Hereditary Mucin Deficiency Caused by Biallelic Loss of Function of MUC5B.

Rationale: Mucin homeostasis is fundamental to airway health. Upregulation of airway mucus glycoprotein MUC5B is observed in diverse common lung diseases and represents a potential therapeutic target. In mice, Muc5b is required for mucociliary clearance and for controlling inflammation after microbial exposure. The consequences of its loss in humans are unclear. Objectives: The goal of this study was to identify and characterize a family with congenital absence of MUC5B protein. Methods: We performed whole-genome sequencing in an adult proband with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infection. Deep phenotyping over a 12-year period included assessments of pulmonary radioaerosol mucociliary clearance. Genotyping with reverse phenotyping was organized for eight family members. Extensive experiments, including immunofluorescence staining and mass spectrometry for mucins, were performed across accessible sample types. Measurements and Main Results: The proband, and her symptomatic sibling who also had extensive sinus disease with nasal polyps, were homozygous for a novel splicing variant in the MUC5B gene (NM_002458.2: c.1938 + 1G>A). MUC5B was absent from saliva, sputum, and nasal samples. Mucociliary clearance was impaired in the proband, and large numbers of apoptotic macrophages were present in sputum. Three siblings heterozygous for the familial MUC5B variant were asymptomatic but had a shared pattern of mild lung function impairments. Conclusions: Congenital absence of MUC5B defines a new category of genetic respiratory disease. The human phenotype is highly concordant with that of the Muc5b-/- murine model. Further study of individuals with decreased MUC5B production could provide unique mechanistic insights into airway mucus biology.

Endoscopic retrograde cholangiopancreatography as a single-modality 'gold-standard' treatment for common bile duct stones in the elderly.

BACKGROUND: There are more octogenarians presenting with gallstone disease each year. Many are not suitable for surgical intervention. An alternative treatment option for common bile duct stones in the elderly is endoscopic retrograde cholangiopancreatography (ERCP) with or without stent insertion. METHODS: We conducted a retrospective study using a prospectively collected database, analysing the outcomes of consecutive patients >80 years old who underwent an ERCP in a single centre for the treatment of common bile duct stones. RESULTS: In total, 156 patients, with a median age of 91 years, underwent an ERCP for choledocholithiasis over a 3-year period. ERCP was successful in 90% of patients but a proportion required repeat intervention. Forty-six (29%) patients had a concurrently inserted stent due to incomplete stone extraction. Six (4%) patients required a post-ERCP cholecystectomy due to ongoing symptoms. The overall ERCP complication rate was 7% (4% Clavien-Dindo 1 and 3% Clavien-Dindo 2), with no cases of post-ERCP pancreatitis or death. Patients were followed up over 5 years following index ERCP. There was a 60% 3-year survival and 30% 5-year survival rate following index ERCP. Importantly, of those who did not survive, only four patients (2.6%) had a death attributable to a biliary cause and none were fit for definitive surgery. CONCLUSIONS: ERCP can be considered as a possible definitive management option for treating common bile duct stones in the elderly, particularly in the comorbid population. Concurrent stenting is an effective temporizing strategy and mitigator of biliary-related readmission, but routine stent changes should be considered. Key messages What is already known on this topic Current guidelines advocate for laparoscopic cholecystectomy and common bile duct exploration in patients with choledocholithiasis. What this study adds Endoscopic retrograde cholangiopancreatography with or without stent insertion is a safe, alternative single-treatment modality for choledocholithiasis in the elderly comorbid population. How this study might affect research, practice, or policy Studies and guidelines evaluating treatment options for choledocholithiasis may be altered to accommodate patient-specific factors, including age and comorbid status, and the concurrent use of stenting as a either a temporizing or longer-term measure for complex stone disease.

Hodgkin Lymphoma in an Adolescent With Isolated Bone Marrow and Bone Involvement: A Case Report and a Review of the Literature.

BACKGROUND: Primary presentation of Hodgkin lymphoma (HL) with bone and/or bone marrow involvement is a rare entity. Diagnostic criteria, treatment approaches, and follow-up strategies for these patients have not been standardized. OBSERVATION: We report a unique case of bone and bone marrow HL in an adolescent male without lymph node involvement. CONCLUSIONS: It is important to keep HL in the differential diagnosis of isolated and multifocal bone lesions. Evidence is needed to define the best management of these patients.

Diagnostic Performance of a Staged Pathway for Imaging Acute Appendicitis in Children.

