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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.

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The capping protein regulator and myosin 1 linker 2 (CARMIL2) deficiency is an autosomal recessive inborn error of immunity (IEI) leading to combined T-cell, B-cell, and NK cell defects. 1,2 CARMIL2, also known as RGD motif, leucine-rich repeats, tropomodulin domain, and proline-rich containing protein (RLTPR), is a member of the CARMIL family. This family consists of three paralogous genes (CARMIL1, CARMIL2, and CARMIL3), producing multidomain proteins with high sequence homology. They contain an N-terminal pleckstrin homology (PH) domain, a leucine-rich repeat (LRR) domain, a homodimerization domain (HD), and a C-terminal domain including a capping protein binding region (CBR) and a proline-rich region (PRR).While all CARMILs have a capacity to bind to the capping proteins and regulate actin assembly, each protein also has a unique cellular function. 3 CARMIL1 activates the Trio-Rac1 pathway to enhance Arp2/3-mediated actin polymerization, 4,5 whereas CARMIL2 binds to cellular membranes via vimentin, and activates T cells by ligating CD28 and CARMA1 to mediate NFk B signaling. 6,7 Mice expressing mutated Carmil2 gene are not able to conduct CD28-mediated activation of its effector protein kinase C theta (PKCθ), abrogating effector memory CD4 + T and regulatory T cells (Treg) development. 7,8 CARMIL2 is also necessary for invadopodia formation, cell polarity, lamellipodial assembly, membrane ruffling, macropinocytosis, and cell migration. 3 The CARMIL3 is expressed mainly in the brain and spinal cord, and identified as oncofetal gene; however, recently, it was demonstrated as essential regulator of the proinflammatory cytokines in macrophages. 3,9 The human CARMIL2 gene was originally identified by Matsuzaka et al. and shown to be downregulated in affected skin cells of psoriasis vulgaris patients. 10 The CARMIL2 protein is expressed in the cytoplasm, especially in the skin, lymphoid tissue, and gastrointestinal system, and was demonstrated to play a role in wound healing. 3 So far, fewer than 40 cases of CARMIL2 deficiency have been reported worldwide. Patients with CARMIL2 deficiency present with a broad range of symptoms, including cutaneous and respiratory allergies mainly characterized by eczematous lesions, early-onset