AUTHOR=Shabrish Snehal , Kelkar Madhura , Yadav Reetika Malik , Bargir Umair Ahmed , Gupta Maya , Dalvi Aparna , Aluri Jahnavi , Kulkarni Manasi , Shinde Shweta , Sawant-Desai Sneha , Kambli Priyanka , Hule Gouri , Setia Priyanka , Jodhawat Neha , Gaikwad Pallavi , Dhawale Amruta , Nambiar Nayana , Gowri Vijaya , Pandrowala Ambreen , Taur Prasad , Raj Revathi , Uppuluri Ramya , Sharma Ratna , Kini Pranoti , Sivasankaran Meena , Munirathnam Deenadayalan , Vedam Ramprasad , Vignesh Pandiarajan , Banday Aaqib , Rawat Amit , Aggarwal Amita , Poddar Ujjal , Girish Meenakshi , Chaudhary Abhijit , Sampagar Abhilasha , Jayaraman Dharani , Chaudhary Narendra , Shah Nitin , Jijina Farah , Chandrakla S. , Kanakia Swati , Arora Brijesh , Sen Santanu , Lokeshwar Madhukar , Desai Mukesh , Madkaikar Manisha TITLE=The Spectrum of Clinical, Immunological, and Molecular Findings in Familial Hemophagocytic Lymphohistiocytosis: Experience From India JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.612583 DOI=10.3389/fimmu.2021.612583 ISSN=1664-3224 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.