INTRODUCTION: The objective of this work is to assess the performance of our staged diagnostic pathway in the evaluation of suspected appendicitis cases in children. The pathway consisted of clinical assessment by the emergency physician, performing initial ultrasound (US), consultation, and clinical reevaluation by the surgery team followed by a repeat focused US scan in inconclusive cases. Computed tomography (CT) was limited to cases where the repeat US remained inconclusive and the clinical reassessment indicated persistent concerns for appendicitis. METHOD: Retrospective review of the electronic medical records of 206 consecutive children who presented to our emergency department with acute abdominal pain and underwent US examination for suspected appendicitis. The imaging findings, management plan, and surgical outcome (in those who underwent surgery) were reviewed. The diagnostic performance of the initial US, repeat US, and the full imaging protocol were evaluated including the negative appendectomy rate (NAR) and the number of CT scans performed. RESULTS: Of the 206 cases, 73 (35.4%) had appendicitis. Computed tomography was performed in 9 (4.3%) of 206 cases. The US/CT ratio was 23:1. Our approach showed a diagnostic accuracy of 95.6% (197/206), sensitivity of 97.3% (73/75), specificity of 93.7% (124/133), positive predictive value of 89.0% (73/82), and negative predictive value of 98.7% (82/95). The NAR was 2.7% (2/72). The accuracy of the protocol is higher than that of the initial US alone (61.2%; 126/206) and that of the repeat US (84.2%; 16/19). CONCLUSION: The strategy of repeating limited focused US followed by CT scan in cases that remain inconclusive has good diagnostic accuracy and reasonable NAR and decreases the number of CT scans.

Sirolimus Treatment of an Infant With Intrathoracic Kaposiform Hemangioendothelioma Complicated by Life-threatening Pleural and Pericardial Effusions.

Kaposiform hemangioendothelioma (KHE) is a rare infiltrative vascular tumor that may be associated with Kasabach-Merritt Phenomenon (KMP), which is a consumptive coagulopathy with potentially life-threatening thrombocytopenia. Management of KHE and KMP is challenging, and currently, there are no standardized validated treatment protocols. Mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of KHE. We describe a term male who presented as a diagnostic dilemma with life-threatening pleural and pericardial effusions and severe thrombocytopenia. After extensive work-up the etiology for his condition was determined to be KHE with KMP. The patient was commenced on sirolimus and responded well to therapy with resolution of KMP.

Preoperative delineation of pulmonary fissural anatomy at multi-detector computed tomography in children with congenital pulmonary malformations and impact on surgical complications and postoperative course.

BACKGROUND: Delineation of the anatomy and integrity of the pulmonary fissures at CT is important because anomalous or incomplete fissures might increase the risk of surgery and of postoperative complications. OBJECTIVE: To preoperatively evaluate the integrity of the pleural fissures in children with congenital lung malformations and determine whether anomalous fissural anatomy is a risk factor for a more complicated surgery and postoperative course. MATERIALS AND METHODS: We reviewed preoperative multi-detector CT scans of consecutive children who underwent open or thoracoscopic resection of a congenital pulmonary malformation from 2008 to 2018, to determine the integrity of the fissural anatomy, and compared these findings with the surgical report. We correlated postoperative factors including operating room time, days in hospital and chest tube with the operating room documented fissural integrity. RESULTS: We saw a significant association between the radiologically determined fissural integrity at CT and the operative findings independently for the right, left and both lungs combined (P<0.001). The sensitivity of CT to determine fissural integrity was 76.9%, specificity 95.2%, positive predictive value 95.2%, negative predictive value 76.9%, and accuracy 85.1%. There was a statistically significant association between size of the pulmonary malformation and the integrity of the fissure(s) (P=0.024). Larger lesions also resulted in a significantly longer hospitalization (P=0.024). CONCLUSION: Chest CT showed high accuracy for delineating fissural anatomy in children with congenital pulmonary malformations, with a good interobserver correlation. Incomplete lung fissures were found more often in children with larger congenital pulmonary malformations. In addition, larger lesions were associated with longer hospital stays. Therefore, children with incomplete fissures may have a longer postoperative course. Analysis of the fissural anatomy should be included in the CT report.

Hyperpolarised 129Xe magnetic resonance imaging to monitor treatment response in children with cystic fibrosis.

