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BACKGROUND: Serum adipokines (leptin and adiponectin) are dysregulated before the onset of metabolic syndrome and hence may be useful biomarkers for screening of cardiometabolic late effects in childhood Acute Lymphoblastic Leukemia (cALL) survivors. METHODS: We compared serum adipokine levels between 40 cALL survivors (aged 10-18 years, >2 years from treatment completion) with similar controls. A multivariable logistic regression analysis was then done to assess the association of metabolic syndrome in cALL survivors with variables including adipokines and other metabolic parameters, demographic and treatment details, and Dual-energy X-ray absorptiometry scan-derived variables. RESULTS: Compared to controls, cALL survivors had a higher prevalence of metabolic syndrome (8/40 vs. 2/40, P = .044) and central obesity (11/40 vs. 4/40, P = 0.042). Median Serum Leptin (7.39 vs. 4.23 ng/ml, P = 0.207) levels and derived Leptin-Adiponectin Ratio (1.44 vs. 0.80, P = 0.598), were higher but not statistically different in our survivors compared to controls; Adiponectin levels were similar (6.07 vs. 5.01 µg/ml, P = 0.283). In the cALL survivors, overweight/obesity (odds ratio [OR] 21.9, P = 0.020) or higher Leptin levels (OR 1.11, P = 0.047), were independently associated with metabolic syndrome. CONCLUSIONS: Serum Leptin, independently predictive of metabolic syndrome in our cALL survivors, may be tested in larger studies to assess its utility in surveillance and initiation of early preventive measures.
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Síndrome Metabólica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/etiologia , Leptina , Adipocinas , Adiponectina , Países em Desenvolvimento , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Obesidade/complicações , Sobreviventes , BiomarcadoresRESUMO
Three-year-old boy who presented with colicky abdominal pain, diarrhoea and vomiting was investigated with computed tomography which revealed a mass in the peripancreatic region. An imaging possibility of duodenal intramural hematoma was considered after reassessment with ultrasound which was subsequently confirmed by magnetic resonance imaging. The development of a spontaneous duodenal hematoma lead to further evaluation of the patient and revealed X linked hyper IgM syndrome.
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Duodenopatias , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1 , Síndrome de Imunodeficiência com Hiper-IgM , Masculino , Humanos , Duodenopatias/etiologia , Duodenopatias/patologia , Duodeno/diagnóstico por imagem , Duodeno/patologia , Hemorragia Gastrointestinal , Hematoma/diagnóstico por imagem , Hematoma/etiologia , Hematoma/patologiaRESUMO
Airway ultrasound (US) is an easily available, portable, radiation-free imaging modality for quick, non-invasive, dynamic evaluation of the airway without sedation. This is useful in children with stridor, which is an emergency due to upper airway obstruction requiring immediate management. Several causes of stridor including laryngomalacia, laryngeal cyst, subglottic hemangioma, vocal cord palsy, and lymphatic malformations can be evaluated accurately. Thin musculature and unossified cartilages in children provide a good acoustic window. Thus, airway US is valuable, but underutilized for the evaluation of children with stridor. In this case-based review, we describe the technique, indications, anatomy, and pathologies on airway US.
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Doenças da Laringe , Sons Respiratórios , Criança , Humanos , Sons Respiratórios/etiologia , Doenças da Laringe/complicações , Doenças da Laringe/diagnóstico por imagemRESUMO
This review is a bird's eye view of the practice of pediatric radiology in India. The key focus of this article is training, certification and employment opportunities for radiologists aspiring to specialise in pediatric radiology. Further, we have traced the growth in academic and research opportunities over the past two decades, as well as given a peep into the future trajectory of this speciality. An understanding of these concepts is key to the expansion of pediatric radiologists not just within India, but across the globe.
