Genotype-phenotype study of familial hemophagocytic lymphohistiocytosis due to perforin mutations

Antonino Trizzino ¹, Udo Zur Stadt ², Ikuio Ueda ³, Kimberly Risma ⁴, Gritta Janka ², Eichii Ishii ⁵, Karen Beutel ², Janos Sumegi ⁴, Sonia Cannella ¹, Daniela Pende ⁶, Amir Mian ⁷, Jan-Inge Henter ⁸, Gillian M Griffiths ⁹, Alessandra Santoro ¹⁰, Alexandra Filipovich ⁴ and Maurizio Arico ^11*

¹ Pediatric Hematology Oncology, Ospedale dei Bambini "G. Di Cristina", ARNAS Civico, Pale, Italy
² Department of Pediatric Hematology Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
³ Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
⁴ Cincinnati Children's Hospital Medical Center, OH, United States
⁵ Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan
⁶ Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
⁷ Arkansas Children Hospital, Arkansa, United States
⁸ Childhood Cancer Research Unit, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
⁹ Sir William Dunn School of Pathology, Oxford, United Kingdom
¹⁰ Ematologia I, A.O. Cervello & Pediatric Hematology Oncology, Ospedale dei Bambini "G. Di Crist, Italy
¹¹ Ospedale dei Bambini G. Di Cristina, Palermo, Italy

^* To whom correspondence should be addressed. E-mail: arico{at}ospedalecivicopa.org.

Accepted 19 August 2007

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.

Keywords: Lymphohistiocytosis, Natural killer, Perforin

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