Pulmonary magnetic resonance imaging using hyperpolarised 129Xe gas (XeMRI) can quantify ventilation inhomogeneity by measuring the percentage of unventilated lung volume (ventilation defect per cent (VDP)). While previous studies have demonstrated its sensitivity for detecting early cystic fibrosis (CF) lung disease, the utility of XeMRI to monitor response to therapy in CF is unknown. The aim of this study was to assess the ability of XeMRI to capture treatment response in paediatric CF patients undergoing inpatient antibiotic treatment for a pulmonary exacerbation.15 CF patients aged 8-18 years underwent XeMRI, spirometry, plethysmography and multiple-breath nitrogen washout at the beginning and end of inpatient treatment of a pulmonary exacerbation. VDP was calculated from XeMRI images obtained during a static breath hold using semi-automated k-means clustering and linear binning approaches.XeMRI was well tolerated. VDP, lung clearance index and the forced expiratory volume in 1 s all improved with treatment; however, response was not uniform in individual patients. Of all outcome measures, VDP showed the largest relative improvement (-42.1%, 95% CI -52.1--31.9%, p<0.0001).These data support further investigation of XeMRI as a tool to capture treatment response in CF lung disease.

Echocardiography Grading for Pulmonary Arteriovenous Malformation Screening in Children with Hereditary Hemorrhagic Telangiectasia.

Transthoracic contrast echocardiography (TTCE) has high sensitivity but low specificity in screening for pulmonary arteriovenous malformations (pAVMs) in children with hereditary hemorrhagic telangiectasia (HHT). Here we describe characteristics of TTCE that might be used to reduce the need for confirmatory computed tomography scans in children with HHT.

Diagnosis of secondary pulmonary lymphangiectasia in congenital heart disease: a novel role for chest ultrasound and prognostic implications.

BACKGROUND: Secondary pulmonary lymphangiectasia is a complication of congenital heart disease that results from chronic pulmonary venous obstruction. OBJECTIVES: We aimed to evaluate the performance of chest ultrasound (US) in diagnosing secondary pulmonary lymphangiectasia and to review the clinical course of children with secondary pulmonary lymphangiectasia. MATERIALS AND METHODS: Chest US was performed on 26 children with hypoplastic left heart syndrome, total anomalous pulmonary venous connection or cor triatriatum in a prospective observational study. Thirteen children had pulmonary venous obstruction (62% male; median age: 17 days old, range: 1-430 days old) and 13 children did not have obstruction (62% male; median age: 72 days old, range: 4-333 days old). US features of secondary pulmonary lymphangiectasia were documented and diagnostic performance was determined. Clinical course of patients with secondary pulmonary lymphangiectasia was reviewed. RESULTS: Eleven of 13 (84.6%) patients in the obstructed group had a clinical and/or biopsy diagnosis of secondary pulmonary lymphangiectasia. Statistically significant chest US criteria for diagnosis were presence of irregular lung surface (likelihood ratio [LR] 6.8, 95% confidence interval [CI] 1.9-25.1), subpleural cystic appearing structures (LR 3.6, 95% CI 1.2-10.7), and combination of subpleural cystic appearing structures and surface irregularity together (LR 10.9, 95% CI 1.6-75.0). Seven of 11 (63.6%) patients with secondary pulmonary lymphangiectasia died during follow-up, the majority due to cardiopulmonary failure or complications. CONCLUSION: Chest US is an accurate and reproducible bedside method for diagnosing secondary pulmonary lymphangiectasia in patients with pulmonary venous obstruction. These patients may have worse prognoses.

Utility of MDCT MIP Postprocessing Reconstruction Images in Children With Hereditary Hemorrhagic Telangiectasia.

OBJECTIVE: The aim of the study was to evaluate whether maximum intensity projection (MIP) images improve the detection and the delineation of the anatomic makeup of pulmonary nodules and/or arteriovenous malformations (pAVMs) in children with hereditary hemorrhagic telangiectasia (HHT). MATERIALS AND METHODS: Two radiologists (D.M., E.I.C.) performed a blinded review of chest multidetector computed tomography scans in 39 children (age, 0-18 years) with proven HHT. Multiplanar 2.5 mm slices were blindly compared with multiplanar MIP for the presence of nodules and/or overt pAVMs and for the ability to identify vessels associated with the pAVMs. Parameters that were assessed included number of definitive nodules, number of definitive pAVMs, and the ability to detect the feeding artery or draining vein in both conventional and MIP images. RESULTS: Our study showed similar detection rates between axial scans and MIP images for the detection of nodules (axial R1: 75 vs 62, P = 0.05; MIPS: 78 vs 86, P = 0.05) and in the determination of definite pAVMS (axials: 21 vs 29, P = 0.0007; MIPS: 27 vs 35, P = 0.01). Statistically significant differences were obtained in the ability to identify the feeding artery and draining vein between standard 2.5 mm slices and MIP images (axials: 13 vs 13, P = 0.0008; MIPS: 27 vs 23, P = 0.01). No other data parameters achieved statistically significance. CONCLUSIONS: Maximum intensity projection images in children with HHT can help identify the presence and the anatomy of pAVMs for future embolization.

