XIAP – X-linked lymphoproliferative disease due to XIAP deficiency

X-linked inhibitor of apoptosis (XIAP) deficiency, caused by hemizygous loss-of-function variants in XIAP (HGNC:592), underlies X-linked lymphoproliferative disease type 2 (MONDO:0010385). Affected males present with life-threatening hemophagocytic lymphohistiocytosis (HLH), immune dysregulation, splenomegaly, and inflammatory bowel disease resembling Crohn’s disease. Female carriers may manifest erythema nodosum or mild IBD in association with random X-chromosome inactivation, confirming X-linked inheritance.

Genetic evidence supports a definitive gene-disease relationship. In an international cohort, 25 symptomatic males bore hemizygous XIAP variants including nonsense and frameshift mutations, with segregation in multiple families ([PMID:23973892]). Additional kindreds demonstrated transmission of LoF alleles with clinical penetrance in male probands and variable expressivity in female carriers ([PMID:25943627]).

The variant spectrum is dominated by frameshift and nonsense mutations in BIR domains, leading to absent or truncated protein. A recurrent family variant, c.672dup (p.Pro225fs), disrupts XIAP expression and function in monocytes, segregating with disease in multiple male probands and symptomatic female carriers ([PMID:25943627]).

Functional assays reveal that XIAP deficiency impairs NOD2-dependent NF-κB activation and lowers the threshold for cell death. Monocytes from patients show severely reduced TNF production upon L18-MDP stimulation (<6% vs 25% in controls) and absent XIAP protein by flow cytometry, establishing a rapid diagnostic test ([PMID:24611904]). CRISPR-engineered myeloid cells confirm that BIR2-domain variants abolish RIPK2 ubiquitylation and NOD2 signaling, while enhancing apoptotic susceptibility ([PMID:28404814]).

Treatment with allogeneic hematopoietic stem cell transplantation (HSCT) is curative, normalizing XIAP expression and resolving IBD and HLH manifestations. Early genetic diagnosis enables timely HSCT planning and family screening, including carrier detection by XIAP expression assays.

Key Take-home: XIAP deficiency is a definitive X-linked primary immunodeficiency with well-characterized LoF variants; integration of genetic testing and functional NOD2 assays guides diagnosis and curative HSCT.

References

• Clinical immunology • 2013 • X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis PMID:23973892
• Journal of clinical immunology • 2015 • Symptomatic males and female carriers in a large Caucasian kindred with XIAP deficiency PMID:25943627
• Clinical and experimental immunology • 2014 • A new functional assay for the diagnosis of X-linked inhibitor of apoptosis (XIAP) deficiency PMID:24611904
• The Journal of biological chemistry • 2017 • Nucleotide-binding oligomerization domain (NOD) signaling defects and cell death susceptibility cannot be uncoupled in X-linked inhibitor of apoptosis (XIAP)-driven inflammatory disease PMID:28404814

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