Genetic predisposition to hemophagocytic lymphohistiocytosis

Report on 500 patients from the Italian registry

Valentina Cetica, Elena Sieni, Daniela Pende, Cesare Danesino, Carmen De Fusco, Franco Locatelli, Concetta Micalizzi, M. C. Putti, A. Biondi, F. Fagioli, Lorenzo Moretta, Gillian M. Griffiths, Lucio Luzzatto, Maurizio Aricò

Research output: Contribution to journalArticle

Abstract

Background Hemophagocytic 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. Objective This work aims to further our understanding of the pathogenic bases of this rare condition based on an analysis of our 25 years of experience. Methods From our registry, we have analyzed a total of 500 unselected patients with HLH. Results Biallelic 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. Conclusion We 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.

Original languageEnglish
Pages (from-to)188-196.e4
JournalJournal of Allergy and Clinical Immunology
Volume137
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

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Hemophagocytic Lymphohistiocytosis
Genetic Predisposition to Disease
Registries
Mutation
Perforin
Gene Dosage

Keywords

  • Hemophagocytic lymphohistiocytosis
  • immunologic tests
  • PRF1
  • UNC13D

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Genetic predisposition to hemophagocytic lymphohistiocytosis : Report on 500 patients from the Italian registry. / Cetica, Valentina; Sieni, Elena; Pende, Daniela; Danesino, Cesare; De Fusco, Carmen; Locatelli, Franco; Micalizzi, Concetta; Putti, M. C.; Biondi, A.; Fagioli, F.; Moretta, Lorenzo; Griffiths, Gillian M.; Luzzatto, Lucio; Aricò, Maurizio.

In: Journal of Allergy and Clinical Immunology, Vol. 137, No. 1, 01.01.2016, p. 188-196.e4.

Research output: Contribution to journalArticle

Cetica, Valentina ; Sieni, Elena ; Pende, Daniela ; Danesino, Cesare ; De Fusco, Carmen ; Locatelli, Franco ; Micalizzi, Concetta ; Putti, M. C. ; Biondi, A. ; Fagioli, F. ; Moretta, Lorenzo ; Griffiths, Gillian M. ; Luzzatto, Lucio ; Aricò, Maurizio. / Genetic predisposition to hemophagocytic lymphohistiocytosis : Report on 500 patients from the Italian registry. In: Journal of Allergy and Clinical Immunology. 2016 ; Vol. 137, No. 1. pp. 188-196.e4.
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abstract = "Background Hemophagocytic 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. Objective This work aims to further our understanding of the pathogenic bases of this rare condition based on an analysis of our 25 years of experience. Methods From our registry, we have analyzed a total of 500 unselected patients with HLH. Results Biallelic 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. Conclusion We 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.",
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AU - Cetica, Valentina

AU - Sieni, Elena

AU - Pende, Daniela

AU - Danesino, Cesare

AU - De Fusco, Carmen

AU - Locatelli, Franco

AU - Micalizzi, Concetta

AU - Putti, M. C.

AU - Biondi, A.

AU - Fagioli, F.

AU - Moretta, Lorenzo

AU - Griffiths, Gillian M.

AU - Luzzatto, Lucio

AU - Aricò, Maurizio

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N2 - Background Hemophagocytic 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. Objective This work aims to further our understanding of the pathogenic bases of this rare condition based on an analysis of our 25 years of experience. Methods From our registry, we have analyzed a total of 500 unselected patients with HLH. Results Biallelic 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. Conclusion We 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.

AB - Background Hemophagocytic 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. Objective This work aims to further our understanding of the pathogenic bases of this rare condition based on an analysis of our 25 years of experience. Methods From our registry, we have analyzed a total of 500 unselected patients with HLH. Results Biallelic 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. Conclusion We 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.

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