Correlation between phenotypic heterogeneity and gene mutational characteristics in familial hemophagocytic lymphohistiocytosis (FHL)
Correlation between phenotypic heterogeneity and gene mutational characteristics in familial hemophagocytic lymphohistiocytosis (FHL)
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DOI：
10.1002/pbc.20511
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发表时间：
2006-04-01
影响因子：
3.2
通讯作者：
Imashuku, S
中科院分区：
文献类型：
--
作者：
Ueda, I;Ishii, E;Imashuku, S
背景家族性噬血细胞性淋巴组织细胞增生症（FHL）根据遗传异常分为FHL 2、FHL 3和其他亚型，最近已成为可能。我们研究了日本这些亚型之间的表型差异。方法.分析了40例临床诊断为FHL的患者。在这些患者中通过流式细胞术分析和/或DNA测序筛选perf异常，并且通过DNA测序进一步检查那些没有perf异常的患者中Munc `13 - 4基因突变的存在。分析其临床特征与基因亚型的相关性。结果在40例HLH患者中，11例患者存在基因突变（归类为FHL2），10例患者存在Munc13 - 4基因突变（FHL3），但19例患者（非FHL2/3）未观察到突变。虽然大多数患者在1岁之前发病，但3例FHL 2错义突变患者的发病时间较晚（7、11和12岁）。FHL 2患者中自然杀伤细胞活性缺陷的发生率较高（9/9 FHL 2，4/9 FHL 3和6/17非FHL 2/3; P = 0.005）。FHL2无义突变患者血清铁蛋白和可溶性白细胞介素2受体水平显著高于其他亚组（P <0.05）。40例HLH患者中有8例涉及EB病毒感染：1例FHL2，1例FHL3，6例非THI-2/3。结论.虽然FHL3的临床特征似乎是同质的，但FHL2的异质性临床特征取决于穿孔素基因突变的性质。关于FHL1或其他新基因突变的非FHL2/3组的特征仍有待进行。儿科血液癌症2006; 46：482 - 488. (c)2005 Wiley-Liss，Inc.
Background. Classification of familial hemophagocytic lympho-histiocytosis (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. Perform abnormality was screened by flow cytometric analysis and/or DNA sequencing in these patients, and those without perform abnormalities were further examined for the presence of mutations in the Munc`13-4 gene by DNA sequencing. The correlation between clinical features and genetic subtypes was investigated. Results. Of the 40 HLH patients, 11 showed perform 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 perform mutations compared to other subgroups (P < 0.05). Epstein-Barr virus infection was involved in 8 of the 40 HLH patients: one FHL2, one FHL3, and six non-THI-2/3. 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. Pediatr Blood Cancer 2006;46:482-488. (c) 2005 Wiley-Liss, Inc.