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Objectives We report the clinical, radiological, laboratory, and neuropathological findings in support of the first diagnosis of lethal, small-vessel cerebral vasculitis triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric patient. Patient description A previously healthy, 8-year-old Hispanic female presented with subacute onset left-sided weakness two weeks after a mild febrile illness. SARS-CoV-2 nasopharyngeal swab was positive. Magnetic resonance imaging (MRI) revealed an enhancing right frontal lobe lesion with significant vasogenic edema. Two brain biopsies of the lesion showed perivascular and intraluminal lymphohistiocytic inflammatory infiltrate consistent with vasculitis. Despite extensive treatment with immunomodulatory therapies targeting primary angiitis of the central nervous system, she experienced neurologic decline and died 93 days after presentation. SARS-CoV-2 testing revealed positive serum IgG and positive cerebrospinal fluid IgM. Comprehensive infectious, rheumatologic, hematologic/oncologic, and genetic evaluation did not identify an alternative etiology. Post-mortem brain autopsy remained consistent with vasculitis. Discussion This is the first pediatric presentation to suggest SARS-CoV-2 can lead to a fatal, post-infectious, inflammatory small-vessel cerebral vasculitis. Our case is unique in including supportive cerebrospinal fluid and post-mortem tissue analysis. While most children recover well from neurologic complications of SARS-CoV-2, we emphasize the potential mortality in a child with no risk factors for severe disease.

Contains fulltext : 249882.pdf (Publisher’s version ) (Closed access) ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

SUMMARY We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extra-cranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches., Graphical Abstract, In brief Brohl et al. perform immunogenomics analysis of a cohort of 788 pediatric extracranial solid tumors and cell lines, representing 14 diagnoses, utilizing RNA sequencing. They broadly describe prognostically relevant immunophenotypes and provide proof of concept of a transcriptomics-informed adoptive cellular therapy approach, validating PRAME as a multi-pediatric cancer immunotherapy target.

Bile salt export pump (BSEP) adenosine triphosphate-binding cassette B11 (ABCB11) is a liver-specific ABC transporter that mediates canalicular bile salt excretion from hepatocytes. Human mutations in ABCB11 cause progressive familial intrahepatic cholestasis type 2. Although over 150 ABCB11 variants have been reported, our understanding of their biological consequences is limited by the lack of an experimental model that recapitulates the patient phenotypes. We applied CRISPR/Cas9-based genome editing technology to knock out abcb11b, the ortholog of human ABCB11, in zebrafish and found that these mutants died prematurely. Histological and ultrastructural analyses showed that abcb11b mutant zebrafish exhibited hepatocyte injury similar to that seen in patients with progressive familial intrahepatic cholestasis type 2. Hepatocytes of mutant zebrafish failed to excrete the fluorescently tagged bile acid that is a substrate of human BSEP. Multidrug resistance protein 1, which is thought to play a compensatory role in Abcb11 knockout mice, was mislocalized to the hepatocyte cytoplasm in abcb11b mutant zebrafish and in a patient lacking BSEP protein due to nonsense mutations in ABCB11. We discovered that BSEP deficiency induced autophagy in both human and zebrafish hepatocytes. Treatment with rapamycin restored bile acid excretion, attenuated hepatocyte damage, and extended the life span of abcb11b mutant zebrafish, correlating with the recovery of canalicular multidrug resistance protein 1 localization.Collectively, these data suggest a model that rapamycin rescues BSEP-deficient phenotypes by prompting alternative transporters to excrete bile salts; multidrug resistance protein 1 is a candidate for such an alternative transporter. (Hepatology 2018;67:1531-1545).

A female infant with a birthweight of 2,925 g is delivered at 38 6/7 weeks of gestation by a 32-year-old gravida 1, para 1 mother. The pregnancy is uncomplicated, and the mother’s evaluation for infection before delivery is negative. The birth occurs via precipitous vaginal delivery and is uneventful except for terminal meconium. At delivery, the infant is initially vigorous with an appropriate heart rate and tone, but she subsequently requires resuscitation because of increased work of breathing and oxygen saturation in the low 60s. She is treated with positive pressure ventilation, and the fraction of inspired oxygen is increased to 100%. Despite positive pressure ventilation, her physical examination findings and oxygen saturation do not improve. Her 1- and 5-minute Apgar scores are 7 each. Initial chest radiography shows a right-sided pneumothorax and pneumomediastinum. Her first capillary blood gas is notable for a pH of 6.9, a partial pressure of carbon dioxide (Pco2) of 101 mm Hg (13.4 kPa), and a base deficit of 13. Needle decompression of the right chest is attempted, after which the infant is intubated and mechanical ventilation is started. Screening infectious laboratory tests are performed and empirical broad-spectrum antibiotics are started. The infant is then transferred to a tertiary care facility for further care. Upon arrival, the infant is switched to a high-frequency oscillator. At this point, repeat chest radiography shows bilateral pneumothoraces and pneumomediastinum, so bilateral chest tubes are …

