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Juvenile xanthogranuloma is a type of non-Langerhans cell histiocytic process that appears primarily in children and is described as a benign lesion. Although they typically present as a cutaneous lesion, it can also present in other areas including within the central nervous system. We report a 6-month-old infant who presented with seizure-like activity who was found to have a single intracranial mass within the right temporal area on magnetic resonance imaging of the head. The mass was biopsied and pathologically identified as a juvenile xanthogranuloma. In order to avoid the morbidity associated with a gross total resection, an intralesional steroid injection was utilized for treatment which our patient tolerated well. Intralesional steroid injection for the treatment of a symptomatic isolated intracranial juvenile xanthogranuloma has not been described but was successful for our patient.

Mosaic KRAS variants and other RASopathy genes cause oculoectodermal, encephalo-cranio-cutaneous lipomatosis, and Schimmelpenning-Feuerstein-Mims syndromes, and a spectrum of vascular malformations, overgrowth and other associated anomalies, the latter of which are only recently being characterized. We describe eight individuals in total (six unreported cases and two previously reported cases) with somatic KRAS variants and variably associated features. Given the findings of somatic overgrowth (in seven individuals) and vascular or lymphatic malformations (in eight individuals), we suggest mosaic RASopathies (mosaic KRAS variants) be considered in the differential diagnosis for individuals presenting with asymmetric overgrowth and lymphatic or vascular anomalies. We expand the association with embryonal tumors, including the third report of embryonal rhabdomyosarcoma, as well as novel findings of Wilms tumor and nephroblastomatosis in two individuals. Rare or novel findings in our series include the presence of epilepsy, polycystic kidneys, and T-cell deficiency in one individual, and multifocal lytic bone lesions in two individuals. Finally, we describe the first use of targeted therapy with a MEK inhibitor for an individual with a mosaic KRAS variant. The purposes of this report are to expand the phenotypic spectrum of mosaic KRAS-related disorders, and to propose possible mechanisms of pathogenesis, and surveillance of its associated findings.

MRI-based R2* mapping may enable reliable and rapid quantification of liver iron concentration (LIC). However, the performance and reproducibility of R2* across acquisition protocols remain unknown. Therefore, the objective of this work was to evaluate the performance and reproducibility of complex confounder-corrected R2* across acquisition protocols, at both 1.5 T and 3.0 T. In this prospective study, 40 patients with suspected iron overload and 10 healthy controls were recruited with IRB approval and informed written consent and imaged at both 1.5 T and 3.0 T. For each subject, acquisitions included four different R2* mapping protocols at each field strength, and an FDA-approved R2-based method performed at 1.5 T as a reference for LIC. R2* maps were reconstructed from the complex data acquisitions including correction for noise effects and fat signal. For each subject, field strength, and R2* acquisition, R2* measurements were performed in each of the nine liver Couinaud segments and the spleen. R2* measurements were compared across protocols and field strength (1.5 T and 3.0 T), and R2* was calibrated to LIC for each acquisition and field strength. R2* demonstrated high reproducibility across acquisition protocols (p > 0.05 for 96/108 pairwise comparisons across 2 field strengths and 9 liver segments, ICC > 0.91 for each field strength/segment combination) and high predictive ability (AUC > 0.95 for four clinically relevant LIC thresholds). Calibration of R2* to LIC was LIC = − 0.04 + 2.62 × 10−2 R2* at 1.5 T and LIC = 0.00 + 1.41 × 10−2 R2* at 3.0 T. Complex confounder-corrected R2* mapping enables LIC quantification with high reproducibility across acquisition protocols, at both 1.5 T and 3.0 T. • Confounder-corrected R2* of the liver provides reproducible R2* across acquisition protocols, including different spatial resolutions, echo times, and slice orientations, at both 1.5 T and 3.0 T. • For all acquisition protocols, high correlation with R2-based liver iron concentration (LIC) quantification was observed. • The calibration between confounder-corrected R2* and LIC, at both 1.5 T and 3.0 T, is determined in this study.

