibitor activity GO:0043027 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased caspase inhibitor activity, annotated with cysteine-type endopeptidase inhibitor activity involved in apoptotic process (GO:0043027). GO:0043027 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Enhanced Activation-Induced Lymphocyte Apoptosis Without XIAP to restrain the apoptotic caspases, lymphocytes from patients die more readily in response to death-receptor and antigen-receptor stimulation.
Defective NOD2 Signaling in Monocytes and Intestinal Epithelium The RING-domain ubiquitin ligase activity of XIAP is required to ubiquitylate RIPK2 and recruit LUBAC to NOD2; XLP2 alleles abolish this step.
Inflammasome Dysregulation and Sustained IL-18 Excess XIAP-deficient patients show a strikingly and persistently elevated serum IL-18 that is not seen in other forms of HLH. The intermediate steps are not established; NOD2-dependent caspase-1 activation is the leading candidate, and patient monocytes stimulated in vitro did not oversecrete IL-18, so the cellular source remains open.
Show evidence (3 references)
PMID:17080092 SUPPORT Human Clinical
"Here, we identify mutations in the gene that encodes the X-linked inhibitor-of-apoptosis XIAP (also termed BIRC4) in patients with XLP from three families without mutations in SAP. These mutations lead to defective expression of XIAP."
The founding report establishes loss of XIAP protein expression from XIAP/BIRC4 mutations as the molecular lesion of this disease.
PMID:23818254 SUPPORT In Vitro
"X-linked Inhibitor of Apoptosis (XIAP) is an essential ubiquitin ligase for pro-inflammatory signalling downstream of the nucleotide-binding oligomerization domain containing (NOD)-1 and -2 pattern recognition receptors."
Identifies the second, ubiquitin-ligase function of XIAP that is lost in this disease, distinct from its caspase-inhibitory role.
PMID:23818254 SUPPORT In Vitro
"Here, we identify the XIAP baculovirus IAP repeat (BIR)2 domain as a hotspot for missense mutations in XLP2."
Locates the recurrent missense alleles to the BIR2 domain, complementing the predominantly truncating allele spectrum.
Enhanced Activation-Induced Lymphocyte Apoptosis
Mechanism confidence: Established
XIAP-deficient T cells are hypersensitive to CD95 (Fas), TRAIL-R and TCR-CD3-driven apoptosis, i.e. to activation-induced cell death. Activated effector lymphocytes are therefore deleted prematurely during an immune response, and the cells that would normally clear an infected target are lost at the moment they are needed. This is the arm of XIAP biology that the IUIS classification records as the functional defect of the disease.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
lymphocyte apoptotic process GO:0070227 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased lymphocyte apoptotic process (GO:0070227). GO:0070227 is a biological process from the Gene Ontology. ↑ INCREASED T cell homeostasis GO:0043029 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell homeostasis (GO:0043029). GO:0043029 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Invariant NKT Cell Depletion Invariant NKT cells depend on XIAP for survival and/or differentiation and are reduced or absent in patients. Whether this reflects the same apoptotic hypersensitivity or a separate developmental requirement is not resolved.
Hypogammaglobulinemia Premature deletion of activated lymphocytes is the most plausible route to the transient hypogammaglobulinemia seen in about a third of patients, but no source traces the humoral defect to a specific step, and its transience argues against a fixed developmental block. The edge is recorded as indirect with unknown intermediates rather than asserting a mechanism the literature does not supply.
Hemophagocytic Lymphohistiocytosis Susceptibility Premature deletion of activated effector lymphocytes leaves the antigen - classically EBV-infected B cells - uncleared, so the immune response is sustained rather than terminated, and the macrophage-activating cytokine loop that defines HLH is allowed to run.
Show evidence (2 references)
PMID:35748970 SUPPORT Other
"Increased T cells susceptibility to apoptosis to CD95 and enhanced activation-induced cell death (AICD)"
The IUIS classification records enhanced CD95-driven apoptosis and activation-induced cell death as the functional defect of XIAP deficiency.
PMID:17080092 SUPPORT Human Clinical
"we show that XIAP is a potent regulator of lymphocyte homeostasis in vivo"
Frames the apoptosis defect as a failure of lymphocyte homeostasis rather than an isolated in-vitro observation.
Invariant NKT Cell Depletion
Mechanism confidence: Provisional
Invariant natural killer T cells are reduced in XIAP-deficient patients, as they are in SAP deficiency. Because iNKT cells are thought to have a key role in the immune response to EBV, this is one of the few features XLP1 and XLP2 genuinely share, and it plausibly contributes to the failure to contain primary EBV infection. The node is graded provisional because the finding is not uniform: the founding Nature report and an independent Japanese cohort both found iNKT cells significantly reduced, but the IUIS classification records the count as low or normal, so a normal iNKT compartment does not exclude the diagnosis and iNKT depletion cannot be the whole explanation for HLH susceptibility.
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.
Downstream
Hemophagocytic Lymphohistiocytosis Susceptibility Loss of iNKT cells degrades the early cellular response to EBV, the commonest HLH trigger in this disease.
Severe Epstein-Barr virus infection Loss of the iNKT compartment degrades the early cellular response to primary EBV, so that infection which is self-limiting in healthy hosts can instead present as severe infectious mononucleosis. The step is graded provisional along with its source node: iNKT counts are low or normal in XIAP deficiency, and severe mononucleosis is a presenting manifestation in a minority of patients rather than the rule, so this is a contributing path to EBV susceptibility and not a sufficient explanation of it.
Show evidence (2 references)
PMID:22228567 SUPPORT Human Clinical
"iNKT cells from patients with XIAP deficiency were significantly decreased as compared with age-matched healthy controls."
Quantitative confirmation of the iNKT deficit in an independent nine-patient cohort.
PMID:35748970 SUPPORT INDIRECT Other
"Normal or Increased activated T cells; low/normal iNK T cells"
The IUIS classification records the iNKT count in XIAP deficiency as low or normal. It supports iNKT depletion as a recognised feature while explicitly noting it is not universal, which is why this node is graded provisional.
Defective NOD2 Signaling in Monocytes and Intestinal Epithelium
Mechanism confidence: Established
XIAP is the essential ubiquitin ligase of the NOD2 pathway: on sensing the bacterial peptidoglycan fragment muramyl dipeptide, NOD2 recruits RIPK2, XIAP ubiquitylates RIPK2, and those chains recruit LUBAC to enable full NF-kappaB activation. XLP2 alleles in either the RING or the BIR2 domain abolish RIPK2 binding or ubiquitylation, so patient monocytes mount defective NOD2-driven cytokine and chemokine responses and patient fibroblasts show a parallel NOD1 defect. NOD2 is the strongest known genetic risk factor for Crohn disease and is central to antibacterial defence at mucosal surfaces, including in Paneth cells, which places this defect directly on the path to the intestinal disease.
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology. paneth cell CL:0000510 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves paneth cell (CL:0000510). CL:0000510 is a cell type from the Cell Ontology. intestinal epithelial cell CL:0002563 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intestinal epithelial cell (CL:0002563). CL:0002563 is a cell type from the Cell Ontology.
NOD2 signaling pathway GO:0070431 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased NOD2 signaling pathway, annotated with nucleotide-binding oligomerization domain containing 2 signaling pathway (GO:0070431). GO:0070431 is a biological process from the Gene Ontology. ↓ DECREASED response to muramyl dipeptide GO:0032495 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased response to muramyl dipeptide (GO:0032495). GO:0032495 is a biological process from the Gene Ontology. ↓ DECREASED NOD2-driven NF-kappaB activation GO:0043123 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased NOD2-driven NF-kappaB activation, annotated with positive regulation of canonical NF-kappaB signal transduction (GO:0043123). GO:0043123 is a biological process from the Gene Ontology. ↓ DECREASED
intestine UBERON:0000160 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in intestine (UBERON:0000160). UBERON:0000160 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Crohn-like Intestinal Inflammation Impaired NOD2-dependent antibacterial and cytokine responses at the intestinal mucosa produce a Crohn-disease-like inflammatory bowel disease.
Show evidence (5 references)
PMID:22607974 SUPPORT In Vitro
"We find that XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly complex (LUBAC) to NOD2."
Defines the molecular step XIAP performs in NOD2 signaling and that is therefore missing in XLP2.
PMID:22607974 SUPPORT In Vitro
"We conclude that XIAP and LUBAC constitute essential ubiquitin ligases in NOD2-mediated inflammatory signaling and propose that deregulation of NOD2 signaling contributes to XLP-2 pathogenesis."
States the authors' conclusion that deregulated NOD2 signaling contributes to XLP2 pathogenesis.
PMID:23818254 SUPPORT In Vitro
"We demonstrate that XLP2-BIR2 mutations severely impair NOD1/2-dependent immune signalling in primary cells from XLP2 patients and in reconstituted XIAP-deficient cell lines."
Demonstrates the NOD1/NOD2 signaling defect in cells taken from patients, not only in engineered lines.
+ 2 more references
Inflammasome Dysregulation and Sustained IL-18 Excess
Mechanism confidence: Provisional
Serum IL-18 in XIAP deficiency is elevated an order of magnitude beyond what is seen in SAP deficiency, perforin deficiency or EBV-associated HLH, spikes with every HLH episode, and - unlike every other pro-inflammatory cytokine measured - stays high in clinical remission. IL-18 is generated by caspase-1 within the inflammasome, and because NOD2 can activate caspase-1 the XIAP-NOD2 axis is the leading candidate route. The mechanism is marked provisional because patient PBMCs stimulated with LPS plus ATP did not oversecrete IL-18 relative to controls, so neither the cellular source nor the trigger is established.
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology. macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
interleukin-18 production GO:0032621 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased interleukin-18 production (GO:0032621). GO:0032621 is a biological process from the Gene Ontology. ↑ INCREASED positive regulation of inflammatory response GO:0050729 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of inflammatory response (GO:0050729). GO:0050729 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hemophagocytic Lymphohistiocytosis Susceptibility The sustained IL-18 excess is proposed to lower the threshold for, and to amplify, the hyperinflammatory episodes; the authors advance it as an additional explanation for HLH susceptibility rather than a demonstrated cause.
