Clinical, immunological, and genetic description of a Mexican cohort of patients with DOCK8 deficiency.

PURPOSE: We aimed to describe the clinical, immunological, and genetic features of patients with DOCK8 deficiency (DOCK8-Def) in a tertiary care center for children. METHODS: Retrospective chart review of patients' clinical, immunological, and genetic characteristics with DOCK8-Def. Genetic analysis was performed with targeted- or whole-exome sequencing; we also assessed DOCK8 protein expression and a lymphoproliferation assay and analyzed survival by the Kaplan-Meier method. RESULTS: We described 11 patients from 8 unrelated kindreds. The median age at symptoms' onset was 10 months (range 1-54 months). The median follow-up time was 53.4 months (4.8-118.8). All patients presented eczema and recurrent sinopulmonary and cutaneous infections. Besides those symptoms, the most frequent manifestations were bronchiectases (8/11), food allergies (6/11), and severe infections (6/11). Infrequent characteristics were detection of CMV in bronchial lavage, C. parvum-driven sclerosing cholangitis, Takayasu vasculitis, neurological syndromes, pulmonary tuberculosis, and lymphomatoid granulomatosis. CONCLUSION: DOCK8-Def has a broad spectrum of manifestations, including allergy, autoimmunity, inflammation, infection, and cancer. The hallmark of this inborn error of immunity is IEI-associated eczema with eosinophilia and increased IgE. Here, we report six new mutations causing human DOCK8 deficiency and symptoms previously unrecognized to occur in DOCK8-Def. Therefore, an early diagnosis of DOCK8-Def is essential to facilitate an adequate treatment such as HSCT.

Why are you hitting yourself? Whole-exome sequencing diagnosis of monogenic autoimmunity.

Inborn errors of immunity may present with autoimmunity and autoinflammation as hallmark clinical manifestations. We aimed to identify the potential monogenic causes of autoimmune disorders in 26 patients from a pediatric reference hospital in Mexico through whole-exome sequencing. We specifically selected patients with a family history of autoimmune diseases, early-onset symptoms, and difficult-to-control autoimmune disorders or autoimmunity associated with infection predisposition. We identified the genetic variants that were compatible with the patients' phenotype in 54% of the patients. Autoimmune diseases are often caused by a combination of genetic factors, but cases that appear at a young age are resistant to treatment or occur in clusters, as well as the presence of autoimmune symptoms alongside infectious diseases should raise suspicion for an underlying inborn error of immunity.

Combined Treatment of Progressive Encephalitis in an X-linked Agammaglobulinemia Patient.

Most patients with X-linked agammaglobulinemia are susceptible to infections, while some cases also suffer from inflammatory or autoimmune complications. We describe a patient with progressive encephalitis who improved after the use of immunomodulatory treatment with corticosteroids, fluoxetine, and nitazoxanide. In most of the cases the evolution of the progressive encephalitis is complicated and catastrophic. Based on our experience and the review of the literature, we propose the use of this combined treatment to control this devastating complication.

Clinical manifestations and expression of CD18 to guide the diagnosis of leukocyte adhesion deficiency type 1: Mexico experience.

BACKGROUND: Leukocyte adhesion deficiency type 1 (LAD-1) is an inborn error of immunity characterized by a defect in leukocyte trafficking. METHODS: Patients with clinical suspicion of LAD-1 were referred to our institution. Complete blood count and flow cytometric analysis, to identify the expression of CD18, CD11b, and the lymphocyte population phenotyping, were performed, and statistical analysis was completed. RESULTS: We report clinical manifestations and immunological findings of six Mexican patients diagnosed with LAD-1. The diagnosis was based on typical clinical presentation, combined with laboratory demonstration of leukocytosis, and significant reduction or near absence of CD18 and its associated molecules CD11a, CD11b, and CD11c on leukocytes. We found atypical manifestations, not described in other countries, such as early-onset autoimmunity or infections caused by certain microorganisms. CONCLUSIONS: Patients with LAD-1 may present with atypical manifestations, making flow cytometry an indispensable tool to confirm the diagnosis. We present the first report of LAD-1 patients in a Latin American country.

Kawasaki Disease Associated with SARS-CoV2 in a Pair of Triplets.

The etiology of Kawasaki disease (KD) and its precise genetic basics remain unknown. Genetic variants affecting immunity have been found in some patients. The occurrence of KD in siblings is rare, but KD pedigrees with multiple affected members have been described in Japan and North America. Cases in twins have been documented. We report 2 pairs of trizygotic triplets who developed KD associated with SARS-CoV2 infection from 2 different families. Our cases show that KD is multifactorial in origin, and both infectious etiology (particularly SARS-CoV2 as in our cases) and genetic factors are relevant in the disease.