Collagen XXII (COL22A1) is a quantitatively minor collagen, which belongs to the family of fibril-associated collagens with interrupted triple helices. Its biological function has been poorly understood. Here, we used a genome-editing approach to generate a loss-of-function mutant in zebrafish col22a1. Homozygous mutant adults exhibit increased incidence of intracranial hemorrhages, which become more prominent with age and after cardiovascular stress. Homozygous col22a1 mutant embryos show higher sensitivity to cardiovascular stress and increased vascular permeability, resulting in a greater percentage of embryos with intracranial hemorrhages. Mutant embryos also exhibit dilations and irregular structure of cranial vessels. To test whether COL22A1 is associated with vascular disease in humans, we analyzed data from a previous study that performed whole-exome sequencing of 45 individuals from seven families with intracranial aneurysms. The rs142175725 single-nucleotide polymorphism was identified, which segregated with the phenotype in all four affected individuals in one of the families, and affects a highly conserved E736 residue in COL22A1 protein, resulting in E736D substitution. Overexpression of human wild-type COL22A1, but not the E736D variant, partially rescued the col22a1 loss-of-function mutant phenotype in zebrafish embryos. Our data further suggest that the E736D mutation interferes with COL22A1 protein secretion, potentially leading to endoplasmic reticulum stress. Altogether, these results argue that COL22A1 is required to maintain vascular integrity. These data further suggest that mutations in COL22A1 could be one of the risk factors for intracranial aneurysms in humans.

Posttransplant lymphoproliferative disorder (PTLD) is a well-described complication of solid organ and bone marrow transplants. The most common presentation is intra-abdominal lymphadenopathy or single or multiple intraparenchymal masses involving the liver, spleen, or kidneys. Here we describe the imaging and pathology findings of an unusual case of PTLD appearing as an intramuscular forearm lesion in a pediatric male. The manifestation of PTLD as an isolated upper extremity mass in a pediatric patient has to our knowledge not been described.

Cytokine release syndrome (CRS) is a phenomenon of immune hyperactivation described in the setting of cellular and bispecific T-cell engaging immunotherapy. Checkpoint blockade using anti-programmed cell death 1 (anti-PD-1) inhibitors is an approach to antitumor immune system stimulation. A 29-year-old female with alveolar soft part sarcoma developed severe CRS after treatment with anti-PD-1 therapy. CRS was characterized by high fevers, encephalopathy, hypotension, hypoxia, hepatic dysfunction, and evidence of coagulopathy, and resolved after infusion of the interleukin-6 inhibitor tocilizumab and corticosteroids.

Variable lung disease was documented in 2 infants with heterozygous TBX4 mutations; their clinical presentations, pathology, and outcomes were distinct. These findings demonstrate that TBX4 gene mutations are associated with neonatal respiratory failure and highlight the wide spectrum of clinicopathological outcomes that have implications for patient diagnosis and management.

Background: Both environmental and genetic factors have been linked to the formation of intracranial aneurysms (IAs), but animal models to explore mechanisms underlying genetic risk factors of IAs in humans are lacking. Methods: To identify additional genes responsible for IA development, whole exome sequencing of the patients from seven selected families was performed. One of the identified variants found in all five affected members of one family was a missense mutation in the highly conserved triple-helix region of the collagen COL22A1 isoform, the function of which has not been previously known. This mutant variant was examined in zebrafish embryonic and adult models. Results: We demonstrated that COL22A1 is expressed in cranial tissues as well as in the cells between myotomes in the trunk and tail region of the zebrafish embryos. Early global overexpression of the human mutant but not human wild-type COL22A1 in the zebrafish embryos interfered with epiboly movements during gastrulation suggesting that the mutation has a deleterious dominant effect. We then used TALEN-engineered nucleases to generate a loss-of-function mutant in zebrafish col22a1 . The homozygous null mutants were viable as adults but exhibited increased abnormal blood accumulations in the eyes and cranial regions, suggestive of hemorrhages. We further notice abnormal lesions existed in the trunks of these adults caused by rupture of blood vessels. A subset of the mutant adults shows cardiac dilation and a phenotype consistent with dilated cardiomyopathy. We further demonstrated that the homozygous embryos show increased sensitivity to cardiovascular stress, which results in a greater percentage of embryos with intracranial hemorrhages. The mutant embryos also exhibited increased vascular permeability as demonstrated by nano-particle injection into the circulation of 4-day post fertilization embryos. Conclusions: Our results suggest that the function of COL22A1 is important in maintaining vascular integrity and that mutations in COL22A1 are a potential one genetic cause for intracranial aneurysms in humans.

A case of invasive, keratinizing squamous cell carcinoma of the larynx in an 8-year-old female treated with laryngectomy is presented. Perinatal exposure to human papilloma virus and constitutional heterozygosity for a FANCC mutation were identified, though FANCC heterozygosity is not known to be cancer predisposing. An additional tumor-associated mutation in NOTCH1 was also identified potentially contributing to oncogenesis. This case illustrates an exceedingly rare type of cancer in the pediatric population and discusses diagnostic workup, evaluation of risk factors for head and neck cancer, and treatment options.

We report on the thyroid involvement with Langerhans cell histiocytosis (LCH) in a 3-year-old male. The patient presented with goiter and primary hypothyroidism. His goiter caused life-threatening airway obstruction. He developed locally invasive disease 4 years after his response to LCH therapy. LCH should be suspected as a cause of goiter and thyroidectomy is recommended.