Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.

Cell adhesion molecules are membrane-bound proteins predominantly expressed in the central nervous system along principal axonal pathways with key roles in nervous system development, neural cell differentiation and migration, axonal growth and guidance, myelination, and synapse formation. Here, we describe ten affected individuals with bi-allelic variants in the neuronal cell adhesion molecule NRCAM that lead to a neurodevelopmental syndrome of varying severity; the individuals are from eight families. This syndrome is characterized by developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity. Computational analyses of NRCAM variants, many of which cluster in the third fibronectin type III (Fn-III) domain, strongly suggest a deleterious effect on NRCAM structure and function, including possible disruption of its interactions with other proteins. These findings are corroborated by previous in vitro studies of murine Nrcam-deficient cells, revealing abnormal neurite outgrowth, synaptogenesis, and formation of nodes of Ranvier on myelinated axons. Our studies on zebrafish nrcamaΔ mutants lacking the third Fn-III domain revealed that mutant larvae displayed significantly altered swimming behavior compared to wild-type larvae (p < 0.03). Moreover, nrcamaΔ mutants displayed a trend toward increased amounts of α-tubulin fibers in the dorsal telencephalon, demonstrating an alteration in white matter tracts and projections. Taken together, our study provides evidence that NRCAM disruption causes a variable form of a neurodevelopmental disorder and broadens the knowledge on the growing role of the cell adhesion molecule family in the nervous system.

Radiological findings in poisoning by synthetic cannabinoids adulterated with brodifacoum.

OBJECTIVES: Severe coagulopathy due to consumption of synthetic cannabinoids adulterated with brodifacoum, a long-acting anticoagulant, is an emerging worldwide hazard. Here, we review the spectrum of imaging findings in adulterated cannabinoid poisoning. MATERIALS AND METHODS: In this retrospective study, we used the Israeli Poison Information Center database to identify patients with cannabinoid-associated coagulopathy who presented to the Rambam Health Care Campus, where most patients were treated during an outbreak in northern Israel between September 2021 and June 2022. All relevant imaging studies for these patients were reviewed. We estimated the sensitivity of findings for cannabinoid-associated coagulopathy. Associations between a continuous variable and a dichotomous outcome were assessed with the Mann-Whitney U test. RESULTS: We identified 48 patients (mean age 40 years ± 9 [SD], 43 males) with 54 hospitalizations due to cannabinoid-associated coagulopathy. Symptomatic hemorrhage was documented in 50 (93%) cases at presentation, most of whom (78%) had hemorrhage from multiple systems. The most common bleeding site was the genitourinary collecting system, with a characteristic sign of suburothelial bleeding in 16/18 of performed abdominal CTs (sensitivity 89% [CI 65-99%] for cannabinoid-associated coagulopathy). Intramural bowel hematomas were noted in 70% (7/10) of CTs of patients with gastrointestinal bleeding. Incidental bleeding sites were identified on imaging in 24% of patients. An increased number of bleeding sites was associated with need for vasopressors (difference in bleeding sites 3.00 [95% CI 0.99-4.00], p = 0.026). CONCLUSION: CT plays a key role in the diagnosis and work-up of adulterated cannabinoid-associated coagulopathy. Characteristic signs include suburothelial hemorrhage and intramural bowel hematomas. CLINICAL RELEVANCE STATEMENT: Recognition of radiological signs of adulterated synthetic cannabinoid-associated coagulopathy is critical for optimizing outbreak control on the public health level and ensuring timely treatment on the individual patient level. KEY POINTS: • Severe coagulopathy due to consumption of synthetic cannabinoids adulterated with brodifacoum, a long-acting anticoagulant, is an emerging worldwide threat. • Characteristic imaging signs include suburothelial bleeding, intramural bowel hematomas, and rare incidental bleeding sites. • Imaging has a pivotal role in optimizing outbreak control and ensuring timely and appropriate treatment.

Endothelin-1 levels are decreased in pediatric Type 1 diabetes and negatively correlate with the carotid intima media thickness.

