First Report on Chronic Granulomatous Disease from Nepal and a Review of CYBC1 Deficiency.

Chronic granulomatous disease (CGD) primarily results from inherited defects in components of the nicotinamide adenine dinucleotide phosphate oxidase enzyme complex. These include gene defects in cytochrome B-245/558 subunit α/ß and neutrophil cytosolic factors 1, 2, and 4. Recently, homozygous loss-of-function variants in cytochrome B-245 chaperone 1 gene (CYBC1) have been discovered to cause CGD (CYBC1-CGD). Data on variant-proven CGD from low-income countries, the most underprivileged regions of the world, remain sparse due to numerous constraints. Herein, we report the first cohort of patients with CGD from Nepal, a low-income country in the Himalayas' challenging terrain. Our report includes a description of a new case of CYBC1 deficiency who was first diagnosed with CGD at our center. Only a dozen cases of CYBC1-CGD have been described in the literature thus far which have been reviewed comprehensively herein. Most of these patients have had significant infections and autoimmune/inflammatory manifestations. Pulmonary and invasive/disseminated bacterial/fungal infections were the most common followed by skin and soft-tissue infections. Inflammatory bowel disease (IBD) was the most common inflammatory manifestation (median age at diagnosis: 9 years) followed by episodes of recurrent/prolonged fever. Other autoimmune/inflammatory manifestations reported in CYBC1-CGD include acute pancreatitis, hemophagocytic lymphohistiocytosis, systemic granulomatosis, interstitial lung disease, arthritis, autoimmune hemolytic anemia, uveitis, nephritis, and eczema. Our analysis shows that patients with CYBC1-CGD are at a significantly higher risk of IBD-like illness as compared to other forms of CGD which merits further confirmatory studies in the future.

Immunologic, Molecular, and Clinical Profile of Patients with Chromosome 22q11.2 Duplications.

PURPOSE: Duplication of chromosome 22q11.2 due to meiotic non-allelic homologous recombination results in a distinct syndrome, chromosome 22q11.2 duplication syndrome that has some overlapping phenotypic features with the corresponding 22q11.2 deletion syndrome. Literature on immunologic aspects of the duplication syndrome is limited. We conducted a retrospective study of 216 patients with this syndrome to better define the key features of the duplication syndrome. METHODS: Single-center retrospective record review was performed. Data regarding demographics, clinical details, and immunological tests were compiled, extracted into a predetermined data collection form, and analyzed. RESULTS: This cohort comprised 113 (52.3%) males and 103 (47.7%) females. The majority (54.6%) of mapped duplications were between low copy repeat regions A-D (LCR22A to -D). Though T cell subsets were relatively preserved, switched memory B cells, immunoglobulins, and specific antibodies were each found to be decreased in a subset of the cohort. One-fifth (17/79, 21.5%) of patients had at least 2 low immunoglobulin values, and panhypogammaglobulinemia was found in 11.7% (9/79) cases. Four children were on regular immunoglobulin replacement therapy. Asthma and eczema were the predominant atopic symptoms in our cohort. CONCLUSION: Significant immunodeficiencies were observed in our cohort, particularly in B cells and antibodies. Our study expands the current clinical understanding and emphasizes the need of immunological studies and multidisciplinary approaches for these patients.

Clinical and Immunological Features, Genetic Variants, and Outcomes of Patients with CD40 Deficiency.

PURPOSE: Inherited deficiencies of CD40 and CD40 ligand (CD40L) reflect the crucial immunological functions of CD40-CD40L interaction/signaling. Although numerous studies have provided a detailed description of CD40L deficiency, reports of CD40 deficiency are scarce. Herein, we describe the characteristics of all reported patients with CD40 deficiency. METHODS: The PubMed, Embase and Web of Science databases were searched for relevant literature published till 7th August 2023. Study deduplication and identification of relevant reports was performed using the online PICO Portal. The data were extracted using a pre-designed data extraction form and the SPSS software was used for analysis. RESULTS: Systematic literature review revealed 40 unique patients with CD40 deficiency. Respiratory tract and gastrointestinal infections were the predominant clinical manifestations (observed in 93% and 57% patients, respectively). Sclerosing cholangitis has been reported in nearly one-third of patients. Cryptosporidium sp. (29%) and Pneumocystis jirovecii (21%) were the most common microbes identified. Very low to undetectable IgG levels and severely reduced/absent switch memory B cells were observed in all patients tested/reported. Elevated IgM levels were observed in 69% patients. Overall, splice-site and missense variants were the most common (36% and 32%, respectively) molecular defects identified. All patients were managed with immunoglobulin replacement therapy and antimicrobial prophylaxis was utilized in a subset. Hematopoietic stem cell transplantation (HSCT) has been performed in 45% patients (curative outcome observed in 73% of these patients). Overall, a fatal outcome was reported in 21% patients. CONCLUSIONS: We provide a comprehensive description of all important aspects of CD40 deficiency. HSCT is a promising curative treatment option for CD40 deficiency.

