title: Correlation between phenotypic heterogeneity and gene mutational characteristics in familial hemophagocytic lymphohistiocytosis (FHL).
abstract: BACKGROUND
  Classification of familial hemophagocytic lymphohistiocytosis (FHL) into FHL2, FHL3, and other subtypes based on genetic abnormalities has recently become possible. We studied the phenotypic differences among these subtypes in Japan.
  
  
  METHODS
  Forty patients clinically diagnosed with FHL were analyzed. Perforin abnormality was screened by flow cytometric analysis and/or DNA sequencing in these patients, and those without perforin abnormalities were further examined for the presence of mutations in the Munc13-4 gene by DNA sequencing. The correlation between clinical features and genetic subtypes was investigated.
  
  
  RESULTS
  Of the 40 HLH patients, 11 showed perforin gene mutations (classified as FHL2) and ten had Munc13-4 gene mutations (FHL3), but neither mutation was noted in 19 patients (non-FHL2/3). Although the majority of the patients developed the disease before the age of 1 year, the onset in three FHL2 patients with missense mutations was late (7, 11, and 12 years). Incidence of deficient natural killer cell activity was higher in FHL2 patients (9/9 FHL2, 4/9 FHL3, and 6/17 non-FHL2/3; P = 0.005). The serum levels of ferritin and soluble interleukin-2 receptor were significantly higher in FHL2 patients with nonsense perforin mutations compared to other subgroups (P < or = 0.05). Epstein-Barr virus infection was involved in 8 of the 40 HLH patients: one FHL2, one FHL3, and six non-FHL2/3.
  
  
  CONCLUSIONS
  Although clinical features of FHL3 appear to be homogeneous, the heterogeneous clinical features of FHL2 depend upon the nature of perforin gene mutations. Characterization of the non-FHL2/3 group with regard to FHL1 or other novel gene mutations remains to be conducted.
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan. u194@koto.kpu-m.ac.jp
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Ueda
authors.forename: Eiichi
authors.initials: E
authors.lastname: Ishii
authors.forename: Akira
authors.initials: A
authors.lastname: Morimoto
authors.forename: Shouichi
authors.initials: S
authors.lastname: Ohga
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sako
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Imashuku
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D018740:Genetic Heterogeneity; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007564:Japan / Q000453:epidemiology; D007694:Killer Cells, Natural / Q000473:pathology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D020125:Mutation, Missense; D054353:Perforin; D010641:Phenotype; D052899:Pore Forming Cytotoxic Proteins; D011379:Prognosis; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
chemical_list: D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; C507969:UNC13D protein, human; D054353:Perforin