Recurrent fever Persistent systemic hyperinflammation manifests clinically as recurrent febrile episodes, often with splenomegaly and cytopenia, which are interpreted as minimal forms of HLH.
Show evidence (2 references)
PMID:24084330 SUPPORT Human Clinical
"Longitudinal examination of two patients demonstrated marked exacerbation of IL-18 levels during every occasion of HLH."
Longitudinal data tie IL-18 excursions to each hyperinflammatory episode within individual patients.
PMID:25666262 SUPPORT Human Clinical
"Recent findings demonstrate the role of XIAP in innate immunity and in the negative regulation of inflammation."
Supports treating loss of XIAP as a release of a brake on inflammation, not only as an apoptosis defect.
Hemophagocytic Lymphohistiocytosis Susceptibility
Mechanism confidence: Established
The convergent consequence of the apoptosis and inflammation arms is a strong, lifelong predisposition to HLH: uncontrolled macrophage and T-cell activation with hypercytokinaemia, fever, cytopenias, hepatosplenomegaly and hemophagocytosis. EBV is the commonest trigger, but a substantial fraction of episodes occur with no demonstrable EBV infection, which is a point of contrast with XLP1. Recurrence is the rule rather than the exception.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
cytokine production involved in immune response GO:0002367 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cytokine production involved in immune response (GO:0002367). GO:0002367 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hemophagocytic lymphohistiocytosis The susceptibility manifests as clinical episodes of HLH, most often beginning in infancy or early childhood.
Splenomegaly Recurrent splenomegaly, often with cytopenia and fever, is interpreted as a minimal or partial form of the same hyperinflammatory process.
Cytopenias Bi- or trilineage peripheral cytopenias accompany the acute hyperinflammatory episodes.
Show evidence (2 references)
PMID:20489057 SUPPORT Human Clinical
"Nine of 10 patients developed HLH by 8 years of age. Most patients presented in infancy, and recurrent HLH was common."
Quantifies the HLH predisposition and its recurrence in a molecularly defined cohort.
PMID:20301580 SUPPORT Human Clinical
"Males with XLP2 are more likely to have HLH without EBV infection, recurrent episodes of HLH (which is not typically seen in those with XLP1), splenomegaly, and gastrointestinal disease, including enterocolitis and perirectal abscesses or fistulae."
GeneReviews states the EBV-independent and recurrent character of HLH in XLP2 and contrasts it explicitly with XLP1.
Crohn-like Intestinal Inflammation
Mechanism confidence: Established
Chronic transmural intestinal inflammation whose clinical presentation and histology overlap with Crohn disease, ranging from chronic hemorrhagic colitis to fistulating and perianal disease. Onset spans infancy to adulthood, and the disease is characteristically severe and difficult to treat with conventional inflammatory-bowel-disease therapy. XIAP deficiency is now regarded as one of the monogenic causes of inherited IBD.
intestinal inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased intestinal inflammatory response, annotated with inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
colon UBERON:0001155 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in colon (UBERON:0001155). UBERON:0001155 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Crohn-like inflammatory bowel disease The tissue-level inflammation presents clinically as a severe, treatment-refractory inflammatory bowel disease.
Show evidence (2 references)
PMID:24942515 SUPPORT Human Clinical
"Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease."
Establishes the Crohn-disease-like character of the intestinal disease both clinically and histologically.
PMID:25666262 SUPPORT Human Clinical
"XIAP deficiency can be considered as one of the genetic causes for inherited IBD."
Places XIAP deficiency among the monogenic causes of inflammatory bowel disease.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for X-linked Lymphoproliferative Disease Due To XIAP 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

8
Blood 4
Hemophagocytic lymphohistiocytosis FREQUENT Hemophagocytosis HP:0012156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemophagocytic lymphohistiocytosis, annotated with Hemophagocytosis (HP:0012156), qualified as temporality recurrent. HP:0012156 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (3 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."
HLH occurred in 76% of 30 XLP2 patients, supporting the FREQUENT (30-79%) band.
PMID:20301580 SUPPORT Human Clinical
"Males with XLP2 are more likely to have HLH without EBV infection, recurrent episodes of HLH (which is not typically seen in those with XLP1), splenomegaly, and gastrointestinal disease, including enterocolitis and perirectal abscesses or fistulae."
Supports both the recurrent temporality and the occurrence of HLH without EBV, the two features that separate XLP2 HLH from XLP1 HLH.
PMID:21119115 SUPPORT Human Clinical
"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%)."
Quantifies the lower per-episode lethality of HLH in XLP2 relative to XLP1.
Cytopenias 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 lists bi- or trilineage cytopenias as a defining feature of the HLH episodes.
PMID:21119115 SUPPORT Human Clinical
"Recurrent splenomegaly often associated with cytopenia and fever was preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably represents minimal forms of HLH as documented by histopathology."
Documents cytopenia as a component of the recurrent splenomegaly-fever episodes.
Hypogammaglobulinemia FREQUENT 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), qualified as temporality transient. HP:0004313 is a phenotype from the Human Phenotype Ontology.
Temporal: TRANSIENT
Show evidence (3 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."
Hypogammaglobulinemia in 33% of 30 XLP2 patients supports the FREQUENT (30-79%) band and quantifies the contrast with XLP1.
PMID:20301580 SUPPORT Human Clinical
"Transient hypogammaglobulinemia has been rarely observed in those with XLP2."
GeneReviews characterises the hypogammaglobulinemia of XLP2 as transient, supporting the TRANSIENT temporality.
PMID:20301580 REFUTE Human Clinical
"Transient hypogammaglobulinemia has been rarely observed in those with XLP2."
The same sentence cuts the other way on frequency. "Rarely observed" is not the FREQUENT (30-79%) band this phenotype carries, so GeneReviews refutes the band even while supporting the temporality. Recorded as a separate REFUTE item rather than folded into the SUPPORT above, since one evidence item cannot carry two directions. The band follows the cohort figure because that is the only quantified estimate; see the phenotype description for why the two sources can both be right.
Lymphoma HP:0002665 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphoma (HP:0002665). HP:0002665 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:20489057 REFUTE Human Clinical
"There were no cases of lymphoma."
No lymphoma occurred in 10 molecularly confirmed XIAP-deficient patients from eight unrelated families.
PMID:21119115 REFUTE Human Clinical
"Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients (17%) had chronic hemorrhagic colitis as documented by histopathology."
Head-to-head comparison of 33 XLP1 and 30 XLP2 patients: lymphoma occurred only in XLP1, and colitis substituted for it in XLP2.
PMID:20301580 REFUTE Human Clinical
"To date, neither lymphoproliferative disease nor common variable immunodeficiency has been reported in males with XLP2."
The GeneReviews chapter states directly that lymphoproliferative disease has not been reported in XLP2.
+ 1 more reference
Cardiovascular 1
Splenomegaly VERY_FREQUENT HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744), qualified as temporality recurrent. HP:0001744 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (2 references)
PMID:21119115 SUPPORT Human Clinical
"Recurrent splenomegaly often associated with cytopenia and fever was preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably represents minimal forms of HLH as documented by histopathology."
Splenomegaly in 87% of XLP2 patients supports the VERY_FREQUENT (80-100%) band and the recurrent temporality.
PMID:23973892 SUPPORT Human Clinical
"These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1)."
Documents isolated splenomegaly as a presenting manifestation in three of 25 patients.
Digestive 1
Crohn-like inflammatory bowel disease OCCASIONAL Inflammation of the large intestine HP:0002037 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Crohn-like colitis, annotated with Inflammation of the large intestine (HP:0002037), qualified as course progressive. HP:0002037 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
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."
Chronic hemorrhagic colitis in 17% of 30 XLP2 patients supports the OCCASIONAL (5-29%) band.
PMID:24942515 SUPPORT Human Clinical
"The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat."
Documents the wide age range at onset and the treatment refractoriness of the intestinal disease.
PMID:20301580 SUPPORT Human Clinical
"Males with XLP2 are more likely to have HLH without EBV infection, recurrent episodes of HLH (which is not typically seen in those with XLP1), splenomegaly, and gastrointestinal disease, including enterocolitis and perirectal abscesses or fistulae."
GeneReviews documents enterocolitis and perirectal abscesses or fistulae as XLP2-preferential gastrointestinal disease.
Immune 1
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). HP:0031693 is a phenotype from the Human Phenotype Ontology.
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 as the trigger in 83% of XLP2 HLH episodes, leaving 17% EBV-independent.
PMID:23973892 SUPPORT Human Clinical
"These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1)."
Documents severe infectious mononucleosis as a presenting manifestation in four of 25 patients.
Metabolism 1
Recurrent fever HP:0001954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent fever (HP:0001954), qualified as temporality recurrent. HP:0001954 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (2 references)
PMID:21119115 SUPPORT Human Clinical
"Recurrent splenomegaly often associated with cytopenia and fever was preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably represents minimal forms of HLH as documented by histopathology."
Documents recurrent fever as part of the characteristic XLP2 hyperinflammatory triad.
PMID:23973892 SUPPORT Human Clinical
"These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1)."
Documents periodic fever as a presenting manifestation independent of overt HLH.
🧬

Genetic Associations

1
XIAP (CAUSATIVE)
Gene: XIAP hgnc:592 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is XIAP (hgnc:592). hgnc:592 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (4 references)
PMID:17080092 SUPPORT Human Clinical
"Here, we identify mutations in the gene that encodes the X-linked inhibitor-of-apoptosis XIAP (also termed BIRC4) in patients with XLP from three families without mutations in SAP. These mutations lead to defective expression of XIAP."
Establishes XIAP/BIRC4 as the causative gene, identified in XLP families without SAP mutations.
PMID:23973892 SUPPORT Human Clinical
"However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients."
Documents the absence of genotype-phenotype correlation and the need for molecular testing rather than functional screening.