Characteristics and outcomes of multisystem inflammatory syndrome in children: A multicenter, retrospective, observational cohort study in Mexico.

Introduction: Multisystem inflammatory syndrome in children associated with coronavirus disease 2019 (MIS-C), a novel hyperinflammatory condition secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is associated with severe outcomes such as coronary artery aneurysm and death. Methods: This multicenter, retrospective, observational cohort study including eight centers in Mexico, aimed to describe the clinical characteristics and outcomes of patients with MIS-C. Patient data were evaluated using latent class analysis (LCA) to categorize patients into three phenotypes: toxic shock syndrome-like (TSSL)-MIS-C, Kawasaki disease-like (KDL)-MIS-C, and nonspecific MIS-C (NS-MIS-C). Risk factors for adverse outcomes were estimated using multilevel mixed-effects logistic regression. Results: The study included 239 patients with MIS-C, including 61 (26%), 70 (29%), and 108 (45%) patients in the TSSL-MIS-C, KDL-MIS-C, and NS-MIS-C groups, respectively. Fifty-four percent of the patients were admitted to the intensive care unit, and 42%, 78%, and 41% received intravenous immunoglobulin, systemic glucocorticoids, and anticoagulants, respectively. Coronary artery dilatation and aneurysms were found in 5.7% and 13.2% of the patients in whom coronary artery diameter was measured, respectively. Any cause in-hospital mortality was 5.4%. Hospitalization after ten days of symptoms was associated with coronary artery abnormalities (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.2-2.0). Age ≥10 years (OR: 5.6, 95% CI: 1.4-2.04), severe underlying condition (OR: 9.3, 95% CI: 2.8-31.0), platelet count <150,000 /mm3 (OR: 4.2, 95% CI: 1.2-14.7), international normalized ratio >1.2 (OR: 3.8, 95% CI: 1.05-13.9), and serum ferritin concentration >1,500 mg/dl at admission (OR: 52, 95% CI: 5.9-463) were risk factors for death. Discussion: Mortality in patients with MIS-C was higher than reported in other series, probably because of a high rate of cases with serious underlying diseases.

Cerebellar Cognitive Affective Syndrome in Mexican Pediatric Patients with Ataxia-Telangiectasia.

Ataxia-telangiectasia (A-T) is a disease caused by mutations in the ATM gene (11q22.3-23.1) that induce neurodegeneration Sasihuseyinoglu AS et al.  Pediatr Allergy Immunol Pulmonol 31(1):9-14, 2018, Teive HAG et al. Parkinsonism Relat Disord 46:3-8, 2018. Clinically, A-T is characterized by ataxia, mucocutaneous telangiectasia, immunodeficiency, and malignancy. Movement disorders have been the most described and well-studied symptoms of A-T. Other studies have reported visuospatial processing disorders, executive function disorders and emotional regulation disorders, which are clinical manifestations that characterize cerebellar cognitive affective syndrome (CCAS) Choy KR et al. Dev Dyn 247(1):33-46, 2018. To describe the neurocognitive and emotional state of pediatric patients with ataxia-telangiectasia and to discuss whether they have cerebellar cognitive affective syndrome. This observational, cross-sectional, and descriptive study included 9 patients with A-T from May 2019 to May 2021. A complete medical history was retrieved, and tests were applied to assess executive functions, visual-motor integration and abilities, language, psychological disorders, and ataxia. Six girls and 3 boys agreed to participate. The age range was 6 to 14 years. The participants included five schoolchildren and four teenagers. Eight patients presented impaired executive functioning. All patients showed some type of error in copying and tracing (distortion) in the performance of visual perceptual abilities. Emotional disorders such as anxiety and depression were observed in six patients. Eight patients presented with dyslalia and impairments in word articulation, all patients presented with ataxia, and seven patients used a wheelchair. All patients presented symptoms consistent with CCAS and had variable cognitive performance.

Is Your Kid Actin Out? A Series of Six Patients With Inherited Actin-Related Protein 2/3 Complex Subunit 1B Deficiency and Review of the Literature.

