Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune dysregulation characterized by hyperactivation of the immune system, excessive cytokine secretion and severe systemic inflammation. HLH is classified as familial (FHL) when associated with mutations in PRF1, UNC13D, STX11, and STXBP2 genes. There is limited information available about the clinical and mutational spectrum of FHL patients in Indian population. This study is a retrospective analysis of 101 molecularly characterized FHL patients over the last 10 years from 20 different referral centers in India. FHL2 and FHL3 together accounted for 84% of cases of FHL in our cohort. Patients belonging to different FHL subtypes were indistinguishable based on clinical and biochemical parameters. However, flow cytometry-based assays viz. perforin expression and degranulation assay were found to be specific and sensitive in diagnosis and classification of FHL patients. Molecular characterization of respective genes revealed 76 different disease-causing mutations including 39 (51%) novel mutations in PRF1, UNC13D, STX11, and STXBP2 genes. Overall, survival was poor (28%) irrespective of the age of onset or the type of mutation in our cohort. Altogether, this article sheds light on the current scenario of FHL in India. Our data reveal a wide genetic heterogeneity of FHL in the Indian population and confirms the poor prognosis of FHL. This study also emphasizes that though mutational analysis is important for diagnostic confirmation of FHL, flow cytometry based assays help significantly in rapid diagnosis and functional validation of novel variants identified.
Highlights
Familial hemophagocytic lymphohistiocytosis (FHL) is a disorder of immune dysregulation characterized by persistent high-grade fever, progressive cytopenias, hepatosplenomegaly and systemic inflammation
50 patients were identified as FHL2, 35 were FHL3, seven were FHL4 and nine were FHL5 based on the defective genes
Perforin expression could be checked by flow cytometry in 40 out of 50 FHL2 and 30 out of 51 FHL3/4/5 patients. 38/40 FHL2 (95%) had significantly lower expression of perforin on NK cells than the healthy controls and FHL patients in other groups (p < 0.001) (Figure 1A). 92.5% of the FHL2 patients had ≤10% perforin expression on NK cells with 62.5% having ≤2% expression on NK cells
Summary
Familial hemophagocytic lymphohistiocytosis (FHL) is a disorder of immune dysregulation characterized by persistent high-grade fever, progressive cytopenias, hepatosplenomegaly and systemic inflammation. It is an autosomal recessive disorder and affects mostly infants and young children, but has been reported in adolescents and adults [1, 2]. Based on the gene mutations observed, FHL is categorized as FHL2 (PRF1), FHL3 (UNC13D), FHL4 (STX11), and FHL5 (STXBP2) encoding for Perforin, Munc, Syntaxin, and Syntaxin binding protein 2, respectively [3]. These proteins play a fundamental role in lymphocyte cytotoxicity. Histiocyte Society has established HLH diagnosis criteria, which includes clinical manifestations and laboratory findings; it does not help in classifying FHL patients and identifying the underline genetic defect
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