AIMS: Better understanding of the timeline and risk factors for the appearance of complications in pediatric Type-1-diabetes is key for developing prevention strategies. We studied endothelial markers and their determinants in adolescents with Type-1-diabetes at different time points from diagnosis. METHODS: A cross-sectional study of 58 adolescents, mean age 15.0 ± 2.4 years; 20 with recent-onset Type-1-diabetes, 20 with over 7 years of Type-1-diabetes and 18 controls. Clinical and biochemical data were collected. Fingertip arterial reactive hyperemia (EndoPAT) and carotid intima-media-thickness (cIMT) were measured to assess endothelial function and structure. RESULTS: Compared to controls, individuals with prolonged Type-1-diabetes had higher mean cIMT (0.49 ± 0.07 mm vs. 0.43 ± 0.05 mm p = 0.021) and maximal cIMT (0.61 ± 0.08 mm 0.52 ± 0.08 mm, p = 0.025). Endothelin-1 levels were significantly lower in subjects with prolonged Type-1-diabetes (1.2 ± 1.0 pg/ml) compared to controls (3.0 ± 1.7, p = 0.008 pg/ml); they negatively correlated with the mean cIMT (c = - 0.291, p = 0.031) and mean 6 months hemoglobin A1c (c = - 0.301, p = 0.022) and positively correlated with mean c-peptide levels (c = 0.356, p = 0.006) and the weekly exercise time (c = 0.485, p < 0.001). Endothelin-1 levels did not correlate with EndoPAT results. CONCLUSIONS: Our results suggest that the early years after the diagnosis of Type-1-diabetes are an important window for prevention of arterial damage in the pediatric population. The trajectories of relationships of Endothelin-1 with metabolic and vascular measures were opposite from the anticipated, yet consistent. Endothelin-1 related indirectly to adverse measures and directly to favorable measures. Decreased Endothelin-1 levels might reflect early stages in endothelial impairment in Type-1-diabetes, yet its' exact role in the development of complications is yet to be unraveled.

Ultrasound-Guided Core Biopsy for Tissue Diagnosis in Pediatric Oncology: 16-Year Experience With 597 Biopsies.

OBJECTIVE. Percutaneous imaging-guided core needle biopsies (CNBs) for cancer diagnosis in pediatric patients are gaining interest because of their availability, lower rate of complications, and high diagnostic power compared with traditional surgical biopsies. Nevertheless, their precise role in the diagnostic algorithm of pediatric oncology is still unknown. The purpose of this study was to report our accumulated 16-year experience with CNB; discuss the availability, safety, and diagnostic accuracy of the procedure and the adequacy of ancillary testing; and compare our findings with the available literature. MATERIALS AND METHODS. Pediatric ultrasound-guided CNBs performed in our hospital between November 2003 and December 2019 were retrospectively studied. Data collection included demographics, clinical and procedural parameters, complications, and final diagnosis. RESULTS. A total of 597 biopsies were performed in 531 patients (132 performed in known oncologic patients and 465 performed to establish diagnosis). The median time between the biopsy request and the procedure was 1 day. Of 432 biopsies performed in patients with malignancies, 12 (2.8%) had false-negative results. In 165 cases of benign pathologic findings, all had true-negative results. Ancillary testing was adequate in all malignant cases. Overall sensitivity, specificity, and accuracy rates were 97.2%, 100%, and 98.0%, respectively. Five biopsies (0.8%) resulted in complications, including one major bleed and one track seeding. CONCLUSION. Our experience shows that ultrasound-guided CNB for suspected malignancy in pediatric patients has a high safety profile, availability, and accuracy rate compared with surgical biopsy. Our fast-track strategy enables early initiation of designated therapy and has the potential to become the procedure of choice.

Atypical pulmonary metastases in children: the spectrum of radiologic findings.

Pulmonary nodules present a diagnostic challenge when they appear as atypical metastases in pediatric oncology patients. Chest computed tomography (CT) is the primary imaging modality for assessing lung nodules. In pediatric populations, Wilms tumor and osteosarcoma are the cancers most likely to produce pulmonary metastasis, both typical and atypical. This pictorial essay provides a thorough description of the specific radiologic features of atypical pediatric pulmonary metastases, and their pathogenesis and differential diagnosis. We also address diagnostic approaches to incidental lung nodules in healthy children found in the literature. Our aim is to help radiologists identify atypical lung metastases on CT, ensuring that children receive prompt, and potentially lifesaving, treatment.