Vascular dysfunction in juvenile idiopathic arthritis: a systematic review and meta-analysis.

We performed a systematic review and meta-analysis of studies evaluating vascular function in patients with JIA. Relevant literature published from 1st January 1965 to 1st March 2022 was searched systematically utilizing PubMed, Web of Science, and Embase databases. Observational studies were included-patients with JIA (classified according to the International League of Associations for Rheumatology criteria) were included as cases (study population) and age/sex-matched healthy participants as controls (comparator group). Outcome measures were differences in non-invasive parameters of vascular function. Online Population, Intervention, Comparison, Outcomes Portal was used for deduplication of studies and data extraction. Review Manager, Comprehensive Meta-analysis, and Meta-Essential softwares were used for data synthesis/analysis (encompassing data pooling and evaluation of heterogeneity and publication bias). Newcastle-Ottawa Scale and GRADEpro GDT software were utilized to assess study quality and certainty of evidence, respectively. Of 338 citations, 17 observational studies with 1423 participants (cases = 757, controls = 666) were included. Carotid intima-media thickness (CIMT) was higher [mean difference (MD) 0.02 mm {95% confidence interval (CI) 0.01-0.04}, p = 0.0006, I2 = 69%] in patients with JIA. Besides, decreased flow-mediated dilatation (FMD) [MD - 2.18% {95%CI - 3.69- - 0.68}, p = 0.004, I2 = 73%] was also observed. Results of studies assessing pulse wave velocity or arterial stiffness could not be pooled due to significant methodological variations. A 'very low' certainty of evidence suggests the presence of vascular dysfunction in JIA. Future longitudinal studies are required to determine whether altered CIMT and FMD in patients with JIA translate to an enhanced risk of (adverse) clinical cardiovascular events. PROSPERO (CRD42022323752).

A Novel CEBPE Variant Causes Severe Infections and Profound Neutropenia.

PURPOSE: Specific granule deficiency (SGD) is a rare inborn error of immunity resulting from loss-of-function variants in CEBPE gene (encoding for transcription factor C/EBPε). Although this genetic etiology has been known for over two decades, only a few patients with CEBPE variant-proven SGD (type I) have been reported. Herein, we describe two siblings with a novel homozygous CEBPE deletion who were noted to have profound neutropenia on initial evaluation. We aimed to evaluate the immunohematological consequences of this novel variant, including profound neutropenia. METHODS: Light scatter characteristics of granulocytes were examined on various automated hematology analyzers. Phagocyte immunophenotype, reactive oxygen species generation, and Toll-like receptor (TLR) signaling were assessed using flow cytometry. Relative expression of genes encoding various granule proteins was studied using RT-PCR. Western blot analysis and luciferase reporter assay were performed to explore variant C/EBPε expression and function. RESULTS: Severe infections occurred in both siblings. Analysis of granulocyte light scatter plots revealed automated hematology analyzers can provide anomalously low neutrophil counts due to abnormal neutrophil morphology. Neutrophils displayed absence/marked reduction of CD15/CD16 expression and overexpression (in a subset) of CD14/CD64. Three distinct populations of phagocytes with different oxidase activities were observed. Impaired shedding of CD62-ligand was noted on stimulation with TLR-4, TLR-2/6, and TLR-7/8 agonists. We demonstrated the variant C/EBPε to be functionally deficient. CONCLUSION: Homozygous c.655_665del variant in CEBPE causes SGD. Anomalous automated neutrophil counts may be reported in patients with SGD type I. Aberrant TLR signaling might be an additional pathogenetic mechanism underlying immunodeficiency in SGD type I.

Association of ITPKC gene polymorphisms rs28493229 and rs2290692 in North Indian children with Kawasaki disease.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) of several genes are linked to the etiopathogenesis of Kawasaki disease (KD). Association of SNPs of inositol 1,4,5-triphosphate-3-kinase C (ITPKC) gene with susceptibility to KD and coronary artery lesions (CALs) has been observed in children of certain ethnicities, but not from others. The present study was planned to explore this genetic association in the North Indian cohort. METHODS: Fifty children with KD and 50 age- and sex-matched controls were studied for two SNPs (rs28493229 and rs2290692) of the ITPKC gene using polymerase chain reaction and restriction fragment length polymorphism. Findings were confirmed by Sanger sequencing. A meta-analysis was also carried out for GG and CC genotypes of the SNPs. RESULTS: There was significant association between KD susceptibility and CG + GG genotype of rs2290692 (p = 0.015, odds ratio = 4.1, 95% confidence interval = 1.38-13.83). None of the single alleles or genotypes of the SNPs of ITPKC were, however, significantly associated with KD susceptibility. A meta-analysis also did not show any significant association of these SNPs to KD susceptibility. CONCLUSIONS: Our findings suggest that ITPKC gene SNPs (rs28493229 and rs2290692) did not have a significant association with susceptibility to KD in children from North India. Larger multicentric studies incorporating different ethnicities are required to understand the genetic basis of KD. IMPACT: While SNP rs28493229 of the ITPKC gene is not found to be associated with susceptibility to KD, the combined genotype of SNP rs2290692 is shown to be associated. Impact of ITPKC gene SNP on KD is different across different races and ethnicities. We could find an association of the combined genotype of rs2290692 with it in the Indian population. This study highlights that phenotype and genotypic association of KD varies with ethnicities. Larger multicentric studies are required to reach a conclusion regarding the genetic association of KD.

