A Germinal Center Checkpoint of AIRE in B Cells Limits Antibody Diversification.

In response to antigens, B cells undergo affinity maturation and class switching mediated by activation-induced cytidine deaminase (AID) in germinal centers (GCs) of secondary lymphoid organs, but uncontrolled AID activity can precipitate autoimmunity and cancer. The regulation of GC antibody diversification is of fundamental importance but not well understood. We found that autoimmune regulator (AIRE), the molecule essential for T cell tolerance, is expressed in GC B cells in a CD40-dependent manner, interacts with AID and negatively regulates antibody affinity maturation and class switching by inhibiting AID function. AIRE deficiency in B cells caused altered antibody repertoire, increased somatic hypermutations, elevated autoantibodies to T helper 17 effector cytokines and defective control of skin Candida albicans. These results define a GC B cell checkpoint of humoral immunity and illuminate new approaches of generating high-affinity neutralizing antibodies for immunotherapy.

MicroRNA dysregulation in the heart and lung of infants with bronchopulmonary dysplasia.

BACKGROUND AND OBJECTIVES: Bronchopulmonary dysplasia (BPD) is a serious complication of preterm birth, resulting in significant morbidity and mortality. Recent studies have suggested that microRNA (miRNA) dysregulation is involved in the pathogenesis of BPD and may serve as biomarkers for early detection. We conducted a directed search for dysregulated miRNAs in lung and heart autopsy samples of infants with histologic BPD. METHODS: We used archived lung and heart samples from BPD (13 lung, 6 heart) and control (24 lung, 5 heart) subjects. To measure miRNA expression, RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue specimens then reverse-transcribed, labeled, and hybridized to miRNA microarrays. The microarrays were scanned, and data were quantile normalized. Statistical analysis with a moderated t-test and control of the false discovery rate (5%) was used to compare normalized miRNA expression values between clinical categories. RESULTS: With our set of 48 samples, 43 miRNAs had a significant difference in expression comparing BPD to non-BPD controls. Among the most statistically significant miRNAs, miR-378b, miRNA-184, miRNA-3667-5p, miRNA-3976, miRNA-4646-5p, and miRNA-7846-3p were all consistently upregulated in both the heart and lung tissues of BPD subjects. The cellular pathway predicted to be most affected by these miRNAs is the Hippo signaling pathway. CONCLUSIONS: This study identifies miRNAs that are similarly dysregulated in postmortem lung and heart samples in subjects with histologic BPD. These miRNAs may contribute to the pathogenesis of BPD, have potential as biomarkers, and may provide insight to novel approaches for diagnosis and treatment.

Early histological changes of bronchopulmonary dysplasia and pulmonary hypertension may precede clinical diagnosis in preterm infants.

Bronchopulmonary Dysplasia (BPD), the commonest complication of prematurity, is defined by treatment with oxygen for ≥28 days. Pulmonary hypertension (PH) often coexists with BPD and is associated with increased mortality. In 42 autopsies, histological changes of BPD and PH were demonstrated in 25 % and 65 % respectively of preterm infants <28 days of age, highlighting the need for early diagnosis and treatment.

Five New Cases of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (MMIHS), with One Case Showing a Novel Mutation.

BACKGROUND: Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a lethal congenital disorder characterized by a large, non-obstructed bladder, microcolon, and lack of proper peristalsis. MATERIALS AND METHODS: Five cases of MMIHS were identified, confirmed histologically and were predominantly female (F:M, 4:1). DNA sequencing was also performed. RESULTS: Four cases showed mutations in the α3 and ß4 nicotinic acetylcholine receptor (ηAChR) subunits (CHRNA3 and CHRNB4, respectively) on chromosome 15q24. The 5th case had a delayed clinical presentation of intussusception at 11 months and showed a novel missense mutation in ATP2B4 on Chromosome 1q32. CONCLUSION: The first four patients showed a previously identified mutation. The 5th patient shows a novel mutation in ATP2B4. This novel gene was associated with a less severe presentation and increases success of multiorgan transplant than the other four patients. This highlights how identifying various mutations may impact prognosis and clinical treatment plans for MMIHS patients.

Revisiting the Newly Modified Criteria for Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) and Reporting Newly Identified Genes.

Background: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia is an inherited cardiomyopathy, characterized by replacement of the RV muscle wall with fibrofatty tissue. The diagnosis is challenging, due to the absence of a unique presentation and a lack of specific reproducible diagnostic criteria. Materials and methods: Slides and additional clinical information including follow up from 16 cases were reviewed. Pediatric criteria of >30% of muscle replacement was used, instead of >40% as used in adults. Results: All 16 cases were confirmed by genetic testing and show ARVC/D. Applying the adult criteria, 7 cases would not have been categorized as ARVC/D. Conclusion: The modified pediatric criteria for ARVC/D should be used for pediatric patients. Better detection will aid in genetic counseling in order to identify those additional family members susceptible to sudden cardiac deaths so they can be followed optimally.

