Clinicopathologic Features of Severe Acute Hepatitis Associated With Adenovirus Infection in Children.

A recent increase in reports of severe acute hepatitis of unknown etiology in children is under investigation. Although adenovirus has been frequently detected, its role remains unclear, and systematic histopathologic analysis is lacking. We conducted a retrospective study of 11 children hospitalized between October 2021 and May 2022 with unexplained acute hepatitis and concurrent adenovirus infection. Liver biopsies collected shortly after admission demonstrated moderately to severely active hepatitis in 8/11 (73%) cases, characterized by marked portal mixed inflammation, moderate-to-severe interface activity, and milder lobular inflammation. Clusters of plasma cells were present in 6/11 (55%) cases, mimicking autoimmune hepatitis. Semiquantitative scoring of 17 discrete histologic features found that greater degrees of portal inflammation, interface activity, bile duct injury, bile ductular reaction, lobular inflammation, Kupffer cell activation, and hepatocyte focal necrosis were significantly more common in these cases in comparison to the control group of unexplained acute severe hepatitis without adenovirus infection. Liver biopsy immunohistochemistry was negative for adenovirus in all cases. Polymerase chain reaction testing of liver tissue was positive for the enteric adenovirus serotypes 41 (species F) in 10/11 (91%) cases. An immunoprofile study of hepatic infiltrating lymphocytes in 1 patient revealed the presence of large numbers of CD3 + and CD4 + lymphocytes. Nine patients received supportive treatment without steroids and recovered without the need for liver transplantation. In summary, liver injury in children with severe acute hepatitis and adenovirus infection is characterized by a hepatitic pattern that resembles severe autoimmune hepatitis and may represent an immune-mediated process associated with viral infection.

Gastric Antral Mucosal Changes in Children With Intestinal Metaplasia.

Objectives: The gastric mucosal change accompanying gastric antral intestinal metaplasia (IM) in the pediatric population and its clinical implications remain unclear. Methods: We retrieved all patients younger than 18 years who had upper GI endoscopy with a pathology diagnosis of antral IM between 2009 and 2020. Each biopsy was evaluated for the presence of dysplasia, Helicobacter pylori, gastritis, and other pathologic changes. Results: A total of 134 patients with antral IM were identified; 72 (53.7%) with coexisting pathology including chronic gastritis (n = 22), reactive gastropathy (n = 16), focal mild chronic inflammation (n = 13), gastric eosinophilia (n = 9), chronic active gastritis associated with (n = 2) and without Helicobacter infection (n = 3), and others (n = 7). The remaining 62 (46.3%) showed isolated IM. Gastric IM increased with age, and was often accompanied by other pathologic changes, especially in female children. Twenty-seven patients had follow up biopsies; 11 of the 27 patients (40.7%) showed persistent IM in at least one repeat biopsies. None demonstrated dysplasia. Conclusions: In children, antral IM increases with age and often coexists with other pathologic changes. Gastric IM could persist for at least months to years in a significant subset of patients with chronic gastritis and gastric eosinophilia.

Therapy-related Myeloid Neoplasms in Children: A Single-institute Study.

Therapy-related myeloid neoplasm (t-MN) in the pediatric population is not well characterized. We studied 12 pediatric patients diagnosed with t-MN in our institution since 2006. The median age at the t-MN diagnoses was 14.8 years (range, 9 to 20 y). The primary malignancies included 9 solid tumors and 3 hematopoietic malignancies. Rhabdomyosarcoma (n=4) was the most common primary malignancy. Five of the 9 patients with solid tumors and all 3 patients with hematopoietic malignancies had primary neoplasms involving bone marrow. The median latency period was 5.2 years (range, 1.8 to 13.8 y). Thrombocytopenia was present in all patients at the t-MN diagnoses. Complete or partial monosomy of chromosome 5 or 7 were the 2 most common cytogenetic abnormalities. A quarter of patients demonstrated a genetic predisposition to t-MN: 1 with Li-Fraumeni syndrome with a germline TP53 R248Q mutation, 1 with Noonan syndrome with a somatic mutation (PTPN11 S502T), and 1 with a constitutive chromosomal translocation [t(X;9)(p22;q34)] and a germline TP53 L130V mutation. Outcomes remain poor. Two patients survived 3 and 5.1 years after hematopoietic stem cell transplantation.

Bloom where you are planted: Hemangioma or malignancy?

