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It is increasingly recognised that diverse genetic respiratory disorders present as severe pulmonary hypertension (PH) in the neonate and young infant, but many controversies and uncertainties persist regarding optimal strategies for diagnosis and management to maximize long-term outcomes. To better define the nature of PH in the setting of developmental lung disorders (DEVLD), in addition to the common diagnoses of bronchopulmonary dysplasia and congenital diaphragmatic hernia, we established a multidisciplinary group of expert clinicians from stakeholder paediatric specialties to highlight current challenges and recommendations for clinical approaches, as well as counselling and support of families. In this review, we characterise clinical features of infants with DEVLD/DEVLD-PH and identify decision-making challenges including genetic evaluations, the role of lung biopsies, the use of imaging modalities, and treatment approaches. The importance of working with team members from multiple disciplines, enhancing communication and providing sufficient counselling services for families is emphasized to create an interdisciplinary consensus.
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Neoplasias Pulmonares , Blastoma Pulmonar , Tomografia Computadorizada por Raios X , Humanos , Blastoma Pulmonar/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Diagnóstico Diferencial , Masculino , Pulmão/diagnóstico por imagem , Radiografia Torácica/métodosRESUMO
BACKGROUND: Invasive fungal disease (IFD) is a frequent complication in pediatric lung transplant recipients, occurring in up to 12% of patients in the first year. Risk factors for infection include impaired lung defenses and intense immunosuppressive regimens. While most IFD occurs from Aspergillus, other fungal conidia are continuously inhaled, and infections with fungi on a spectrum of human pathogenicity can occur. CASE REPORT: We report a case of a 17-year-old lung transplant recipient in whom Irpex lacteus and Rhodotorula species were identified during surveillance bronchoscopy. She was asymptomatic and deemed to be colonized by Irpex lacteus and Rhodotorula species following transplant. 2 years after transplantation, she developed a fever, respiratory symptoms, abnormal lung imaging, and histological evidence of acute and chronic bronchitis on transbronchial biopsy. After developing symptoms concerning for a pulmonary infection and graft dysfunction, she was treated for a presumed IFD. Unfortunately, further diagnostic testing could not be performed at this time given her tenuous clinical status. Despite the initiation of antifungal therapy, her graft function continued to decline resulting in a second lung transplantation. CONCLUSIONS: This case raises the concern for IFD in lung transplant recipients from Irpex species. Further investigation is needed to understand the pathogenicity of this organism, reduce the incidence and mortality of IFD in lung transplant recipients, and refine the approach to diagnosis and manage the colonization and isolation of rare, atypical fungal pathogens in immunocompromised hosts.
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Infecções Fúngicas Invasivas , Transplante de Pulmão , Polyporales , Rhodotorula , Adolescente , Feminino , Humanos , Antifúngicos/uso terapêutico , Broncoscopia , Pulmão , Transplante de Pulmão/efeitos adversos , TransplantadosRESUMO
OBJECTIVE: We hypothesized that reticence to address a groin mass may result in late presentation of testicular/paratesticular malignancy in early puberty through adolescence. METHODS: Malignant testicular and paratesticular tumors (malignant germ cell tumors and rhabdomyosarcomas) diagnosed at our institution from 1994-2023 for patients aged 11-20 were included. Clinicopathologic features were recorded, and statistically analyzed. RESULTS: Eighty-five cases were identified. Patient ages ranged from 11 to 20 years (mean 17 years, median 16 years). The greatest tumor dimension ranged from 0.8 to 18.0 cm (mean 4.4 cm, median 3.5 cm). Ten tumors (11.8% of cases) were ≥10.0 cm. In the 11-13-year-old age group, 100% of tumors (3/3) were ≥10 cm. The proportion of tumors ≥10 cm was significantly higher in the 11-13-year-old age group than in either the 14-16-year-old (P<0.001) or 17-20-year-old (P<0.001) age groups. CONCLUSION: This adolescent cohort with malignant testicular and paratesticular tumors showed a high proportion (11.8%) of very large (≥10 cm) tumors. Although the reasons are unknown and likely multifactorial, this study suggests that adolescents, particularly the 11-13 year age group, are a vulnerable population.
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Neoplasias dos Genitais Masculinos , Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Masculino , Humanos , Adolescente , Criança , Adulto Jovem , Adulto , Neoplasias Testiculares/diagnósticoRESUMO
This case report describes a patient treated for ocular lesions who died suddenly at age 8 years and was diagnosed postmortem with Carney complex.