PMID:22228567 SUPPORT Human Clinical
"Seven out of eight patients showed decreased XIAP protein expression."
Quantifies the sensitivity limitation of XIAP protein screening: one of eight tested patients had normal expression.
+ 1 more reference
💊

Medical Actions

4
Allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning
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 therapy that removes the underlying defect, replacing the XIAP-deficient haematopoietic compartment and, in reported cases, fully restoring intestinal homeostasis. Conditioning intensity is the critical variable and XIAP deficiency is an explicit exception to standard practice: in the international survey, only one of seven patients given busulfan-containing myeloablative conditioning survived, with deaths from transplant-related toxicity including venoocclusive disease and pulmonary haemorrhage, plausibly because losing XIAP's antiapoptotic function sensitises tissues to conditioning injury. Reduced-intensity conditioning gave 55% survival overall and 86% among those in HLH remission at transplant. Myeloablative regimens should not be used; reduced-intensity regimens should be used with caution and, where possible, only after HLH remission is achieved.
Mechanism Target:
RESTORES XIAP Loss of Function — Donor haematopoiesis supplies XIAP-competent lymphocytes and monocytes, restoring both the caspase-inhibitory and the NOD2-scaffolding functions in the haematopoietic compartment.
Show evidence (1 reference)
PMID:24942515 SUPPORT Human Clinical
"In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis."
Demonstrates that replacing the XIAP-deficient haematopoietic compartment corrects the downstream intestinal disease.
Show evidence (4 references)
PMID:23131490 SUPPORT Human Clinical
"Survival was poor in the MAC group, with only 1 patient surviving (14%). Most deaths were from transplantation-related toxicities, including venoocclusive disease and pulmonary hemorrhage."
Quantifies the excess toxicity of myeloablative conditioning that makes XIAP deficiency an exception to standard transplant practice.
PMID:23131490 SUPPORT Human Clinical
"We conclude that MAC regimens should not be used for patients with XIAP deficiency. It is possible that the loss of XIAP and its antiapoptotic functions contributes to the high incidence of toxicities observed with MAC regimens."
States the recommendation against myeloablative conditioning and its mechanistic rationale in XIAP biology.
PMID:23131490 SUPPORT Human Clinical
"RIC regimens should be pursued with caution and, if possible, efforts should be made to ensure HLH remission before HCT in these patients."
States the recommendation for reduced-intensity conditioning and for achieving HLH remission before transplant.
+ 1 more reference
HLH-directed immunochemotherapy
Action: HLH-directed pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is HLH-directed pharmacotherapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
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. dexamethasone CHEBI:41879 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dexamethasone (CHEBI:41879). CHEBI:41879 is a therapeutic agent from Chemical Entities of Biological Interest. 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.
Acute hyperinflammatory episodes are treated with the standard HLH approach: etoposide and corticosteroids, with rituximab considered where EBV drives the episode, plus cyclosporine in many reported cases. This suppresses the episode and is used as a bridge to transplant; it does not correct the underlying defect, and recurrence after treatment is characteristic of this disease.
Mechanism Target:
INHIBITS Hemophagocytic Lymphohistiocytosis Susceptibility — Etoposide and corticosteroids suppress the activated T cells and macrophages driving the episode; rituximab depletes the EBV-infected B cells that trigger it. The underlying XIAP defect is untouched, so the predisposition persists.
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 specifies etoposide, steroids and rituximab as the supportive treatment of HLH in XLP.
Show evidence (2 references)
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."
Identifies the standard HLH-directed supportive regimen used in XLP, including XLP2.
PMID:23131490 SUPPORT Human Clinical
"Preparative regimen and HLH activity affected outcomes, and of RIC patients reported to be in remission from HLH, survival is 86% (P = .03)."
Achieving HLH remission before transplant materially improves survival, which is the main reason HLH-directed therapy is given as a bridge.
Management of XIAP-associated inflammatory bowel disease
Action: pharmacotherapy for inflammatory bowel diseaseNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pharmacotherapy for inflammatory bowel disease, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
The Crohn-like IBD of XIAP deficiency is treated along conventional inflammatory-bowel-disease lines, but it is characteristically severe and difficult to treat, and standard therapy is often inadequate - which is why XIAP deficiency should be considered in refractory paediatric-onset Crohn disease and why transplant is escalated to when medical management fails. Colitis and cholangitis warrant active surveillance in XLP2.
Mechanism Target:
MODULATES Crohn-like Intestinal Inflammation — Conventional IBD therapy suppresses the mucosal inflammatory response without correcting the underlying NOD2 signaling defect, which is the likely reason for its limited efficacy here.
Show evidence (1 reference)
PMID:24942515 SUPPORT Human Clinical
"The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat."
Documents the limited response of XIAP-associated IBD to available therapy.
Show evidence (2 references)
PMID:20301580 SUPPORT Human Clinical
"monitor for signs and symptoms of colitis and cholangitis in those with XLP2"
GeneReviews makes colitis and cholangitis surveillance an XLP2-specific management recommendation.
PMID:24942515 SUPPORT Human Clinical
"In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis."
Establishes transplant as the escalation when medical management of the intestinal disease fails.
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
Immunoglobulin substitution (IVIG or subcutaneous IgG) is given to the subset of patients with hypogammaglobulinemia. In XLP2 the humoral defect is typically transient, so the requirement is often temporary, unlike in XLP1.
Target Phenotypes: Hypogammaglobulinemia HP:0004313 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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."
Identifies IVIG or IgG as the standard treatment for the hypogammaglobulinemia component.
PMID:20301580 SUPPORT Human Clinical
"Transient hypogammaglobulinemia has been rarely observed in those with XLP2."
Supports the transient and less universal nature of the humoral defect in XLP2, which qualifies the indication.
🔬

Biochemical Markers

1
Serum interleukin-18 (INCREASED)
Context: Serum IL-18 in XIAP deficiency reaches concentrations an order of magnitude above those seen in SAP deficiency, perforin deficiency (FHL2) or EBV-associated HLH, spikes with every HLH episode, and remains elevated in clinical remission after other pro-inflammatory cytokines have normalised. That persistence makes it a candidate disease-activity marker rather than a simple acute-phase reactant. Reported in a 10-patient cohort; it has not been prospectively validated as a diagnostic or monitoring test.
Pathograph Readouts
Readout Of Inflammasome Dysregulation and Sustained IL-18 Excess Positive Monitoring
Serum IL-18 tracks the hyperinflammatory node, rising with each HLH episode and remaining above normal between episodes.
Show evidence (1 reference)
PMID:24084330 SUPPORT Human Clinical
"Longitudinal examination of two patients demonstrated marked exacerbation of IL-18 levels during every occasion of HLH."
Longitudinal within-patient data show IL-18 tracking disease activity.
Show evidence (1 reference)
PMID:24084330 SUPPORT Human Clinical
"The concentration of interleukin (IL)-18 was strikingly elevated in the patients presented with HLH, and remained high after the recovery from HLH although levels of other pro-inflammatory cytokines approached the normal range."
Establishes both the magnitude of the IL-18 elevation and its persistence outside acute episodes.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population-based prevalence estimate exists for XLP2. The disease is described only through case series: 33 XLP1 versus 30 XLP2 patients in the largest comparative cohort, 25 patients in the German-led series of presenting manifestations, 19 transplanted patients in the international HSCT survey, 10 in the Cincinnati series and nine in the Japanese series, with substantial overlap between them. No Orphanet prevalence class is quoted because none was consulted for this record; the band rests on the case-series count alone.
Show evidence (2 references)
PMID:25666262 SUPPORT Human Clinical
"The X-linked inhibitor of apoptosis (XIAP) deficiency, also known as the X-linked lymphoproliferative syndrome type 2 (XLP-2), is a rare primary immunodeficiency."
A dedicated review characterises the disease as rare, supporting a qualitative rather than numeric prevalence class.
PMID:21119115 SUPPORT Human Clinical
"Here, a comparison of the clinical phenotypes associated with XLP-1 and XLP-2 was performed in cohorts of 33 and 30 patients, respectively."
The largest published XLP2 cohort assembled internationally numbered 30 patients, supporting a cases-in-literature measure.
{ }

Source YAML

click to show 
name: X-linked Lymphoproliferative Disease Due To XIAP Deficiency
creation_date: '2026-09-01T00:00:00Z'
category: Genetic
synonyms:
- XLP2
- XIAP deficiency
- X-linked lymphoproliferative syndrome type 2
- XIAP-related lymphoproliferative disease, X-linked
- BIRC4 deficiency
description: >-
  X-linked lymphoproliferative disease type 2 (XLP2) is caused by hemizygous
  loss-of-function variants in XIAP (also called BIRC4), which encodes the
  X-linked inhibitor of apoptosis protein. Despite sharing the XLP name and the
  susceptibility to Epstein-Barr virus with SAP/SH2D1A deficiency (XLP1), XIAP
  deficiency is a clinically distinct disease. Its core triad is recurrent
  hemophagocytic lymphohistiocytosis (HLH) - often EBV-triggered but frequently
  occurring without any demonstrable EBV infection - recurrent splenomegaly
  with cytopenias and fever, and a severe, treatment-refractory Crohn-like
  inflammatory bowel disease. The single most useful discriminator from XLP1 is
  a negative one: lymphoma, which affects roughly a third of XLP1 patients, has
  not been reported in males with XLP2, and common variable immunodeficiency has
  likewise not been described in them. XIAP has two largely separable functions
  that map onto the two clinical arms of the disease. Through its BIR domains it
  inhibits apoptotic caspases, so its loss makes lymphocytes hypersensitive to
  CD95-, TRAIL-R- and TCR-driven activation-induced cell death and depletes
  invariant NKT cells, degrading control of EBV and predisposing to HLH.
