Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience.

CARD11-associated diseases are monogenic inborn errors of immunity involving immunodeficiency, predisposition to malignancy and immune dysregulation such as lymphoproliferation, inflammation, atopic and autoimmune manifestations. Defects in CARD11 can present as mutations that confer a complete or a partial loss of function (LOF) or contrarily, a gain of function (GOF) of the affected gene product. We report clinical characteristics, immunophenotypes and genotypes of 15 patients from our center presenting with CARD11-associated diseases. Index cases are pediatric patients followed in our immunology division who had access to next generation sequencing studies. Variant significance was defined by functional analysis in cultured cells transfected with a wild type and/or with mutated hCARD11 constructs. Cytoplasmic aggregation of CARD11 products was evaluated by immunofluorescence. Nine index patients with 9 unique heterozygous CARD11 variants were identified. At the time of the identification, 7 variants previously unreported required functional validation. Altogether, four variants showed a GOF effect as well a spontaneous aggregation in the cytoplasm, leading to B cell expansion with NF-κB and T cell anergy (BENTA) diagnosis. Additional four variants showing a LOF activity were considered as causative of CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS). The remaining variant exhibited a neutral functional assay excluding its carrier from further analysis. Family segregation studies expanded to 15 individuals the number of patients presenting CARD11-associated disease. A thorough clinical, immunophenotypical, and therapeutic management evaluation was performed on these patients (5 BENTA and 10 CADINS). A remarkable variability of disease expression was clearly noted among BENTA as well as in CADINS patients, even within multiplex families. Identification of novel CARD11 variants required functional studies to validate their pathogenic activity. In our cohort BENTA phenotype exhibited a more severe and expanded clinical spectrum than previously reported, e.g., severe hematological and extra hematological autoimmunity and 3 fatal outcomes. The growing number of patients with dysmorphic facial features strengthen the inclusion of extra-immune characteristics as part of the CADINS spectrum. CARD11-associated diseases represent a challenging group of disorders from the diagnostic and therapeutic standpoint, especially BENTA cases that can undergo a more severe progression than previously described.

Pediatric Inflammatory Bowel Disease: A Multicenter Study of Changing Trends in Argentina Over the Past 30 Years.

Purpose: To analyze the characteristics of pediatric inflammatory bowel disease (IBD) over the past three decades in Argentina and determine if there are differences between the first two decades and the past decade. Methods: We conducted a retrospective multicenter analytical study in children with IBD between 0 and 18 years of age diagnosed between 1987 and 2017 in three tertiary health centers in Argentina. The evaluation included clinical characterization, endoscopy, histology, and imaging data together with therapeutic strategies. The patients were divided into two groups: Group 1, diagnosed between 1987 and 2007, and Group 2, diagnosed between 2008 and 2017. Results: Of the 756 patients included, 409 (54%) had ulcerative colitis (UC), 250 (33%) had Crohn's disease (CD), and 97 (13%) had IBD-unclassified (IBD-U). The positive family history was 3.8%, which was more frequent among children under two years of age (6.7%). There were no significant differences in clinical presentation and extraintestinal manifestations between periods, with hepatic manifestations being the most frequent. In the last decade, we found an upward trend in CD, a downward trend in UC/IBD-U, even after adjustment for socioeconomic status, and a decrease of 50% in surgical treatments coinciding with the advent of biological therapy. Conclusion: This is the first multicenter cohort study in a Latin American country to describe clinical, endoscopic, and therapeutic data across the past 30-year period. Although CD was responsible for the overall increase in incidence, UC was still prevalent in this region.