Introduction:
Hemophagocytic Lymphohistiocytosis (HLH) is characterized by systemic hyperinflammatory life-threatening syndrome where individuals present with fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia and high levels of ferritin in blood. First studies led to the classification of familial HLH as a disease of systemic hypercytokinaemia where inflammatory cytokines and cytotoxic cells seem to play an important role. In this work, we present a spectrum of genetic variants that contribute to HLH susceptibility.
Methods:
By functional assays we intend to assess the function of cytotoxic cells. Next-generation sequencing was performed in all patients. In some cases, the variants detected were confirmed by Sanger sequencing. Biochemical and in silico studies were performed to complement genetic or functional studies.
Results:
In this study we reported a cohort of over 20 no related patients diagnosed with HLH according to the clinical criteria. We detected homozygous and compound heterozygous variants in genes highly related to HLH (PFR1, UNC13D, STX11, STXBP2 and LYST) and genes not clearly associated with HLH (RIPK1, MVK, TCF3 and TREX1). In addition, we found one non-coding variant in STXBP2, and one patient with all clinical manifestation for Griscelli syndrome but no mutations were detected in the coding regions for this gene, biochemical studies confirm a severe reduction in the expression of Rab27. Finally, we identified heterozygous variants in STXBP2, PRF1 and STX11; further studies demonstrated that the heterozygous variants in STXBP2 had a dominant negative role, in contrast, heterozygous variants in PRF1 and STX11 were presented in the context of systemic idiopathic juvenile arthritis.
Conclusion:
These findings describe the broad spectrum of genetic variants that contribute to HLH susceptibility and the importance of functional, biochemical and in silico studies to confirm appropriate diagnostics. This study also shows the importance of continuing investigations that provided mechanistic understanding of different pathways that can promote HLH.