  Through its RING domain it is the essential ubiquitin ligase that
  ubiquitylates RIPK2 and recruits LUBAC to NOD2, so its loss cripples
  NOD2/NOD1-dependent NF-kappaB signaling in monocytes and intestinal
  epithelium and produces the Crohn-like colitis. A third strand, inflammasome
  dysregulation with strikingly and persistently elevated serum IL-18,
  accompanies and probably amplifies the hyperinflammatory episodes.
disease_term:
  preferred_term: XIAP deficiency (XLP2)
  term:
    id: MONDO:0010385
    label: X-linked lymphoproliferative disease due to XIAP deficiency
parents:
- X-linked lymphoproliferative syndrome
- Inborn error of immunity
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      XIAP deficiency is an inborn error of immunity in the IUIS immune
      dysregulation group, with hemophagocytic lymphohistiocytosis and
      hyperinflammation as its defining clinical problem.
    evidence:
    - reference: PMID:25666262
      reference_title: XIAP deficiency syndrome in humans.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The X-linked inhibitor of apoptosis (XIAP) deficiency, also known as the
        X-linked lymphoproliferative syndrome type 2 (XLP-2), is a rare primary
        immunodeficiency.
      explanation: >-
        Establishes XIAP deficiency as a primary immunodeficiency, placing it in
        Harrison's immunology/rheumatology Part.
  - classification_value: GASTROINTESTINAL
    notes: >-
      A severe, treatment-refractory Crohn-like inflammatory bowel disease is one
      of the three defining manifestations of XIAP deficiency and is frequently
      the presenting or only problem, so the disease also belongs to the
      gastrointestinal Part.
    evidence:
    - reference: PMID:24942515
      reference_title: >-
        Characterization of Crohn disease in X-linked inhibitor of
        apoptosis-deficient male patients and female symptomatic carriers.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        IBD in patients with XIAP deficiency is similar to Crohn disease and is
        associated with defective NOD2 function in monocytes.
      explanation: >-
        Characterises the intestinal disease of XIAP deficiency as a
        Crohn-disease-like inflammatory bowel disease, a gastrointestinal
        disorder.
    - reference: PMID:23973892
      reference_title: >-
        X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of
        presenting manifestations beyond hemophagocytic lymphohistiocytosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These included Crohn-like bowel disease (n=6), severe infectious
        mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1),
        periodic fever (n=1), fistulating skin abscesses (n=1) and severe
        Giardia enteritis (n=1).
      explanation: >-
        Crohn-like bowel disease was the single commonest non-HLH presenting
        manifestation in this cohort, supporting a gastrointestinal
        classification alongside the immunologic one.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      XLP2 is a monogenic X-linked disorder diagnosed by demonstrating a
      hemizygous germline XIAP variant.
    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: >-
        GeneReviews establishes XLP2 as a Mendelian, hemizygous germline
        disorder, supporting the genetics Part.
  iuis_category:
    classification_value: immune dysregulation
    notes: >-
      IUIS 2022 phenotypic classification, Table 4 "Diseases of immune
      dysregulation", section 7 "Susceptibility to EBV and Lymphoproliferative
      Conditions" (PMID:35748970).
    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: "XIAP deficiency (XLP2) XIAP XL 300079"
      explanation: >-
        The IUIS 2022 Table 4 row for XIAP deficiency (XLP2) places the disease
        in the diseases-of-immune-dysregulation category, with X-linked
        inheritance and OMIM 300079.
    - 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 subsection of the IUIS immune-dysregulation table under which
        the XIAP deficiency row sits.
inheritance:
- name: X-linked recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    XLP2 is inherited in an X-linked manner and is caused by hemizygous germline
    loss-of-function variants in XIAP. Heterozygous female carriers are usually
    asymptomatic, but carriers with skewed X-chromosome inactivation favouring
    the mutant allele can develop HLH and inflammatory bowel disease.
  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 X-linked mode of inheritance for XLP, including XLP2.
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There are, however, increasing numbers of reports of affected females with
      unfavorable (skewed) X-chromosome inactivation favoring the X chromosome
      with the pathogenic variant who develop HLH, inflammatory bowel disease,
      and erythema nodosum.
    explanation: >-
      Documents symptomatic heterozygous females with skewed X-inactivation, the
      qualification to the X-linked recessive pattern.
  - reference: PMID:24942515
    reference_title: >-
      Characterization of Crohn disease in X-linked inhibitor of
      apoptosis-deficient male patients and female symptomatic carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Importantly, we report that it is not restricted to male patients because
      we identified 2 symptomatic female heterozygous carriers of XIAP
      mutations.
    explanation: >-
      Independent documentation that heterozygous female carriers can be
      symptomatic, qualifying the recessive X-linked pattern.
pathophysiology:
- name: XIAP Loss of Function
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Hemizygous germline XIAP/BIRC4 variants - most often nonsense, frameshift or
    splice alleles that abolish protein expression, and a smaller set of
    missense alleles clustered in the BIR2 and RING domains - eliminate or
    cripple XIAP protein. XIAP has two separable activities that both fail: its
    N-terminal BIR domains inhibit the apoptotic caspases, and its C-terminal
    RING domain provides the ubiquitin ligase activity required for NOD1/NOD2
    signaling. Loss of the first drives the lymphocyte-apoptosis arm of the
    disease; loss of the second drives the intestinal-inflammation arm.
  genetic_context:
    gene:
      preferred_term: XIAP
      term:
        id: hgnc:592
        label: XIAP
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: caspase inhibitor activity
    term:
      id: GO:0043027
      label: cysteine-type endopeptidase inhibitor activity involved in apoptotic process
    modifier: DECREASED
  biological_processes:
  - preferred_term: XIAP-mediated ubiquitylation of RIPK2
    term:
      id: GO:0016567
      label: protein ubiquitination
    modifier: DECREASED
  evidence:
  - reference: PMID:17080092
    reference_title: XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we identify mutations in the gene that encodes the X-linked
      inhibitor-of-apoptosis XIAP (also termed BIRC4) in patients with XLP from
      three families without mutations in SAP. These mutations lead to defective
      expression of XIAP.
    explanation: >-
      The founding report establishes loss of XIAP protein expression from
      XIAP/BIRC4 mutations as the molecular lesion of this disease.
  - reference: PMID:23818254
    reference_title: >-
      Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent
      immune signalling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      X-linked Inhibitor of Apoptosis (XIAP) is an essential ubiquitin ligase
      for pro-inflammatory signalling downstream of the nucleotide-binding
      oligomerization domain containing (NOD)-1 and -2 pattern recognition
      receptors.
    explanation: >-
      Identifies the second, ubiquitin-ligase function of XIAP that is lost in
      this disease, distinct from its caspase-inhibitory role.
  - reference: PMID:23818254
    reference_title: >-
      Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent
      immune signalling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we identify the XIAP baculovirus IAP repeat (BIR)2 domain as a
      hotspot for missense mutations in XLP2.
    explanation: >-
      Locates the recurrent missense alleles to the BIR2 domain, complementing
      the predominantly truncating allele spectrum.
  downstream:
  - target: Enhanced Activation-Induced Lymphocyte Apoptosis
    causal_link_type: DIRECT
    description: >-
      Without XIAP to restrain the apoptotic caspases, lymphocytes from patients
      die more readily in response to death-receptor and antigen-receptor
      stimulation.
    evidence:
    - reference: PMID:17080092
      reference_title: XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We show that apoptosis of lymphocytes from XIAP-deficient patients is
        enhanced in response to various stimuli including the T-cell antigen
        receptor (TCR)-CD3 complex, the death receptor CD95 (also termed Fas or
        Apo-1) and the TNF-associated apoptosis-inducing ligand receptor
        (TRAIL-R).
      explanation: >-
        Directly links loss of XIAP to enhanced lymphocyte apoptosis in patient
        cells.
  - target: Defective NOD2 Signaling in Monocytes and Intestinal Epithelium
    causal_link_type: DIRECT
    description: >-
      The RING-domain ubiquitin ligase activity of XIAP is required to
      ubiquitylate RIPK2 and recruit LUBAC to NOD2; XLP2 alleles abolish this
      step.
    evidence:
    - reference: PMID:22607974
      reference_title: >-
        The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in
        inflammation and innate immunity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Remarkably, XLP-2-derived XIAP variants have impaired ubiquitin ligase
        activity, fail to ubiquitylate RIPK2, and cannot facilitate NOD2
        signaling.
      explanation: >-
        Shows that the patient-derived XIAP variants themselves are the cause of
        the NOD2 signaling failure.
  - target: Inflammasome Dysregulation and Sustained IL-18 Excess
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      XIAP-deficient patients show a strikingly and persistently elevated serum
      IL-18 that is not seen in other forms of HLH. The intermediate steps are
      not established; NOD2-dependent caspase-1 activation is the leading
      candidate, and patient monocytes stimulated in vitro did not
      oversecrete IL-18, so the cellular source remains open.
    evidence:
    - reference: PMID:24084330
      reference_title: >-
        Sustained elevation of serum interleukin-18 and its association with
        hemophagocytic lymphohistiocytosis in XIAP deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The concentration of interleukin (IL)-18 was strikingly elevated in the
        patients presented with HLH, and remained high after the recovery from
        HLH although levels of other pro-inflammatory cytokines approached the
        normal range.
      explanation: >-
        Documents an IL-18 abnormality specific to XIAP deficiency that persists
        outside acute episodes, consistent with a constitutive consequence of
        XIAP loss.
- name: Enhanced Activation-Induced Lymphocyte Apoptosis
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    XIAP-deficient T cells are hypersensitive to CD95 (Fas), TRAIL-R and
    TCR-CD3-driven apoptosis, i.e. to activation-induced cell death. Activated
    effector lymphocytes are therefore deleted prematurely during an immune
    response, and the cells that would normally clear an infected target are
    lost at the moment they are needed. This is the arm of XIAP biology that the
    IUIS classification records as the functional defect of the disease.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: lymphocyte apoptotic process
    term:
      id: GO:0070227
      label: lymphocyte apoptotic process
    modifier: INCREASED
  - preferred_term: T cell homeostasis
    term:
      id: GO:0043029
      label: T cell homeostasis
    modifier: DECREASED
  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: >-
      Increased T cells susceptibility to apoptosis to CD95 and enhanced
      activation-induced cell death (AICD)
    explanation: >-
      The IUIS classification records enhanced CD95-driven apoptosis and
      activation-induced cell death as the functional defect of XIAP deficiency.
