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

Autor: Franco Locatelli, Lorenzo Moretta, Concetta Micalizzi, Valentina Cetica, Elena Sieni, Carmen De Fusco, Franca Fagioli, Cesare Danesino, Maria Caterina Putti, Maurizio Aricò, Andrea Biondi, Lucio Luzzatto, Gillian M. Griffiths, Daniela Pende
Přispěvatelé: Griffiths, Gillian [0000-0003-0434-5842], Apollo - University of Cambridge Repository, Cetica, V, Sieni, E, Pende, D, Danesino, C, De Fusco, C, Locatelli, F, Micalizzi, C, Putti, M, Biondi, A, Fagioli, F, Moretta, L, Griffiths, G, Luzzatto, L, Aricò, M
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
PRF1
Hemophagocytic
immunologic tests
Disease
Hemophagocytic lymphohistiocytosis
HSCT
Hematopoietic stem cell transplantation
FHL
Familial hemophagocytic lymphohistiocytosis
NK
Natural killer
immunologic test
Immunology and Allergy
Registries
Child
Lymphohistiocytosis
biology
Familial Hemophagocytic Lymphohistiocytosis
Middle Aged
3. Good health
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
Italy
Child
Preschool
Female
Hemophagocytosis
Hemophagocytic lymphohistiocytosi
Adult
Adolescent
Immunology
Lymphohistiocytosis
Hemophagocytic
03 medical and health sciences
Young Adult
XLP
X-linked lymphoproliferative syndrome
UNC13D
Humans
Infant
Infant
Newborn
Membrane Proteins
Perforin
Genetic Predisposition to Disease
Immune Deficiencies
Infection
and Systemic Immune Disorders
medicine
Genetic predisposition
Preschool
business.industry
medicine.disease
Newborn
HLH
Hemophagocytic lymphohistiocytosis
030104 developmental biology
Macrophage activation syndrome
biology.protein
hemophagocytic lymphohistiocytosis
MAS
Macrophage activation syndrome
business
Zdroj: The Journal of Allergy and Clinical Immunology
ISSN: 0091-6749
DOI: 10.1016/j.jaci.2015.06.048
Popis: 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.
Databáze: OpenAIRE
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