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This review is intended to familiarize readers with an emerging group of fungal infections that mostly manifest in immunocompetent individuals. This group was initially considered endemic to the tropics, but increasing worldwide prevalence has been reported. The organisms have been divided into dominant non-invasive forms and dominant invasive forms for ease of understanding. The non-invasive organisms include the group Entomophthoromycota, under which two genera Basidiobolus and Conidiobolus, have been identified as human pathogens. They present with plaques in the extremities and rhinofacial region, respectively. The invasive organisms are dematiaceous fungi (phaeohypomycosis), which includes Cladophialophora and Exophiala among others. They cause invasion of deep tissues, with the central nervous system being the most common target. The mycology, epidemiology, diagnosis, and treatment options have been summarized in brief. The clinical presentation, imaging manifestations, differentiation from other common infections and malignancies that show similar features have been detailed.
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HISTORY: A 10-year-old North Indian boy presented with swelling of multiple joints in his hands for the past 3 years. This swelling involved the small joints of his hands and some restriction of joint movement, without any associated tenderness or morning stiffness. No other joints were symptomatically involved. Prior to visiting our hospital, he had received disease-modifying antirheumatoid drugs for suspected juvenile idiopathic arthritis, without any clinical benefit. On examination, the metacarpophalangeal and interphalangeal joints were nontender but had swelling and flexion deformities. He also had a short stature (below the third centile) for his age. Inflammatory markers, including erythrocyte sedimentation rate (7 mm per hour; normal range, 0-22 mm per hour) and C-reactive protein level (1.5 mg/L; normal level, <10 mg/L), were normal, and the rheumatoid factor test result was negative. A skeletal survey of the patient was performed and is shown in Figures 1-6.
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Artrite Juvenil , Artrite Reumatoide , Masculino , Humanos , Criança , Articulações , Radiografia , MãosRESUMO
HISTORY: A 10-year-old North Indian boy presented with swelling of multiple joints in his hands for the past 3 years. This swelling involved the small joints of his hands and some restriction of joint movement, without any associated tenderness or morning stiffness. No other joints were symptomatically involved. Prior to visiting our hospital, he had received disease-modifying antirheumatoid drugs for suspected juvenile idiopathic arthritis, without any clinical benefit. On examination, the metacarpophalangeal and interphalangeal joints were nontender but had swelling and flexion deformities. He also had a short stature (below the third centile) for his age. Inflammatory markers, including erythrocyte sedimentation rate (7 mm per hour; normal range, 0-22 mm per hour) and C-reactive protein level (1.5 mg/L; normal level, <10 mg/L), were normal, and the rheumatoid factor test result was negative. A skeletal survey of the patient was performed.
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Artrite Juvenil , Mãos , Masculino , Humanos , Criança , Extremidade Superior , HospitaisRESUMO
Mosaic variegated aneuploidy syndrome 2 (MVA2) (MIM# 614114) is a rare autosomal recessive condition caused by biallelic loss of function variants in the CEP57 gene. MVA2 is characterized by a variable phenotype ranging from poor growth to facial dysmorphism, short stature and congenital heart defects. Only 11 families and 5 pathogenic variants of MVA2 have been described so far. Intragenic duplication of 11 nucleotides (c.915_925dup11) in homozygous or compound heterozygous state is the commonest genetic aberration (10/13). We describe the first Indian family with two siblings with a novel homozygous splice site variant (c.382+2T>C) in CEP57. Molecular characterization demonstrated skipping of exon 3 due to the variant with protein modeling predicting subsequent complete loss of function. This is the first report of a splice site variation in CEP57 leading to MVA2.
