| dc.description.abstract | Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium
infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of
disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study,
we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide,
including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in
these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5–7 years). The main clinical
manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated
cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel
phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of
memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels
were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was
33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7)
was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R
signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease
pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which
should thus be considered as early as possible following molecular diagnosis. | tr_TR |
