Isolated Brain Cysts in Children Afflicted with Congenital Cytomegalovirus.

In our clinic, isolated brain cysts identified via early ultrasound are considered as central nervous system involvement in infants with children with congenital cytomegalovirus (cCMV). All infants were diagnosed with caudothalamic or subependymal cysts. When treated according to the cCMV protocol, these patients have an excellent prognosis and no neurological sequelae. Further data on the significance of different cysts in relation to cCMV is warranted.

Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling.

Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germ line loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular, and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss of function of ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.

[NEXT-GENERATION SEQUENCING PERFORMED IN PATIENTS RAISING THE SUSPICION OF AN INBORN ERROR OF METABOLISM UNCOVERED A HOMOZYGOUS VARIANT IN YARS1 ALLOWING A NOVEL THERAPEUTIC TRIAL].

INTRODUCTION: Inborn-Errors of Metabolism (IEM) are genetic disorders resulting from mutations in genes encoding proteins involved in biochemical-metabolic pathways. However, some IEMs lack specific biochemical markers. Early incorporation of next-generation-sequencing (NGS) including whole exome sequencing (WES) into the diagnostic algorithm of IEMs herein provided, increases diagnostic accuracy, permits genetic counseling and improves therapeutic options. This is exemplified by diseases affecting aminoacyl-tRNA synthetases (ARSs), enzymes involved in protein translation. Recent studies showed that supplementing amino-acids to cell-culture and patients with ARSs deficiencies resulted in improvement of biochemical and clinical parameters, respectively.

Exome sequencing links the SUMO protease SENP7 with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia.

BACKGROUND: SUMOylation involves the attachment of small ubiquitin-like modifier (SUMO) proteins to specific lysine residues on thousands of substrates with target-specific effects on protein function. Sentrin-specific proteases (SENPs) are proteins involved in the maturation and deconjugation of SUMO. Specifically, SENP7 is responsible for processing polySUMO chains on targeted substrates including the heterochromatin protein 1α (HP1α). METHODS: We performed exome sequencing and segregation studies in a family with several infants presenting with an unidentified syndrome. RNA and protein expression studies were performed in fibroblasts available from one subject. RESULTS: We identified a kindred with four affected subjects presenting with a spectrum of findings including congenital arthrogryposis, no achievement of developmental milestones, early respiratory failure, neutropenia and recurrent infections. All died within four months after birth. Exome sequencing identified a homozygous stop gain variant in SENP7 c.1474C>T; p.(Gln492*) as the probable aetiology. The proband's fibroblasts demonstrated decreased mRNA expression. Protein expression studies showed significant protein dysregulation in total cell lysates and in the chromatin fraction. We found that HP1α levels as well as different histones and H3K9me3 were reduced in patient fibroblasts. These results support previous studies showing interaction between SENP7 and HP1α, and suggest loss of SENP7 leads to reduced heterochromatin condensation and subsequent aberrant gene expression. CONCLUSION: Our results suggest a critical role for SENP7 in nervous system development, haematopoiesis and immune function in humans.

External lumbar drainage in progressive pediatric idiopathic intracranial hypertension.

OBJECTIVE: Pediatric idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure despite normal cerebrospinal fluid and neuroimaging findings. Initial management is typically medical; however, nearly 10% of children will eventually require surgery for persistent headache and/or vision loss. External lumbar drainage, which is a considerably safer treatment option, has not been adequately analyzed in children with medically refractory IIH. METHODS: The authors conducted a single-institution retrospective analysis of children with medically refractory IIH who had undergone external lumbar drain (ELD) placement because of worsening papilledema, reflected as increased retinal nerve fiber layer (RNFL) thickness on optical coherence tomography (OCT) testing. The main outcome measures were effects of external lumbar drainage on papilledema resolution, symptoms, and vision. RESULTS: The authors analyzed the medical records of 13 children with IIH (11 girls, mean age 15.0 ± 2.3 years) whose mean CSF opening pressure was 45.5 ± 6.8 cm H2O. In all children, the average global RNFL thickness in both eyes significantly increased at ELD placement (right eye 371.8 ± 150.2 µm, left eye 400.3 ± 96.9 µm) compared with presentation thickness (right eye 301.6 ± 110.40 µm, left eye 350.2 ± 107.7 µm) despite acetazolamide medical therapy (20-30 mg/kg/day), leading to ELD placement after 9.5 ± 6.9 days (range 3-29 days). After ELD insertion, there was headache resolution, gradual and continuous improvement in optic disc thickness, and preservation of good vision. CONCLUSIONS: ELD placement in children with medically refractory IIH who demonstrated worsening papilledema with increased RNFL thickening on OCT testing typically results in symptom relief and disc edema resolution with good visual outcome, often preventing the need for additional definitive surgeries that carry greater failure and morbidity risks.