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Morte Súbita , Olho , Criança , HumanosRESUMO
Bacteria evolving within human hosts encounter selective tradeoffs that render mutations adaptive in one context and deleterious in another. Here, we report that the cystic fibrosis-associated pathogen Burkholderia dolosa overcomes in-human selective tradeoffs by acquiring successive point mutations that alternate phenotypes. We sequenced the whole genomes of 931 respiratory isolates from two recently infected patients and an epidemiologically-linked, chronically-infected patient. These isolates are contextualized using 112 historical genomes from the same outbreak strain. Within both newly infected patients, diverse parallel mutations that disrupt O-antigen expression quickly arose, comprising 29% and 63% of their B. dolosa communities by 3 years. The selection for loss of O-antigen starkly contrasts with our previous observation of parallel O-antigen-restoring mutations after many years of chronic infection in the historical outbreak. Experimental characterization revealed that O-antigen loss increases uptake in immune cells while decreasing competitiveness in the mouse lung. We propose that the balance of these pressures, and thus whether O-antigen expression is advantageous, depends on tissue localization and infection duration. These results suggest that mutation-driven alternation during infection may be more frequent than appreciated and is underestimated without dense temporal sampling.
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Vascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world's most afflicted cardiovascular conditions, including pulmonary arterial hypertension (PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells (SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here, we report that hypoxia-inducible factor 2α (HIF2α) expression is increased in the lung tissues of PAH patients, and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension (PH) models, we show that HIF2α is a major molecular regulator for the transformation of pericytes into SMC-like cells. Pericyte-selective HIF2α overexpression in mice exacerbates PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the crucial role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH.
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Hipertensão Pulmonar , Remodelação Vascular , Camundongos , Humanos , Animais , Pericitos/metabolismo , Células Endoteliais/metabolismo , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Hipóxia/genética , Hipóxia/metabolismo , PulmãoRESUMO
Hypoxic reprogramming of vasculature relies on genetic, epigenetic, and metabolic circuitry, but the control points are unknown. In pulmonary arterial hypertension (PAH), a disease driven by hypoxia inducible factor (HIF)-dependent vascular dysfunction, HIF-2α promoted expression of neighboring genes, long noncoding RNA (lncRNA) histone lysine N-methyltransferase 2E-antisense 1 (KMT2E-AS1) and histone lysine N-methyltransferase 2E (KMT2E). KMT2E-AS1 stabilized KMT2E protein to increase epigenetic histone 3 lysine 4 trimethylation (H3K4me3), driving HIF-2α-dependent metabolic and pathogenic endothelial activity. This lncRNA axis also increased HIF-2α expression across epigenetic, transcriptional, and posttranscriptional contexts, thus promoting a positive feedback loop to further augment HIF-2α activity. We identified a genetic association between rs73184087, a single-nucleotide variant (SNV) within a KMT2E intron, and disease risk in PAH discovery and replication patient cohorts and in a global meta-analysis. This SNV displayed allele (G)-specific association with HIF-2α, engaged in long-range chromatin interactions, and induced the lncRNA-KMT2E tandem in hypoxic (G/G) cells. In vivo, KMT2E-AS1 deficiency protected against PAH in mice, as did pharmacologic inhibition of histone methylation in rats. Conversely, forced lncRNA expression promoted more severe PH. Thus, the KMT2E-AS1/KMT2E pair orchestrates across convergent multi-ome landscapes to mediate HIF-2α pathobiology and represents a key clinical target in pulmonary hypertension.