The use of mass spectrometry for protein identification and quantification in cerebrospinal fluid (CSF) is at the forefront of research efforts to identify and explore biomarkers for the early diagnosis and prognosis of neurologic disorders. Here we implemented a 4-plex N,N-dimethyl leucine (DiLeu) isobaric labeling strategy in a longitudinal study aiming to investigate protein dynamics in children with B-cell acute lymphoblastic leukemia (B-cell ALL) undergoing chemotherapy. The temporal profile of CSF proteome during chemotherapy treatment at weeks 5, 10-14, and 24-28 highlighted many differentially expressed proteins, such as neural cell adhesion molecule, neuronal growth regulator 1, and secretogranin-3, all of which play important roles in neurodegenerative diseases. A total of 63 proteins were significantly altered across all of the time points investigated. The most over-represented biological processes from gene ontology analysis included platelet degranulation, complement activation, cell adhesion, fibrinolysis, neuron projection, regeneration, and regulation of neuron death. We expect that results from this and future studies will provide a means to monitor neurotoxicity and develop strategies to prevent central nervous system injury in response to chemotherapy in children.

Immune thrombocytopenia (ITP) is characterized by isolated thrombocytopenia of unclear etiology. We present a unique case of an 8-year-old girl with chronic ITP who was subsequently diagnosed with T-lymphoblastic lymphoma at age 11. The clinical course was complicated by the occurrence of nonepileptiform events with bizarre behavior changes following the administration of nelarabine and intrathecal and high-dose systemic methotrexate. This case highlights an unusual co-occurrence of hematologic malignancy and chronic ITP in an otherwise healthy child. We speculate that underlying genetic or immunologic lesions may predispose a subset of pediatric ITP patients to the development of hematologic malignancies.

The purpose of this study was to ( a) determine the frequency of diagnostic errors in pediatric cancer, ( b) categorize errors, and ( c) underscore themes associated with misdiagnosis. This is a retrospective cohort study at a tertiary children’s hospital of 265 patients with new oncologic diagnoses. The diagnostic error rate was 28%. Compared with those with no diagnostic error, those in whom there was an error were more likely to have ( a) more visits before diagnosis ( P < .001), ( b) not been seen in an acute care setting ( P = .03), ( c) inappropriate treatment ( P < .001), and ( d) misinterpreted laboratory studies or imaging ( P < .001). Themes in diagnostic errors were lack of appropriate evaluation for persistent symptoms (47%), failure to recognize signs and symptoms suggestive of malignancy (45%), and misinterpretation of tests (8%). Clinicians should consider diagnostic evaluation for multiple visits for the same complaint or a constellation of signs and symptoms suggestive of malignancy.

Neurologic dysfunction during acute lymphoblastic leukemia treatment is commonly associated with chemotherapy. Nonchemotherapy contributions should be considered for persistent atypical symptoms. We describe a boy with acute lymphoblastic leukemia who developed recurrent fevers, diarrhea, progressive ataxia, and neuropsychiatric impairment during maintenance chemotherapy. He was found to have cytomegalovirus in his serum and colon, but not in his cerebrospinal fluid. Instead, his cerebrospinal fluid revealed oligoclonal bands not present in the serum, suggesting an autoimmune process. Prompt treatment with ganciclovir and immunotherapy resulted in marked clinical improvement. Early recognition and treatment of an autoimmune encephalitis is paramount for optimal clinical outcome.

We recently developed a novel amine-reactive mass-defect-based chemical tag, dimethyl pyrimidinyl ornithine (DiPyrO), for quantitative proteomic analysis at the MS(1) level. In this work, we further extend the application of the DiPyrO tag, which provides amine group reactivity, optical detection capability, and improved electrospray sensitivity, to quantify N-linked glycans enzymatically released from glycoproteins in the glycosylamine form. Duplex DiPyrO tags that differ in mass by 45.3 mDa were used to label the glycosylamine moieties of freshly released N-glycosylamines from glycoprotein standards and human serum proteins. We demonstrate that both MALDI-LTQ-Orbitrap and nano-HILIC LC/MS/MS Fusion Lumos Orbitrap platforms are capable of resolving the singly or multiply charged N-glycans labeled with mass-defect DiPyrO tags. Dynamic range of quantification, based on MS(1) peak intensities, was evaluated across 2 orders of magnitude. With optimized N-glycan release conditions, glycosylamine labeling conditions, and MS acquisition parameters, the N-glycan profiles and abundances in human serum proteins of cancer patients before and after chemotherapy were compared. Moreover, this study also opens a door for using well-developed amine-reactive tags for relative quantification of glycans, which could be widely applied.