[THE ROLE OF BONE SCINTIGRAPHY IN THE DIAGNOSIS OF CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS IN CHILDREN].

INTRODUCTION: This case report presents a teenage girl hospitalized due to fever, left wrist pain and elevated inflammatory markers. These clinical findings, as well as a lytic lesion seen on plain radiographs and MRI in the distal left radius, led to the working diagnosis of acute osteomyelitis. Following 4 weeks of antibiotic therapy, a bone scan was conducted due to inadequate clinical response. It showed additional skeletal lesions and led to the final diagnosis of chronic recurrent multifocal osteomyelitis (CRMO). Treatment was changed to anti-inflammatory medications with a good response. This article presents key features of CRMO and emphasizes the role of skeletal scintigraphy in establishing the diagnosis.

The Modified Bosniak Classification for Intermediate-Risk Renal Cysts in Children.

OBJECTIVES: To examine correlations of the modified Bosniak categories assigned by radiologists to histological results and inter-rater reliability, focusing on intermediate-risk lesions. MATERIALS AND METHODS: The data of pediatric patients who underwent surgery for intermediate-risk complex renal cyst at a tertiary medical center in 2006-2019 were collected retrospectively. Four pediatric radiologists from 2 different medical centers reviewed the available imaging scans, and assigned each to one of the four modified Bosniak classification categories. Binary cohorts of the Bosniak categories (I-II vs III-IV) were compared to the histological results. Diagnostic accuracy (benign- vs intermediate-risk lesion) was calculated for each radiologist and for each imaging modality. Krippendorff's α test was used to measure inter-rater reliability. RESULTS: The cohort included seven children, each with 1 complex cyst that was rated as intermediate-risk on pathological study. The median age was 1.5 years (IQR 1, 11.9). A correct classification was made in 41/56 imaging readings (sensitivity 73.2%). Applying Krippendorff's test to the binary Bosniak cohorts yielded poor inter-rater agreement (α = 0.08). CONCLUSION: Implementation of the modified Bosniak classification in children caused a disconcerting underestimation of intermediate risk. There was a low inter-rater consistency for the categories intended to guide decisions regarding surgery or conservative management. The findings suggest that clinicians should be cautious using the modified Bosniak system for children.

The great mimicker: Phenotypic overlap between constitutional mismatch repair deficiency and Tuberous Sclerosis complex.

Constitutional mismatch repair deficiency is a rare cancer predisposition syndrome caused by biallelic mutations in one of the four mismatch repair genes. Patients are predisposed to various tumors including hematological malignancies, brain tumors and colorectal carcinomas. Phenotypic overlap with Neurofibromatosis-1 is well known, with most patients presenting with café-au-lait macules. Other common features include axillary and/or inguinal freckling and intracranial MRI foci of high T2W/FLAIR signal intensity similar to the typical FASI seen in Neurofibromatosis-1. In this cohort of eight patients with constitutional mismatch repair deficiency we describe overlapping phenotypical features with Tuberous Sclerosis complex. In addition to "ash-leaf like" hypomelanotic macules (five patients), we detected intracranial tuber-like lesions (three patients), renal cysts (three patients) and renal angiomyolipomas (two patients). All our patients also had Neurofibromatosis-1 like features, mainly café-au-lait macules. This study suggests that features of Tuberous sclerosis especially when overlapping with those of Neurofibromatosis 1 or malignancies atypical for these syndromes should raise the possibility of constitutional mismatch repair deficiency. Correct diagnosis is essential for appropriate genetic counseling and pre-emptive cancer surveillance.

Four-dimensional Computed Tomography (4DCT) for Preoperative Localization of Parathyroid Adenomas.

BACKGROUND: Four-dimensional parathyroid computed tomography (4DCT) is a relatively new parathyroid imaging technique that provides functional and highly detailed anatomic information about parathyroid tumors. OBJECTIVES: To assess the accuracy of 4DCT for the preoperative localization of parathyroid adenomas (PTAs) in patients with biochemically confirmed primary hyperparathyroidism (PHPT) and a history of failed surgery or unsuccessful localization using 99mTc-sestamibi scanning and ultrasonography. METHODS: Between January 2013 and January 2015, 55 patients with PHPT underwent 4DCT at Hillel Yaffe Medical Center, Hadera, Israel. An initial unenhanced scan was followed by an IV contrast injection of nonionic contrast material (120 ml of at 4 ml/s). Scanning was repeated 25, 60, and 90 seconds after the initiation of IV contrast administration. An experienced radiologist blinded to the earlier imaging results reviewed the 4DCT for the presence and location (quadrant) of the suspected PTAs. At the time of the study, 28 patients had undergone surgical exploration following 4DCT and we compared their scans with the surgical findings. RESULTS: 4DCT accurately localized 96% (27/28) of abnormal glands, all of which were hypervascular and showed characteristic rapid enhancement on 4DCT that could be distinguished from Level II lymph nodes. Surgery found hypovascular cystic PTA in one patient who produced a negative 4DCT scan. All patients had solitary PTAs. The scan at 90 seconds provided no additional information and was abandoned during the study. CONCLUSIONS: 4DCT accurately localized hypervascular parathyroid lesions and distinguished them from other tissues. A three-phase scanning protocol may suffice.