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Hipertensão Pulmonar , RNA Longo não Codificante , Humanos , Ratos , Animais , Camundongos , Alelos , Hipertensão Pulmonar/genética , Histonas , RNA Longo não Codificante/genética , Roedores , Lisina , Hipertensão Pulmonar Primária Familiar , Hipóxia/genética , Metiltransferases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genéticaRESUMO
Importance: Antemortem infection is a risk factor for sudden infant death syndrome (SIDS)-the leading postneonatal cause of infant mortality in the developed world. Manifestations of infection and inflammation are not always apparent in clinical settings or by standard autopsy; thus, enhanced resolution approaches are needed. Objective: To ascertain whether a subset of SIDS cases is associated with neuroinflammation and occult infection. Design, Setting, and Participants: In this case-control study, postmortem fluids from SIDS cases and controls collected between July 2011 and November 2018 were screened for elevated inflammatory markers, specifically cerebrospinal fluid (CSF) neopterin and CSF and serum cytokines. CSF, liver, and brain tissue from SIDS cases with elevated CSF neopterin were subjected to metagenomic next-generation sequencing (mNGS) to probe for infectious pathogens. Brainstem tissue from a subset of these cases was analyzed by single-nucleus RNA sequencing (snRNAseq) to measure cell type-specific gene expression associated with neuroinflammation and infection. All tissue and fluid analyses were performed from April 2019 to January 2023 in a pathology research laboratory. Included was autopsy material from infants dying of SIDS and age-matched controls dying of known causes. Exposures: There were no interventions or exposures. Main Outcomes and Measures: CSF neopterin levels were measured by high-performance liquid chromatography. Cytokines were measured by multiplex fluorometric assay. mNGS was performed on liver, CSF, brain, and brainstem tissue. snRNAseq was performed on brainstem tissue. Results: A cohort of 71 SIDS cases (mean [SD] age, 55.2 [11.4] postconceptional weeks; 42 male [59.2%]) and 20 controls (mean [SD] age, 63.2 [16.9] postconceptional weeks; 11 male [55.0%]) had CSF and/or serum available. CSF neopterin was screened in 64 SIDS cases and 15 controls, with no exclusions. Tissues from 6 SIDS cases were further analyzed. For CSF neopterin measures, SIDS samples were from infants with mean (SD) age of 54.5 (11.3) postconceptional weeks (38 male [59.4%]) and control samples were from infants with mean (SD) age of 61.5 (17.4) postconceptional weeks (7 male [46.7%]). A total of 6 SIDS cases (9.3%) with high CSF neopterin were identified, suggestive of neuroinflammation. mNGS detected human parechovirus 3 (HPeV3) in tissue and CSF from 1 of these 6 cases. snRNAseq of HPeV3-positive brainstem tissue (medulla) revealed dramatic enrichment of transcripts for genes with predominately inflammatory functions compared with 3 age-matched SIDS cases with normal CSF neopterin levels. Conclusions and Relevance: Next-generation molecular tools in autopsy tissue provide novel insight into pathogens that go unrecognized by normal autopsy methodology, including in infants dying suddenly and unexpectedly.
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Encefalite , Morte Súbita do Lactente , Lactente , Humanos , Masculino , Pessoa de Meia-Idade , Morte Súbita do Lactente/genética , Morte Súbita do Lactente/patologia , Doenças Neuroinflamatórias , Estudos de Casos e Controles , Multiômica , Neopterina , Tronco Encefálico/patologia , Encefalite/complicações , CitocinasRESUMO
A multitude of lung disorders ranging from congenital and genetic anomalies to iatrogenic complications can affect the neonate or the infant within the first year of life. Neonatal and infant chest imaging, predominantly by plain radiography and computed tomography, is frequently employed to aid in diagnosis and management; however, these disorders can be challenging to differentiate due to their broad-ranging, and frequently overlapping radiographic features. A systematic and practical approach to imaging interpretation which includes recognition of radiologic patterns, utilization of commonly accepted nomenclature and classification, as well as interpretation of imaging findings in conjunction with clinical history can not only assist radiologists to suggest the diagnosis, but also aid clinicians in management planning. The contents of this article were endorsed by the leadership of both the World Federation of Pediatric Imaging (WFPI), and the International Society of Pediatric Thoracic Imaging (ISPTI).
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Pneumopatias , Lactente , Recém-Nascido , Criança , Humanos , Pneumopatias/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Pulmão/diagnóstico por imagemRESUMO
In sudden unexplained death in pediatrics (SUDP) the cause of death is unknown despite an autopsy and investigation. The role of copy number variations (CNVs) in SUDP has not been well-studied. Chromosomal microarray (CMA) data are generated for 116 SUDP cases with age at death between 1 and 28 months. CNVs are classified using the American College of Medical Genetics and Genomics guidelines and CNVs in our cohort are compared to an autism spectrum disorder (ASD) cohort, and to a control cohort. Pathogenic CNVs are identified in 5 of 116 cases (4.3%). Variants of uncertain significance (VUS) favoring pathogenic CNVs are identified in 9 cases (7.8%). Several CNVs are associated with neurodevelopmental phenotypes including seizures, ASD, developmental delay, and schizophrenia. The structural variant 47,XXY is identified in two cases (2/69 boys, 2.9%) not previously diagnosed with Klinefelter syndrome. Pathogenicity scores for deletions are significantly elevated in the SUDP cohort versus controls (p = 0.007) and are not significantly different from the ASD cohort. The finding of pathogenic or VUS favoring pathogenic CNVs, or structural variants, in 12.1% of cases, combined with the observation of higher pathogenicity scores for deletions in SUDP versus controls, suggests that CMA should be included in the genetic evaluation of SUDP.