A novel heterozygous loss-of-function DCC Netrin 1 receptor variant in prenatal agenesis of corpus callosum and review of the literature.

Agenesis of the corpus callosum (ACC) is a common prenatally-detected brain anomaly. Recently, an association between mutations in the DCC Netrin 1 receptor (DCC) gene and ACC, with or without mirror movements, has been demonstrated. In this manuscript, we present a family with a novel heterozygous frameshift mutation in DCC, review the available literature, and discuss the challenges involved in the genetic counseling for recently discovered disorders with paucity of medical information. We performed whole exome sequencing in a healthy nonconsanguineous couple that underwent two pregnancy terminations due to prenatal diagnosis of ACC. A heterozygous variant c.2774dupA (p.Asn925Lysfs*17) in the DCC gene was demonstrated in fetal and paternal DNA samples, as well as in a healthy 4-year-old offspring. When directly questioned, both father and child reported having mirror movements not affecting quality of life. Segregation analysis demonstrated the variant in three paternal siblings, two of them having mirror movements. Brain imaging revealed normal corpus callosum. Summary of literature data describing heterozygous loss-of-function variants in DCC (n = 61) revealed 63.9% penetrance for mirror movements, 9.8% for ACC, and 5% for both. No significant neurodevelopmental abnormalities were reported among the seven published patients with DCC loss-of-function variants and ACC. Prenatal diagnosis of ACC should prompt a specific anamnesis regarding any neurological disorder, as well as intentional physical examination of both parents aimed to detect mirror movements. In suspicious cases, detection of DCC pathogenic variants might markedly improve the predicted prognosis, alleviate the parental anxiety, and possibly prevent pregnancy termination.

Neonatal frontal lobe: sonographic reference values and suggested clinical use.

BACKGROUND: Intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus (PHHC) remain major problems among premature infants. The need, timing and type of ventricular drainage are based on sonographic ventricular measures, without assessment of the dimensions of the frontal lobe. The aim of our study was to establish new reference values for sonographic frontal lobe cortico-ventricular thickness (FL-CVT) in a large cohort of infants. METHODS: All normal head ultrasound scans that were performed in our center during the first 4 days of life between January 2014 and December 2016 were retrospectively evaluated. RESULTS: Scans were evaluated and plotted to create a reference range for the thickness of the frontal lobe in normal infants of 24-40 weeks' gestation. The FL-CVT increased significantly during gestation. Calculating the area under the curve of the FL-CVT in 9 infants with post-hemorrhagic-hydrocephalus (PHHC) reveals a 20% mean loss of FL-CVT. The impact of increasing ventricular dilatation and of the various ventricular drainage procedures on the frontal lobe growth were described in two infants demonstrating the potential clinical value of this tool. CONCLUSIONS: Head ultrasound provides a simple, non-invasive method for measuring the thickness of the frontal lobe, which grows significantly between 24 and 40 weeks' gestation. In premature infants with PHHC, we suggest the use of the FL-CVT measure, in addition to ventricular size measures, as a direct assessment of the impact of the enlarged ventricles on the surrounding brain parenchyma. This could assist in the management of PHHC and determine the need and optimal timing for intervention.

Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine.

Glycine is a major neurotransmitter that activates inhibitory glycine receptors and is a co-agonist for excitatory glutamatergic N-methyl-D-aspartate (NMDA) receptors. Two transporters, GLYT1 and GLYT2, regulate extracellular glycine concentrations within the CNS. Dysregulation of the extracellular glycine has been associated with hyperekplexia and nonketotic hyperglycinemia. Here, we report four individuals from two families who presented at birth with facial dysmorphism, encephalopathy, arthrogryposis, hypotonia progressing to hypertonicity with startle-like clonus, and respiratory failure. Only one individual survived the respiratory failure and was weaned off ventilation but has significant global developmental delay. Mildly elevated cerebrospinal fluid (CSF) glycine and normal serum glycine were observed in two individuals. In both families, we identified truncating mutations in SLC6A9, encoding GLYT1. We demonstrate that pharmacologic or genetic abolishment of GlyT1 activity in mice leads to mildly elevated glycine in the CSF but not in blood. Additionally, previously reported slc6a9-null mice and zebrafish mutants also display phenotypes consistent with the affected individuals we examined. Our data suggest that truncating SLC6A9 mutations lead to a distinct human neurological syndrome hallmarked by mildly elevated CSF glycine and normal serum glycine.

