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STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5
  1. Valentina Cetica1,
  2. Alessandra Santoro2,
  3. Kimberly C Gilmour3,
  4. Elena Sieni1,
  5. Karin Beutel1,
  6. Daniela Pende4,
  7. Stefania Marcenaro5,
  8. Florian Koch6,7,
  9. Samantha Grieve8,
  10. Rachel Wheeler3,
  11. Fang Zhao8,
  12. Udo zur Stadt6,7,
  13. Gillian M Griffiths8,
  14. Maurizio Aricò1
  1. 1Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer, Florence, Italy
  2. 2U.O. Ematologia I, A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy
  3. 3Centre for Immunodeficiency, Great Ormond Street Hospital, London UK
  4. 4Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
  5. 5DIMES, University of Genoa, Genoa, Italy
  6. 6Research Institute Children's Cancer Center, Hamburg, Germany
  7. 7University Medical Center Hamburg, Department of Pediatric Hematology and Oncology, Eppendorf, Germany
  8. 8Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, CB2 0XY, UK
  1. Correspondence to Maurizio Aricò Direttore Dipartimento Oncoematologia Pediatrica e Cure Domiciliari Azienda Ospedaliero-Universitaria Meyer Viale Pieraccini, 24 50139 Firenze, Italy; m.arico{at}


Background Familial haemophagocytic lymphohistiocytosis (FHL) is a rare immune deficiency with uncontrolled inflammation; the clinical course usually starts within the first years of life, and is usually fatal unless promptly treated and then cured with haematopoietic stem cell transplant. FHL is caused by genetic mutations resulting in defective cell cytotoxicity; three disease related genes have been identified to date: perforin, Munc13-4 and syntaxin-11. A fourth gene, STXBP2, has been identified very recently as responsible for a defect in Munc18-2 in FHL-5.

Aims To describe the result of the screening of families with HLH and previously unassigned genetic defects.

Methods Patients with HLH diagnosed according to current diagnostic criteria, and who lacked mutations in the PRF1, Munc13-4, and STX11 genes were sequenced for mutations in STXBP2. Functional study was performed when material was available.

Results Among the 28 families investigated, 4 (14%) with biallelic STXBP2 mutations were identified. They originated from Italy, England, Kuwait and Pakistan. The p.Pro477Leu resulting from c.1430C>T, and p.Arg405Gln resulting from the single c.1214G>A nucleotide change are known, while we contribute two novel mutations: p.Glu132Ala resulting from c.395A>C, and p.Gly541Ser, resulting from c.1621G>A. The detrimental effect of the p.Gly541Ser mutation was documented biochemically and functionally in NK and CD8 cells. Additional polymorphisms are also described.

Conclusion These data expand current knowledge on the genetic heterogeneity of FHL and suggest that patients with FHL5 may have different results in degranulation assays under different conditions.

  • Degranulation
  • syntaxin
  • cytotoxicity
  • molecular genetics
  • haematology (incl Blood transfusion)

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  • Competing interest None.

  • Patient consent Not required.

  • Ethics approval AOU Meyer, Florence Italy.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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