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Large cell calcifying Sertoli cell tumour (LCCSCT) is a type of testicular sex cord-stromal tumour that may occur sporadically or in the context of Carney complex and other genetic syndromes. A subset is clinically malignant, and the molecular mechanisms that drive such aggressive behaviour remain unknown. METHODS AND RESULTS: We analysed 21 samples from 20 patients with LCCSCT (12 non-metastasising and eight metastasising) using PRKAR1A immunohistochemistry (IHC) and next-generation sequencing. All tumours except two (cases 17 and 20, both metastasising) demonstrated loss of PRKAR1A expression. Among 11 cases with interpretable sequencing results, all harboured pathogenic single nucleotide variants of PRKAR1A. Evidence of loss of heterozygosity (LOH) of PRKAR1A was present in all tumours with interpretable zygosity data, but the mechanisms of LOH were different for non-metastasising and metastasising tumours. Non-metastasising tumours demonstrated only copy-neutral LOH, while metastasising tumours demonstrated a spectrum of mechanisms of LOH, including copy-loss LOH, two concurrent mutations or copy-neutral LOH. Relevant molecular findings in non-metastasising LCCSCT were limited to PRKAR1A variants. In contrast, all metastasising LCCSCTs with interpretable data harboured additional pathogenic variants, including (but not restricted to) BRCA2 mutations with evidence of LOH and bi-allelic CDKN2A/B deletions. Three patients harboured PRKAR1A variants of inferred germline origin, including one with Carney complex and two without known syndromic features. CONCLUSIONS: This study further confirms that PRKAR1A IHC is a useful diagnostic tool for both non-metastasising and metastasising tumours and suggests that molecular analyses can be helpful to identify non-metastasising tumours with malignant potential in selected patients. Importantly, these results highlight that germline assessment could be beneficial for all patients presenting with LCCSCT.
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Complexo de Carney , Tumor de Células de Sertoli , Tumores do Estroma Gonadal e dos Cordões Sexuais , Neoplasias Testiculares , Masculino , Humanos , Tumor de Células de Sertoli/genética , Tumor de Células de Sertoli/química , Neoplasias Testiculares/metabolismo , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , MutaçãoRESUMO
A male infant presented at term with neonatal respiratory failure and pulmonary hypertension. His respiratory symptoms improved initially, but he exhibited a biphasic clinical course, re-presenting at 15 months of age with tachypnea, interstitial lung disease, and progressive pulmonary hypertension. We identified an intronic TBX4 gene variant in close proximity to the canonical donor splice site of exon 3 (hg 19; chr17:59543302; c.401 + 3 A > T), also carried by his father who had a typical TBX4-associated skeletal phenotype and mild pulmonary hypertension, and by his deceased sister who died shortly after birth of acinar dysplasia. Analysis of patient-derived cells demonstrated a significant reduction in TBX4 expression resulting from this intronic variant. Our study illustrates the variable expressivity in cardiopulmonary phenotype conferred by TBX4 mutation and the utility of genetic diagnostics in enabling accurate identification and classification of more subtly affected family members.
