Genetic predisposition to hemophagocytic lymphohistiocytosis: Report on 500 patients from the Italian registry

Abstract

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease affecting mostly children but also adults and characterized by hyperinflammatory features. A subset of patients, referred to as having familial hemophagocytic lymphohistiocytosis (FHL), have various underlying genetic abnormalities, the frequencies of which have not been systematically determined previously.ObjectiveThis work aims to further our understanding of the pathogenic bases of this rare condition based on an analysis of our 25 years of experience.MethodsFrom our registry, we have analyzed a total of 500 unselected patients with HLH.ResultsBiallelic pathogenic mutations defining FHL were found in 171 (34%) patients; the proportion of FHL was much higher (64%) in patients given a diagnosis during the first year of life. Taken together, mutations of the genes PRF1 (FHL2) and UNC13D (FHL3) accounted for 70% of cases of FHL. Overall, a genetic diagnosis was possible in more than 90% of our patients with FHL. Perforin expression and the extent of degranulation have been more useful for diagnosing FHL than hemophagocytosis and the cytotoxicity assay. Of 281 (56%) patients classified as having “sporadic” HLH, 43 had monoallelic mutations in one of the FHL-defining genes. Given this gene dosage effect, FHL is not strictly recessive.ConclusionWe suggest that the clinical syndrome HLH generally results from the combined effects of an exogenous trigger and genetic predisposition. Within this combination, different weights of exogenous and genetic factors account for the wide disease spectrum that ranges from HLH secondary to severe infection to FHL.

Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages

“…87,88 However, a proportion of suspected primary cases await molecular definition. 89 The clinical symptoms usually become evident during the first years of life, although onset into adulthood has been reported. 90 Patients may suffer from 1 or several acute episodes that may be rapidly progressive.…”

Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities

“…Today, 30-40% of molecularly diagnosed patients possesses a mutation in PRF1, classifying them as FHL-2 (Cetica et al, 2016). Upon degranulation of CTLs or NK cells, perforin monomers are released into the immune synapse, where they polymerize in the target cell membrane to form pores, through which granzymes enter to induce apoptosis (Sieni et al, 2014;de Saint Basile et al, 2015).…”

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study

“…Secondary HLH (sHLH), more common in adults, is often associated with underlying conditions including severe infections, malignancies, or inflammatory disorders. 2,[7][8][9] Both primary HLH and sHLH are often triggered by infections. 10 Clinical manifestations of HLH include prolonged fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia.…”