Vascular anomalies comprise a spectrum of disorders characterized by the abnormal development or growth of blood and lymphatic vessels. These growths have unique features and diverse behaviors, mandating a multidisciplinary approach in their evaluation, diagnosis, and management. Here we describe the case of a male toddler presenting with an abdominal mass, originally treated as a metastatic retroperitoneal tumor, but subsequently felt to represent a vascular anomaly.

Pleuropulmonary blastoma in an adolescent.

Primary pulmonary malignancies are rare in childhood. The most common, pleuropulmonary blastoma (PPB), has an incidence of 25-50 cases per year in the United States (Knight and et al., 2019) [1]. The majority of children are diagnosed with PPB before the age of four years. PPB is divided into subtypes I, Ir (type I-regressed), II, and III, which correlates to the age of diagnosis and patient prognosis [2,3]. Here we report an unusual presentation of PPB in a teen-aged female who presented with a one month history of a non-productive cough.

Recurrent Skin Langerhan Cell Histiocytosis Successfully Treated With Indomethacin Monotherapy.

Langerhans cell histiocytosis (LCH) often has a recurrent and refractory course despite multiagent treatment modalities. Common relapse treatments include intense or prolonged cytotoxic chemotherapy regimens. There are a few prior reports that the nonsteroidal anti-inflammatory drug indomethacin demonstrated activity against bone LCH. Here we report indomethacin as a successful treatment for a case of chronic skin LCH that failed multiple prior chemotherapy regimens. This experience supports the need for trials to investigate indomethacin as a treatment for LCH both in the relapsed or refractory setting as well as potential combination or maintenance therapy in newly diagnosed patients.

Prevalence of chronic rhinosinusitis in bronchiectasis patients suspected of ciliary dyskinesia.

BACKGROUND: Mucociliary clearance is a main defense mechanism of the airway and is impaired in ciliary dyskinesia. The objective of this study was to evaluate the prevalence of chronic rhinosinusitis (CRS) and its characteristics in bronchiectasis patients suspected of harboring ciliary dyskinesia. METHODS: Bronchiectasis patients referred to a rhinology clinic for nasal brush biopsy (NBB) were included in this study. NBB was performed using a curettage technique whereby ciliated epithelial cells were obtained from the surface of the inferior nasal turbinate. Results of transmission electron microscopy findings, primary ciliary dyskinesia (PCD) gene (35 genes) analyses (Invitae), and sinus computed tomography (CT) scans were reviewed. RESULTS: Twenty-three patients (age, 54 ± 2.9 years) were referred for NBB between 2015 and 2018. Thirteen patients (56.5%) met the criteria for diagnosis of CRS. Nineteen patients had ciliary ultrastructural defects. The most common finding was compound cilia (n = 11, 47.8%). Five patients (21.7%) had central microtubule defects (CMD) with higher forced expiratory volume in 1 second (FEV1 ) at the time of referral than those without CMD (CMD+ , 91 ± 3.7%; CMD- , 73.5 ± 5.7%; p = 0.023). Of 15 subjects with a PCD gene panel, 67% (9 of 15) carried at least 1 gene associated with PCD. Only 1 patient reached diagnosis of PCD. Approximately 50% of non-PCD carriers had a smoking history (p < 0.05). Lund-Mackay scores did not significantly differ between PCD and non-PCD carriers (p = 0.72). CONCLUSION: Nearly half of bronchiectasis patients referred for NBB had concurrent CRS. The presence of ciliary abnormalities was not amplified in bronchiectasis patients with CRS compared to those without CRS. Extrinsic factors may be related to ciliary structural abnormalities in non-PCD gene carriers.

Clinicopathologic Features of a Series of Primary Renal CIC-rearranged Sarcomas With Comprehensive Molecular Analysis.