  - reference: PMID:17080092
    reference_title: XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we show that XIAP is a potent regulator of lymphocyte homeostasis in vivo
    explanation: >-
      Frames the apoptosis defect as a failure of lymphocyte homeostasis rather
      than an isolated in-vitro observation.
  downstream:
  - target: Invariant NKT Cell Depletion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Invariant NKT cells depend on XIAP for survival and/or differentiation and
      are reduced or absent in patients. Whether this reflects the same
      apoptotic hypersensitivity or a separate developmental requirement is not
      resolved.
    evidence:
    - reference: PMID:17080092
      reference_title: XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We also found that XIAP-deficient patients, like SAP-deficient patients,
        have low numbers of natural killer T-lymphocytes (NKT cells), indicating
        that XIAP is required for the survival and/or differentiation of NKT
        cells.
      explanation: >-
        Establishes the iNKT deficit and attributes it to a XIAP requirement for
        NKT survival or differentiation.
  - target: Hypogammaglobulinemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Premature deletion of activated lymphocytes is the most plausible route to
      the transient hypogammaglobulinemia seen in about a third of patients, but
      no source traces the humoral defect to a specific step, and its transience
      argues against a fixed developmental block. The edge is recorded as
      indirect with unknown intermediates rather than asserting a mechanism the
      literature does not supply.
    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
      directness: INDIRECT
      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: >-
        Establishes that hypogammaglobulinemia occurs in XLP2 and at roughly half
        the XLP1 rate; the cohort reports the association, not the mechanistic
        path from lymphocyte apoptosis to it, which is why this edge is typed
        indirect with unknown intermediates.
  - target: Hemophagocytic Lymphohistiocytosis Susceptibility
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Premature deletion of activated effector lymphocytes leaves the antigen -
      classically EBV-infected B cells - uncleared, so the immune response is
      sustained rather than terminated, and the macrophage-activating cytokine
      loop that defines HLH is allowed to run.
    evidence:
    - reference: PMID:20489057
      reference_title: >-
        XIAP deficiency: a unique primary immunodeficiency best classified as
        X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked
        lymphoproliferative disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Lymphocyte defects thought to contribute to HLH development in
        SLAM-Associated Protein deficiency were not observed in XIAP deficiency.
      explanation: >-
        Establishes that the route to HLH in XIAP deficiency is not the
        SAP-deficiency route, supporting a distinct, apoptosis-driven mechanism
        with intermediates that are only partly mapped.
    - reference: PMID:24084330
      reference_title: >-
        Sustained elevation of serum interleukin-18 and its association with
        hemophagocytic lymphohistiocytosis in XIAP deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In XIAP deficiency, hemophagocytic lymphohistiocytosis (HLH) occurs more
        frequently and recurrence is common. However, the underlying mechanisms
        remain mostly unknown.
      explanation: >-
        Confirms the strong HLH predisposition while stating explicitly that the
        intervening mechanism is incompletely known.
- name: Invariant NKT Cell Depletion
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Invariant natural killer T cells are reduced in XIAP-deficient patients, as
    they are in SAP deficiency. Because iNKT cells are thought to have a key role
    in the immune response to EBV, this is one of the few features XLP1 and XLP2
    genuinely share, and it plausibly contributes to the failure to contain
    primary EBV infection. The node is graded provisional because the finding is
    not uniform: the founding Nature report and an independent Japanese cohort
    both found iNKT cells significantly reduced, but the IUIS classification
    records the count as low or normal, so a normal iNKT compartment does not
    exclude the diagnosis and iNKT depletion cannot be the whole explanation for
    HLH susceptibility.
  cell_types:
  - preferred_term: invariant (type I) NKT cell
    term:
      id: CL:0000921
      label: type I NK T cell
  evidence:
  - reference: PMID:22228567
    reference_title: Clinical and genetic characteristics of XIAP deficiency in Japan.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      iNKT cells from patients with XIAP deficiency were significantly decreased
      as compared with age-matched healthy controls.
    explanation: >-
      Quantitative confirmation of the iNKT deficit in an independent
      nine-patient cohort.
  - 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
    directness: INDIRECT
    snippet: >-
      Normal or Increased activated T cells; low/normal iNK T cells
    explanation: >-
      The IUIS classification records the iNKT count in XIAP deficiency as low
      or normal. It supports iNKT depletion as a recognised feature while
      explicitly noting it is not universal, which is why this node is graded
      provisional.
  downstream:
  - target: Hemophagocytic Lymphohistiocytosis Susceptibility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of iNKT cells degrades the early cellular response to EBV, the
      commonest HLH trigger in this disease.
    evidence:
    - reference: PMID:17080092
      reference_title: XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The observation that XIAP-deficiency and SAP-deficiency are both
        associated with a defect in NKT cells strengthens the hypothesis that
        NKT cells have a key role in the immune response to EBV.
      explanation: >-
        Connects the iNKT deficit to impaired anti-EBV immunity, the pathway to
        EBV-triggered HLH.
  - target: Severe Epstein-Barr virus infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of the iNKT compartment degrades the early cellular response to
      primary EBV, so that infection which is self-limiting in healthy hosts
      can instead present as severe infectious mononucleosis. The step is
      graded provisional along with its source node: iNKT counts are low or
      normal in XIAP deficiency, and severe mononucleosis is a presenting
      manifestation in a minority of patients rather than the rule, so this is
      a contributing path to EBV susceptibility and not a sufficient
      explanation of it.
    evidence:
    - reference: PMID:17080092
      reference_title: XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The observation that XIAP-deficiency and SAP-deficiency are both
        associated with a defect in NKT cells strengthens the hypothesis that
        NKT cells have a key role in the immune response to EBV.
      explanation: >-
        The mechanistic bridge from the iNKT deficit to impaired EBV control.
        INDIRECT because the authors argue the role of NKT cells in anti-EBV
        immunity from the convergence of two genotypes rather than measuring
        EBV control directly.
    - reference: PMID:23973892
      reference_title: >-
        X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of
        presenting manifestations beyond hemophagocytic lymphohistiocytosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These included Crohn-like bowel disease (n=6), severe infectious
        mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1),
        periodic fever (n=1), fistulating skin abscesses (n=1) and severe
        Giardia enteritis (n=1).
      explanation: >-
        Establishes the clinical endpoint of this edge, severe infectious
        mononucleosis, in four of 25 patients, and by its position in that list
        shows it is one presentation among several rather than the dominant one.
- name: Defective NOD2 Signaling in Monocytes and Intestinal Epithelium
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    XIAP is the essential ubiquitin ligase of the NOD2 pathway: on sensing the
    bacterial peptidoglycan fragment muramyl dipeptide, NOD2 recruits RIPK2,
    XIAP ubiquitylates RIPK2, and those chains recruit LUBAC to enable full
    NF-kappaB activation. XLP2 alleles in either the RING or the BIR2 domain
    abolish RIPK2 binding or ubiquitylation, so patient monocytes mount
    defective NOD2-driven cytokine and chemokine responses and patient
    fibroblasts show a parallel NOD1 defect. NOD2 is the strongest known genetic
    risk factor for Crohn disease and is central to antibacterial defence at
    mucosal surfaces, including in Paneth cells, which places this defect
    directly on the path to the intestinal disease.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: paneth cell
    term:
      id: CL:0000510
      label: paneth cell
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  biological_processes:
  - preferred_term: NOD2 signaling pathway
    term:
      id: GO:0070431
      label: nucleotide-binding oligomerization domain containing 2 signaling pathway
    modifier: DECREASED
  - preferred_term: response to muramyl dipeptide
    term:
      id: GO:0032495
      label: response to muramyl dipeptide
    modifier: DECREASED
  - preferred_term: NOD2-driven NF-kappaB activation
    term:
      id: GO:0043123
      label: positive regulation of canonical NF-kappaB signal transduction
    modifier: DECREASED
  locations:
  - preferred_term: intestine
    term:
      id: UBERON:0000160
      label: intestine
  evidence:
  - reference: PMID:22607974
    reference_title: >-
      The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in
      inflammation and innate immunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We find that XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin
      chain assembly complex (LUBAC) to NOD2.
    explanation: >-
      Defines the molecular step XIAP performs in NOD2 signaling and that is
      therefore missing in XLP2.
  - reference: PMID:22607974
    reference_title: >-
      The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in
      inflammation and innate immunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We conclude that XIAP and LUBAC constitute essential ubiquitin ligases in
      NOD2-mediated inflammatory signaling and propose that deregulation of NOD2
      signaling contributes to XLP-2 pathogenesis.
    explanation: >-
      States the authors' conclusion that deregulated NOD2 signaling contributes
      to XLP2 pathogenesis.
  - reference: PMID:23818254
    reference_title: >-
      Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent
      immune signalling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We demonstrate that XLP2-BIR2 mutations severely impair NOD1/2-dependent
      immune signalling in primary cells from XLP2 patients and in reconstituted
      XIAP-deficient cell lines.
    explanation: >-
      Demonstrates the NOD1/NOD2 signaling defect in cells taken from patients,
      not only in engineered lines.
  - reference: PMID:24942515
    reference_title: >-
      Characterization of Crohn disease in X-linked inhibitor of
      apoptosis-deficient male patients and female symptomatic carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte
      chemoattractant protein 1 (MCP-1) production, as well as IL-10, in
      response to NOD2 and Toll-like receptor 2/4 costimulation.
    explanation: >-
      Documents the functional consequence in patient monocytes: failure to
      produce NOD2-driven chemokines and IL-10.