Recurrent lupus enteritis in a child-chase the calm before the storm.

Systemic lupus erythematosus (SLE) is a complex multisystemic autoimmune disease. Lupus enteritis (LE), one of the less commonly described manifestations of childhood SLE, presents with relatively nonspecific clinical and laboratory features. In addition, recurrent episodes of LE occurring in temporal proximity are rare in children. Presence of disease activity at other sites (which may not be seen universally) supports the diagnosis of LE in an appropriate setting. Because of its potential role to cause ischemic complications, early recognition and prompt treatment are necessary for a good outcome. Herein, we describe a child with recurrent LE with an interval of about 3 months between the first and the second episode. The first episode correlated with systemic disease activity and bowel thickening was noted on abdominal ultrasonography. This episode was successfully managed with intravenous methylprednisolone pulse therapy. Conversely, the second episode was not associated with significant clinical and laboratory evidence of disease activity at other sites and the initial abdominal ultrasonography was non-contributory. Diagnostic and therapeutic delays, hence, led to the development of fatal complications. We highlight that a high index of suspicion of LE and a timely aggressive treatment is imperative for optimal outcomes even in rare pediatric cases of recurrent LE that may have normal imaging findings initially and may not be associated with systemic lupus erythematosus disease activity index (SLEDAI).

Retinal vasculopathy in children with systemic lupus erythematosus: report of two cases.

Systemic lupus erythematosus (SLE) is a chronic, autoimmune, multisystem disease associated with a variable clinical course. SLE is more severe and is associated with higher mortality in children compared to adults. Eye involvement may be seen in up to a third of patients. Retinal vasculopathy is rare in children with SLE. We report two such cases. Both patients in this series had cotton-wool spots on fundus examination, and fundus fluorescein angiography revealed findings of occlusive micro-angiopathy. These findings are characteristic of lupus retinal vasculopathy. Fundus examination is crucial in diagnosing retinal vasculopathy. All children with SLE must be evaluated in detail to detect any retinal abnormalities and should be managed with aggressive immunosuppression to save their vision.

An uncommon overlap of two common rheumatological disorders.

Juvenile systemic lupus erythematosus (SLE) is a heterogeneous multisystem autoimmune disease. Kawasaki disease is a common vasculitic disorder in children that manifests with fever and mucocutaneous involvement. While overlap of childhood SLE with other rheumatological disorders has been described, it is extremely unusual in the context of Kawasaki disease. We report two children who had SLE and developed features of Kawasaki disease simultaneously, and the second child had myocarditis which could be a manifestation of Kawasaki disease rather than SLE. Two or more rheumatological diseases may coexist at the same time and one must always be vigilant.

Epidermal necrolysis as the presenting manifestation of pediatric lupus.

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) represents the spectrum of skin lesions characterized by rashes, exfoliation, and sloughing usually following drug intake. Occasionally, TEN-like cutaneous manifestations have also been described with systemic lupus erythematosus. Recognition of lupus in a child presenting with TEN-like skin changes is clinically challenging and requires a high degree of suspicion. We describe the case of a child who had epidermal necrolysis as the presenting feature of lupus and had severe neurological complications. TEN-like skin changes in association with severe neurological complications in pediatric lupus are uncommon. Lupus must be considered in the differential diagnosis of a child presenting with epidermal necrolysis with no provocative risk factors such as a history of exposure to medications.

Primitive Neuroectodermal Tumor in a Child with Human Immunodeficiency Virus Infection: A Rare Association.

Children with human immunodeficiency virus (HIV) infection are reported to have various malignancies, most common being Non-Hodgkin lymphoma. Despite higher risk of malignancies, brain tumors are infrequently described in these children. We report Primitive Neuroectodermal tumor (PNET) in a young boy with HIV infection. PNET has never been described in association with HIV infection. Though a causative association cannot be established, it does emphasize that with longer survivals on effective antiretroviral therapy, we may see a wide range of malignancies more frequently.