Magnetic resonance imaging of the mediastinum, chest wall and pleura in children.

The acceptance of applications for the use of chest MRI in children has been somewhat slow and selective. The use of MRI to image chest wall lesions is likely the most common and widely used indication, aside from the widespread and somewhat sophisticated use of MRI in imaging the cardiovascular structures of the chest. In this respect, fairly standard variations of T1-W, T2-W and contrast-enhanced imaging can be used, similar to the sequences used for musculoskeletal lesions elsewhere in the body. Imaging of the anterior mediastinal masses should be performed in conjunction with a detailed pre-test clinical examination to determine potential cardiovascular compromise. MRI in the setting of middle mediastinal adenopathy, congenital mediastinal cysts or posterior mediastinal masses, however, has been shown to be more effective and more comprehensive than multidetector CT. Although sonographic imaging is the initial modality of choice for pleural abnormalities, MR imaging is extremely effective and clinically useful in the setting of a potentially ambiguous sonographic examination. Faster imaging protocols are likely to increase the acceptance of MRI to replace multidetector CT for many pediatric chest lesions.

Pulmonary arterial hypertension in children: diagnosis using ratio of main pulmonary artery to ascending aorta diameter as determined by multi-detector computed tomography.

BACKGROUND: The ratio of the transverse diameter of the main pulmonary artery (MPA) to ascending aorta as determined at multi-detector CT is a tool that can be used to assess the pulmonary arterial size in cases of pulmonary arterial hypertension in children. OBJECTIVE: To establish a ratio of MPA to ascending aorta diameter using multi-detector CT imaging suggestive of pulmonary arterial hypertension in children. We hypothesize that a defined ratio of MPA to ascending aorta is identifiable on multi-detector CT and that higher ratios can be used to reliably diagnose the presence of pulmonary arterial hypertension in children. MATERIALS AND METHODS: We calculated the multi-detector CT ratio of MPA to ascending aorta diameter in 44 children with documented pulmonary arterial hypertension by right heart catheterization and in 44 age- and gender-matched control children with no predisposing factors for pulmonary arterial hypertension. We compared this multi-detector-CT-determined ratio with the MPA pressure in the study group, as well as with the ratio of MPA to ascending aorta in the control group. A threshold ratio value was calculated to accurately identify children with pulmonary arterial hypertension. RESULTS: Children with documented primary pulmonary arterial hypertension have a significantly higher ratio of MPA to ascending aorta (1.46) than children without pulmonary arterial hypertension (1.11). A ratio of 1.3 carries a positive likelihood of 34 and a positive predictive value of 97% for the diagnosis of pulmonary arterial hypertension. CONCLUSION: The pulmonary arteries were larger in children with pulmonary arterial hypertension than in a control group of normal children. A CT-measured ratio of MPA to ascending aorta of 1.3 should raise the suspicion of pulmonary arterial hypertension in children.

Main Pulmonary Artery-to-Ascending Aorta Diameter Ratio in Healthy Children on MDCT.

OBJECTIVE: This study was performed to ascertain whether the adult ratio of 1:1 of the diameter of the main pulmonary artery (MPA) to the diameter of the ascending aorta (AA) (referred to hereafter as the MPA-to-AA ratio) on MDCT is applicable to children. MATERIALS AND METHODS: Our hypothesis, which is based on experiential observation, is that the MPA-to-AA ratio would be higher than 1 in healthy children. A retrospective analysis of vessel calibers in a population of children without pulmonary hypertension who had undergone MDCT was performed. RESULTS: The MPA-to-AA ratio was statistically significantly higher in children of all ages than in adults. We would, therefore, submit that the normal MPA-to-AA ratio in children on MDCT is greater than 1 and closer to 1.09. CONCLUSION: The demonstration of an MPA segment that is slightly larger than the AA in children undergoing MDCT should not suggest a diagnosis of pulmonary arterial hypertension.

Imaging of systemic vasculitis in childhood.