  - reference: PMID:24942515
    reference_title: >-
      Characterization of Crohn disease in X-linked inhibitor of
      apoptosis-deficient male patients and female symptomatic carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nucleotide binding and oligomerization domain containing 1
      (NOD1)-mediated IL-6 and IL-8 production was defective in fibroblasts from
      XIAP-deficient patients.
    explanation: >-
      Extends the signaling defect to NOD1 in a non-haematopoietic patient cell
      type.
  downstream:
  - target: Crohn-like Intestinal Inflammation
    causal_link_type: DIRECT
    description: >-
      Impaired NOD2-dependent antibacterial and cytokine responses at the
      intestinal mucosa produce a Crohn-disease-like inflammatory bowel disease.
    evidence:
    - reference: PMID:24942515
      reference_title: >-
        Characterization of Crohn disease in X-linked inhibitor of
        apoptosis-deficient male patients and female symptomatic carriers.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        IBD in patients with XIAP deficiency is similar to Crohn disease and is
        associated with defective NOD2 function in monocytes.
      explanation: >-
        Directly links the NOD2 functional defect to the Crohn-like intestinal
        disease in the same patients.
- name: Inflammasome Dysregulation and Sustained IL-18 Excess
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    Serum IL-18 in XIAP deficiency is elevated an order of magnitude beyond what
    is seen in SAP deficiency, perforin deficiency or EBV-associated HLH, spikes
    with every HLH episode, and - unlike every other pro-inflammatory cytokine
    measured - stays high in clinical remission. IL-18 is generated by
    caspase-1 within the inflammasome, and because NOD2 can activate caspase-1
    the XIAP-NOD2 axis is the leading candidate route. The mechanism is marked
    provisional because patient PBMCs stimulated with LPS plus ATP did not
    oversecrete IL-18 relative to controls, so neither the cellular source nor
    the trigger is established.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: interleukin-18 production
    term:
      id: GO:0032621
      label: interleukin-18 production
    modifier: INCREASED
  - preferred_term: positive regulation of inflammatory response
    term:
      id: GO:0050729
      label: positive regulation of inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:24084330
    reference_title: >-
      Sustained elevation of serum interleukin-18 and its association with
      hemophagocytic lymphohistiocytosis in XIAP deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Longitudinal examination of two patients demonstrated marked exacerbation
      of IL-18 levels during every occasion of HLH.
    explanation: >-
      Longitudinal data tie IL-18 excursions to each hyperinflammatory episode
      within individual patients.
  - reference: PMID:25666262
    reference_title: XIAP deficiency syndrome in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recent findings demonstrate the role of XIAP in innate immunity and in the
      negative regulation of inflammation.
    explanation: >-
      Supports treating loss of XIAP as a release of a brake on inflammation,
      not only as an apoptosis defect.
  downstream:
  - target: Hemophagocytic Lymphohistiocytosis Susceptibility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The sustained IL-18 excess is proposed to lower the threshold for, and to
      amplify, the hyperinflammatory episodes; the authors advance it as an
      additional explanation for HLH susceptibility rather than a demonstrated
      cause.
    evidence:
    - reference: PMID:24084330
      reference_title: >-
        Sustained elevation of serum interleukin-18 and its association with
        hemophagocytic lymphohistiocytosis in XIAP deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These findings may suggest the association between HLH susceptibility
        and high serum IL-18 levels in XIAP deficiency.
      explanation: >-
        The authors state the association between IL-18 and HLH susceptibility
        in hedged terms, which is why this edge is indirect and the node is
        provisional.
  - target: Recurrent fever
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Persistent systemic hyperinflammation manifests clinically as recurrent
      febrile episodes, often with splenomegaly and cytopenia, which are
      interpreted as minimal forms of HLH.
    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: >-
        Recurrent splenomegaly often associated with cytopenia and fever was
        preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably
        represents minimal forms of HLH as documented by histopathology.
      explanation: >-
        Documents recurrent fever with splenomegaly and cytopenia as the
        characteristic hyperinflammatory presentation of XLP2.
- name: Hemophagocytic Lymphohistiocytosis Susceptibility
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    The convergent consequence of the apoptosis and inflammation arms is a
    strong, lifelong predisposition to HLH: uncontrolled macrophage and T-cell
    activation with hypercytokinaemia, fever, cytopenias, hepatosplenomegaly and
    hemophagocytosis. EBV is the commonest trigger, but a substantial fraction of
    episodes occur with no demonstrable EBV infection, which is a point of
    contrast with XLP1. Recurrence is the rule rather than the exception.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: cytokine production involved in immune response
    term:
      id: GO:0002367
      label: cytokine production involved in immune response
    modifier: INCREASED
  evidence:
  - reference: PMID:20489057
    reference_title: >-
      XIAP deficiency: a unique primary immunodeficiency best classified as
      X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked
      lymphoproliferative disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nine of 10 patients developed HLH by 8 years of age. Most patients
      presented in infancy, and recurrent HLH was common.
    explanation: >-
      Quantifies the HLH predisposition and its recurrence in a molecularly
      defined cohort.
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Males with XLP2 are more likely to have HLH without EBV infection,
      recurrent episodes of HLH (which is not typically seen in those with
      XLP1), splenomegaly, and gastrointestinal disease, including enterocolitis
      and perirectal abscesses or fistulae.
    explanation: >-
      GeneReviews states the EBV-independent and recurrent character of HLH in
      XLP2 and contrasts it explicitly with XLP1.
  downstream:
  - target: Hemophagocytic lymphohistiocytosis
    causal_link_type: DIRECT
    description: >-
      The susceptibility manifests as clinical episodes of HLH, most often
      beginning in infancy or early childhood.
    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 HLH in a 30-patient XLP2 cohort against a matched XLP1
        comparison group.
  - target: Splenomegaly
    causal_link_type: DIRECT
    description: >-
      Recurrent splenomegaly, often with cytopenia and fever, is interpreted as
      a minimal or partial form of the same hyperinflammatory process.
    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: >-
        Recurrent splenomegaly often associated with cytopenia and fever was
        preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably
        represents minimal forms of HLH as documented by histopathology.
      explanation: >-
        Links splenomegaly to the HLH process and quantifies its strong
        preference for XLP2 over XLP1.
  - target: Cytopenias
    causal_link_type: DIRECT
    description: >-
      Bi- or trilineage peripheral cytopenias accompany the acute
      hyperinflammatory episodes.
    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 lists cytopenias among the defining features of the HLH
        episodes that dominate this disease.
- name: Crohn-like Intestinal Inflammation
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Chronic transmural intestinal inflammation whose clinical presentation and
    histology overlap with Crohn disease, ranging from chronic hemorrhagic
    colitis to fistulating and perianal disease. Onset spans infancy to
    adulthood, and the disease is characteristically severe and difficult to
    treat with conventional inflammatory-bowel-disease therapy. XIAP deficiency
    is now regarded as one of the monogenic causes of inherited IBD.
  biological_processes:
  - preferred_term: intestinal inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  locations:
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  evidence:
  - reference: PMID:24942515
    reference_title: >-
      Characterization of Crohn disease in X-linked inhibitor of
      apoptosis-deficient male patients and female symptomatic carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical presentation and histology of IBD in patients with XIAP
      deficiency overlapped with those of patients with Crohn disease.
    explanation: >-
      Establishes the Crohn-disease-like character of the intestinal disease
      both clinically and histologically.
  - reference: PMID:25666262
    reference_title: XIAP deficiency syndrome in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "XIAP deficiency can be considered as one of the genetic causes for inherited IBD."
    explanation: >-
      Places XIAP deficiency among the monogenic causes of inflammatory bowel
      disease.
  downstream:
  - target: Crohn-like inflammatory bowel disease
    causal_link_type: DIRECT
    description: >-
      The tissue-level inflammation presents clinically as a severe,
      treatment-refractory inflammatory bowel disease.
    evidence:
    - reference: PMID:24942515
      reference_title: >-
        Characterization of Crohn disease in X-linked inhibitor of
        apoptosis-deficient male patients and female symptomatic carriers.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The age at onset was variable (from 3 months to 41 years), and IBD was
        severe and difficult to treat.
      explanation: >-
        Documents the clinical severity and treatment refractoriness of the
        intestinal disease.
phenotypes:
- name: Hemophagocytic lymphohistiocytosis
  category: Clinical
  description: >-
    Recurrent HLH is the dominant clinical problem, affecting roughly three
    quarters of patients and typically beginning in infancy or early childhood.
    Two features distinguish it from HLH in XLP1: episodes recur, and a
    substantial minority occur with no demonstrable EBV infection. Lethality per
    episode is nonetheless lower than in XLP1.
  phenotype_term:
    preferred_term: Hemophagocytic lymphohistiocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
    temporality: RECURRENT
  frequency: FREQUENT
  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: >-
      HLH occurred in 76% of 30 XLP2 patients, supporting the FREQUENT (30-79%)
      band.
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Males with XLP2 are more likely to have HLH without EBV infection,
      recurrent episodes of HLH (which is not typically seen in those with
      XLP1), splenomegaly, and gastrointestinal disease, including enterocolitis
      and perirectal abscesses or fistulae.
    explanation: >-
      Supports both the recurrent temporality and the occurrence of HLH without
      EBV, the two features that separate XLP2 HLH from XLP1 HLH.
  - 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: >-
      Quantifies the lower per-episode lethality of HLH in XLP2 relative to
      XLP1.
- name: Splenomegaly
  category: Clinical
  description: >-
    Recurrent splenomegaly, usually accompanied by cytopenia and fever, is the
    single most discriminating positive feature of XLP2, present in 87% of
    patients versus 7% of XLP1 patients. Histopathology supports interpreting
    these episodes as minimal forms of HLH. Isolated splenomegaly can be the
    presenting manifestation.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
    temporality: RECURRENT
  frequency: VERY_FREQUENT
  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: >-
      Recurrent splenomegaly often associated with cytopenia and fever was
      preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably
      represents minimal forms of HLH as documented by histopathology.
    explanation: >-
      Splenomegaly in 87% of XLP2 patients supports the VERY_FREQUENT (80-100%)
      band and the recurrent temporality.
  - reference: PMID:23973892
    reference_title: >-
      X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of
      presenting manifestations beyond hemophagocytic lymphohistiocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These included Crohn-like bowel disease (n=6), severe infectious
      mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1),
      periodic fever (n=1), fistulating skin abscesses (n=1) and severe
      Giardia enteritis (n=1).
    explanation: >-
      Documents isolated splenomegaly as a presenting manifestation in three of
      25 patients.