BACKGROUND: Hereditary actin-related protein 2/3 complex subunit 1B deficiency is characterized clinically by ear, skin, and lung infections, bleeding, eczema, food allergy, asthma, skin vasculitis, colitis, arthritis, short stature, and lymphadenopathy. OBJECTIVE: We aimed to describe the clinical, laboratory, and genetic features of six patients from four Mexican families. METHODS: We performed exome sequencing in patients of four families with suspected actinopathy, collected their data from medical records, and reviewed the literature for reports of other patients with actin-related protein 2/3 complex subunit 1B deficiency. RESULTS: Six patients from four families were included. All had recurrent infections, mainly bacterial pneumonia, and cellulitis. A total of 67% had eczema whereas 50% had food allergies, failure to thrive, hepatomegaly, and bleeding. Eosinophilia was found in all; 84% had thrombocytopenia, 67% had abnormal-size platelets and anemia. Serum levels of IgG, IgA, and IgE were highly increased in most; IgM was normal or low. T cells were decreased in 67% of patients, whereas B and NK cells were increased in half of patients. Two of the four probands had compound heterozygous variants. One patient was successfully transplanted. We identified 28 other patients whose most prevalent features were eczema, recurrent infections, failure to thrive, bleeding, diarrhea, allergies, vasculitis, eosinophilia, platelet abnormalities, high IgE/IgA, low T cells, and high B cells. CONCLUSION: Actin-related protein 2/3 complex subunit 1B deficiency has a variable and heterogeneous clinical spectrum, expanded by these cases to include keloid scars and Epstein-Barr virus chronic hepatitis. A novel deletion in exon 8 was shared by three unrelated families and might be the result of a founder effect.

Amaurosis as an initial presentation of Takayasu arteritis in children.

Visual disturbances in Takayasu arteritis (TA) are common but tend to be late manifestations of the disease. However, its presence at diagnosis must alert TA to avoid sight disabilities. Herein, we present two children with TA that debuted with vision loss, and the results of the literature review displayed 58 subjects with vision loss before the diagnosis of TA. The world English literature was reviewed by searching the PubMed database of the National Library of Medicine for the terms "Takayasu Arteritis" and "Blindness" or "Amaurosis fugax", from 190 to 2021. Cases eligible must present vision loss before or at TA diagnosis. Our two patients who presented with amaurosis fulfilled the criteria for TA diagnosis. The first patient had a bilateral and transient visual loss, whereas the second had monocular and permanent amaurosis. Both patients were cursed with hypertension and demonstrated large vessel compromise; their clinical picture improved with corticosteroids and immunosuppressant therapy. We identified in the literature review sixteen patients with TA in case reports and 42 in case series, plus our two cases presented herein with monocular or bilateral vision loss at the time of diagnosis. Previous literature indicated that amaurosis represents a severely advanced disease. Herein, we reported two children with amaurosis as their pivotal symptom; they had significant head and neck vascular alterations, so prompt and aggressive treatment is needed to prevent disease progression and disability. Transient or permanent vision loss must alert the physician to include Takayasu arteritis in the differential diagnosis.

Therapeutic plasma exchange in refractory macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a case-based review.

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of arthritis of autoimmune aetiology. Systemic-onset juvenile idiopathic arthritis (soJIA) presents with fever, transient erythematous rash, hepatomegaly, splenomegaly, lymphadenopathy, and serositis. SoJIA presents multiple complications, and the most severe is the macrophage activation syndrome (MAS); the timely treatment of MAS must be established early and aggressively to avoid a fatal outcome. Therapeutic plasma exchange has anecdotally been used in refractory cases. A 66-month-old male with a 1-year illness characterized by evening-predominant, intermittent fever, adenomegalies, urticarial-like rash, arthralgia, and arthritis. Biochemical analysis revealed anaemia, leukocytosis, neutrophilia, hypertriglyceridemia, hyperferritinemia, and hypofibrinogenemia; bone marrow aspirate showed hemophagocytosis. He was diagnosed with SoJIA complicated with MAS. He received multiple treatments with IV human gammaglobulin, cyclosporine, dexamethasone, and tocilizumab without improvement. Plasma replacement treatment was performed. Afterwards, he presented significant improvement. After 3-year-follow-up, he remains in good general condition. We present a refractory case of soJIA complicated with MAS successfully treated with plasma exchange.

Cyclosporin for treatment of refractory multisystemic inflammatory syndrome in a child.

Multisystemic inflammatory syndrome in children is an inflammatory condition with multiorgan dysfunction that manifest late in the course of Severe acute respiratory syndrome coronavirus 2 infection. We present a 12-year-old boy with a history of fever, vomiting, diarrhoea, and abdominal pain. He developed shock with ventricular dysfunction and pericardial effusion. He was diagnosed with multisystemic inflammatory syndrome in children and treatment with intravenous immunoglobulins, corticosteroids, and tocilizumab proved to be ineffective. Eventually, the patient responded to cyclosporin-A treatment. Multisystemic inflammatory syndrome in children has been treated with immunoglobulins and glucocorticoids and in refractory cases biologics and cyclosporin-A have been used. Intravenous and oral cyclosporin-A seems to be a safe and effective alternative treatment for refractory multisystemic inflammatory syndrome in children patients.

