STXBP2 – Familial Hemophagocytic Lymphohistiocytosis Type 5

STXBP2 encodes syntaxin‐binding protein 2 (Munc18-2), a Sec1/Munc18 family member essential for SNARE‐mediated lytic granule exocytosis in cytotoxic lymphocytes. Biallelic STXBP2 variants cause an autosomal recessive hyperinflammatory disorder, familial hemophagocytic lymphohistiocytosis type 5 ([MONDO:0013135]). Clinically, affected individuals present in infancy with fever, hepatosplenomegaly, cytopenias, and hemophagocytosis.

Genetic evidence includes identification of biallelic STXBP2 mutations in ≥60 unrelated probands across >28 families, with segregation in multiple consanguineous and outbred pedigrees ([PMID:19804848], [PMID:20558610], [PMID:22451424]). The inheritance mode is autosomal recessive. The variant spectrum spans missense (e.g., c.1214G>C (p.Arg405Pro)), frameshift (e.g., c.859_883del (p.Leu287fs)), and splice-site changes. Exon 15 splice-site mutations correlate with later onset and milder degranulation defects ([PMID:22451424]). No individual variant or family has been consistently disputed.

Functional studies demonstrate that patient‐derived NK and cytotoxic T cells exhibit markedly reduced CD107a degranulation and cytotoxicity, which are rescued by interleukin‐2 stimulation ([PMID:20558610]). Structural assays reveal that pathogenic missense variants disrupt the STXBP2–syntaxin-11 interaction, destabilizing both proteins and impairing SNARE‐complex assembly ([PMID:19804848]). In intestinal organoid models, Munc18-2 deficiency recapitulates microvillus inclusion and barrier defects, explaining the colitis and intractable diarrhea seen in some patients ([PMID:30364784]).

The phenotypic spectrum of FHL5 includes fever (HP:0001945), hepatosplenomegaly (HP:0001433), thrombocytopenia (HP:0001873), hypofibrinogenemia (HP:0011900), hemophagocytosis (HP:0012156), and, in approximately one‐third, severe diarrhea and colitis (HP:0002018, HP:0002583) that may persist post–hematopoietic stem cell transplantation ([PMID:36503158]). Standard therapy combines immunosuppression and HSCT, although gastrointestinal manifestations often require adjunctive treatments.

No conflicting evidence disputes STXBP2’s role in FHL5. The concordance of genetic segregation, quantitative functional deficits, and rescue experiments establishes a loss‐of‐function mechanism. Additional studies in diverse populations continue to expand the variant catalogue and support universal diagnostic testing of STXBP2 in suspected HLH.

Key Take‐home: Biallelic STXBP2 mutations cause autosomal recessive FHL5 by disrupting Munc18-2–syntaxin-11–mediated granule exocytosis, with definitive genetic and functional evidence guiding diagnosis, family counseling, and therapeutic decisions.

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
• Blood • 2010 • Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2. PMID:20558610
• Blood • 2012 • Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). PMID:22451424
• Cellular and Molecular Gastroenterology and Hepatology • 2018 • Dynamic Formation of Microvillus Inclusions During Enterocyte Differentiation in Munc18-2-Deficient Intestinal Organoids. PMID:30364784
• Clinical Immunology (Orlando, Fla.) • 2023 • Monogenic inflammatory bowel disease with STXBP2 mutations is not resolved by hematopoietic stem cell transplantation but can be alleviated via immunosuppressive drug therapy. PMID:36503158

Evidence Based Scoring (AI generated)