Giant Anal Fibroepithelial Polyp in a Healthy Teenage Boy: A Case Report and Literature Review.

Background: Fibroepithelial polyps of the anus have been described as mucosal hypertrophy in response to chronic irritation or tissue damage. Lesions usually remain small and mostly present in elderly adults with local disease. Case Report: An otherwise healthy 15-year-old male presented with a giant pedunculated mass projecting out of the anal verge that enlarged over 2 years, causing discomfort. Results: Upon surgical excision and histologic examination, the mass resembled a fibroepithelial polyp with numerous dilated lymphatics. Conclusions: While literature describes the spectrum of pathology possible in such lesions, often consisting of a mixture of stromal and epithelial components, dilated lymphatics are less common. This giant anal fibroepithelial polyp characterized by edematous stroma and numerous dilated lymphatics is consistent with lymphangioma. To our knowledge, this presentation is novel in this age group with no underlying risk factors.

Chronic Recurrent Multifocal Osteomyelitis (CRMO): A Study of 12 Cases from One Institution and Literature Review.

BACKGROUND: CRMO is a sterile auto inflammatory bone disease that affects the pediatric population. Recently, single gene mutations in LPIN2, DIRA, and IL1RN have been reported in murine models of CRMO. MATERIALS AND METHODS: The medical records and histopathological slides of twelve patients were reviewed. RESULTS: The diagnosis was determined by multiple lesions, imaging, negative cultures, bone biopsy, and lack of antibiotic response. Biopsy showed early neutrophilic infiltrates, and older lesions showed lymphoplasmacytic infiltrates and fibrosis. Patients were treated with anti-inflammatory medication with some lesions completely resolving. CONCLUSION: Bone biopsy aids the diagnosis of CRMO in correlation with clinical presentation, imaging, and culture findings. Our findings indicate the kinetics of CRMO is not well defined and the fibrosis may be reached after months, in contrast to the previously reported several years. We hope that these genetic mutations can be further studied in human models to describe the genetics behind CRMO.

Juvenile Xanthogranuloma of the Pancreas in a Pediatric Patient Mimicking Pancreatic Neoplasm With High CA 19-9: Case Report and Literature Review.

Juvenile xanthogranuloma (JXG) is a rare, non-Langerhans cell histiocytosis. It is usually a benign and self-limiting condition. The most common sites are skin and soft tissue. Pancreatic involvement is extremely rare. We present an unusual case of a 13-month-old female child with JXG of the pancreas and elevated cancer antigen 19-9. JXG should always be considered as a differential diagnosis for pediatric patients presenting with a pancreatic mass, solid and/or cystic in nature. Therefore, avoiding unnecessary invasive diagnostic procedures.

Histopathology of the Conduction System in Long QT Syndrome.

Background: While much is known about the channelopathy disorder Long QT Syndrome (LQTS), the histopathological findings and their implications on the disease have remained largely unexplored to date. In this review, we discuss the background of LQTS and highlight the importance of histological findings in the absence of genetic markers or when genetic testing is unavailable.Materials and methods: Three pediatric cases of LQTS were identified, evaluated histologically, and compared to two adult cases.Results: Histological examination of three pediatric LQTS patients demonstrated fibrotic alterations to the cardiac conduction system with markedly decreased conductive tissue density and volume. Both adult cases revealed fibrosis with similar reductions in tissue volume.Conclusion: When diagnostic methods such as genetic testing are unavailable, histopathology offers clinicians an alternative tool for postmortem diagnosis of LQTS when considered alongside clinical presentation. Confirmation of diagnosis in a proband can prevent the death of relatives in hereditary LQTS.

Anti-NMDA receptor encephalitis in an adolescent with a cryptic ovarian teratoma.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease frequently associated with ovarian teratomas. In cases where an ovarian teratoma is identified, treatment involves prompt removal of the ovarian teratoma, resulting in significant clinical improvement and decreased incidence of relapse. We present the case of a 14-year-old female patient admitted for progressively worsening psychiatric and neurological status, diagnosed with anti-NMDAR encephalitis, and negative initial imaging for ovarian pathology. She was in the hospital for 8 months requiring admission to the intensive care unit and multiple courses of immunotherapy before clinical improvement. Three months after discharge, she was readmitted with clinical relapse and repeat imaging showed an ovarian teratoma. Removal of the teratoma resulted in sustained clinical improvement with return to baseline and no further relapse. Our case report highlights the importance of maintaining a high suspicion for an underlying ovarian teratoma in a female patient with anti-NMDAR encephalitis, even when initial imaging is negative. Currently, there are limited data on recommendations for repeat imaging. Therefore, we recommend repeat imaging in patients resistant to multiple lines of treatment or presenting with clinical relapse.

