title: Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations.
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.
  
  
  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%), <or=2% in 18 (26%), 3-<or=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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pediatric Hematology Oncology, Ospedale dei Bambini G. Di Cristina, ARNAS Civico, Palermo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Trizzino
authors.forename: U
authors.initials: U
authors.lastname: zur Stadt
authors.forename: I
authors.initials: I
authors.lastname: Ueda
authors.forename: K
authors.initials: K
authors.lastname: Risma
authors.forename: G
authors.initials: G
authors.lastname: Janka
authors.forename: E
authors.initials: E
authors.lastname: Ishii
authors.forename: K
authors.initials: K
authors.lastname: Beutel
authors.forename: J
authors.initials: J
authors.lastname: Sumegi
authors.forename: S
authors.initials: S
authors.lastname: Cannella
authors.forename: D
authors.initials: D
authors.lastname: Pende
authors.forename: A
authors.initials: A
authors.lastname: Mian
authors.forename: J-I
authors.initials: JI
authors.lastname: Henter
authors.forename: G
authors.initials: G
authors.lastname: Griffiths
authors.forename: A
authors.initials: A
authors.lastname: Santoro
authors.forename: A
authors.initials: A
authors.lastname: Filipovich
authors.forename: M
authors.initials: M
authors.lastname: Aricò
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005006:Ethnicity; D005260:Female; D016368:Frameshift Mutation; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007694:Killer Cells, Natural / Q000276:immunology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000208:ethnology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D054353:Perforin / Q000235:genetics*; D010641:Phenotype
chemical_list: D054353:Perforin