Emergency Physician-Administered Sedation for Pneumatic Reduction of Ileocolic Intussusception in Children: A Case Series.

BACKGROUND: Ileocolic intussusception is a major cause for intestinal obstruction in early childhood. Reduction of intussusception, in the vast majority of institutions, is performed on awake children, without sedation. OBJECTIVE: The aim of this study was to report the course of the first patients who were sedated by emergency physicians for pneumatic reduction of intussusception (PRI). METHODS: We conducted a case series analysis of prospectively collected data on patients undergoing PRI, using a sedation recording tool. This tool uses standardized definitions from the Quebec guidelines for terminology and reporting adverse events in emergency medicine. Recording of time interval measurements and adverse events was performed by the emergency physician and nurse. RESULTS: Between February 2016 and March 2018, 11 males and 3 females, with a median age of 11 months (interquartile range [IQR] 6-20 months), underwent sedation for PRI by five attending pediatric emergency physicians. All of the reductions were successful and without complications. Eight patients received ketamine and propofol, 5 received ketamine, and 1 received ketamine and midazolam. Median times for the presedation phase, procedure, sedation, physiologic recovery and emergency department recovery were: 131 min (IQR 79-104 min), 10.5 min (IQR, 9-12 min), 21 min (IQR, 20-30 min), 25 min (IQR, 23-30 min), and 108 min (IQR, 82-161 min), respectively. Four respiratory adverse events that required intervention were recorded. All were effectively treated with airway repositioning, suctioning, oxygen administration, or bag-mask ventilation. CONCLUSIONS: The first series of patients sedated for PRI by emergency physicians is reported. Our initial findings suggest the feasibility of emergency physician-administered sedation for PRI.

A PET/MR Imaging Approach for the Integrated Assessment of Chemotherapy-induced Brain, Heart, and Bone Injuries in Pediatric Cancer Survivors: A Pilot Study.

Purpose To develop a positron emission tomography (PET)/magnetic resonance (MR) imaging protocol for evaluation of the brain, heart, and joints of pediatric cancer survivors for chemotherapy-induced injuries in one session. Materials and Methods Three teams of experts in neuroimaging, cardiac imaging, and bone imaging were tasked to develop a 20-30-minute PET/MR imaging protocol for detection of chemotherapy-induced tissue injuries of the brain, heart, and bone. In an institutional review board-approved, HIPAA-compliant, prospective study from April to July 2016, 10 pediatric cancer survivors who completed chemotherapy underwent imaging of the brain, heart, and bone with a 3-T PET/MR imager. Cumulative chemotherapy doses and clinical symptoms were correlated with the severity of MR imaging abnormalities by using linear regression analyses. MR imaging measures of brain perfusion and metabolism were compared among eight patients who were treated with methotrexate and eight untreated age-matched control subjects by using Wilcoxon rank-sum tests. Results Combined brain, heart, and bone examinations were completed within 90 minutes. Eight of 10 cancer survivors had abnormal findings on brain, heart, and bone images, including six patients with and two patients without clinical symptoms. Cumulative chemotherapy doses correlated significantly with MR imaging measures of left ventricular ejection fraction and end-systolic volume, but not with the severity of brain or bone abnormalities. Methotrexate-treated cancer survivors had significantly lower cerebral blood flow and metabolic activity in key brain areas compared with control subjects. Conclusion The feasibility of a single examination for assessment of chemotherapy-induced injuries of the brain, heart, and joints was shown. Earlier detection of tissue injuries may enable initiation of timely interventions and help to preserve long-term health of pediatric cancer survivors. © RSNA, 2017 Online supplemental material is available for this article.

