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

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.

Keywords: Hemophagocytic lymphohistiocytosis; PRF1; UNC13D; immunologic tests.

Fig 1

Distribution of patients with FHL (biallelic mutations; gray bars) or sporadic HLH (no biallelic mutations; white bars), according to age at diagnosis. The number of patients for each age group is indicated within each bar. *P < .001, χ² test.

Fig 2

Diagnosis and classification of HLH. Distribution of 500 patients with HLH according to the presence or absence of biallelic mutations in any of the FHL-related genes is shown. Not all patients were investigated for the 3 functional assays. In 275 patients functional testing was followed by mutation analysis. Patients were classified as having sporadic HLH if they had no evidence of a severe functional defect and did not have biallelic mutations in any FHL-related genes. Patients were classified as having genetic HLH (or FHL) if they had biallelic mutations, with the only exception of 15 patients given a diagnosis of FHL for clinical reasons in whom mutations were not found. A possible simple explanation is that the underlying gene or genes have yet to be discovered. Their details are summarized in Table E3.

Fig 3

Breakdown of the different genetic subtypes in 171 patients with FHL or FHL-related disease. For each subtype, the name of the gene, the abbreviation of the disease subtype, the absolute number, and the percentage are shown. Furthermore, we include as FHL one subgroup of 15 patients with either familial recurrence and/or refractory/recurrent disease despite specific therapy and/or repeatedly documented severe functional defect in degranulation or cytotoxicity assays (see Table E3).

Fig 4

Intrafamilial variation of age at onset of FHL in 26 families with more than 1 affected case. In families 23 and 26, 3 affected cases are reported. In families 4, 9, and 18, the siblings were concordant twins. *This sibling of patient 24 is now 25 years old and has not yet had the disease. The FHL genetic subtype is indicated at the bottom, with the exception of family 25 (FHL5) and family 26 (Griscelli syndrome type 2). The type of mutations are abbreviated as follows: C, combination of 1 nonsense and 1 missense mutation; M, biallelic missense mutations; N, biallelic nonsense mutations. **Case 25, FHL5; case 26, Griscelli syndrome type 2.

Fig 5

The risk of HLH results from the interaction of a predisposed genotype and environmental triggering factor or factors. Genotype is intended as in the FHL-related genes (PRF1, UNC13D, STX11, STXBP2, RAB27A, LYST, SH2D1A, XIAP, and AP3B1). Patients with sporadic HLH and no mutation found might harbor mutation(s) in other gene(s) currently not identified as FHL related. Selected patients might have HLH, classified as sporadic, as the presenting clinical manifestation of juvenile idiopathic systemic arthritis (MAS). Common viral pathogens can behave as a trigger for both HLH or FHL; among them, EBV or other herpesviruses are the most frequently reported.