- name: Crohn-like inflammatory bowel disease
  category: Clinical
  description: >-
    A severe, treatment-refractory inflammatory bowel disease that clinically and
    histologically resembles Crohn disease, including chronic hemorrhagic
    colitis, enterocolitis, and perirectal abscesses or fistulae. Age at onset
    spans three months to 41 years. It is frequently the presenting - sometimes
    the only - manifestation, and standard IBD therapy is often inadequate.
  phenotype_term:
    preferred_term: Crohn-like colitis
    term:
      id: HP:0002037
      label: Inflammation of the large intestine
    clinical_course: PROGRESSIVE
  frequency: OCCASIONAL
  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: >-
      Chronic hemorrhagic colitis in 17% of 30 XLP2 patients supports the
      OCCASIONAL (5-29%) band.
  - reference: PMID:24942515
    reference_title: >-
      Characterization of Crohn disease in X-linked inhibitor of
      apoptosis-deficient male patients and female symptomatic carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The age at onset was variable (from 3 months to 41 years), and IBD was
      severe and difficult to treat.
    explanation: >-
      Documents the wide age range at onset and the treatment refractoriness of
      the intestinal disease.
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Males with XLP2 are more likely to have HLH without EBV infection,
      recurrent episodes of HLH (which is not typically seen in those with
      XLP1), splenomegaly, and gastrointestinal disease, including enterocolitis
      and perirectal abscesses or fistulae.
    explanation: >-
      GeneReviews documents enterocolitis and perirectal abscesses or fistulae
      as XLP2-preferential gastrointestinal disease.
- name: Recurrent fever
  category: Clinical
  description: >-
    Recurrent febrile episodes, usually together with splenomegaly and
    cytopenia, reflect the underlying hyperinflammatory state. Periodic fever can
    be the presenting manifestation in the absence of frank HLH.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
    temporality: RECURRENT
  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: >-
      Recurrent splenomegaly often associated with cytopenia and fever was
      preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably
      represents minimal forms of HLH as documented by histopathology.
    explanation: >-
      Documents recurrent fever as part of the characteristic XLP2
      hyperinflammatory triad.
  - reference: PMID:23973892
    reference_title: >-
      X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of
      presenting manifestations beyond hemophagocytic lymphohistiocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These included Crohn-like bowel disease (n=6), severe infectious
      mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1),
      periodic fever (n=1), fistulating skin abscesses (n=1) and severe
      Giardia enteritis (n=1).
    explanation: >-
      Documents periodic fever as a presenting manifestation independent of
      overt HLH.
- name: Cytopenias
  category: Laboratory
  description: >-
    Bi- or trilineage peripheral cytopenias (anemia, thrombocytopenia and/or
    neutropenia) accompany the acute hyperinflammatory episodes and the recurrent
    splenomegaly.
  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 lists bi- or trilineage cytopenias as a defining feature of
      the 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: >-
      Recurrent splenomegaly often associated with cytopenia and fever was
      preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably
      represents minimal forms of HLH as documented by histopathology.
    explanation: >-
      Documents cytopenia as a component of the recurrent splenomegaly-fever
      episodes.
- name: Hypogammaglobulinemia
  category: Laboratory
  description: >-
    Hypogammaglobulinemia occurs in roughly a third of XLP2 patients, about half
    the rate seen in XLP1, and GeneReviews describes it as typically transient
    rather than the sustained humoral deficiency of XLP1. Common variable
    immunodeficiency has not been reported in males with XLP2.

    The two cited sources disagree on how common it is, and the disagreement is
    left visible rather than resolved: the 33% figure comes from a comparative
    cohort that measured immunoglobulins systematically, whereas GeneReviews
    calls it rarely observed. Transience is the likely reconciliation — a deficit
    that resolves is one a cross-sectional cohort catches and a clinical
    description does not dwell on — but that is an inference, not something
    either source states. The FREQUENT band follows the quantified estimate;
    the GeneReviews sentence is recorded against it as a REFUTE item.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
    temporality: TRANSIENT
  frequency: FREQUENT
  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: >-
      Hypogammaglobulinemia in 33% of 30 XLP2 patients supports the FREQUENT
      (30-79%) band and quantifies the contrast with XLP1.
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transient hypogammaglobulinemia has been rarely observed in those with XLP2."
    explanation: >-
      GeneReviews characterises the hypogammaglobulinemia of XLP2 as transient,
      supporting the TRANSIENT temporality.
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Transient hypogammaglobulinemia has been rarely observed in those with XLP2."
    explanation: >-
      The same sentence cuts the other way on frequency. "Rarely observed" is
      not the FREQUENT (30-79%) band this phenotype carries, so GeneReviews
      refutes the band even while supporting the temporality. Recorded as a
      separate REFUTE item rather than folded into the SUPPORT above, since one
      evidence item cannot carry two directions. The band follows the cohort
      figure because that is the only quantified estimate; see the phenotype
      description for why the two sources can both be right.
- name: Severe Epstein-Barr virus infection
  category: Clinical
  description: >-
    EBV is the common trigger of HLH in XLP2, and severe infectious
    mononucleosis can be the presenting manifestation. Unlike XLP1, however, a
    meaningful fraction of XLP2 hyperinflammatory episodes arise with no
    demonstrable EBV infection, so EBV susceptibility does not define the
    disease.
  phenotype_term:
    preferred_term: Severe Epstein-Barr virus infection
    term:
      id: HP:0031693
      label: Severe Epstein Barr virus infection
  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 as the trigger in 83% of XLP2 HLH episodes, leaving 17%
      EBV-independent.
  - reference: PMID:23973892
    reference_title: >-
      X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of
      presenting manifestations beyond hemophagocytic lymphohistiocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These included Crohn-like bowel disease (n=6), severe infectious
      mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1),
      periodic fever (n=1), fistulating skin abscesses (n=1) and severe
      Giardia enteritis (n=1).
    explanation: >-
      Documents severe infectious mononucleosis as a presenting manifestation in
      four of 25 patients.
- name: Lymphoma
  category: Clinical
  description: >-
    Lymphoma is NOT a feature of XIAP deficiency, and this negative is the
    single most useful discriminator from XLP1, where roughly 30% of patients
    develop lymphoma. Three independent cohorts and the GeneReviews chapter all
    record its absence. The absence was one of the arguments for reclassifying
    XIAP deficiency as an X-linked familial HLH rather than a true
    lymphoproliferative syndrome. Absence of reported cases in cohorts of this
    size is not proof of zero risk, but no case has been described.
  phenotype_term:
    preferred_term: Lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:20489057
    reference_title: >-
      XIAP deficiency: a unique primary immunodeficiency best classified as
      X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked
      lymphoproliferative disease.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "There were no cases of lymphoma."
    explanation: >-
      No lymphoma occurred in 10 molecularly confirmed XIAP-deficient patients
      from eight unrelated families.
  - 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: REFUTE
    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: >-
      Head-to-head comparison of 33 XLP1 and 30 XLP2 patients: lymphoma occurred
      only in XLP1, and colitis substituted for it in XLP2.
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, neither lymphoproliferative disease nor common variable
      immunodeficiency has been reported in males with XLP2.
    explanation: >-
      The GeneReviews chapter states directly that lymphoproliferative disease
      has not been reported in XLP2.
  - reference: PMID:20489057
    reference_title: >-
      XIAP deficiency: a unique primary immunodeficiency best classified as
      X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked
      lymphoproliferative disease.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      XIAP deficiency was originally observed to be associated with a high
      incidence of hemophagocytic lymphohistiocytosis (HLH) and a lack of
      lymphoma, suggesting that classification of XIAP deficiency as a cause of
      XLP may not be entirely accurate.
    explanation: >-
      States the lack of lymphoma as the basis for reclassifying the disease
      away from XLP.
biochemical:
- name: Serum interleukin-18
  presence: INCREASED
  context: >-
    Serum IL-18 in XIAP deficiency reaches concentrations an order of magnitude
    above those seen in SAP deficiency, perforin deficiency (FHL2) or
    EBV-associated HLH, spikes with every HLH episode, and remains elevated in
    clinical remission after other pro-inflammatory cytokines have normalised.
    That persistence makes it a candidate disease-activity marker rather than a
    simple acute-phase reactant. Reported in a 10-patient cohort; it has not
    been prospectively validated as a diagnostic or monitoring test.
  readouts:
  - target: Inflammasome Dysregulation and Sustained IL-18 Excess
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Serum IL-18 tracks the hyperinflammatory node, rising with each HLH
      episode and remaining above normal between episodes.
    evidence:
    - reference: PMID:24084330
      reference_title: >-
        Sustained elevation of serum interleukin-18 and its association with
        hemophagocytic lymphohistiocytosis in XIAP deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Longitudinal examination of two patients demonstrated marked
        exacerbation of IL-18 levels during every occasion of HLH.
      explanation: >-
        Longitudinal within-patient data show IL-18 tracking disease activity.
  evidence:
  - reference: PMID:24084330
    reference_title: >-
      Sustained elevation of serum interleukin-18 and its association with
      hemophagocytic lymphohistiocytosis in XIAP deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The concentration of interleukin (IL)-18 was strikingly elevated in the
      patients presented with HLH, and remained high after the recovery from
      HLH although levels of other pro-inflammatory cytokines approached the
      normal range.
    explanation: >-
      Establishes both the magnitude of the IL-18 elevation and its persistence
      outside acute episodes.
genetic:
- name: XIAP
  gene_term:
    preferred_term: XIAP
    term:
      id: hgnc:592
      label: XIAP
  association: CAUSATIVE
  notes: >-
    XLP2 is caused by hemizygous germline loss-of-function variants in XIAP,
    also known as BIRC4 (OMIM 300079; the XLP2 phenotype is OMIM 300635). Most
    reported alleles are nonsense, frameshift or splice variants that abolish or
    severely reduce XIAP protein, which is why flow cytometry for intracellular
    XIAP is a useful but imperfect screen. A minority are missense alleles
    concentrated in the BIR2 and RING domains. Neither genotype nor residual
    protein expression predicts the clinical phenotype, so molecular testing is
    required for diagnosis.
  evidence:
  - reference: PMID:17080092
    reference_title: XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we identify mutations in the gene that encodes the X-linked
      inhibitor-of-apoptosis XIAP (also termed BIRC4) in patients with XLP from
      three families without mutations in SAP. These mutations lead to defective
      expression of XIAP.
    explanation: >-
      Establishes XIAP/BIRC4 as the causative gene, identified in XLP families
      without SAP mutations.