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Transtornos Cromossômicos , Irmãos , Humanos , Transtornos Cromossômicos/genética , Síndrome , Mosaicismo , Mutação , Aneuploidia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Nucleares/genéticaRESUMO
AIM: The aim of our study is to present our experience in the management and outcome of Wilms tumor with intracaval thrombus. MATERIALS AND METHODS: All children with Wilms tumor with intracaval thrombus who presented to us from July 2000 to December 2017 were reviewed retrospectively. We evaluated the tumor stage, management, and outcomes in these patients. RESULTS: Thirty-four patients were included in the study. The median age of presentation was 48 months (11 to 84 mo). Preoperative chemotherapy was given in 32 (94%), with a median duration of 8 weeks. Intracaval thrombus completely resolved in 9 (26%) children after neoadjuvant chemotherapy. Surgical intervention for residual inferior vena cava (IVC) thrombus was performed in 32 patients. The median follow-up was 30 months (5 to 150 mo). At the last follow-up, 24 patients (70%) were alive and disease free. The 5-year overall survival (OS) and event-free survival were 67% (95% confidence interval, 50% to 84%) and 59% (95% confidence interval, 42% to 76%). The OS in children with nonmetastatic disease (94%) was significantly higher than those with metastases (29%; P <0.01). The OS in children with complete resolution of IVC thrombus (100%) was significantly higher than those with persistent thrombus (48%; P =0.025). Analysis of survival outcomes in children with nonmetastatic disease (stage III) revealed no significant difference on comparison with cohort with stage III disease with absence of IVC thrombus. The P -value was 0.224 and 0.53 for 5-year OS and event-free survival, respectively. CONCLUSION: The management of Wilms tumor can be complicated by the presence of caval thrombus. Patients with metastasis have a significantly poor outcome. Patients in whom, there is complete resolution of intracaval thrombus on neoadjuvant chemotherapy have a significantly higher OS.
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Neoplasias Renais , Trombose , Trombose Venosa , Tumor de Wilms , Humanos , Criança , Pré-Escolar , Neoplasias Renais/complicações , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Estudos Retrospectivos , Terapia Neoadjuvante , Veia Cava Inferior/patologia , Tumor de Wilms/complicações , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/patologia , Trombose/patologia , Trombose Venosa/etiologia , Trombose Venosa/complicaçõesRESUMO
Polyarteritis nodosa (PAN) is a medium-vessel vasculitis presenting with cutaneous and multisystem involvement with considerable morbidity. The necrotizing vasculitis in PAN typically involves renal, celiac, and mesenteric vascular beds. Coronary artery involvement is a characteristic feature of Kawasaki disease, another medium-vessel vasculitis; however, it has been rarely reported with PAN. Here, we present 2 cases with PAN involving coronaries mimicking Kawasaki disease. A 3.5-year-old boy with classical features of Kawasaki disease with giant coronary aneurysm refractory to IVIg, methylprednisolone, infliximab presented with persistent rise in inflammatory markers and gastrointestinal bleeding. Digital subtraction angiography (DSA) revealed celiac artery branches stenosis and beading suggestive of PAN. Another 2-year-old girl presented with persistent fever, abdominal pain, and distension. She had hypertension, hepatomegaly, and splenomegaly on examination. Echocardiography revealed multiple coronary aneurysms and DSA revealed numerous renal artery aneurysms. Coronary aneurysm although is a rare presentation of childhood PAN, and can mimic Kawasaki disease. Although both are medium-vessel vasculitis differentiation between these two entities is pivotal, as there are differences in treatment modalities, duration of immunomodulatory therapy, and the outcome. This manuscript describes the salient differences which can help differentiate PAN masquerading as Kawasaki disease at initial presentation.