CIC-rearranged sarcomas rarely occur in visceral organs including the kidney. The most common fusion partner with CIC is the DUX4 gene, but variant fusion partners have also been reported. Herein, we describe the clinicopathologic features and comprehensive molecular profiling of 4 cases of primary renal CIC-rearranged sarcomas. All cases occurred in females, age range 13 to 82 years and included 3 resections and 1 needle biopsy specimen. There was a tendency for development of metastatic disease predominantly to the lungs and poor disease outcome despite different treatment strategies. Histologically, variable round cell (20% to 100%), spindle cell (0% to 80%), and rhabdoid morphologies (0% to 20%) were seen. By immunohistochemistry diffuse WT1 nuclear (2 to 3+, ∼90%) labeling was present in 1 case, with cytoplasmic staining in the others (3+, 40% to 75%). CD99 was focally positive in all 4 cases (≤10%); 1 case each was diffusely positive for c-myc (2 to 3+, ∼90%) and ETV4 (3+, ∼90%); 1 case was focally positive for c-myc (2+, ∼5%) and calretinin (2+, ∼5%); and all cases were negative for cytokeratin and NKX2.2. CIC rearrangement by fluorescence in situ hybridization was present in the 3 cases tested. Comprehensive genomic profiling (CGP) of 3 cases revealed a CIC-DUX4 fusion in 2 cases, and 1 CIC-NUTM1 fusion. All 4 CIC-rearranged renal sarcomas had low mutation burden, and except HLA-A and MLL mutations lacked genomic alterations in other oncogenic drivers. Material from the needle biopsy was insufficient for CGP but that case was positive with the DUX4 immunohistochemical stain as were the 2 CIC-DUX4 tumors. In conclusion, CIC-rearranged sarcomas rarely occur in the kidney with a tendency for poor outcome and in this series we illustrate an example with CIC-NUTM1 fusion, an emerging variant, at a visceral site. Testing by fluorescence in situ hybridization or CGP is optimal to avoid missing cases that harbor variant fusion partners.

Subclinical inflammation phenotypes and long-term outcomes after pediatric kidney transplantation.

The implementation of surveillance biopsies in pediatric kidney transplantation remains controversial. Surveillance biopsies detect subclinical injury prior to clinical dysfunction, which could allow for early interventions that prolong allograft survival. We conducted a single-center retrospective cohort study of 120 consecutive pediatric kidney recipients, of whom 103 had surveillance biopsies ≤6 months posttransplant. We tested the hypothesis that subclinical inflammation (borderline or T cell-mediated rejection without clinical dysfunction) is associated with a 5-year composite endpoint of acute rejection and allograft failure. Overall, 36% of subjects had subclinical inflammation, which was associated with increased hazard for the composite endpoint (adjusted hazard ratio 2.89 [1.27, 6.57]; P < .01). Subjects with treated vs untreated subclinical borderline rejection had a lower incidence of the composite endpoint (41% vs 67%; P < .001). Subclinical vascular injury (subclinical inflammation with Banff arteritis score > 0) had a 78% incidence of the composite endpoint vs 11% in subjects with no major surveillance abnormalities (P < .001). In summary, we showed that subclinical inflammation phenotypes were prevalent in pediatric kidney recipients without clinical dysfunction and were associated with increased acute rejection and allograft failure. Once prospectively validated, our data would support implementation of surveillance biopsies as standard of care in pediatric kidney transplantation.

TLE1 Expression in Malignant Rhabdoid Tumor and Atypical Teratoid/Rhabdoid Tumor.

Malignant rhabdoid tumors (MRT; atypical teratoid/rhabdoid tumor [ATRT] in the central nervous system) are aggressive tumors in infants and children which can overlap with other sarcomas, such as synovial sarcoma (SS). The gold standard for SS diagnosis is characterization of the t(X;18) chromosomal translocation. However, stratification of cases for molecular analysis is not always straightforward or feasible. Recent literature suggests transducer-like enhancer of split 1 (TLE1) protein expression may distinguish SS from certain histologic mimics; however, this has not been investigated in MRT and ATRT. We stained whole-tissue sections of 18 archived cases of MRT and ATRT with TLE1. Nuclear expression was scored using a 4-tiered (0, 1+, 2+, and 3+) scale describing staining intensity, extent, or combination of both. The majority of MRT and ATRT cases showed some TLE1 immunoreactivity (n = 16; 89% for ≥1 + staining); 14 (78%) of total cases showed ≥2 + positivity using any of the 3 scoring systems. Over half (n = 10; 56%) of cases showed ≥2 + staining; 4 (22%) cases showed 3 + strong and diffuse TLE1 staining measured by all scoring systems in agreement. Although still of potential use, we urge caution in the interpretation of TLE1 when the differential diagnosis includes both SS and MRT or ATRT.

Whole exome sequencing identified sixty-five coding mutations in four neuroblastoma tumors.

Neuroblastoma is a pediatric tumor characterized by histologic heterogeneity, and accounts for ~15% of childhood deaths from cancer. The five-year survival for patients with high-risk stage 4 disease has not improved in two decades. We used whole exome sequencing (WES) to identify mutations present in three independent high-risk stage 4 neuroblastoma tumors (COA/UAB-3, COA/UAB -6 and COA/UAB -8) and a stage 3 tumor (COA/UAB-14). Among the four tumors WES analysis identified forty-three mutations that had not been reported previously, one of which was present in two of the four tumors. WES analysis also corroborated twenty-two mutations that were reported previously. No single mutation occurred in all four tumors or in all stage 4 tumors. Three of the four tumors harbored genes with CADD scores ≥20, indicative of mutations associated with human pathologies. The average depth of coverage ranged from 39.68 to 90.27, with >99% sequences mapping to the genome. In summary, WES identified sixty-five coding mutations including forty-three mutations not reported previously in primary neuroblastoma tumors. The three stage 4 tumors contained mutations in genes encoding protein products that regulate immune function or cell adhesion and tumor cell metastasis.

