STXBP2 – STXBP2-related hereditary hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis type 5 (FHL5) is caused by autosomal recessive mutations in the STXBP2 gene, encoding Munc18-2, a Sec1/Munc18 family protein essential for SNARE-mediated cytotoxic granule exocytosis. STXBP2 binds syntaxin-11 to drive the terminal fusion of lytic granules in NK and CD8+ T cells; loss of this function results in uncontrolled immune activation characteristic of hereditary hemophagocytic lymphohistiocytosis (PMID:19804848).

Biallelic STXBP2 variants have been reported in over 100 patients, including 37 probands from 28 unrelated families, confirming autosomal recessive inheritance. Pathogenic alleles span missense (e.g., c.1214G>A (p.Arg405Gln)) and splice-site changes (c.1247-1G>C), with consistent segregation of affected siblings (PMID:20798128; PMID:22451424).

Clinical presentation typically occurs within the first years of life but can be delayed by hypomorphic alleles. Hallmark features include recurrent fever (HP:0001945), hepatosplenomegaly (HP:0001433; HP:0001744), pancytopenia (HP:0001876), hypofibrinogenemia (HP:0011900), and, in early-onset cases, severe diarrhea. Atypical manifestations such as sensorineural hearing loss and bleeding diathesis further expand the phenotypic spectrum.

Functional assays in patient-derived NK and CTL demonstrate profoundly reduced CD107a expression and impaired cytotoxicity, which are restored by IL-2 stimulation or wild-type STXBP2 complementation, confirming a loss-of-function mechanism (PMID:19884660; PMID:22451424). Mouse knockout and patient organoid models corroborate defective secretory trafficking beyond immune cells.

No studies dispute STXBP2’s causal role in FHL5. The accumulation of robust genetic, segregation, and concordant functional data establishes a definitive gene–disease relationship. Prompt genetic diagnosis informs initiation of the HLH-2004 protocol and early allogeneic hematopoietic stem cell transplantation, the only curative intervention.

Key Take-home: Biallelic STXBP2 mutations definitively cause autosomal recessive FHL5 by disrupting Munc18-2–syntaxin-11–mediated granule fusion; genetic screening is essential for rapid diagnosis and effective treatment.

References

• American Journal of Human Genetics • 2009 • Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. PMID:19804848
• Journal of Medical Genetics • 2010 • STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5. PMID:20798128
• Blood • 2012 • Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). PMID:22451424
• The Journal of Clinical Investigation • 2009 • Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. PMID:19884660

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