Manish Butte

A 23-Year-Old Man with Hyper-IgM Syndrome Presenting with Asymptomatic Violaceous Facial Plaques.

Dermatopathology (Basel). 2019 Oct-Dec;6(4):246-250

Authors: Barrios M, Nathan N, Trowbridge R, Plovanich M, Nazarian RM, Kroshinsky D

Abstract
Tumid lupus is a rare subtype of chronic cutaneous lupus that is characterized by urticaria-like photosensitive plaques. Unlike discoid lupus, it has minimal to no surface change and resolves without scarring. On pathological examination, it may be distinguished from other types of lupus by abundant interstitial mucin deposits. Herein, we describe a case of tumid lupus in a 23-year-old Kuwaiti male with hyper-IgM syndrome. To our best knowledge, this is the first report of tumid lupus in a patient with a primary immunodeficiency.

PMID: 32083062 [PubMed]

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Functions of Tfh Cells in Common Variable Immunodeficiency.

Front Immunol. 2020;11:6

Authors: Le Saos-Patrinos C, Loizon S, Blanco P, Viallard JF, Duluc D

Abstract
Common variable immunodeficiency is the most common clinical primary immunodeficiency in adults. Its hallmarks are hypogammaglobulinemia and compromised B-cell differentiation into memory or antibody-secreting cells leading to recurrent infections. This disease is heterogeneous, with some patients harboring multiple complications such as lymphoproliferative disorders, autoimmune manifestations, or granulomatous inflammation. The mechanisms leading to these complications remain elusive despite numerous associations found in the literature. For instance, although described as a B cell intrinsic disease, numerous abnormalities have been reported in other immune cell compartments. Here, we tuned our attention to follicular helper T cells, a CD4+ T cell population specialized in B cell help, considering the recent publications showing an involvement of these cells in CVID pathogenesis.

PMID: 32082308 [PubMed – in process]

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Newborn Screening for Primary Immunodeficiencies: The Gaps, Challenges, and Outlook for Developing Countries.

Front Immunol. 2019;10:2987

Authors: El-Sayed ZA, Radwan N

Abstract
Primary immunodeficiency diseases (PIDs) are genetically inherited diseases characterized by an increased susceptibility to infections, autoimmunity, lymphoproliferation, and malignancies. PIDs are under-diagnosed and the registered cases and reported prevalence are far below the estimated numbers especially in countries with large population and high consanguinity rates. Delays in diagnosis yield major morbidities and mortalities with resultant increased economic burden. Newborn screening using TRECs and KRECs, currently being implemented in some countries, is aimed through early diagnosis, to overcome the delays in the diagnosis and hence the poor outcome of some of the severe PIDs. However, the limited resources in developing countries challenges the implementation of newborn PID screening programs. There are considerable gaps in our knowledge that must be bridged. Setting the norms of TRECs and KRECs for each country is needed. Furthermore, some PIDs that might present in the neonatal period could not be detected by the current screening programs, and their diagnosis requires clinical expertise. Not to mention, local guidelines for the management of patients diagnosed by NBS should be set forth. Also, in the absence of NBS, clinicians should be aware of the early manifestations of PID. All these mandate conducting studies genuine to each country, developing programs for raising public awareness and clinical training of physicians to attain the required immunological skills.

PMID: 32082296 [PubMed – in process]

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Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease.

Nat Commun. 2020 Feb 21;11(1):995

Authors: Serra EG, Schwerd T, Moutsianas L, Cavounidis A, Fachal L, Pandey S, Kammermeier J, Croft NM, Posovszky C, Rodrigues A, Russell RK, Barakat F, Auth MKH, Heuschkel R, Zilbauer M, Fyderek K, Braegger C, Travis SP, Satsangi J, Parkes M, Thapar N, Ferry H, Matte JC, Gilmour KC, Wedrychowicz A, Sullivan P, Moore C, Sambrook J, Ouwehand W, Roberts D, Danesh J, Baeumler TA, Fulga TA, Karaminejadranjbar M, Ahmed A, Wilson R, Barrett JC, Elkadri A, Griffiths AM, COLORS in IBD group investigators, Oxford IBD cohort study investigators, INTERVAL Study, Swiss IBD cohort investigators, UK IBD Genetics Consortium, NIDDK IBD Genetics Consortium, Snapper SB, Shah N, Muise AM, Wilson DC, Uhlig HH, Anderson CA

Abstract
Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10-10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10-10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.

PMID: 32081864 [PubMed – in process]

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North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Position Paper on the Evaluation and Management for Patients With Very Early-onset Inflammatory Bowel Disease.

J Pediatr Gastroenterol Nutr. 2020 Mar;70(3):389-403

Authors: Kelsen JR, Sullivan KE, Rabizadeh S, Singh N, Snapper S, Elkadri A, Grossman AB

Abstract
The rate of pediatric inflammatory bowel disease (IBD) has been increasing over the last decade and this increase has occurred most rapidly in the youngest children diagnosed <6 years, known as very early-onset inflammatory bowel disease (VEO-IBD). These children can present with more extensive and severe disease than older children and adults. The contribution of host genetics in this population is underscored by the young age of onset and the distinct, aggressive phenotype. In fact, monogenic defects, often involving primary immunodeficiency genes, have been identified in children with VEO-IBD and have led to targeted and life-saving therapy. This position paper will discuss the phenotype of VEO-IBD and outline the approach and evaluation for these children and what factors should trigger concern for an underlying immunodeficiency. We will then review the immunological assays and genetic studies that can facilitate the identification of the underlying diagnosis in patients with VEO-IBD and how this evaluation may lead to directed therapies. The position paper will also aid the pediatric gastroenterologist in recognizing when a patient should be referred to a center specializing in the care of these patients. These guidelines are intended for pediatricians, allied health professionals caring for children, pediatric gastroenterologists, pediatric pathologists, and immunologists.

