Case report: Neonatal-onset inflammatory bowel disease due to novel compound heterozygous mutations in DUOX2

Very Early Onset Inflammatory Bowel Disease (VEO-IBD) is potentially associated with genetic disorders of the intestinal epithelial barrier or inborn errors of immunity (IEI). Dual oxidase 2 (DUOX2), an H2O2-producing NADPH oxidase expressed at apical enterocyte membranes, plays a crucial role in innate defense response. Biallelic DUOX2 mutations have been described only in two patients with VEO-IBD to date. We report the case of a 1-month-old female infant who presented persistent high C-reactive protein (CRP) levels from birth and anemia. Positive occult blood and very high calprotectin in the stool were detected and abdominal ultrasound showed thickened last ileal loop. Full endoscopy evaluation revealed important colon stenosis with multiple pseudo-polyploidy formations that resulted refractory to steroid therapy, requiring a partial colic resection. Histological examination of biopsy samples showed morphological features of IBD. Whole Exome Sequencing (WES) disclosed compound heterozygous variants in the DUOX2 gene: the pathogenic c.2524C>T; p.Arg842Ter and the variant of uncertain significance (VUS) c.3175C>T; p.Arg1059Cys. Molecular and functional studies showed the presence of mutant DUOX2 in the intestinal epithelium of the patient, albeit with at least 50% decreased catalytic activity. In conclusion, we describe the third patient to date with compound heterozygous variants of DUOX2, responsible for monogenic neonatal-IBD. This case expands the knowledge about Mendelian causes of VEO-IBD and DUOX2 deficiency. We suggest that DUOX2 should be part of the diagnostic evaluation of patients with suspected monogenic VEO-IBD

Radiosensitivity in patients affected by ARPC1B deficiency: a new disease trait?

Actin-related protein 2/3 complex subunit 1B (ARPC1B) deficiency is a recently described inborn error of immunity (IEI) presenting with combined immunodeficiency and characterized by recurrent infections and thrombocytopenia. Manifestations of immune dysregulation, including colitis, vasculitis, and severe dermatitis, associated with eosinophilia, hyper-IgA, and hyper-IgE are also described in ARPC1B-deficient patients. To date, hematopoietic stem cell transplantation seems to be the only curative option for patients. ARPC1B is part of the actin-related protein 2/3 complex (Arp2/3) and cooperates with the Wiskott–Aldrich syndrome protein (WASp) in the regulation of the actin cytoskeleton remodeling and in driving double-strand break clustering for homology-directed repair. In this study, we aimed to investigate radiosensitivity (RS) in ARPC1B-deficient patients to assess whether it can be considered an additional disease trait. First, we performed trio-based next-generation-sequencing studies to obtain the ARPC1B molecular diagnosis in our index case characterized by increased RS, and then we confirmed, using three different methods, an increment of radiosensitivity in all enrolled ARPC1B-deficient patients. In particular, higher levels of chromatid-type aberrations and γH2AX foci, with an increased number of cells arrested in the G2/M-phase of the cell cycle, were found in patients’ cells after ionizing radiation exposition and radiomimetic bleomycin treatment. Overall, our data suggest increased radiosensitivity as an additional trait in ARPC1B deficiency and support the necessity to investigate this feature in ARPC1B patients as well as in other IEI with cytoskeleton defects to address specific clinical follow-up and optimize therapeutic interventions

Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder

Halolike Phenomenon Around a Café au Lait Spot Superimposed on a Mongolian Spot

An 8-month-old Caucasian infant with neurofibromatosis type 1 presented with a congenital plexiform neurofibroma and multiple caf\ue9 au lait spots. A pale area surrounded one of the caf\ue9 au lait spots located on the left gluteus in the area of dermal melanocytosis. This halolike phenomenon results from the disappearance of the Mongolian spot around the caf\ue9 au lait spots, revealing normal pigmented skin. This sign has been described rarely in the literature and the pathogenic mechanism is unclear

Host Defenses to Viruses: Lessons from Inborn Errors of Immunity

The constant battle between viruses and their hosts leads to their reciprocal evolution. Viruses regularly develop survival strategies against host immunity, while their ability to replicate and disseminate is countered by the antiviral defense mechanisms that host mount. Although most viral infections are generally controlled by the host’s immune system, some viruses do cause overt damage to the host. The outcome can vary widely depending on the properties of the infecting virus and the circumstances of infection but also depends on several factors controlled by the host, including host genetic susceptibility to viral infections. In this narrative review, we provide a brief overview of host immunity to viruses and immune-evasion strategies developed by viruses. Moreover, we focus on inborn errors of immunity, these being considered a model for studying host response mechanisms to viruses. We finally report exemplary inborn errors of both the innate and adaptive immune systems that highlight the role of proteins involved in the control of viral infections

Bimetallic Co\u2013M (M = Cu, Ag, and Au) Carbonyl Complexes Supported by N-Heterocyclic Carbene Ligands: Synthesis, Structures, Computational Investigation, and Catalysis for Ammonia Borane Dehydrogenation