The term "systemic vasculitis" encompasses a diverse set of diseases linked by the presence of blood-vessel inflammation that are often associated with critical complications. These diseases are uncommon in childhood and are frequently subjected to a delayed diagnosis. Although the diagnosis and treatment may be similar for adult and childhood systemic vasculitides, the prevalence and classification vary according to the age group under investigation. For example, Kawasaki disease affects children while it is rarely encountered in adults. In 2006, the European League Against Rheumatism (EULAR) and the Pediatric Rheumatology European Society (PReS) proposed a classification system for childhood vasculitis adopting the system devised in the Chapel Hill Consensus Conference in 1993, which categorizes vasculitides according to the predominant size of the involved blood vessels into small, medium and large vessel diseases. Currently, medical imaging has a pivotal role in the diagnosis of vasculitis given recent developments in the imaging of blood vessels. For example, early diagnosis of coronary artery aneurysms, a serious complication of Kawasaki disease, is now possible by magnetic resonance imaging (MRI) of the heart and multidetector computed tomography (MDCT); positron emission tomography/CT (PET/CT) helps to assess active vascular inflammation in Takayasu arteritis. Our review offers a unique approach using the integration of the proposed classification criteria for common systemic childhood vasculitides with their most frequent imaging findings, along with differential diagnoses and an algorithm for diagnosis based on common findings. It should help radiologists and clinicians reach an early diagnosis, therefore facilitating the ultimate goal of proper management of affected children.

Pediatric abdominal radiograph use, constipation, and significant misdiagnoses.

OBJECTIVE: To determine the proportion of children diagnosed with constipation assigned a significant alternative diagnosis within 7 days (misdiagnosis), if there is an association between abdominal radiograph (AXR) performance and misdiagnosis, and features that might identify children with misdiagnoses. STUDY DESIGN: We conducted a retrospective cohort study of consecutive children <18 years who presented to a pediatric emergency department in Toronto, between 2008 and 2010. Children assigned an International Statistical Classification of Diseases and Related Health Problems 10th Revision code consistent with constipation were eligible. Misdiagnosis was defined as an alternative diagnosis during the subsequent 7 days that resulted in hospitalization or an outpatient procedure that included a surgical or radiologic intervention. Constipation severity was classified employing text word categorization and the Leech score. RESULTS: 3685 eligible visits were identified. Mean age was 6.6 ± 4.4 years. AXR was performed in 46% (1693/3685). Twenty misdiagnoses (0.5%; 95% CI 0.4, 0.8) were identified (appendicitis [7%], intussusception [2%, bowel obstruction [2%], other [9%]). AXR was performed more frequently in misdiagnosed children (75% vs 46%; P = .01). These children more often had abdominal pain (70% vs 49%; P = .04) and tenderness (60% vs 32%; P =.01). Children in both groups had similar amounts of stool on AXR (P = .38) and mean Leech scores (misdiagnosed = 7.9 ± 3.4; not misdiagnosed = 7.7 ± 2.9; P = .85). CONCLUSIONS: Misdiagnoses in children with constipation are more frequent in those in whom an AXR was performed and those with abdominal pain and tenderness. The performance of an AXR may indicate diagnostic uncertainty; in such cases, the presence of stool on AXR does not rule out an alternative diagnosis.

Neuroendocrine tumor in liver with positive ACTH receptor: a case report.

A rare case of possible primary ectopic adrenocorticotropic hormone (ACTH)-producing tumor in the liver mimicking a liver hemangioma is reported. A 9-year-old boy, with Cushing syndrome, was referred for the assessment of ectopic ACTH-producing tumor. Ultrasound, CT scan, and MRI of the abdomen revealed a liver lesion suggestive of a hemangioma. (111)In-octreotide scintigraphy revealed focal activity in the liver, indicative of a somatostatin-positive lesion. (99m)Tc-labeled RBC scintigraphy was negative for hemangioma. After surgical resection of the tumor, the cortisol level converted to a normal range indicative of a rare possible primary ACTH-producing tumor in the liver, which was confirmed by histopathology.

MR imaging of the chest in children.

The application of magnetic resonance imaging (MRI) to diseases of the pediatric chest has been complicated, selective and cautious. More specifically, MRI of the pediatric lung has been a highly anticipated technique that has inherent great potential for improved imaging of the chest without the use of ionizing radiation. Practical issues impede the transition from multidetector computed tomography (MDCT) to MRI in some chest diseases in children, while other disease states are intrinsically easier to image using MRI. More rapid respiratory and cardiac rates, patient instability, sedation requirements, and the low physical density of water in the lung, hinder the requirement for maximal spatial and contrast resolution. This review is intended to serve as a functional review of the practical and currently applicable ways in which the transition of imaging the non-cardiac aspects of the pediatric chest from MDCT to MRI can be done in a clinically useful way.