Bifocal primary pancreatic Burkitt's lymphoma in a 4-year-old child.

Pancreatic tumors are uncommon in children and rarely result in biliary obstruction. Primary pancreatic Burkitt's lymphoma is an exceptionally rare entity with only a few cases described in the literature. We present a case of a bifocal primary pancreatic Burkitt's lymphoma in a 4-year-old child presenting with jaundice. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:171-174, 2017.

Sonographic evaluation of renovascular hypertension in the pediatric population: State-of-the-art.

Hypertension in children affects 2-5% of the pediatric population. Identifying secondary causes of hypertension is crucial, as some of these entities may be treatable. Renovascular hypertension accounts for 5-10% of the secondary causes of hypertension in children and is mainly related to fibromuscular dysplasia and neurofibromatosis type 1. Ultrasonographic evaluation of the kidneys, including Doppler interrogation, is the recommended primary screening tool. A comprehensive study of the upper abdomen and retroperitoneum allows for identification of additional underlying etiologies. The purpose of this review is to emphasize the different causes of renovascular hypertension in children one can diagnose during the initial ultrasonographic evaluation. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:282-292, 2017.

Lung Clearance Index (LCI) in Patients with Bronchiolitis Obliterans: A Preliminary Report and Comparison to Cystic Fibrosis Patients.

INTRODUCTION: Bronchiolitis obliterans (BO) is a chronic airway disease following an insult to the lower respiratory tract. Lung clearance index (LCI) measures ventilation inhomogeneity and has been studied in cystic fibrosis (CF). We aimed to evaluate LCI in BO and to compare it to LCI in CF patients. METHODS: LCI was measured in BO patients, compared to CF patients, and correlated with spirometry and CT findings. RESULTS: Twenty BO patients and 26 CF patients (with similar mean age and BMI) underwent evaluation. FEV1 % and FEF25-75 % predicted were significantly lower in the BO group (60.5 ± 17.8 vs. 72.7 ± 20.7, p = 0.041, and 42.8 ± 22.8 vs. 66.4 ± 37.4, p = 0.017, respectively). In both groups, LCI was inversely correlated with FVC %, FEV1 %, and FEF25-75 % predicted. LCI  % was slightly higher (190.4 ± 63.5 vs. 164.9 ± 39.4, p = 0.1) and FRC gas % (measured by multiple breath washout) was significantly higher in the BO group (92.5 ± 35.9 vs. 71.3 ± 18, p = 0.014). The strength of statistical association between the lower FEF25-75 % values and the higher LCI values was stronger in BO patients. CONCLUSIONS: Similar to CF, LCI may provide estimation of ventilation inhomogeneity in BO. The results indicate greater small airway involvement and air trapping in BO. Further prospective longitudinal studies evaluating the correlation of LCI measurements with multiple clinical and physiological parameters should be performed to assess the clinical benefit of LCI measurement in BO.

Ultrasound-guided core biopsy as the primary tool for tissue diagnosis in pediatric oncology.

INTRODUCTION: Traditionally in pediatric oncology, biopsies were incisional, with a recent alternative of percutaneous imaging-guided biopsies. In our department, ultrasound (US)-guided core biopsy is the first choice for tissue diagnosis in the pediatric population. We retrospectively reviewed our experience and assessed the accuracy rate, safety, and availability of the procedure. MATERIALS AND METHODS: Pediatric US-guided biopsies performed in our hospital between November 2003 and November 2011 were studied. Data collection included demographics, clinical and procedural data, and follow-up. RESULTS: A total of 213 biopsies were performed on 191 patients: 40 known oncologic patients and 173 to establish diagnosis. Seventeen biopsies were excluded, as malignancy was not suspected. Sixty-five percent of the patients had a biopsy within a day. A total of 138 biopsies with tumor at the biopsy site were correctly diagnosed and 4 were missed. Fifty-eight patients were negative for tumor. The sensitivity of our ultrasound-guided core biopsy is 97.1%, specificity 100%, and accuracy 97.9%.We found no complication related to sedation, and 2 procedural complications-bleeding from the biopsy site and seeding of tumor cells-were reported. DISCUSSION: We find US-guided core biopsy for suspected malignancy in the pediatric population to be highly available, safe, and very accurate, having a potential to become the procedure of choice.

