rss
J Med Genet 2008;45:15-21 doi:10.1136/jmg.2007.052670
  • Original article

Genotype–phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations

  1. A Trizzino1,
  2. U zur Stadt2,
  3. I Ueda3,
  4. K Risma4,
  5. G Janka2,
  6. E Ishii5,
  7. K Beutel2,
  8. J Sumegi4,
  9. S Cannella1,
  10. D Pende6,
  11. A Mian7,
  12. J-I Henter8,
  13. G Griffiths9,
  14. A Santoro1,10,
  15. A Filipovich4,
  16. M Aricò1,
  17. for the Histiocyte Society HLH Study group
  1. 1
    Pediatric Hematology Oncology, Ospedale dei Bambini ”G. Di Cristina”, ARNAS Civico, Palermo, Italy
  2. 2
    Department of Pediatric Hematology Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
  3. 3
    Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
  4. 4
    Cincinnati Children's Hospital Medical Center, OH, USA
  5. 5
    Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan
  6. 6
    Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
  7. 7
    Arkansas Children Hospital, Arkansa, USA
  8. 8
    Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  9. 9
    Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK
  10. 10
    Ematologia I, A.O. Cervello, Palermo, Italy
  1. M Aricò, Pediatric Hematology Oncology, Ospedale dei Bambini ”G. Di Cristina”, Via Benedettini 1, 90134 Palermo, Italy; arico{at}ospedalecivicopa.org
  • Received 29 June 2007
  • Revised 16 August 2007
  • Accepted 19 August 2007
  • Published Online First 14 September 2007

Abstract

Background: PRF1 gene mutations are associated with familial haemophagocytic lymphohistiocytosis type 2 (FHL2). Genotype–phenotype analysis, previously hampered by limited numbers of patients, was for the first time performed by data pooling from five large centres worldwide.

Patients and methods: Members of the Histiocyte Society were asked to report cases of FHL2 on specific forms. Data were pooled in a common database and analysed.

Results: The 124 patients had 63 different mutations (including 15 novel mutations): 11 nonsense, 10 frameshift, 38 missense and 4 in-frame deletions. Some mutations were found more commonly: 1122 G→A (W374X), associated with Turkish origin, in 32 patients; 50delT (L17fsX22) associated with African/African American origin, in 21 patients; and 1090-91delCT (L364fsX), in 7 Japanese patients. Flow cytometry showed that perforin expression was absent in 40, reduced in 6 and normal in 4 patients. Patients presented at a median age of 3 months (quartiles: 2, 3 and 13 months), always with fever, splenomegaly and thrombocytopenia. NK activity was absent in 36 (51%), ≤2% in 18 (26%), 3–≤5% in 10 (14%), >5% in 4 (6%), “reduced” in 2 (3%) (not reported, n = 54). Nonsense mutations were significantly associated with younger age at onset (p<0.001) and absent natural killer activity (p = 0.008).

Conclusion: PRF1 mutations are spread over the functional domains. Specific mutations are strongly associated with Turkish, African American and Japanese ethnic groups. Later onset and residual cytotoxic function are observed in patients with at least one missense mutation.

Footnotes

  • Competing interests: None declared.

This Article

  1. Abstract
  2. Full text
  3. PDF
  4. All versions of this article:
    1. jmg.2007.052670v1
    2. 45/1/15 most recent

Responses

  1. Submit a response
  2. No responses published

Register for free content

The full back archive is now available for all BMJ Journals. Institutional subscribers may access the entire archive as part of their subscription. Personal subscribers will also have access to all content when logged in. Non-subscribers who register have free access to all articles published before 2006 right back to volume 1 issue 1. Register here to access the free archive of all BMJ Journals.

Don't forget to sign up for content alerts so you keep up to date with all the articles as they are published.