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BACKGROUND: Non-invasive biomarkers for early chemotherapeutic response in Ewing sarcoma family of tumors (ESFT) are useful for optimizing existing treatment protocol. PURPOSE: To assess the role of diffusion-weighted magnetic resonance imaging (MRI) in the early evaluation of chemotherapeutic response in ESFT. MATERIAL AND METHODS: A total of 28 patients (mean age = 17.2 ± 5.6 years) with biopsy proven ESFT were analyzed prospectively. Patients underwent MRI acquisition on a 1.5-T scanner at three time points: before starting neoadjuvant chemotherapy (baseline), after first cycle chemotherapy (early time point), and after completion of chemotherapy (last time point). RECIST 1.1 criteria was used to evaluate the response to chemotherapy and patients were categorized as responders (complete and partial response) and non-responders (stable and progressive disease). Tumor diameter, absolute apparent diffusion coefficient (ADC), and normalized ADC (nADC) values in the tumor were measured. Baseline parameters and relative percentage change of parameters after first cycle chemotherapy were assessed for early detection of chemotherapy response. RESULTS: The responder:non-responder ratio was 21:7. At baseline, ADC ([0.864 ± 0.266 vs. 0.977 ± 0.246]) × 10-3mm2/s; P = 0.205) and nADC ([0.740 ± 0.254 vs. 0.925 ± 0.262] × 10-3mm2/s; P = 0.033) among responders was lower than the non-responders and predicted response to chemotherapy with AUCs of 0.6 and 0.735, respectively. At the early time point, tumor diameter (27% ± 14% vs. 4.6% ± 10%; P = 0.002) showed a higher reduction and ADC (75% ± 44% vs. 52% ± 72%; P = 0.039) and nADC (81% ± 44% vs. 48% ± 67%; P = 0.008) showed a higher increase in mean values among responders than the non-responders and identified chemotherapy response with AUC of 0.890, 0.723, and 0.756, respectively. CONCLUSION: Baseline nADC and its change after the first cycle of chemotherapy can be used as non-invasive surrogate markers of early chemotherapeutic response in patients with ESFT.
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Sarcoma de Ewing , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/tratamento farmacológico , Resultado do Tratamento , Imagem de Difusão por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética , Critérios de Avaliação de Resposta em Tumores Sólidos , Terapia NeoadjuvanteRESUMO
The use of musculoskeletal (MSK) ultrasound (US) in pediatric rheumatology has expanded rapidly with various diagnostic and therapeutic indications. Unlike magnetic resonance imaging (MRI), US allows real-time dynamic assessment, evaluation of multiple joints in a single session and comparison with contralateral limb. However, a long learning curve and lack of experience with MSK US in pediatric patients still precludes its routine use at many imaging centers. It is prudent for pediatric radiologists to be aware of normal US appearances of the growing MSK structures to avoid their misinterpretation as pathology. The normal MSK US findings in children which can be confused with pathology and create diagnostic difficulty can arise due to variable states of maturation of bones, cartilage and tendons, complex anatomical locations, accessory structures, and artifacts. Herein, we describe the various technical and interpretive challenges encountered with MSK US in pediatric patients.
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Osso e Ossos , Doenças Musculoesqueléticas , Humanos , Criança , Ultrassonografia , Imageamento por Ressonância Magnética/métodos , Extremidades , Tendões , Doenças Musculoesqueléticas/diagnóstico por imagemRESUMO
BACKGROUND: Whole-body magnetic resonance imaging (MRI) has been investigated by multiple authors as a radiation-free alternative to positron emission tomography computed tomography (PET-CT) in children with lymphoma. OBJECTIVE: To evaluate the sensitivity, specificity, and diagnostic odds ratio of whole-body MRI compared to PET-CT for the staging of pediatric lymphoma. METHODS: The databases PubMed, Embase, and Scopus were searched for studies that reported the accuracy of whole-body MRI compared to PET-CT for lymphoma staging in children. Data was collected from included studies to formulate 2 × 2 contingency tables, including the number of true positive, true negative, false positive, and false negative. The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated. Summary receiver operating characteristic curves were drawn and the area under the curve (AUC) calculated. In addition, the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS 2) tool was used to assess the risk of bias and applicability concerns. RESULTS: A total of seven studies were included in the final analysis. Of these, six studies used unenhanced whole-body MRI. The pooled sensitivity of whole-body MRI-based staging was 95.8%, while the pooled specificity was 21.8%. The DOR for whole-body MRI was 1.19. For extranodal staging, the pooled sensitivity was 88.9%, specificity was 97.4%, and DOR was 25.29. The partial AUC for overall staging was 0.63, whereas that for extranodal staging stood at 0.88. Based on the QUADAS 2 tool, all seven studies were at risk of bias (six at high risk, one at unclear risk). CONCLUSION: Whole-body MRI has high sensitivity for staging of pediatric lymphoma and may be a useful alternative to PET-CT.
