Genes at the Crossroad of Primary Immunodeficiencies and Cancer

Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders affecting one or multiple components of the innate and/or adaptive immune system. Currently, over 300 underlying genetic defects have been discovered. The most common clinical findings in patients with PIDs are infections, autoimmunity, and malignancies. Despite international efforts, the cancer risk associated with PIDs, given the heterogeneous character of this group of diseases, is difficult to estimate. The diverse underlying mechanisms of cancer in PID add another layer of complexity. Treatment of cancer within a context of PID is complicated by serious toxicities and long-term effects, including second malignancies. This review will focus on the little-known crossroad between PID and cancer genes and the value thereof for directing future research on our understanding of cancer in PID and for the identification of early cancer biomarkers in PID patients

Multisystem inflammatory syndrome in children related to COVID-19: A systematic review

Importance. In April 2020, multiple reports of an association between a hyperinflammatory, Kawasaki-like condition and SARS-CoV-2 were published and termed as pediatric inflammatory multisystem syndrome (PIMS) or multisystem inflammatory syndrome (MIS). A thorough characterization of this syndrome (demographics, presentation, diagnosis, and outcome) is currently lacking. Objective. We aimed to perform a systematic review of published cases of this novel multisystem inflammatory syndrome in children associated with COVID-19. Evidence review. A literature search of Pubmed, Embase, BioRxiv, MedRxiv and COVID-19 specific research repositories (Cochrane COVID‐19 Study Register and the World Health Organization (WHO) COVID‐19 Global Research Database) was conducted from December 30th, 2019 to June 30th, 2020. Publications describing inflammatory syndromes associated with COVID-19 were included. Of 333 unique publications, 229 records were excluded based on title and abstract. After screening the full text, 40 observational studies and case reports were included, comprising 687 cases (published between May 9th, 2020 and June 30th, 2020). Findings. In contrast to classic Kawasaki disease, epidemiological enrichment for adolescents (median age 9 [6.0-12.3]) and ethnic minorities (35.8% black and 24.5% Hispanic/Latino) was observed. There was a male predominance (59.1%). Apart from obesity (24.4%), pre-existing conditions were infrequent. The majority suffered from gastrointestinal (87.2%) and cardiocirculatory (79.2%) manifestations. Respiratory symptoms (51.2%) were less frequent. Over half of patients (56.3%) presented with hemodynamic shock, and critical care interventions were often necessary (inotropics (56.5%), mechanical ventilation (22.9%), non-invasive ventilation (30.6%), extracorporal membrane oxygenation (ECMO;4.5%)). Anti-SARS-CoV-2 IgG and RT-PCR were positive in respectively 69.4% and 36.7%. Eleven deaths were reported (1.6%). The RCPCH case definition proved to be most comprehensive comprising all single cases. In contrast, WHO and CDC MIS definitions are more stringent, with the CDC case definition often missing severe cases requiring intensive care (n = 33 out of 95 cases). Conclusions and Relevance. This novel pediatric multisystem hyperinflammatory condition, associated with COVID-19, is characterized by a severe and heterogeneous disease spectrum. Despite frequent intensive care interventions, mortality rate was low and short-term outcome favorable. Long-term follow-up of possible chronic complications and additional clinical research, to elucidate the underlying immunological pathogenesis and possible genetic predisposition is crucial

A computational pipeline for the diagnosis of CVID patients

Common variable immunodeficiency (CVID) is one of the most frequently diagnosed primary antibody deficiencies (PADs), a group of disorders characterized by a decrease in one or more immunoglobulin (sub) classes and/or impaired antibody responses caused by inborn defects in B cells in the absence of other major immune defects. CVID patients suffer from recurrent infections and disease-related, non-infectious, complications such as autoimmune manifestations, lymphoproliferation, and malignancies. A timely diagnosis is essential for optimal follow-up and treatment. However, CVID is by definition a diagnosis of exclusion, thereby covering a heterogeneous patient population and making it difficult to establish a definite diagnosis. To aid the diagnosis of CVID patients, and distinguish them from other PADs, we developed an automated machine learning pipeline which performs automated diagnosis based on flow cytometric immunophenotyping. Using this pipeline, we analyzed the immunophenotypic profile in a pediatric and adult cohort of 28 patients with CVID, 23 patients with idiopathic primary hypogammaglobulinemia, 21 patients with IgG subclass deficiency, six patients with isolated IgA deficiency, one patient with isolated IgM deficiency, and 100 unrelated healthy controls. Flow cytometry analysis is traditionally done by manual identification of the cell populations of interest. Yet, this approach has severe limitations including subjectivity of the manual gating and bias toward known populations. To overcome these limitations, we here propose an automated computational flow cytometry pipeline that successfully distinguishes CVID phenotypes from other PADs and healthy controls. Compared to the traditional, manual analysis, our pipeline is fully automated, performing automated quality control and data pre-processing, automated population identification (gating) and deriving features from these populations to build a machine learning classifier to distinguish CVID from other PADs and healthy controls. This results in a more reproducible flow cytometry analysis, and improves the diagnosis compared to manual analysis: our pipelines achieve on average a balanced accuracy score of 0.93 (+/- 0.07), whereas using the manually extracted populations, an averaged balanced accuracy score of 0.72 (+/- 0.23) is achieved