Impact of Increased Visceral Fat Measured by CT on Colon Adenocarcinoma Stage.

PURPOSE: Obesity is considered a risk factor for colon cancer. Worse outcome observed in colon cancer patients with obesity may have several mechanisms. However, the influence of obesity on colon cancer stage is yet to be clarified. The objective of this study was to determine the relationship between obesity and stage on presentation. METHODS: This is a retrospective analysis of patients' files in one university affiliated medical center. Included in this study were non-metastatic patients who underwent colectomy for adenocarcinoma of the colon in whom both the preoperative abdominal computed tomography and the postoperative pathology report were available for evaluation. Abdominal computed tomography measurement of retroperitoneal fat thickness was used as an indicator of obesity. Data was analyzed according to quartiles of fat thickness. RESULTS: Of 83 patients, 38 were males and 45 were females. Median age was 71 years (range 43-90 years). Increased retroperitoneal fat thickness was not associated with advanced T and N stages on presentation. Rather, patients in the first quartile presented with the worst T and N stages. The proportion of patients with T3 and T4 tumors was 95, 76.2, 66.7, and 66.7% in quartiles 1, 2, 3, and 4, respectively (p = 0.0327), while the proportion of patients with positive lymph node metastasis was 60, 23.8, 23.8, and 42.9% in quartiles 1, 2, 3, and 4, respectively (p = 0.0319). CONCLUSIONS: The data presented here does not support the association of obesity with worse stage at presentation of colon cancer, and other possible mechanisms for worse outcome should be sought.

Sonographic Diagnosis of Complicated Cholecystitis.

OBJECTIVES: Early detection of the complications of cholecystitis is important for clinical management, yet only a small percentage of patients have a correct diagnosis before surgery. The purpose of our study was to identify sonographic findings that are associated with complicated cholecystitis. METHODS: Sonographic, surgical, and pathologic reports were reviewed for 70 patients who underwent early cholecystectomies from January 2010 to August 2014. Sonograms were assessed for 16 independent variables. Statistical analyses were performed to evaluate associations between various sonographic features and complicated cholecystitis. RESULTS: Sonographic signs associated with complicated cholecystitis (P< .05) were a greater short-axis gallbladder diameter (mean, 4.4 versus 4.0 cm), a greater mean wall thickness (5.6 versus 4.2 mm), and the likelihood of wall striations, gallbladder echogenic content, pericholecystic free fluid, and local inflammatory fat changes. Specific sonographic signs, such as sloughed intraluminal membranes, were detected in a small percentage of cases (10%). None of the sonographic features evaluated in this study was found to be sensitive and specific enough to indicate complicated cholecystitis. In most cases, sonograms reflected severe inflammation, with multiple sonographic signs. CONCLUSIONS: Although multiple sonographic signs are associated with complicated cholecystitis, none of them is sensitive and specific enough to definitively diagnose it. Sonograms usually reflect severe inflammation, with numerous sonographic signs. Thus, in the right clinical context, sonograms of severe cholecystitis should alert radiologists to the possibility of complications.

Giant colonic diverticulum: radiographic and MDCT characteristics.

Giant colonic diverticulum (GCD), defined as a diverticulum larger than 4 cm, is a rare entity that is generally a manifestation of colonic diverticular disease. Because of its rarity and its variable and non-specific presentation, the diagnosis of GCD depends mainly on imaging findings. Knowledge of the spectrum of radiographic and CT features of the GCD is important in making the correct diagnosis and potentially preventing complications. This review focuses on imaging findings characteristic of GCD as well as its complications and radiographic mimics. Teaching points • Giant colonic diverticulum is a rare complication of diverticulosis.• The most common symptom is abdominal pain presenting in approximately 70 % of patients.• Diagnosis is based on imaging findings with plain abdominal radiographs and MDCT.• Treatment consists of en bloc resection of the diverticulum and affected adjacent colon.

Diagnosis of gallbladder perforation by ultrasound.