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Linfoma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Criança , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios X/métodos , Sensibilidade e Especificidade , Imagem Corporal Total/métodos , Linfoma/diagnóstico por imagem , Linfoma/patologia , Tomografia por Emissão de Pósitrons , Estadiamento de Neoplasias , Fluordesoxiglucose F18 , Compostos RadiofarmacêuticosRESUMO
Imaging is crucial in the diagnostic work-up and follow-up after treatment in children with thoracic tuberculosis (TB). Despite various technological advances in imaging modalities, chest radiography is the primary imaging modality for initial care and in emergency settings, especially in rural areas and where resources are limited. Ultrasonography (US) of the thorax in TB is one of the emerging applications of US as a radiation-free modality in children. Magnetic resonance imaging (MRI) is the ideal radiation-free, emerging imaging modality for thoracic TB in children. However, only limited published data is available regarding the utility of MRI in thoracic TB. In this pictorial review, we demonstrate the use of US and rapid lung MRI in evaluating children with thoracic TB, specifically for mediastinal lymphadenopathy and pulmonary complications of TB.
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Radiologia , Tuberculose , Criança , Humanos , Tuberculose/diagnóstico por imagem , Radiografia , Ultrassonografia/métodos , Imageamento por Ressonância Magnética/métodosRESUMO
INTRODUCTION: Hepatocellular carcinoma (HCC) is a common primary malignancy of the liver but is rare in the paediatric age group; thus, it may be misdiagnosed as the more common tumour, hepatoblastoma. Management varies in both these tumours, and pathological diagnosis thus plays an important role for definitive therapy. Only a few case reports available in the literature have described the cytological characteristics of paediatric HCC. The present study was thus planned to evaluate the cytomorphological features of paediatric HCC. METHODS: Cases diagnosed with HCC on ultrasound-guided fine needle aspiration cytology over a period of 14 years were retrieved. The cases were evaluated for detailed cytological features including cellularity, architecture, sinusoidal wrapping, trabecular thickness, necrosis, anisonucleosis, chromatin, nucleoli, nuclear contours, bi- or multinucleation, intranuclear and intracytoplasmic inclusions, naked nuclei, extra-medullary haematopoiesis, monomorphism, and nuclear overlapping. RESULTS: Twelve cases of HCC were included in the study. The median age at diagnosis was 10 years. Serum alpha-fetoprotein level was raised in most of them. Five of the 12 cases were characterised as moderately differentiated, three as poorly differentiated, two as well differentiated, and two as the fibrolamellar type of HCC. Cytohistological correlation was performed in seven cases. CONCLUSIONS: Ultrasound-guided fine needle aspiration serves as a useful tool to diagnose paediatric HCC and differentiate it from other primary hepatic malignancies, especially hepatoblastoma which closely mimics HCC in this age group, as serum alpha protein levels and imaging findings are unable to distinguish these two tumours.
