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


CONCLUSIONS
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.
Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer Children Hospital, Florence, Italy.
Valentina
V
Cetica
Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer Children Hospital, Florence, Italy.
Elena
E
Sieni
Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Daniela
D
Pende
Medical Genetics, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Cesare
C
Danesino
Pediatric Hematology and Oncology, Pausilipon Hospital, Naples, Italy.
Carmen
C
De Fusco
Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, and the University of Pavia, Pavia, Italy.
Franco
F
Locatelli
Istituto Giannina Gaslini, Genoa, Italy.
Concetta
C
Micalizzi
Clinic of Pediatric Hematology Oncology, Padua Hospital, Padua, Italy.
Maria Caterina
MC
Putti
Pediatric Clinic, University of Milan Bicocca, San Gerardo Hospital/Fondazione MBBM, Monza, Italy.
Andrea
A
Biondi
Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Turin, Italy.
Franca
F
Fagioli
Istituto Giannina Gaslini, Genoa, Italy.
Lorenzo
L
Moretta
Cambridge Institute for Medical Research, University of Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, United Kingdom.
Gillian M
GM
Griffiths
Istituto Toscano Tumori (I.T.T.), Florence, Italy.
Lucio
L
Luzzatto
Istituto Toscano Tumori (I.T.T.), Florence, Italy; Azienda Sanitaria Provinciale, Ragusa, Italy. Electronic address: maurizio.arico@asp.rg.it.
Maurizio
M
Aricò
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007558:Italy; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics* / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D054353:Perforin / Q000235:genetics; D012042:Registries; D055815:Young Adult
D008565:Membrane Proteins; C510468:PRF1 protein, human; C507969:UNC13D protein, human; D054353:Perforin
Hemophagocytic lymphohistiocytosis; PRF1; UNC13D; immunologic tests