Sporadic Hemophagocytic Lymphohistiocytosis (sHLH): A Polygenic Disease? a Report of French National, Prospective, Cohort of 205 Patients

Coralie Bloch-Queyrat^1,2, Jean Philippe Jais³, Marine Gil⁴, Brigitte Bader-Meunier⁵, Olivier Hermine^6,7 and Genevieve de Saint-Basile⁴, ¹Clinical Research Unit, University Hospital Paris Seine Saint Denis, AP-HP, Bobigny, France, ²Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications INSERM U 1163 / CNRS ERL 8254 Institut IMAGINE, Paris, paris, France, ³Biostatstical Departement, Department of biostatistics Necker Enfants Malades Hospital, AP-HP, Paris, France, ⁴Normal and pathological homeostasis of the immune system laboratory Institut IMAGINE Paris, Paris, France, ⁵Pediatric Rheumatology & Immunology, Pediatric Rheumatology & Immunology, Necker hospital, Imagine Institution, Paris, France, ⁶Department of Hematology, Hôpital Necker, Paris, France, ⁷Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications INSERM U 1163 / CNRS ERL 8254 Labex on Red cell and iron metabolism Institut IMAGINE, Paris, France

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Clinical research, Genetic disorders, immune activation, immune deficiency and macrophage activation syndrome

Session Information

Date: Monday, November 14, 2016

Session Title: Genetics, Genomics and Proteomics - Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: The role of genetic factors in the occurrence and/or severity of sHLH is not yet known. Therefore, from 2010 to 2016, we performed a national, prospective, cohort study to analysis HLH-associated genes (Lyst, perforine, Munc 13-4, syntaxine-11, STXBP-2, SH2D1, XIAP, Rab-27, Itk) in sHLH.

Methods: We included 190 adults and 15 children fulfilling adapted Histiocyte Society criteria. Data collected included: (i) clinical and biological features, (ii) malignant, autoimmune or infectious associated diseases, (iii) treatment and evolution at M0 and M12. HLH associated-genes could be sequenced in 185 patients and analyzed in 147. Mutational profiles of Non Synonymous (NS), rare variants (frequency < 1% or 5% in reference populations) were compared to control populations issued from the “1000 genomes” project and in house repositories.

Results: Heterozygous (n=111) and homozygous (n=2) rare variants were identified in 80 patients. For 26 patients, rare variants were localized in 2 or 3 genes. Compared with control populations, overall rare variants frequency didn’t differ significantly. However, rare variants (frequency < 1% or < 5%) affecting 2 or more genes in patients were significantly different from controls (p<0.0002 and p< 0.03). Combinations of rare variants were enriched with perforin and RAB27a or STXBP2 genes. sHLH were associated with hematologic malignancies and autoimmune diseases in 51 and 20 cases respectively, and idiopathic in 75 cases with infectious trigger in half of the cases. Severity of sHLH (relapsing cases, ICU transfer, or death) is significantly correlated with the presence of combination of rare variants (p=0,0043), especially in the groups of autoimmune diseases or idiopathic.

Conclusion: In conclusion, genes of primary HLH may also be involved in sHLH physiopathology and outcome.

Disclosure: C. Bloch-Queyrat, None; J. P. Jais, None; M. Gil, None; B. Bader-Meunier, None; O. Hermine, None; G. de Saint-Basile, None.

To cite this abstract in AMA style:

Bloch-Queyrat C, Jais JP, Gil M, Bader-Meunier B, Hermine O, de Saint-Basile G. Sporadic Hemophagocytic Lymphohistiocytosis (sHLH): A Polygenic Disease? a Report of French National, Prospective, Cohort of 205 Patients [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/sporadic-hemophagocytic-lymphohistiocytosis-shlh-a-polygenic-disease-a-report-of-french-national-prospective-cohort-of-205-patients/. Accessed March 25, 2019.

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