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Carcinoma Hepatocelular , Hepatoblastoma , Neoplasias Hepáticas , Humanos , Criança , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Hepatoblastoma/diagnóstico , Hepatoblastoma/patologia , Biópsia por Agulha FinaRESUMO
OBJECTIVE: To determine the utility of whole-body magnetic resonance imaging (WB MRI) to predict relapse in children with juvenile idiopathic arthritis (JIA) in clinical remission. METHODS: Consecutive patients with JIA who fulfilled the Wallace criteria for remission were recruited into this longitudinal pilot study and underwent WB MRI. A radiological score was devised, incorporating synovitis, bone marrow edema, sacroiliitis, enthesitis, and bone erosions. Two readers independently scored the MR data sets. The same score was calculated for both knee joints individually and correlated with outcome for that joint. Score-based models incorporating clinical and laboratory variables were generated. Logistic regression analysis was done to determine predictors for relapse. Receiver operating characteristic curve was drawn for significant variables. RESULTS: Twenty-two children (median age, 12 years; interquartile range, 9.5-14.25 years) were included in the final analysis. At 24 months' follow-up, 15 joints in 5 children relapsed; knee was the most common site. Seven knee joints had disease relapse. On univariate analysis, synovitis and total score on WB MRI were significant predictors of relapse at follow-up, with odds ratios of 9.46 (bias-corrected 95% confidence interval, 3.07-29.13) and 2.8 (bias-corrected 95% confidence interval, 1.23-6.39) respectively. Two models, which included a higher number of joints involved at presentation and abrupt drug withdrawal strategy as predictor variables, were also statistically significant (odds ratio, approximately 1.9). On multivariate analysis of the predictors variables in models where p < 0.6, it was found that only synovitis score and total score were near statistical significance ( p = 0.06); no clinical or laboratory variables were significant. The areas under the receiver operating characteristic curve for relapse prediction were approximately 0.82, 0.87, 0.79, and 0.81 for synovitis score, total MRI score, and both models, respectively. CONCLUSION: Synovitis on WB MRI is the strongest independent predictor for disease relapse in children with JIA in remission.
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Artrite Juvenil , Sinovite , Criança , Humanos , Artrite Juvenil/diagnóstico por imagem , Artrite Juvenil/patologia , Imageamento por Ressonância Magnética/métodos , Projetos Piloto , Imagem Corporal Total , Sinovite/diagnóstico por imagem , Doença Crônica , RecidivaRESUMO
Introduction Although nephroblastomas are frequently treated without prior biopsy, there are the occasional other pediatric renal tumors that require different management. In the literature, there are around 30 primary renal germ cell tumors (GCT), including four cases of Yolk sac tumor (YST). We present another primary renal YST.Case report: A five-year-old boy was diagnosed as Wilms tumor on radiology and needle biopsy. He received chemotherapy, with no response. The post-chemotherapy resection specimen revealed a YST.Conclusion: Renal YST may be indistinguishable from Wilms tumor clinically and radiologically. For pre-biopsy chemotherapy management protocols, serum tumor markers such as AFP may be recommended to identify the occasional GCT, including YST. Pre-chemotherapy needle biopsies may lead to misdiagnosis, and may require confirmation by an experienced pathologist or central review.
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Tumor do Seio Endodérmico , Neoplasias Renais , Neoplasias Embrionárias de Células Germinativas , Tumor de Wilms , Masculino , Criança , Humanos , Pré-Escolar , Tumor do Seio Endodérmico/diagnóstico , Tumor do Seio Endodérmico/patologia , Saco Vitelino/patologia , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Tumor de Wilms/diagnóstico , Neoplasias Renais/diagnósticoRESUMO
Objective: To evaluate the hepatic vasculature/tumor relations in hepatoblastoma patients with three-dimensional (3D) reformatted images after triple-phase multi-detector computed tomography (MDCT) and to compare these with the surgical findings to judge the accuracy of this investigation. Materials and Methods: The study was carried out in hepatoblastoma patients after appropriate neo-adjuvant chemotherapy, prior to resection. Images were postprocessed at a dedicated workstation for multi-planar reformations, maximum intensity projection, curved planar reformations, and volume-rendered technique reconstructions. The reporting was done as per a specific protocol by both the radiologist and surgeon (per-operative findings) and the accuracy of MDCT ascertained as per concordance between the surgical and imaging findings. Results: Fourteen children (13 boys, 1 girl) underwent surgery. Clinically, relevant information regarding vascular, tumor involvement, and interface with vessels was provided by the study in all cases. Although all tumors were deemed resectable on preoperative imaging, one procedure was abandoned due to an unanticipated portal cavernoma. While a few anatomical variations were unexpectedly encountered during surgery, there was good concordance overall between findings on imaging and surgical exploration. Conclusions: MDCT with 3D reformatting provides accurate virtual representations of the hepatic tumor. This allows simulation of surgical resection with decreased risk of vascular injury and postoperative liver failure.