Genes at the crossroad of primary immunodeficiencies and cancer

Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders affecting one or multiple components of the innate and/or adaptive immune system. Currently, over 300 underlying genetic defects have been discovered. The most common clinical findings in patients with PIDs are infections, autoimmunity, and malignancies. Despite international efforts, the cancer risk associated with PIDs, given the heterogeneous character of this group of diseases, is difficult to estimate. The diverse underlying mechanisms of cancer in PID add another layer of complexity. Treatment of cancer within a context of PID is complicated by serious toxicities and long-term effects, including second malignancies. This review will focus on the little-known crossroad between PID and cancer genes and the value thereof for directing future research on our understanding of cancer in PID and for the identification of early cancer biomarkers in PID patients

A 475 years-old founder effect involving IL12RB1: a highly prevalent mutation conferring Mendelian susceptibility to mycobacterial diseases in European descendants

Mutations in IFNGR1, IFNGR2, IL12RB1, IL12B, STAT1 and NEMO result in a common clinical phenotype known as Mendelian Susceptibility to Mycobacterial Diseases (MSMD). Interleukin-12 receptor 01 (IL12R beta 1) deficiency is the most common genetic etiology for MSMD. Known mutations affecting IL12RB1 are recessively inherited and are associated with null response to both IL-12 and IL-23. Mutation IL12RB1 1623_1624delinsTT was originally described in 5 families from European origin (2 from Germany: I from Cyprus, France and Belgium). Interestingly, this same mutation was found in an unexpectedly high prevalence among IL-12R beta 1 deficient patients in Argentina: 5-out-of-6 individuals born to unrelated families carried this particular change. To determine whether mutation 1623_1624delinsTT represents a DNA mutational hotspot or a founder effect, 34 polymorphic markers internal or proximal to IL12RB1 were studied in the Argentinean and the Belgian patients. A common haplotype spanning 1.45-3.51 Mb was shared by all chromosomes carrying mutation 1623_1624delinsTT, and was not detected on 100 control chromosomes. Applying a modified likelihood-based method the age of the most recent common ancestor carrying mutation 1623_1624delinsTT was estimated in 475 years (95% CI, 175-1275), which is the time when the Spaniards initiated the colonization of the Americas. Mutation 1623_1624delinsTT represents the first founder effect described on IL-12R beta 1, the most frequently affected gene in MSMD, and affecting patients with European ancestors. The reason(s) behind the persistency of this mutation across multiple generations, its relative high prevalence, and any potential selective advantage are yet to be established

Early-onset primary antibody deficiency resembling common variable immunodeficiency challenges the diagnosis of Wiedeman-Steiner and Roifman syndromes

Syndromic primary immunodeficiencies are rare genetic disorders that affect both the immune system and other organ systems. More often, the immune defect is not the major clinical problem and is sometimes only recognized after a diagnosis has been made based on extra-immunological abnormalities. Here, we report two sibling pairs with syndromic primary immunodeficiencies that exceptionally presented with a phenotype resembling early-onset common variable immunodeficiency, while extra-immunological characteristics were not apparent at that time. Additional features not typically associated with common variable immunodeficiency were diagnosed only later, including skeletal and organ anomalies and mild facial dysmorphism. Whole exome sequencing revealed KMT2-Aassociated Wiedemann-Steiner syndrome in one sibling pair and their mother. In the other sibling pair, targeted testing of the known disease gene for Roifman syndrome (RNU4ATAC) provided a definite diagnosis. With this study, we underline the importance of an early-stage and thorough genetic assessment in paediatric patients with a common variable immunodeficiency phenotype, to establish a conclusive diagnosis and guide patient management. In addition, this study extends the mutational and immunophenotypical spectrum of Wiedemann-Steiner and Roifman syndromes and highlights potential directions for future pathophysiological research

FLH Type 5 Caused by a Novel Mutation in STXBP2 Gene: An Unusual Cause of Failure to Thrive and Diarrhea in Infancy

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