Identification of germline variants in adults with hemophagocytic lymphohistiocytosis

Abstract

Key Points Some germline variants are predicted to disrupt protein function in HLH-associated genes. Such variants are neither enriched in adult-onset HLH nor associated with specific clinical or laboratory features of HLH.

Contribution of clonal hematopoiesis to adult-onset hemophagocytic lymphohistiocytosis

“…We analyzed a cohort of 88 adult patients who met HLH-2004 diagnostic criteria, as described previously. 2 The average age of the cohort was 54 years (range, 18-81), and the majority were male (55%). A precipitating etiology was identified in most cases (77%), with some having multiple etiologies (16%), including malignancy (44% lymphoid, 9% myeloid, and 3% solid), infection (30%), and autoimmune disease (17%).…”

“…Genomic DNA was isolated from peripheral blood and bone marrow aspirate samples (DNeasy Kit; Qiagen, Hilden, Germany) of patients who met HLH-2004 diagnostic criteria treated at 5 clinical institutions between 2001 and 2018. 2 In the 2016 revised classification, analysis of histiocytoses and neoplasms of the macrophagedendritic cell lineages, secondary HLH, or HLH of unknown origin were assigned to group H. 7 Hybrid capture of exons from 98 genes was performed on the genomic DNA samples with a custom SureSelect system (Agilent Technologies, Santa Clara, CA; supplemental Table 1, available on the Blood Web site) followed by library preparation and sequencing on the Illumina platform (San Diego, CA). Mutations were identified with Varscan 2.2.3 and annotated using ANNOVAR.…”

“…1 In contrast to familial (or primary) HLH, which is associated with pathogenic germline variants, adult-onset HLH is rarely associated with germline variants and often occurs in the context of a precipitating etiology, such as malignancy, infection, or autoimmune disease, that leads to chronic immune stimulation with dysregulated regulatory feedback loops. 2,3 Because hematologic malignancies are strongly associated with HLH, we hypothesized that premalignant hematopoietic states would also predispose to HLH. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated phenomenon in which individuals without a hematologic malignancy have a clonal population of blood cells bearing a leukemiaassociated somatic mutation at a variant allele fraction (VAF) of at least 2%.…”

Hemophagocytic lymphohistiocytosis in a child with human immunodeficiency virus infection – a case report

“…Five types of hereditary or familial HLH were described in the literature [ 2 ] and they are caused by mutations in adaptor related protein complex 3 subunit beta 1 ( AP3B1 ), biogenesis of lysosomal organelles complex 1 subunit 6 ( BLOC1S6 ), Bruton’s tyrosine kinase ( BTK ), CD27 , interleukin-2 (IL-2) receptor subunit gamma ( IL2RG ), IL-2 inducible T-cell kinase ( ITK ), lysosomal trafficking regulator ( LYST ), magnesium transporter 1 ( MAGT1 ), perforin 1 ( PRF1 ), RAB27A, member Ras oncogene family ( RAB27A ), SH2 domain containing 1A ( SH2D1A ), solute carrier family 7 member 7 ( SLC7A7 ), syntaxin ( STX ) 3 , STX11 , STX binding protein 2 ( STXBP2 ), Unc-13 homolog D ( UNC13D ), and X-linked inhibitor of apoptosis ( XIAP ) genes. Primary HLH is autosomal recessive inherited and diagnosis is established by molecular genetic testing.…”

No association between <i>ECSIT</i> germline mutations and hemophagocytic lymphohistiocytosis in natural killer/T-cell lymphoma

“…One limitation of our study is not being able to examine whether germline variants in genes associated with familial HLH are enriched in patients with NKTCL-associated HLH. However, recent studies have not shown an association of biallelic pathogenic variants in HLH-associated genes with adult HLH, albeit in cohorts that comprise a mixture of lymphoma and non-lymphoma subtypes (9,10). Ultimately, additional efforts to define disruptive variants in a larger number of genes, in expanded cohorts of adults with lymphoma associated HLH, may further refine our understanding and treatment of this devastating condition.…”