PURPOSE: The aim of this study was to identify possible pitfalls in the sonographic evaluation of perforated gallbladders. METHODS: This is a retrospective analysis of sonograms of 11 patients diagnosed by surgery or pathology with perforated gallbladder. Sonograms were evaluated for multiple sonographic features. RESULTS: Only three patients (27%) were diagnosed correctly with gallbladder perforation by ultrasonography prior to surgery. Gangrenous cholecystitis was reported in 10 cases (90%). Visualization of a wall defect was demonstrated in only five cases (45%) and was associated with a focal echogenic soft-tissue mass. CONCLUSION: Missed perforations by ultrasound may partially result from technical inadequacies.

The diagnostic accuracy of pericolonic fat extension and attenuation for colorectal tumors.

OBJECTIVE: To evaluate the utility of quantitative analysis of the extension and attenuation of pericolonic fat in the local staging of colorectal cancer (CRC) using multi detector computed tomography (MDCT). MATERIALS AND METHODS: This was a retrospective study of 110 patients who were operated due to pathologically proven CRC from January 2007 to January 2010, and who underwent preoperative MDCT of the abdomen and pelvis with administration of intravenous contrast material and image acquisition during the portal venous phase. The mean age was 69 years (range of 38-90 years). Pathological reports were reviewed for TNM staging. All MDCT studies were reviewed by two certified radiologists for maximal and minimal tumor diameter, extent of the infiltrated pericolonic fat (measured in mm), attenuation of the infiltrated pericolonic fat (measured in Hounsfield units), and attenuation of normally appearing fat next to the tumor. The sensitivity and specificity of these parameters in detecting patients with ≥ T3 CRC were calculated. RESULTS: The overall sensitivity, specificity, and accuracy of pericolonic fat infiltration in detecting patients with ≥T3 stage were 95% (95% CI, 89.0-98.7%), 20% (5.8-43.7%), and 81.9% (74.7-89%) respectively. The mean extent and attenuation of the infiltrated pericolonic fat, in addition to the maximal tumor diameter, were higher in the ≥T3 group (p<0.05). By defining threshold values to these parameters, the positive predictive value for detecting ≥T3 stage tumors approaches 100%. CONCLUSION: Quantitative analysis of pericolonic fat increased the accuracy of MDCT in the detection of local tumor spread in CRC.

The prevalence of pulmonary embolism among patients suffering from acute exacerbations of chronic obstructive pulmonary disease.

The clinical diagnosis of acute pulmonary embolism (PE) in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) is often difficult due to the similarity in the presenting symptoms of the two conditions. The purpose of this study was to determine the prevalence of PE in patients with acute exacerbation of COPD. Forty-nine consecutive patients admitted to our medical center for acute exacerbation of COPD were investigated for PE (whether or not clinically suspected), following a standardized algorithm based on D-dimer testing and computed tomography pulmonary angiography (CTPA). PE was ruled out by a D-dimer value <500 µg/L in 20 (41 %) patients and by negative CTPA in 40 (82 %). PE was confirmed in 9 patients. The prevalence of PE was 18 %. One patient with normal D-dimer had PE. Presenting symptoms and signs were similar between patients who did and did not have PE. PE was detected in 18 % of COPD patients who were hospitalized for an acute exacerbation. This finding supports the systematic evaluation of PE in hospitalized COPD exacerbated patients.

Role of Plain Abdominal Radiographs in the Evaluation of Patients with Non-Traumatic Abdominal Pain.

BACKGROUND: Plain abdominal radiographs are still performed as a first imaging examination to evaluate abdominal pain in the emergency department (ED), despite uncertainty regarding their utility. OBJECTIVES: To describe the frequency and outcomes of the use of plain abdominal radiographs in the diagnosis of patients presenting with acute non-traumatic abdominal pain in the ED of a medical center. METHODS: We retrospectively reviewed the records of patients presenting to the ED with acute abdominal pain during a 6 month period. Further imaging (computed tomography, ultrasonography), when performed, was compared with the abdominal radiography. RESULTS: Of 573 consecutive patients, 300 (52%) underwent abdominal radiography. Findings were normal in 88% (n = 264), non-specific in 7.3% (n = 22), and abnormal in 4.7% (n = 14). For those with normal results, no further imaging was ordered for 43% (114/264). Of the 57% (150/264) who had follow-up imaging, 65% (98/150) showed abnormal findings. In 9 (3%) of the 300 patients, abdominal radiography identified bowel perforations and obstructions, and treatment was provided without the need for further radiologic examination. CONCLUSIONS: The use of plain abdominal radiography is still common despite the high rate of false positive results. Efforts are needed to decrease the indiscriminate use of radiography in patients presenting with abdominal symptoms.