The reaction of Na[Co(CO)4] with M(IPr)Cl (M = Cu, Ag, and Au; IPr = C3N2H2(C6H3 iPr2)2) affords the neutral heterometallic complexes [Co(CO)4{M- (IPr)}] (M = Cu, 1; Ag, 2; and Au, 3). Formation of 2 is accompanied by traces of [Ag(IPr)2][Ag{Co(CO)4}2] (4). The reaction of Na[Co(CO)4] with M(IMes)Cl (IMes = C3N2H2(C6H2Me3)2) results in mixtures of [Co(CO)4{M(IMes)}] (M = Cu, 5; Ag, 6; and Au, 7) and [M(IMes)2][M{Co(CO)4}2] (M = Cu, 8; Ag, 9; and Au, 10). In the cases of Cu and Ag, ionic complexes 8 and 9 are the major products, whereas neutral species 7 is the major product for Au. All species 1 1210 have been spectroscopically characterized by IR and 1H and 13C{1H} NMR spectroscopy. Moreover, the molecular structures of 2, 3, and 8 have been determined by single-crystal X-ray diffraction (SC-XRD). Bimetallic Co 12M 12NHC complexes 1 123 and 7 129 have been tested as catalysts for the dehydrogenation of ammonia 12borane (AB) in THF as solvent, and their performances compared to [Fe(CO)4{M(NHC)}2], M(NHC)Cl, and Na[Co(CO)4]. DFT computations have been performed to provide information on the structure, IR spectroscopy, and the thermodynamics of Co 12M carbonyl clusters

Characterization of AR-CGD female patient with a novel homozygous deletion in CYBC1 gene presenting with unusual clinical phenotype

chronic granulomatous disease (CGD) is a human IEI caused by mutations in genes encoding the NADPH oxidase subunits, the enzyme responsible for the respiratory burst. CGD patients have severe life-threatening infections, hyperinflammation and immune dysregulation. recently, an additional autosomal recessive AR-CGD (type 5) caused by mutations in CYBC1/EROS gene was identified.We report a AR-CGD5 patient with a novel loss of function (LOF) homozygous deletion c.8_7del in the CYBC1 gene including the initiation ATG codon that leads to failure of CYBC1/EROS protein expression and presenting with an unusual clinical manifestation of childhood-onset sarcoidosis-like disease requiring multiple immuno-suppressive therapies. we described an abnormal gp91phox protein expression/function in the patient's neu-trophils and monocytes (about 50%) and a severely compromised B cell subset (gp91phox < 15%; DHR+ < 4%). our case-report emphasized the importance of considering a diagnosis of AR-CGD5 deficiency even in absence of typical clinical and laboratory findings

Targeted treatment of autoimmune cytopenias in primary immunodeficiencies

Primary Immunodeficiencies (PID) are a group of rare congenital disorders of the immune system. Autoimmune cytopenia (AIC) represents the most common autoimmune manifestation in PID patients. Treatment of AIC in PID patients can be really challenging, since they are often chronic, relapsing and refractory to first line therapies, thus requiring a broad variety of alternative therapeutic options. Moreover, immunosuppression should be fine balanced considering the increased susceptibility to infections in these patients. Specific therapeutic guidelines for AIC in PID patients are lacking. Treatment choice should be guided by the underlying disease. The study of the pathogenic mechanisms involved in the genesis of AIC in PID and our growing ability to define the molecular underpinnings of immune dysregulation has paved the way for the development of novel targeted treatments. Ideally, targeted therapy is directed against an overexpressed or overactive gene product or substitutes a defective protein, restoring the impaired pathway. Actually, the molecular diagnosis or a specific drug is not always available. However, defining the category of PID or the immunological phenotype can help to choose a semi-targeted therapy directed towards the suspected pathogenic mechanism. In this review we overview all the therapeutic interventions available for AIC in PID patients, according to different immunologic targets. In particular, we focus on T and/or B cells targeting therapies. To support decision making in the future, prospective studies to define treatment response and predicting/stratifying biomarkers for patients with AIC and PID are needed

Activated phosphoinositide 3-dinase delta syndrome (APDS): An update

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a recently described form of inborn error of immunity (IEI) caused by heterozygous mutations in PIK3CD or PIK3R1 genes, respectively, encoding leukocyte-restricted catalytic p110δ subunit and the ubiquitously expressed regulatory p85 α subunit of the phosphoinositide 3-kinase δ (PI3Kδ). The first described patients with respiratory infections, hypogammaglobulinemia with normal to elevated IgM serum levels, lymphopenia, and lymphoproliferation. Since the original description, it is becoming evident that the onset of disease may be somewhat variable over time, both in terms of age at presentation and in terms of clinical and immunological complications. In many cases, patients are referred to various specialists such as hematologists, rheumatologists, gastroenterologists, and others, before an immunological evaluation is performed, leading to delay in diagnosis, which negatively affects their prognosis. The significant heterogeneity in the clinical and immunological features affecting APDS patients requires awareness among clinicians since good results with p110δ inhibitors have been reported, certainly ameliorating these patients' quality of life and prognosis