Calcineurin inhibitors and renal biopsy in children with idiopathic nephrotic syndrome.

Idiopathic nephrotic syndrome (NS) is common in children, and most patients respond to corticosteroid therapy. Patients who relapse may need additional immunosuppression with cyclophosphamide, mycophenolate mofetil, calcineurin inhibitors (CNI), or rituximab. Many such patients undergo protocol renal biopsies before and after the initiation of CNI therapy. The main objective of our study was to assess the role of protocol renal biopsies in the monitoring of CNI-induced nephrotoxicity in patients with steroid-dependent (SD)/frequent relapse (FR) NS. We did an Institutional Review Board (IRB)-approved retrospective chart review of patients who were diagnosed with NS at the Children's Hospital of Michigan from January 2000 to June 2019. Study inclusion criteria were a diagnosis of NS, age 1 - 21 years at initial diagnosis, SD/FR clinical course, patients with initial steroid resistance with renal biopsy showing minimal change disease, and renal biopsy before and after CNI initiation. The data is presented on 24 patients who met study inclusion criteria. Only 3 patients (12.5%) showed evidence of chronic CNI nephrotoxicity after a median treatment 66.5 months (range 12 - 153 months). Our study revealed that a baseline renal biopsy before starting CNI therapy for children with FR/SDNS is not necessary. A renal biopsy may be considered after 2 - 3 years of CNI administration in selected few cases in whom the diagnosis of CNI nephrotoxicity might help change the management.

Correlation Between E6 and E7 Oncogenes and Malignant Transformation of Laryngeal Papillomatosis (LP) with Human Papillomavirus (HPV) in Pediatric Population.

INTRODUCTION: Laryngeal papillomatosis (LP) is the most common benign neoplasm affecting the upper respiratory tract mucosa in children. The most common genotypes of HPV associated with LP are types 6 and 11. Methods: Among 187 patients identified in our institution with LP, four cases showed malignant transformation to invasive squamous carcinoma. Results: These patients had tumors with HPV viruses that showed high expression of oncogene E6 and E7 and low expression of E2. Conclusion: Malignant transformation of LP is associated with oncogenic expression of E6 and E7.

Pediatric Right Ventricular Cardiac Steatosis following Immunosuppressive Treatment.

Background Right ventricular myocardial fatty infiltration has been observed in pediatric cardiac allografts with an associated decrease in graft life expectancy. A possible explanation included an immunosuppressant drug effect which prompted us to examine common factors between non-cardiac transplanted immunosuppressed patients and postmortem hearts of pediatric patients who died of non-cardiac causes.Materials and Methods Sixty-one of 1,030 pediatric autopsies were from immunosuppressed children who were treated with corticosteroids for malignant tumors, non-cardiac transplantations, or other chronic clinical conditions. 62 children who died for non-medical reasons served as controls. Cardiac H&E autopsy slides were examined for right ventricular fatty infiltration.Results There was a significant increase in right ventricular fatty infiltration in patients that were non-cardiac transplanted and immunosuppressed compared to controls. None of the index patients had other features of arrhythmogenic right ventricular dysplasia.Conclusions Immunosuppression may lead to right ventricular fatty infiltration in childhood.

A Novel COL1A1-CAMTA1 Rearrangement in Cranial Fasciitis.

Cranial fasciitis is an uncommon benign fibroblastic tumor, generally histologically identical to nodular fasciitis. It develops almost exclusively in children. Cranial fasciitis manifests clinically as a painless rapidly growing solitary nodule in the head and neck area, frequently eroding the underlying bone. Thus, this entity is often confused with aggressive lesions such as sarcomas, both clinically and radiologically. Histopathologic examination is essential to differentiate between cranial fasciitis and fibrohistiocytic or even sarcomatous lesions observed in children. In this article, we present a case of cranial fasciitis with intracranial extension in a 2-year-old boy. Although USP6 rearrangement has recently been recognized as a recurring alteration in nodular fasciitis, we present a novel COL1A1-CAMTA1 fusion in this lesion.

Cardiac Magnetic Resonance Imaging Macroscopic Fibro-Fatty Infiltration of the Myocardium in Pediatric Patients with Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia.

Background: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited, progressive form of cardiomyopathy, which is characterized by fibrofatty replacement of the myocardium. While the gold standard for diagnosis remains pathologic evaluation of biopsy, advances in noninvasive imaging, including cardiac magnetic resonance imaging (CMRI), have led to improved clinical diagnosis.Case report: We report three additional cases of pediatric patients that have pathologically confirmed ARVC/D with CMRI images, demonstrating extensive macroscopic fatty infiltration of the right and left ventricular myocardium. The identification using CMRI allowed timely transplantation and patient survival.Conclusion: Our study is designed to highlight how fibrofatty changes are minimal using CMRI in the pediatric population and how this can be a valuable tool to provide an additional method of diagnosis.