Underlying Inborn Errors of Immunity in Patients With Evans Syndrome and Multilineage Cytopenias: A Single-Centre Analysis

Abstract

BackgroundEvans syndrome (ES) is a rare disorder classically defined as the simultaneous or sequential presence of autoimmune haemolytic anaemia and immune thrombocytopenia, but it has also been described as the presence of at least two autoimmune cytopenias. Recent reports have shown that ES is often a manifestation of an underlying inborn error of immunity (IEI) that can benefit from specific treatments.AimsThe aim of this study is to investigate the clinical and immunological characteristics and the underlying genetic background of a single-centre cohort of patients with ES.MethodsData were obtained from a retrospective chart review of patients with a diagnosis of ES followed in our centre. Genetic studies were performed with NGS analysis of 315 genes related to both haematological and immunological disorders, in particular IEI.ResultsBetween 1985 and 2020, 40 patients (23 men, 17 women) with a median age at onset of 6 years (range 0–16) were studied. ES was concomitant and sequential in 18 (45%) and 22 (55%) patients, respectively. Nine of the 40 (8%) patients had a positive family history of autoimmunity. Other abnormal immunological features and signs of lymphoproliferation were present in 24/40 (60%) and 27/40 (67%) of cases, respectively. Seventeen out of 40 (42%) children fit the ALPS diagnostic criteria. The remaining 21 (42%) and 2 (5%) were classified as having an ALPS-like and an idiopathic disease, respectively. Eighteen patients (45%) were found to have an underlying genetic defect on genes FAS, CASP10, TNFSF13B, LRBA, CTLA4, STAT3, IKBGK, CARD11, ADA2, and LIG4. No significant differences were noted between patients with or without variant and between subjects with classical ES and the ones with other forms of multilineage cytopenias.ConclusionsThis study shows that nearly half of patients with ES have a genetic background being in most cases secondary to IEI, and therefore, a molecular evaluation should be offered to all patients.

TACI variants as underlying condition in autoimmune neutropenia: Description of four cases

“…Early recognition of the type of AINP is critical to offer the best monitoring program and optimal therapy possibly tailored to the underlying disorder (i.e., immunoglobulin replacement), particularly in light of severe clinical findings such as PRCA, which may appear over the course of the disease. This specific type of evolution, as indicated by recent findings from our group, 8,9 outlines the need to investigate the underlying PID/PIRD in childhood marrow failure.…”

“…7 For example, cytopenia can be caused by impaired marrow cell production, as observed in aplastic anemia (AA) and PRCA, or increased destruction of peripheral blood cells, as seen in Evans' syndrome. [8][9] The case reported by Bergman gives us an opportunity to share the experience of the Pediatric Hematology Unit of the IRCCS, G. Gaslini Research Hospital on autoimmune/idiopathic neutropenia, which was initially considered an acquired disorder but was eventually shown to be an immune dysregulation associated with TACI variants. 1).…”

Pathogenesis of refractory ITP: Overview

“…Germline mutations in several immunoregulatory genes have been identified in over 50% of patients, including in CTLA4, STAT 3, LRBA, FAS and CASP10, among others. [20][21][22][23] ITP is also a frequent presenting or delayed feature in common variable immune deficiency, autoimmune lymphoproliferative syndrome, IgG/IgA deficiency, CTLA haploinsufficiency and IPEX, among diverse Immunoregulatory disorders in which loss or especially gain of function secondary to germline or somatic gene mutations have been identified (reviewed in Ref. [24]).…”

Paediatric‐onset Evans syndrome: Breaking away from refractory immune thrombocytopenia

“…Moreover, at least 80% of those pES patients will progress to various clinical or biological immunopathological manifestations (IM) with age. [12][13][14][15] And those pES patients have been shown to be associated with various underlying genetic defects in up to 65% of cases [16][17][18][19] (Table 1).…”