Hemophagocytic lymphohistiocytosis: review of etiologies and management

George, Melissa R

The first genetic defect described in FHL was a mutation in the perforin gene (PRF1) in 1999 by Stepp et al. 208 Perforin is found in secretory granules of cytotoxic cells and plays an important role in apoptosis and immune modulation. Perforin mutations are causative in the majority of FHL cases, accounting for up to 58%, and are considered a defining feature of FHL-2. 31, 125, 183, 186, [209] [210] [211] [212] [213] [214] [215] [216] [217] [218] [219] [220] [221] Patients presenting later in life may have residual perforin expression, but patients presenting in early childhood usually have no perforin in their NK-or CD8+ cells. The HLH Study Group of the Histiocyte Society identified 63 specific mutations within the perforin gene that demonstrate varying prevalence among ethnic groups. Three of the more common mutations were specifically associated with Turkish, African/African American, and Japanese origins, respectively. A common perforin polymorphism C272T (A91V) seen in late-onset FHL has been demonstrated to lead to a dysfunctional perforin. 212, 222 More detailed discoveries about the role of perforin in HLH, lymphoma, and other immune-mediated diseases have been recently described. 3 1,210,212,213,216,218,222-229 Genes involved in cytotoxic granule exocytosis have been demonstrated to bear mutations in FHL-3, FHL-4, and FHL-5. FHL-3 cases, which account for 10%-32% of genetic HLH feature UNC13D mutations. 30 The essential role of the UNC13D gene in the fusion of cytolytic granules and involvement in FHL was first described in 2003 by Feldmann et al. 230 Patients with disruptive mutations presented at a younger age than FHL-3 patients with missense mutations, but older than FHL-2 patients. FHL-3 is marked by more central nervous system involvement than the other subclasses. 30, 180, 182, 211, 218, [231] [232] [233] [234] [235] [236] [237] FHL-4 is characterized by SYNTAXIN11 (STX11) mutations and is found almost exclusively in patients of Turkish/Kurdish descent. 31, 211, [238] [239] [240] The gene mutation causing FHL-5 was described as recently as 2009 by Zur Stadt et al and also by Côte et al. 28, [240] [241] [242] [243] The FHL-1 locus on chromosome 9p21.3-q22 codes for a yet unknown gene and protein involved in the development of FHL-1 and accounts for fewer cases of FHL at approximately 10%. 212 Aside from FHL, the immune deficiency syndromes associated with HLH, including CHS-1, GS, and XLPS can be grouped based on molecular features. Similar to FHL, from a molecular standpoint, CHS-1 and GS can be characterized by intracellular vesicle content, docking, and fusion defects. Both are characterized by albinism, neutrophil granule dysfunction, and recurrent infections. XLPS on the other hand is molecularly distinct in that XLPS lacks normal immune function of T-lymphocytes rather than having neutrophil granule defects. Genetic defects associated with these conditions are presented in Table 7 .