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Genotype–phenotype study of familial haemophagocytic lymphohistiocytosis type 3
  1. Elena Sieni1,
  2. Valentina Cetica1,
  3. Alessandra Santoro2,
  4. Karin Beutel1,3,
  5. Elena Mastrodicasa4,
  6. Marie Meeths5,6,
  7. Benedetta Ciambotti1,
  8. Francesca Brugnolo1,
  9. Udo zur Stadt7,
  10. Daniela Pende8,
  11. Lorenzo Moretta9,
  12. Gillian M Griffiths10,
  13. Jan-Inge Henter5,
  14. Gritta Janka3,
  15. Maurizio Aricò1
  1. 1Department of Pediatric Hematology and Oncology, Azienda Ospedaliero-Universitaria Meyer, Florence, Italy
  2. 2U.O. Ematologia I, A.O.Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy
  3. 3Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  4. 4S.C. di Oncoematologia Pediatrica con Trapianto di CSE, Ospedale “S.M. della Misericordia” A.O. Perugia, Italy
  5. 5Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  6. 6Clinical Genetics Unit,Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm,Sweden
  7. 7Research Institute Children's Cancer Center, Hamburg, Germany
  8. 8Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
  9. 9IRCCS Istituto Giannina Gaslini, Genoa, Italy
  10. 10Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK
  1. Correspondence to Dr Maurizio Aricò, Dipartimento Oncoematologia Pediatrica, Azienda Ospedaliero-Universitaria Meyer, Viale Pieraccini, 24, 50139 Firenze; m.arico{at}


Background Mutations of UNC13D are causative for familial haemophagocytic lymphohistiocytosis type 3 (FHL3; OMIM 608898).

Objective To carry out a genotype–phenotype study of patients with FHL3.

Methods A consortium of three countries pooled data on presenting features and mutations from individual patients with biallelic UNC13D mutations in a common database.

Results 84 patients with FHL3 (median age 4.1 months) were reported from Florence, Italy (n=54), Hamburg, Germany (n=18), Stockholm, Sweden (n=12). Their ethnic origin was Caucasian (n=57), Turkish (n=10), Asian (n=7), Hispanic (n=4), African (n=3) (not reported (n=3)). Thrombocytopenia was present in 94%, splenomegaly in 96%, fever in 89%. The central nervous system (CNS) was involved in 49/81 (60%) patients versus 36% in patients with FHL2 (p=0.001). A combination of fever, splenomegaly, thrombocytopenia and hyperferritinaemia was present in 71%. CD107a expression, NK activity and Munc 13-4 protein expression were absent or reduced in all but one of the evaluated patients. 54 different mutations were observed, including 15 new ones: 19 missense, 14 deletions or insertions, 12 nonsense, nine splice errors. None was specific for ethnic groups. Patients with two disruptive mutations were younger than patients with two missense mutations (p<0.001), but older than comparable patients with FHL2 (p=0.001).

Conclusion UNC13D mutations are scattered over the gene. Ethnic-specific mutations were not identified. CNS involvement is more common than in FHL2; in patients with FHL3 and disruptive mutations, age at diagnosis is significantly higher than in FHL2. The combination of fever, splenomegaly, thrombocytopenia and hyperferritinaemia appears to be the most easily and frequently recognised clinical pattern and their association with defective granule release assay may herald FHL3.

  • Haematology (including blood transfusion)
  • immunology (including allergy)

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  • Funding This work was partly supported by the following sources: European Union 7th Framework Program under grant agreement No HEALTH-F2-2008-201461; “Antonio Pinzino - Associazione per la Ricerca sulle Sindromi Emofagocitiche (ARSE)”; “Noi per Voi per il Meyer Onlus”; Italian Ministry of Health, Bando “Malattie Rare 2008”; A.O.U. Meyer; Swedish Children's Cancer Foundation, the Swedish Research Council, the Cancer and Allergy Foundation of Sweden, the Swedish Cancer Foundation, the Karolinska Institutet and the Stockholm County Council.

  • Ethics approval This study was conducted with the approval of the Department of Pediatric Hematology and Oncology, Azienda Ospedaliero-Universitaria Meyer, Florence, Italy.

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