Clinical manifestations and expression of CD18 to guide the diagnosis of leukocyte adhesion deficiency type 1

Background: Leukocyte adhesion deficiency type 1 (LAD-1) is an inborn error of immunity characterized by a defect in leukocyte trafficking. Methods: Patients with clinical suspicion of LAD-1 were referred to our institution. Complete blood count and flow cytometric analysis, to identify the expression of CD18, CD11b, and the lymphocyte population phenotyping, were performed, and statistical analysis was completed. Results: We report clinical manifestations and immunological findings of six Mexican patients diagnosed with LAD-1. The diagnosis was based on typical clinical presentation, combined with laboratory demonstration of leukocytosis, and significant reduction or near absence of CD18 and its associated molecules CD11a, CD11b, and CD11c on leukocytes. We found atypical manifestations, not described in other countries, such as early-onset autoimmunity or infections caused by certain microorganisms. Conclusions: Patients with LAD-1 may present with atypical manifestations, making flow cytometry an indispensable tool to confirm the diagnosis. We present the first report of LAD-1 patients in a Latin American country (AU)

Activating de novo monoallelic variants causing inborn errors of immunity in two unrelated children born of HIV-seroconcordant couples.

INTRODUCTION: Around 20% of all inborn errors of immunity (IEI) are autosomal dominant or monoallelic, either by haploinsufficiency, negative dominance, or gain of function (GOF). GOF phenotypes usually include autoinflammation, autoimmunity, lymphoproliferation, allergies, and some infections. CASE SERIES: We describe the cases of two unrelated patients born of HIV-seroconcordant parents. Both patients are HIV-negative but carry de novo GOF missense variants that resulted in inflammatory lymphoproliferative IEI diseases: signal transducer and activator of transcription 3 (STAT3)-GOF and phosphatidylinositol 3-kinase, catalytic delta (PIK3CD)-GOF. Both variants were found through whole-exome sequencing and confirmed by Sanger.An 11-year-old male with recurrent sinopulmonary infections, dysmorphism, growth delay, bronchiectasis, and mild mental retardation, as well as lymphopenia, thrombocytopenia, and high immunoglobulin M. Both his parents were known to be HIV-positive under anti-retroviral treatment. HIV infection was repeatedly ruled out in the patient, whom through whole-exome sequencing was found to have a heterozygous missense variant in exon 24 of PIK3CD, a hotspot transition, and the most reported variant in PIK3CD-GOF patients.A 6-year-old male with autoimmune hemolytic anemia, lymphoproliferation, short stature, and intractable diarrhea. Both his parents were found to be HIV-positive. HIV was repeatedly ruled out in the patient by ELISA and viral load. He was found to have a heterozygous missense/splice variant in exon 22 of STAT3, a hotspot transition, and the most reported variant in STAT3-GOF patients. DISCUSSION: The AID/APOBEC3 A-H family of proteins are cytidine deaminases that induce G>A hypermutation in both the invading viral DNA and the host genome, which results in stop codons inside the endogenized retroviral sequence. Both variants found in our patients are G to A transitions. Retroviral infection might thus have resulted in host genome instability, and our patients' rare congenital diseases are the unfortunate consequence of somatic hypermutation in one of their parents' gametes.

Not enough by half: NFAT5 haploinsufficiency in two patients with Epstein-Barr virus susceptibility.

Introduction: The transcription factor Nuclear factor of activated T cells 5 (NFAT5), pivotal in immune regulation and function, can be induced by osmotic stress and tonicity-independent signals. Objective: We aimed to investigate and characterize two unrelated patients with Epstein-Barr virus susceptibility and no known genetic etiology. Methods: After informed consent, we reviewed the electronic charts, extracted genomic DNA, performed whole-exome sequencing, filtered, and prioritized their variants, and confirmed through Sanger sequencing, family segregation analysis, and some functional assays, including lymphoproliferation, cytotoxicity, and characterization of natural killer cells. Results: We describe two cases of pediatric Mexican patients with rare heterozygous missense variants in NFAT5 and EBV susceptibility, a school-age girl with chronic-active infection of the liver and bowel, and a teenage boy who died of hemophagocytic lymphohistiocytosis. Discussion: NFAT5 is an important regulator of the immune response. NFAT5 haploinsufficiency has been described as an immunodeficiency syndrome affecting both innate and adaptive immunity. EBV susceptibility might be another manifestation in the spectrum of this disease.

Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations.

Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients' B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.