Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes

Abstract

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M− group). The M+ group displayed more severe disease than the M− group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.

Second‐line treatment trends and long‐term outcomes of 392 children with chronic immune thrombocytopenic purpura: the French experience over the past 25 years

“…A recent Austrian study presented the management of 81 children with cITP but included 17 cases of ES (Sipurzynski et al , 2016). We consider ES patients to be a distinct subgroup of ITPs as 65% of cases are likely to be caused by PID (Aladjidi et al , 2011; Besnard et al , 2018; Hadjadj et al , 2019). Patients with cITP are to be monitored over time for features of inherited platelet diseases, ES or secondary causes (Fiore et al , 2016; HAS, 2017).…”

Horn of plenty: Value of the international registry for pediatric chronic myeloid leukemia

“…By this highly flexible approach the pediatric CML registry is analogue to other pediatric registries for rare hematological diseases which are acting successfully on a national basis, e.g . National Centre of Reference for Autoimmune Cytopenia in Children (CEREVANCE) in Bordeaux/France[ 20 , 21 ], the German PID-NET registry serving as the first national registry of patients with primary immunodeficiencies[ 22 , 23 ], or on an international basis ( e.g ., Intercontinental Cooperative Immune Thrombocytopenic Purpura Study Group[ 24 ], Severe Chronic Neutropenia International Registry[ 25 ]).…”

Fatal Hypogammaglobulinemia 3 Years after Rituximab in a Patient with Immune Thrombocytopenia: An Underlying Genetic Predisposition?

“…DNA extracted using standard methods [6] from the bone-marrow sample obtained when she had Pneumocystis jiroveci pneumonia was subjected to next-generation sequencing. Exons from genomic DNA underwent PCR ampli cation according to standard protocols [5]. e PCR ampli cons were then sequenced in both directions and analyzed with ApE-A plasmid Editor v2.0.45.…”

“…In a recent study, Vandrovcova et al screened a cohort of 130 adult patients with persistent or chronic primary ITP for mutations in the FAS gene and identi ed two potentially functional mutations in two patients with atypical ALPS clinical features [4]. Otherwise, Evans syndrome, characterized by the combination of autoimmune hemolytic anemia and ITP, is potentially genetically determined in at least 65% of cases in pediatric population [5]. So, these observations raise the possibility of a genetic defect in ITP young people, mostly in a context of immunode ciency, and ALPS mutations must primarily be investigated.…”