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Testicular juvenile granulosa cell tumors (JGCTs) are a rare type of sex cord-stromal tumor, accounting for <5% of all neoplasms of the prepubertal testis. Previous reports have demonstrated sex chromosome anomalies in a small subset of cases, but the molecular alterations associated with JGCTs remain largely undescribed. We evaluated 18 JGCTs using massive parallel DNA and RNA sequencing panels. The median patient age was <1 month (range, newborn to 5 months). The patients presented with scrotal or intra-abdominal masses/enlargement, and all underwent radical orchiectomy (17 unilateral and 1 bilateral). The median tumor size was 1.8 cm (range, 1.3-10.5 cm). Histologically, the tumors were purely cystic/follicular or mixed (ie, solid and cystic/follicular). All cases were predominantly epithelioid, with 2 exhibiting prominent spindle cell components. Nuclear atypia was mild or absent, and the median number of mitoses was 0.4/mm2 (range, 0-10/mm2). Tumors frequently expressed SF-1 (11/12 cases, 92%), inhibin (6/7 cases, 86%), calretinin (3/4 cases, 75%), and keratins (2/4 cases, 50%). Single-nucleotide variant analysis demonstrated the absence of recurrent mutations. RNA sequencing did not detect gene fusions in 3 cases that were sequenced successfully. Recurrent monosomy 10 was identified in 8 of 14 cases (57%) with interpretable copy number variant data, and multiple whole-chromosome gains were present in the 2 cases with significant spindle cell components. This study demonstrated that testicular JGCTs harbor recurrent loss of chromosome 10 and lack the GNAS and AKT1 variants described in their ovarian counterparts.
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Tumor de Células da Granulosa , Neoplasias Ovarianas , Tumores do Estroma Gonadal e dos Cordões Sexuais , Neoplasias Testiculares , Masculino , Recém-Nascido , Feminino , Humanos , Lactente , Tumor de Células da Granulosa/genética , Cromossomos Humanos Par 10 , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Neoplasias Ovarianas/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologiaRESUMO
Childhood interstitial lung disease (chILD) refers to a diverse group of rare diffuse parenchymal lung diseases affecting infants and children, previously associated with considerable diagnostic confusion due to a lack of information regarding their clinical, imaging, and histopathologic features. Due to improved lung biopsy techniques, established pathologic diagnostic criteria, and a new structured classification system, there has been substantial improvement in the understanding of chILD over the past several years. The main purpose of this article is to review the latest advances in the imaging evaluation of pediatric interstitial lung disease within the framework of the new classification system.
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Doenças Pulmonares Intersticiais , Criança , Diagnóstico por Imagem , Humanos , Lactente , Pulmão/diagnóstico por imagem , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico por imagemRESUMO
The pathobiology of in situ pulmonary thrombosis in acute respiratory distress syndrome (ARDS) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is incompletely characterized. In human pulmonary artery endothelial cells (HPAECs), hypoxia increases neural precursor cell expressed, developmentally downregulated 9 (NEDD9) and induces expression of a prothrombotic NEDD9 peptide (N9P) on the extracellular plasma membrane surface. We hypothesized that the SARS-CoV-2-ARDS pathophenotype involves increased pulmonary endothelial N9P. Paraffin-embedded autopsy lung specimens were acquired from patients with SARS-CoV-2-ââââââARDS (n = 13), ARDS from other causes (n = 10), and organ donor controls (n = 5). Immunofluorescence characterized the expression of N9P, fibrin, and transcription factor 12 (TCF12), a putative binding target of SARS-CoV-2 and known transcriptional regulator of NEDD9. We performed RNA-sequencing on normal HPAECs treated with normoxia or hypoxia (0.2% O2) for 24 h. Immunoprecipitation-liquid chromatography-mass spectrometry (IP-LC-MS) profiled protein-protein interactions involving N9P relevant to thrombus stabilization. Hypoxia increased TCF12 messenger RNA significantly compared to normoxia in HPAECs in vitro (+1.19-fold, p = 0.001; false discovery rate = 0.005), and pulmonary endothelial TCF12 expression was increased threefold in SARS-CoV-2-ARDS versus donor control lungs (p < 0.001). Compared to donor controls, pulmonary endothelial N9P-fibrin colocalization was increased in situ in non-SARS-CoV-2-ARDS and SARS-CoV-2-ARDS decedents (3.7 ± 1.2 vs. 10.3 ± 3.2 and 21.8 ± 4.0 arb. units, p < 0.001). However, total pulmonary endothelial N9P was increased significantly only in SARS-CoV-2-ARDS versus donor controls (15 ± 4.2 vs. 6.3 ± 0.9 arb. units, p < 0.001). In HPAEC plasma membrane isolates, IP-LC-MS identified a novel protein-protein interaction between NEDD9 and the ß3-subunit of the αvß3-integrin, which regulates fibrin anchoring to endothelial cells. In conclusion, lethal SARS-CoV-2-ARDS is associated with increased pulmonary endothelial N9P expression and N9P-fibrin colocalization in situ. Further investigation is needed to determine the pathogenetic and potential therapeutic relevance of N9P to the thrombotic pathophenotype of SARS-CoV-2-ARDS.