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Genotype-phenotype study of familial hemophagocytic lymphohistiocytosis due to perforin mutations
  1. Antonino Trizzino (triznino{at}hotmail.com)
  1. Pediatric Hematology Oncology, Ospedale dei Bambini ”G. Di Cristina”, ARNAS Civico, Pale, Italy
    1. Udo Zur Stadt (zurstadt{at}uke.uni-hamburg.de)
    1. Department of Pediatric Hematology Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
      1. Ikuio Ueda
      1. Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
        1. Kimberly Risma (kimberly.risma{at}cchmc.org)
        1. Cincinnati Children's Hospital Medical Center, OH, United States
          1. Gritta Janka (janka{at}uke.uni-hamburg.de)
          1. Department of Pediatric Hematology Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
            1. Eichii Ishii (ishiei{at}m.ehime-u.ac.jp)
            1. Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan
              1. Karen Beutel (beutel{at}uke.uni-hamburg.de)
              1. Department of Pediatric Hematology Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
                1. Janos Sumegi (janos.sumegi{at}cchmc.org)
                1. Cincinnati Children's Hospital Medical Center, OH, United States
                  1. Sonia Cannella (laboncoped{at}ospedalecivicopa.org)
                  1. Pediatric Hematology Oncology, Ospedale dei Bambini ”G. Di Cristina”, ARNAS Civico, Pale, Italy
                    1. Daniela Pende (daniela.pende{at}istge.it)
                    1. Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
                      1. Amir Mian (mianamir{at}uams.edu)
                      1. Arkansas Children Hospital, Arkansa, United States
                        1. Jan-Inge Henter (jan.inge.henter{at}kbh.ki.se)
                        1. Childhood Cancer Research Unit, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
                          1. Gillian M Griffiths (gg305{at}cam.ac.uk)
                          1. Sir William Dunn School of Pathology, Oxford, United Kingdom
                            1. Alessandra Santoro (santoro.al{at}libero.it)
                            1. Ematologia I, A.O. Cervello & Pediatric Hematology Oncology, Ospedale dei Bambini ”G. Di Crist, Italy
                              1. Alexandra Filipovich (lisa.filipovich{at}chmcc.org)
                              1. Cincinnati Children's Hospital Medical Center, OH, United States
                                1. Maurizio Arico (arico{at}ospedalecivicopa.org)
                                1. Ospedale dei Bambini G. Di Cristina, Palermo, Italy

                                  Abstract

                                  Background: PRF1 gene mutations are associated with familial hemophagocytic lymphohistiocytosis type 2 (FHL2). Genotype-phenotype analysis, previously hampered by limited number of patients, was performed for the first time by data pooling from 5 large centers 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 data-based and analysed. Results: The 124 patients had 63 different mutations, including 15 novel: 11 nonsense, 10 frameshift, 38 missense, 4 in-frame deletions. Some mutations were found more frequently: 1122 G>A (W374X), associated with Turkish origin, in 32 patients; 50delT (L17fsX22) associated with Afro(American) origin, in 21; 1090-91delCT (L364fsX), in 7 Japanese patients. Perforin expression was absent at flow-cytometry in 40, reduced in 6, 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 to ≤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 NK activity (p=0.008). Conclusion: PRF1 mutations are spread over the functional domains. Specific mutations are tightly associated with Turkish, Afro-American, and Japanese ethnic groups. Later onset and residual cytotoxic function are observed in patients with at least one missense mutation.

                                  • Lymphohistiocytosis
                                  • Natural killer
                                  • Perforin

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