A loss-of-function mutation in NaPi-IIa and renal Fanconi's syndrome.

We describe two siblings from a consanguineous family with autosomal recessive Fanconi's syndrome and hypophosphatemic rickets. Genetic analysis revealed a homozygous in-frame duplication of 21 bp in SLC34A1, which encodes the renal sodium-inorganic phosphate cotransporter NaPi-IIa, as the causative mutation. Functional studies in Xenopus laevis oocytes and in opossum kidney cells indicated complete loss of function of the mutant NaPi-IIa, resulting from failure of the transporter to reach the plasma membrane. These findings show that disruption of the human NaPi-IIa profoundly impairs overall renal phosphate reabsorption and proximal-tubule function and provide evidence of the critical role of NaPi-IIa in human renal phosphate handling.

Sternal pseudotumor of childhood: don't touch the lesion.

The common approach to rapidly growing peristernal lesions in young infants is oncologic consultation, imaging, and early tissue diagnosis. We represent 3 such cases with unique sonographic findings favoring nonaggressive lesions named self-limiting sternal tumors of childhood, in which a conservative approach of sonographic follow-up was chosen. We review the typical sonographic characteristics in this rather new and rare entity, separating it from the more aggressive group of lesions in this location and age group, and suggest that the classic appearance should imply a wait-and-see approach, with sonographic follow-up studies rather than invasive intervention.

Early interim FDG PET/CT prediction of treatment response and prognosis in pediatric Hodgkin disease-added value of low-dose CT.

BACKGROUND: Interim 18F-FDG PET helps predict outcome and tailor treatment in adults with Hodgkin disease (HD). OBJECTIVE: The purpose of this study was to assess predictive values of interim 18F-FDG PET/CT in children with HD and to define the potential added value to interim PET of low-dose CT. MATERIALS AND METHODS: Children were prospectively enrolled August 2002-April 2007. PET/low-dose CT was performed at staging, after 2 cycles, at the end of treatment and during follow-up (mean 45 months). Treatment was unchanged regardless of interim results. PET and low-dose CT were read independently. RESULTS: Of 34 enrolled children (ages 3-17 years), 27 achieved complete response, 4 had progressive disease and 3 had relapse. Interim PET alone had positive and negative predictive values of 67% and 89%, respectively. Interim low-dose CT alone had positive and negative predictive values of 35% and 100%, respectively. Interim PET/CT had positive and negative predictive values of 75% and 96%, respectively. CONCLUSIONS: Early interim PET/CT was a good predictor of outcome. Integrated PET and low-dose CT improved the predictive value in children with HD.

Challenges in DICER1-Associated Lung Disease.

Pleuropulmonary blastoma (PPB) is a tumor occurring almost exclusively in infants and young children. This is the most common primary-lung malignancy in childhood. There is age-associated progression through a distinctive sequence of pathologic changes, from a purely multicystic lesion type I to a high-grade sarcoma type II and III. While complete resection is the cornerstone treatment for type I PPB, aggressive chemotherapy with a less favorable prognosis is associated with type II and III. DICER1 germline mutation is positive in 70% of children with PPB. Diagnosis is challenging, as it resembles congenital pulmonary airway malformation (CPAM) in imaging. Although PPB is an extremely rare malignancy, over the past five years we have encountered several children diagnosed with PPB in our medical center. Herein, we present some of these children and discuss diagnostic, ethical, and therapeutic challenges.

Pediatric negative pressure pulmonary edema: Case series and review of the literature.

INTRODUCTION: Negative pressure pulmonary edema (NPPE) is a potentially life-threatening complication that develops rapidly following acute upper airway obstruction. The condition is rare, dramatic but resolves quickly. Prompt recognition and appropriate supportive treatment may prevent unnecessary investigations and iatrogenic complications. METHODS: We describe a spectrum of etiologies and clinical manifestation of pediatric NPPE in our center and review of previous publications. CONCLUSION: The etiology for the development of NPPE in children has shifted over the years. Although dramatic in presentation, this type of pulmonary edema often resolves quickly with minimal support.