Pediatric Anaplastic Embryonal Rhabdomyosarcoma: Targeted Therapy Guided by Genetic Analysis and a Patient-Derived Xenograft Study.

Therapy for rhabdomyosarcoma (RMS) has generally been limited to combinations of conventional cytotoxic agents similar to regimens originally developed in the late 1960s. Recently, identification of molecular alterations through next-generation sequencing of individual tumor specimens has facilitated the use of more targeted therapeutic approaches for various malignancies. Such targeted therapies have revolutionized treatment for some cancer types. However, malignancies common in children, thus far, have been less amenable to such targeted therapies. This report describes the clinical course of an 8-year-old female with embryonal RMS having anaplastic features. This patient experienced multiple relapses after receiving various established and experimental therapies. Genomic testing of this RMS subtype revealed mutations in BCOR, ARID1A, and SETD2 genes, each of which contributes to epigenetic regulation and interacts with or modifies the activity of histone deacetylases (HDAC). Based on these findings, the patient was treated with the HDAC inhibitor vorinostat as a single agent. The tumor responded transiently followed by subsequent disease progression. We also examined the efficacy of vorinostat in a patient-derived xenograft (PDX) model developed using tumor tissue obtained from the patient's most recent tumor resection. The antitumor activity of vorinostat observed with the PDX model reflected clinical observations in that obvious areas of tumor necrosis were evident following exposure to vorinostat. Histologic sections of tumors harvested from PDX tumor-bearing mice treated with vorinostat demonstrated induction of necrosis by this agent. We propose that the evaluation of clinical efficacy in this type of preclinical model merits further evaluation to determine if PDX models predict tumor sensitivity to specific agents and/or combination therapies.

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

Regulation of alveolar septation by microRNA-489.

MicroRNAs (miRs) are small conserved RNA that regulate gene expression. Bioinformatic analysis of miRNA profiles during mouse lung development indicated a role for multiple miRNA, including miRNA-489. miR-489 increased on completion of alveolar septation [postnatal day 42 (P42)], associated with decreases in its conserved target genes insulin-like growth factor-1 (Igf1) and tenascin C (Tnc). We hypothesized that dysregulation of miR-489 and its target genes Igf1 and Tnc contribute to hyperoxia-induced abnormal lung development. C57BL/6 mice were exposed to normoxia (21%) or hyperoxia (85% O2) from P4 to P14, in combination with intranasal locked nucleic acid against miR-489 to inhibit miR-489, cytomegalovirus promoter (pCMV)-miR-489 to overexpress miR-489, or empty vector. Hyperoxia reduced miR-489 and increased Igf1 and Tnc. Locked nucleic acid against miR-489 improved lung development during hyperoxia and did not alter it during normoxia, whereas miR-489 overexpression inhibited lung development during normoxia. The 3' untranslated region in vitro reporter studies confirmed Igf1 and Tnc as targets of miR-489. While miR-489 was of epithelial origin and present in exosomes, its targets Igf1 and Tnc were produced by fibroblasts. Infants with bronchopulmonary dysplasia (BPD) had reduced lung miR-489 and increased Igf1 and Tnc compared with normal preterm or term infants. These results suggest increased miR-489 is an inhibitor of alveolar septation. During hyperoxia or BPD, reduced miR-489 and increased Igf1 and Tnc may be inadequate attempts at compensation. Further inhibition of miR-489 may permit alveolar septation to proceed. The use of specific miRNA antagonists or agonists may be a therapeutic strategy for inhibited alveolarization, such as in BPD.

Surgical and Anesthetic Management of a Mediastinal Fatty Tumor: Lipoblastoma.

Lipoblastoma is a rare fatty tumor that is diagnosed almost exclusively in children. Presentation often consists of respiratory symptoms; chest computed tomography shows a hypodense, low, attenuated mediastinal mass. Surgical approach and anesthetic management are dependent on the location of the tumor and the degree of airway compression; in most cases, a thoracotomy is performed, although a sternotomy is used in selected cases. Final diagnosis can be confirmed using molecular genetic analysis; a genetic hallmark of lipoblastoma is the rearrangement of chromosomal region 8q12 and the PLAG1 gene. Tumor recurrence is rare when a complete resection is performed.

