Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathological immune activation characterized by clinical signs and symptoms of extreme inflammation. It results from the uninhibited proliferation and activation of cells of the macrophage lineage and leads to the production of excess amounts of pro-inflammatory cytokines. The familial form of HLH disease is due to mutations in several genes necessary for natural killer (NK) cell and T cell granule-mediated cytotoxic function. These genes are involved in sorting, trafficking, docking, and fusion of cytotoxic granules containing granzymes A and B and perforin to the cell membrane of the target cell (using the proteins LYST, AP-3 complex, Rab27a, Munc 13–4, Munc 18–2, syntaxin 11). Defect in any of those proteins results in defective cytotoxicity. Consequently, genes included in these steps play valuable roles in the pathogenesis of familial HLH disease including perforin (PRF1) gene in which defect causes familial HLH type 2 (FHL2). A 2-year-old boy suffered from hepatosplenomegaly and fever. He fulfilled the required criteria for the diagnosis of HLH according to HLH-2004 diagnostic criteria. We screened the patient for the presence of mutations in the coding exons and of PRF1 gene by PCR amplification of genomic DNA followed by direct sequencing of the PCR products. We report a novel homozygous deletion/insertion frameshift mutation in PRF1 gene (M28393: exon 2: c.536delAinsCG p.F178fs). We treated him with HLH 2004 protocol of treatment and showed a remarkable response with resolution of fever and decrement in the size of hepatosplenomegaly. Our study discovered a novel frameshift mutation in PRF1 gene in an infant with HLH disease, and it is the first report of this type of mutation in Egyptian patients with this disease.

中文翻译：

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导致埃及婴儿2型家族性噬血细胞淋巴组织细胞增生症的穿孔素基因新突变：病例报告

噬血细胞性淋巴组织细胞增生症 (HLH) 是一种病理性免疫激活综合征，其特征是极端炎症的临床体征和症状。它是巨噬细胞谱系细胞不受抑制的增殖和激活的结果，并导致产生过量的促炎细胞因子。HLH 疾病的家族性形式是由于自然杀伤 (NK) 细胞和 T 细胞颗粒介导的细胞毒功能所必需的几个基因发生突变。这些基因参与含有颗粒酶 A 和 B 以及穿孔素的细胞毒性颗粒与靶细胞细胞膜的分选、运输、对接和融合（使用蛋白质 LYST、AP-3 复合物、Rab27a、Munc 13-4、Munc 18-2，语法在 11)。任何这些蛋白质的缺陷都会导致细胞毒性缺陷。最后，这些步骤中包含的基因在家族性 HLH 疾病的发病机制中发挥重要作用，包括穿孔素 (PRF1) 基因，其中缺陷导致家族性 HLH 2 型 (FHL2)。一名 2 岁男孩患有肝脾肿大和发烧。符合HLH-2004诊断标准中HLH的诊断标准。我们通过基因组 DNA 的 PCR 扩增和 PCR 产物的直接测序来筛选患者的编码外显子和 PRF1 基因是否存在突变。我们报告了 PRF1 基因中的一种新型纯合缺失/插入移码突变（M28393：外显子 2：c.536delAinsCG p.F178fs）。我们用 HLH 2004 治疗方案对他进行了治疗，并显示出显着的反应，发烧消退和肝脾肿大的大小减小。