Novel mutation in perforin gene causing familial hemophagocytic lymphohistiocytosis type 2 in an Egyptian infant: case report

Abstract

Background 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). Case presentation 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. Conclusions 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.

Accuracy of the Criteria for Hemophagocytic Lymphohistiocytosis

“…HLH is a very rare and potentially lethal syndrome with an ineffective hyperinflammatory immune response and incidence of 1-2 cases per million in Europe and Japan [12]. HLH is divided into primary (genetic or familial) and secondary (acquired) types [2-4, 6, 7, 13].…”

“…A certain role is assigned to cytokines, whose actions lead to fever, phagocytosis, coagulopathy, lipidic changes, and cytope-Int J Clin Exp Pathol 2020;13 (12):3139-3148 nia. Activation of macrophages leads to alterations of lipidic enzymes and hyperferritinemia [14].…”

“…HPC is not a common sign of secondary HLH when it occurs and can only be observed in the later stages of disease progression. On bone marrow examination, HPC can be appreciated in half to two-third of HLH patients [12]. Low or absent NK cell activity is detected in primary HLH, but its activity fluctuates over time in the secondary type.…”

“…5) The clinical criteria that determined the diagnosis of HLH in accordance with the recom-Int J Clin Exp Pathol 2020;13 (12):3139-3148 mendations of the Histiocyte Society (Table 2) [8][9][10][11].…”

“…In regular clinical practice, not every physician has experience with HLH, and the presence of hemophagocytosis in bone marrow aspirates or on biopsies of any other tissue is often considered as the gold standard for diagnosis. However, it can be observed after blood transfusion, in patients with advanced malignancies, Int J Clin Exp Pathol 2020;13 (12):3139-3148 or in critically ill patients with sepsis without connection with HLH [7,8].…”