PMID: 32079889 [PubMed – in process]

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FHLdb: A Comprehensive Database on the Molecular Basis of Familial Hemophagocytic Lymphohistiocytosis.

Front Immunol. 2020;11:107

Authors: Viñas-Giménez L, Padilla N, Batlle-Masó L, Casals F, Rivière JG, Martínez-Gallo M, de la Cruz X, Colobran R

Abstract
Background: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders. The lack of comprehensive disease-specific mutation databases may hinder or delay classification of the genetic variants found in samples from these patients. This is especially true for familial hemophagocytic lymphohistiocytosis (FHL), a life-threatening PID classically considered an autosomal recessive condition, but with increasingly demonstrated genetic heterogeneity. Objective: The aim of this study was to build an open-access repository to collect detailed information on the known genetic variants reported in FHL. Methods: We manually reviewed more than 120 articles to identify all reported variants related to FHL. We retrieved relevant information about the allelic status, the number of patients with the same variant, and whether functional assays were done. We stored all the data retrieved in a PostgreSQL database and then built a website on top of it, using the Django framework. Results: The database designed (FHLdb) (https://www.biotoclin.org/FHLdb) contains comprehensive information on reported variants in the 4 genes related to FHL (PRF1, UNC13D, STXBP2, STX11). It comprises 240 missense, 69 frameshift, 51 nonsense, 51 splicing, 10 in-frame indel, 7 deep intronic, and 5 large rearrangement variants together with their allelic status, carrier(s) information, and functional evidence. All genetic variants have been classified as pathogenic, likely pathogenic, uncertain significance, likely benign or benign, according to the American College of Medical Genetics guidelines. Additionally, it integrates information from other relevant databases: clinical evidence from ClinVar and UniProt, population allele frequency from ExAC and gnomAD, and pathogenicity predictions from well-recognized tools (e.g., PolyPhen-2, SIFT). Finally, a diagram depicts the location of the variant relative to the gene exon and protein domain structures. Conclusion: FHLdb includes a broad range of data on the reported genetic variants in familial HLH genes. It is a free-access and easy-to-use resource that will facilitate the interpretation of molecular results of FHL patients, and it illustrates the potential value of disease-specific databases for other PIDs.

PMID: 32076423 [PubMed – in process]

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Alimentary necrobacillosis in alpacas.

J Vet Diagn Invest. 2020 Feb 18;:1040638720906409

Authors: Carvallo FR, Uzal FA, Flores C, Diab SS, Giannitti F, Crossley B, Wünschmann A

Abstract
Ulcers of the oral cavity, esophagus, and gastric compartments of South American camelids are uncommon. Multifocal-to-coalescing ulcers were identified in the oral cavity, esophagus, and/or gastric compartments of 5 alpacas submitted for postmortem examination. Fusobacterium necrophorum was isolated from the lesions in all alpacas, in combination with other aerobic and anaerobic bacteria. In 4 of these cases, F. necrophorum-associated lesions were considered secondary to neoplasia or other chronic debilitating conditions; in 1 case, the alimentary ulcers were considered the most significant autopsy finding. It is not known if this agent acted as a primary or opportunistic agent in mucosal membranes previously damaged by a traumatic event, chemical insult, immunodeficiency, or any other debilitating condition of the host.

PMID: 32070228 [PubMed – as supplied by publisher]

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The co-occurrence of Wilson disease and X-linked agammaglobulinemia in one family highlights the promising diagnostic potential of proteolytic analysis.

Mol Genet Genomic Med. 2020 Feb 17;:e1172

Authors: Poskanzer SA, Thies J, Collins CJ, Myers CT, Dayuha R, Duong P, Yi F, Chang IJ, Ochs HD, Torgerson TR, Hahn SH

Abstract
BACKGROUND: We report the first case of a family with co-occurrence of Wilson disease (WD), an autosomal recessive disorder of copper metabolism, and X-linked agammaglobulinemia (XLA), a primary immunodeficiency disorder (PIDD) that features marked reduction in circulating B lymphocytes and serum immunoglobulins.
METHODS AND RESULTS: Through utilization of a multiplexed biomarker peptide quantification method known as the immuno-SRM assay, we were able to simultaneously and independently identify which family members are affected with WD and which are affected with XLA using dried blood spots (DBS).
CONCLUSION: Being able to delineate multiple diagnoses using proteolytic analysis from a single DBS provides support for implementation of this methodology for clinical diagnostic use as well as large-scale population screening, such as newborn screening (NBS). This could allow for early identification and treatment of affected individuals with WD or XLA, which have been shown to reduce morbidity and decrease mortality in these two populations.

PMID: 32067425 [PubMed – as supplied by publisher]

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