Shone variant with large eustachian valve: implication for repair and heart transplantation.

We present a case of a neonate with Shone complex in addition to the underdevelopment of the right ventricle associated with dysplasia and stenosis of the tricuspid valve. Because of lack of effective surgical options, the patient was transplanted at the age of 8days. A gradient was noted in the postoperative period across the inferior vena cava anastomosis. At reoperation, a prominent myxomatous Eustachian valve was resected. We believe the large Eustachian valve was likely responsible for the right-sided pathology.

Multiple native flavin reductases in camphor-metabolizing Pseudomonas putida NCIMB 10007: functional interaction with two-component diketocamphane monooxygenase isoenzymes.

Although they have been studied for nearly 50 years, the source of the FMNH2 needed for effective biooxidation by the 2,5- and 3,6-diketocamphane monooxygenase (DKCMO) isoenzymes induced by the growth of Pseudomonas putida NCIMB 10007 (ATCC 17453) on camphor remains incompletely characterized. Prior studies have focussed exclusively on enzymes present in cells harvested during late-exponential-phase growth despite considerable circumstantial evidence that the flavin reductase (FR) component of these multicomponent monooxygenases is subject to growth-phase-dependent variation. In this study, a number of alternative FMNH2-generating activities, including both conventional FRs and enzymes also able to serve as ferric reductases, were isolated from camphor-grown cells, and the relative level, and hence potential contribution, of these various proteins shown to vary considerably depending on the point of harvest of NCIMB 10007 within exponential-phase growth. While two constitutive monomeric ferric reductases (molecular masses 27.0 and 28.5 kDa) were found to be the major relevant sources of FMNH2 during the initial stages of growth on camphor-based media, a significant subsequent contribution throughout the mid- to late-exponential phases of growth was also made by the camphor-induced homodimeric 37.0 kDa FR Fred, recently reported to serve such a role exclusively. The possible involvement of camphor-induced putidaredoxin reductase (51.0 kDa) as a contributory activity was also investigated and considered. Studies with highly purified preparations of the isofunctional DKCMOs confirmed the potential of the various reductases to function effectively as sources of the requisite FMNH2 to both monooxygenases at different times throughout growth on camphor.

Intestinal epithelial apoptosis initiates gut mucosal injury during extracorporeal membrane oxygenation in the newborn piglet.

Neonates and young infants exposed to extracorporeal circulation during extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass are at risk of developing a systemic inflammatory response syndrome with multi-organ dysfunction. We used a piglet model of ECMO to investigate the hypothesis that epithelial apoptosis is an early event that precedes villous damage during ECMO-related bowel injury. Healthy 3-week-old piglets were subjected to ECMO for up to 8 h. Epithelial apoptosis was measured in histopathological analysis, nuclear imaging, and terminal deoxynucleotidyl transferase dUTP nick end labeling. Plasma intestinal fatty acid-binding protein (I-FABP) levels were measured by enzyme immunoassay. Intestinal mast cells were isolated by fluorescence-assisted cell sorting. Cleaved caspase-8, caspase-9, phospho-p38 MAPK, and fas ligand expression were investigated by immunohistochemistry, western blots, and reverse transcriptase-quantitative PCR. Piglet ECMO was associated with increased gut epithelial apoptosis. Extensive apoptotic changes were noted on villus tips and in scattered crypt cells after 2 h of ECMO. After 8 h, the villi were denuded and apoptotic changes were evident in a majority of crypt cells. Increased circulating I-FABP levels, a marker of gut epithelial injury, showed that epithelial injury occurred during ECMO. We detected increased cleaved caspase-8, but not cleaved caspase-9, in epithelial cells indicating that the extrinsic apoptotic pathway was active. ECMO was associated with increased fas ligand expression in intestinal mast cells, which was induced through activation of the p38 mitogen-activated protein kinase. We conclude that epithelial apoptosis is an early event that initiates gut mucosal injury in a piglet model of ECMO.

Polyarteritis nodosa in childhood: recognition of early dermatologic signs may prevent morbidity.

Systemic polyarteritis nodosa (PAN) is a vasculitis that affects small to medium-size arteries. Onset in childhood is rare and can cause significant morbidity. Often, cutaneous manifestations can provide early clues toward diagnosis. This article describes a case of childhood systemic PAN that presented with fever, a necrotic skin lesion, and oral ulceration. Intestinal perforation complicated this case. Prompt recognition of childhood PAN is important to prevent serious complications.