  - reference: PMID:23973892
    reference_title: >-
      X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of
      presenting manifestations beyond hemophagocytic lymphohistiocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, neither genotype nor protein expression nor results from cell
      death studies were clearly associated with the clinical phenotype. Only
      mutation analysis can reliably identify affected patients.
    explanation: >-
      Documents the absence of genotype-phenotype correlation and the need for
      molecular testing rather than functional screening.
  - reference: PMID:22228567
    reference_title: Clinical and genetic characteristics of XIAP deficiency in Japan.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven out of eight patients showed decreased XIAP protein expression."
    explanation: >-
      Quantifies the sensitivity limitation of XIAP protein screening: one of
      eight tested patients had normal expression.
  - reference: PMID:23818254
    reference_title: >-
      Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent
      immune signalling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we identify the XIAP baculovirus IAP repeat (BIR)2 domain as a
      hotspot for missense mutations in XLP2.
    explanation: >-
      Locates the missense allele hotspot to the BIR2 domain, complementing the
      predominantly truncating spectrum.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based prevalence estimate exists for XLP2. The disease is
    described only through case series: 33 XLP1 versus 30 XLP2 patients in the
    largest comparative cohort, 25 patients in the German-led series of
    presenting manifestations, 19 transplanted patients in the international HSCT
    survey, 10 in the Cincinnati series and nine in the Japanese series, with
    substantial overlap between them. No Orphanet prevalence class is quoted
    because none was consulted for this record; the band rests on the case-series
    count alone.
  evidence:
  - reference: PMID:25666262
    reference_title: XIAP deficiency syndrome in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The X-linked inhibitor of apoptosis (XIAP) deficiency, also known as the
      X-linked lymphoproliferative syndrome type 2 (XLP-2), is a rare primary
      immunodeficiency.
    explanation: >-
      A dedicated review characterises the disease as rare, supporting a
      qualitative rather than numeric prevalence class.
  - 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: >-
      Here, a comparison of the clinical phenotypes associated with XLP-1 and
      XLP-2 was performed in cohorts of 33 and 30 patients, respectively.
    explanation: >-
      The largest published XLP2 cohort assembled internationally numbered 30
      patients, supporting a cases-in-literature measure.
treatments:
- name: Allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning
  description: >-
    Allogeneic HSCT is the only therapy that removes the underlying defect,
    replacing the XIAP-deficient haematopoietic compartment and, in reported
    cases, fully restoring intestinal homeostasis. Conditioning intensity is the
    critical variable and XIAP deficiency is an explicit exception to standard
    practice: in the international survey, only one of seven patients given
    busulfan-containing myeloablative conditioning survived, with deaths from
    transplant-related toxicity including venoocclusive disease and pulmonary
    haemorrhage, plausibly because losing XIAP's antiapoptotic function
    sensitises tissues to conditioning injury. Reduced-intensity conditioning
    gave 55% survival overall and 86% among those in HLH remission at
    transplant. Myeloablative regimens should not be used; reduced-intensity
    regimens should be used with caution and, where possible, only after HLH
    remission is achieved.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: XIAP Loss of Function
    treatment_effect: RESTORES
    description: >-
      Donor haematopoiesis supplies XIAP-competent lymphocytes and monocytes,
      restoring both the caspase-inhibitory and the NOD2-scaffolding functions in
      the haematopoietic compartment.
    evidence:
    - reference: PMID:24942515
      reference_title: >-
        Characterization of Crohn disease in X-linked inhibitor of
        apoptosis-deficient male patients and female symptomatic carriers.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis."
      explanation: >-
        Demonstrates that replacing the XIAP-deficient haematopoietic
        compartment corrects the downstream intestinal disease.
  evidence:
  - reference: PMID:23131490
    reference_title: >-
      Allogeneic hematopoietic cell transplantation for XIAP deficiency: an
      international survey reveals poor outcomes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Survival was poor in the MAC group, with only 1 patient surviving (14%).
      Most deaths were from transplantation-related toxicities, including
      venoocclusive disease and pulmonary hemorrhage.
    explanation: >-
      Quantifies the excess toxicity of myeloablative conditioning that makes
      XIAP deficiency an exception to standard transplant practice.
  - reference: PMID:23131490
    reference_title: >-
      Allogeneic hematopoietic cell transplantation for XIAP deficiency: an
      international survey reveals poor outcomes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that MAC regimens should not be used for patients with XIAP
      deficiency. It is possible that the loss of XIAP and its antiapoptotic
      functions contributes to the high incidence of toxicities observed with
      MAC regimens.
    explanation: >-
      States the recommendation against myeloablative conditioning and its
      mechanistic rationale in XIAP biology.
  - reference: PMID:23131490
    reference_title: >-
      Allogeneic hematopoietic cell transplantation for XIAP deficiency: an
      international survey reveals poor outcomes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RIC regimens should be pursued with caution and, if possible, efforts
      should be made to ensure HLH remission before HCT in these patients.
    explanation: >-
      States the recommendation for reduced-intensity conditioning and for
      achieving HLH remission before transplant.
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For individuals with XLP2, many manifestations of disease can be improved
      with HSCT; however, there are more complications in these individuals.
    explanation: >-
      GeneReviews confirms both the benefit and the excess complication rate of
      HSCT specifically in XLP2.
- name: HLH-directed immunochemotherapy
  description: >-
    Acute hyperinflammatory episodes are treated with the standard HLH approach:
    etoposide and corticosteroids, with rituximab considered where EBV drives the
    episode, plus cyclosporine in many reported cases. This suppresses the
    episode and is used as a bridge to transplant; it does not correct the
    underlying defect, and recurrence after treatment is characteristic of this
    disease.
  treatment_term:
    preferred_term: HLH-directed pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: etoposide
      term:
        id: CHEBI:4911
        label: etoposide
    - preferred_term: dexamethasone
      term:
        id: CHEBI:41879
        label: dexamethasone
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: Hemophagocytic Lymphohistiocytosis Susceptibility
    treatment_effect: INHIBITS
    description: >-
      Etoposide and corticosteroids suppress the activated T cells and
      macrophages driving the episode; rituximab depletes the EBV-infected B
      cells that trigger it. The underlying XIAP defect is untouched, so the
      predisposition persists.
    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 specifies etoposide, steroids and rituximab as the supportive
        treatment of HLH in XLP.
  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: >-
      Identifies the standard HLH-directed supportive regimen used in XLP,
      including XLP2.
  - reference: PMID:23131490
    reference_title: >-
      Allogeneic hematopoietic cell transplantation for XIAP deficiency: an
      international survey reveals poor outcomes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Preparative regimen and HLH activity affected outcomes, and of RIC
      patients reported to be in remission from HLH, survival is 86% (P = .03).
    explanation: >-
      Achieving HLH remission before transplant materially improves survival,
      which is the main reason HLH-directed therapy is given as a bridge.
- name: Management of XIAP-associated inflammatory bowel disease
  description: >-
    The Crohn-like IBD of XIAP deficiency is treated along conventional
    inflammatory-bowel-disease lines, but it is characteristically severe and
    difficult to treat, and standard therapy is often inadequate - which is why
    XIAP deficiency should be considered in refractory paediatric-onset Crohn
    disease and why transplant is escalated to when medical management fails.
    Colitis and cholangitis warrant active surveillance in XLP2.
  treatment_term:
    preferred_term: pharmacotherapy for inflammatory bowel disease
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Crohn-like Intestinal Inflammation
    treatment_effect: MODULATES
    description: >-
      Conventional IBD therapy suppresses the mucosal inflammatory response
      without correcting the underlying NOD2 signaling defect, which is the
      likely reason for its limited efficacy here.
    evidence:
    - reference: PMID:24942515
      reference_title: >-
        Characterization of Crohn disease in X-linked inhibitor of
        apoptosis-deficient male patients and female symptomatic carriers.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The age at onset was variable (from 3 months to 41 years), and IBD was
        severe and difficult to treat.
      explanation: >-
        Documents the limited response of XIAP-associated IBD to available
        therapy.
  evidence:
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      monitor for signs and symptoms of colitis and cholangitis in those with
      XLP2
    explanation: >-
      GeneReviews makes colitis and cholangitis surveillance an XLP2-specific
      management recommendation.
  - reference: PMID:24942515
    reference_title: >-
      Characterization of Crohn disease in X-linked inhibitor of
      apoptosis-deficient male patients and female symptomatic carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis."
    explanation: >-
      Establishes transplant as the escalation when medical management of the
      intestinal disease fails.
- name: Immunoglobulin replacement therapy
  description: >-
    Immunoglobulin substitution (IVIG or subcutaneous IgG) is given to the
    subset of patients with hypogammaglobulinemia. In XLP2 the humoral defect is
    typically transient, so the requirement is often temporary, unlike in XLP1.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_phenotypes:
  - preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  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: >-
      Identifies IVIG or IgG as the standard treatment for the
      hypogammaglobulinemia component.
  - reference: PMID:20301580
    reference_title: X-Linked Lymphoproliferative Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transient hypogammaglobulinemia has been rarely observed in those with XLP2."
    explanation: >-
      Supports the transient and less universal nature of the humoral defect in
      XLP2, which qualifies the indication.
references:
- reference: PMID:20301580
  title: X-Linked Lymphoproliferative Disease.
  tags:
  - GeneReviews
📚

References & Deep Research

References

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