Pediatric-onset Evans syndrome: Heterogeneous presentation and high frequency of monogenic disorders including LRBA and CTLA4 mutations

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

“…181 In patients with immunoregulatory disorders, rituximab has been administered thus far to patients with FOXP3, CD25, CTLA4, LRBA, and STAT3 GOF mutations in combination with other drugs. 53,74,88,89,100,182 Rituximab has not been tested yet in patients with BACH2 deficiency, but it might not necessarily be beneficial because of already low memory B-cell counts and decreased immunoglobulin levels in this syndrome. 97 Indeed, in children with systemic lupus erythematosus (SLE)-associated cytopenia treated with rituximab, 3 of 4 patients with pre-existing low IgG levels developed persistent hypogammaglobulinemia after rituximab that required immunoglobulin replacement.…”

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case‐based review

“…Of note, RALD is associated with the presence of activating somatic mutations in KRAS or NRAS . Advances in sequencing have led to the discovery of a variety of other monogenic defects that are associated with an ALPS‐like phenotype including autosomal recessive disorders such as loss‐of‐function mutations in LRBA and autosomal dominant disorders such as CTLA4 haploinsufficiency, and gain‐of‐function mutations in PIK3CD and STAT3 as examples …”

“…Primary immune regulatory disorders associated with monogenic defects of genes involved in immune regulatory pathways have been recently identified in patients with multisystem autoimmunity and immunodeficiency. Organ‐specific autoimmunity such as autoimmune cytopenia (AIC), inflammatory bowel disease, autoimmune endocrinopathy, and arthritis are the presenting features in many of these patients, as well as hyperinflammation and nonmalignant lymphoproliferation . Advances in genetic sequencing have supported an expanding list of genetic defects in immune regulatory pathways leading to primary immune regulatory disorders.…”

“…Organ-specific autoimmunity such as autoimmune cytopenia (AIC), inflammatory bowel disease, autoimmune endocrinopathy, and arthritis are the presenting features in many of these patients, as well as hyperinflammation and nonmalignant lymphoproliferation. [1][2][3][4][5] efforts among immunologists, hematologists, and oncologists as well as rheumatologists to develop multidisciplinary clinics aimed at providing state-of-the-science care for these unique and often complex patients. Herein, we will address the clinical and immunologic spectrum of these disorders.…”

Bortezomib treatment of steroid‐refractory Evans syndrome in children

“…(2)In line with the rapidity of response and furthermore, lasting recovery after a single dose of bortezomib following a flare in the first case, smaller and/or fewer doses could be sufficient to induce responses. (3)Bortezomib has been well tolerated without any evidence of peripheral neuropathy (a frequent side effect in patients with multiple myeloma), infections, or any other adverse effects.Increased recognition of underlying monogenic mutations in various immune response genes in ES patients raises the possibility of new targeted therapeutic interventions that would eventually prevent autoantibody production along with control of accompanying systemic processes 11,12. Such novel targeted therapies are being currently investigated with some promising results 13,14.…”