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Primary microcephaly and Seckel syndrome are rare genetically and clinically heterogenous brain development disorders. Several exonic/splicing mutations are reported for these disorders to date, but â¼40% of all cases remain unexplained. We aimed to uncover the genetic correlate(s) in a family of multiple siblings with microcephaly. A novel homozygous intronic variant (NC_000013.10:g.25459823T>C) in CENPJ (13q12) segregating with all four affected male siblings was identified by exome sequencing and validated by targeted linkage approach (logarithm of the odds score 1.8 at θ 0.0). RT-PCR of CENPJ in affected siblings using their EBV derived cell lines showed aberrant transcripts suggestive of exon skipping confirmed by Sanger sequencing. Significantly reduced wild type transcript/protein in the affected siblings having the splice variant indicates a leaky gene expression of pathological relevance. Based on known CENPJ function, assessing for mitotic alterations revealed defect in centrosome duplication causing mono/multicentrosome(s) at prophase, delayed metaphase, and unequal chromosomal segregation in patient cells. Clinical features witnessed in this study expand the spectrum of CENPJ-associated primary microcephaly and Seckel syndrome. Furthermore, besides the importance of regulatory variants in classical monogenic disorders these findings provide new insights into splice site biology with possible implications for ASO-based therapies.
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Nanismo , Microcefalia , Centrômero/patologia , Nanismo/genética , Humanos , Masculino , Microcefalia/genética , Microcefalia/patologia , Proteínas Associadas aos Microtúbulos/genética , Mutação , Linhagem , Sítios de Splice de RNA , Splicing de RNARESUMO
HISTORY: An 11-year-old girl presented to the pediatric gastroenterology outpatient department of our institution with gradually increasing painless abdominal distention. The distention started 2 years earlier and was not associated with any other constitutional symptoms, vomiting, diarrhea, jaundice, hematemesis, or melaena. She reported early satiety and heaviness in the lower abdomen. The abdominal swelling was predominantly in the infraumbilical region and was soft at palpation. She was the first child of nonconsanguineous parents and had an uneventful perinatal course after a normal vaginal delivery. Her developmental milestones were normal. She had an average scholastic performance at school. There was no history of visual problems, seizures, or inappropriate behaviors. She had an early menarche 2 years previously. Her menstrual cycles were regular, and there was no abnormal vaginal discharge. Her breast development was normal (Tanner stage III), while pubic and axillary hair were absent (Tanner stage I). She was short for her age (104 cm; normal range, 120-154 cm). There was no history of short stature among her siblings or parents. Laboratory investigations were performed to measure thyroid-stimulating hormone (1354.34 µIU/mL; normal range, 0.35-5.5 µIU/mL), triiodothyronine (<2.5 ng/dL [0.0385 pmol/L]; normal range, 100-200 ng/dL [1.54-3.08 pmol/L]), thyroxine (1.35 µg/dL [17.37 nmol/L]; normal range, 5-12 µg/dL [64.35-154.44 nmol/L]), ß-human chorionic gonadotropin (<1.2 mIU/mL; normal, <5 mIU/mL), luteinizing hormone (0.08 mIU/mL; normal range, 0.1-6.0 mIU/mL), and follicle-stimulating hormone (6.93 mIU/mL; normal range, 0.3-2.0 mIU/mL) levels. Complete blood count was normal. An abdominal mass was suspected, and abdominopelvic CT was performed and followed by US; these examinations revealed multiple large cysts in both ovaries (Figs 1, 2A, 2B). The uterus was pubertal in shape, and endometrial thickness was 9 mm, representing normal follicular phase measurement. Serum CA-125 and inhibin levels were normal. To evaluate short stature, radiographs of the hand (Fig 3) and pelvis (Fig 3B) were obtained as part of a limited skeletal survey, keeping in mind the possible skeletal changes associated with hypothyroidism. In view of the hypothyroidism, US of neck was also performed (Fig 4). Treatment was started based on the clinical and radiologic parameters, and the child's condition improved with medical treatment.