Von Willebrand factor (VWF) contains binding sites for platelets and for vascular collagens to facilitate clot formation at sites of injury. Although previous work has shown that VWF can bind type IV collagen (collagen 4), little characterization of this interaction has been performed. We examined the binding of VWF to collagen 4 in vitro and extended this characterization to a murine model of defective VWF-collagen 4 interactions. The interactions of VWF and collagen 4 were further studied using plasma samples from a large study of both healthy controls and subjects with different types of von Willebrand disease (VWD). Our results show that collagen 4 appears to bind VWF exclusively via the VWF A1 domain, and that specific sequence variations identified through VWF patient samples and through site-directed mutagenesis in the VWF A1 domain can decrease or abrogate this interaction. In addition, VWF-dependent platelet binding to collagen 4 under flow conditions requires an intact VWF A1 domain. We observed that decreased binding to collagen 4 was associated with select VWF A1 domain sequence variations in type 1 and type 2M VWD. This suggests an additional mechanism through which VWF variants may alter hemostasis.

BACKGROUND AND PURPOSE: Intrinsic T1-hyperintense signal has recently been reported in the deep gray nuclei on brain MR imaging after multiple doses of gadolinium-based contrast agents. Most reports have included adult patients and excluded those undergoing radiation or chemotherapy. We investigated whether T1 shortening is also observed in children and tried to determine whether radiochemotherapy is a risk factor for this phenomenon. MATERIALS AND METHODS: In this single-center retrospective study, we reviewed clinical charts and images of all patients 18 years of age or younger with ≥4 gadobenate dimeglumine–enhanced MRIs for 6 years. Seventy-six children (mean age, 9.3 years; 60 unconfounded by treatment, 16 with radiochemotherapy) met the selection criteria (>4 MR imaging examinations; mean, 8). T1 signal intensity ratios for the dentate to pons and globus pallidus to thalamus were calculated and correlated with number of injections, time interval, and therapy. RESULTS: Among the 60 children without radiochemotherapy, only 2 had elevated T1 signal intensity ratios (n = 20 and 16 injections). Twelve of the 16 children with radiochemotherapy showed elevated signal intensity ratios. Statistical analysis demonstrated a significant signal intensity ratio change for the number of injections (P < .001) and amount of gadolinium (P = .008), but not for the interscan time interval (P = .35). There was a significant difference in the average signal intensity ratio change between those with and without radiochemotherapy (P < .001). Chart review revealed no new neurologic deficits in any patients, related to their underlying conditions and prior surgeries. CONCLUSIONS: Compared with published adult series, children show a similar pattern of T1 hyperintense signal changes of the dentate and globus pallidus after multiple gadobenate dimeglumine injections. The T1 signal changes in children may have a later onset but are accelerated by radiochemotherapy.

Purpose MR-based quantification of liver magnetic susceptibility may enable field strength-independent measurement of liver iron concentration (LIC). However, susceptibility quantification is challenging, due to nonlocal effects of susceptibility on the B0 field. The purpose of this work is to demonstrate feasibility of susceptibility-based LIC quantification using a fat-referenced approach. Methods Phantoms consisting of vials with increasing iron concentrations immersed between oil/water layers, and 27 subjects (9 controls/18 subjects with liver iron overload) were scanned. Ferriscan (1.5 T) provided R2-based reference LIC. Multiecho three-dimensional-SPGR (1.5 T/3 T) enabled fat-water, B0- and R2*-mapping. Phantom iron concentration (mg Fe L−1) was estimated from B0 differences (ΔB0) between vials and neighboring oil. Liver susceptibility and LIC (mg Fe g−1 dry tissue) was estimated from ΔB0 between the lateral right lobe of the liver and adjacent subcutaneous adipose tissue. Results Estimated phantom iron concentrations had good correlation with true iron concentrations (1.5 T:slope = 0.86, intercept = 0.72, r2 = 0.98; 3 T:slope = 0.85, intercept = 1.73, r2 = 0.98). In liver, ΔB0 correlated strongly with R2* (1.5 T:r2 = 0.86; 3 T:r2 = 0.93) and B0-LIC had good agreement with Ferriscan-LIC (slopes/intercepts nearly 1.0/0.0, 1.5 T:r2 = 0.67, slope = 0.93 ± 0.13, P ≈ 0.50, intercept = 1.93 ± 0.78, P ≈ 0.02; 3 T:r2 = 0.84, slope = 1.01 ± 0.09, P ≈ 0.90, intercept = 0.23 ± 0.52, P ≈ 0.68). Discussion Fat-referenced, susceptibility-based LIC estimation is feasible at both field strengths. This approach may enable improved susceptibility mapping in the abdomen. Magn Reson Med 70:648–656, 2013. © 2013 Wiley Periodicals, Inc.

MR-based quantification of liver magnetic susceptibility may enable field strength-independent measurement of liver iron concentration (LIC). However, susceptibility quantification is challenging, due to nonlocal effects of susceptibility on the B0 field. The purpose of this work is to demonstrate feasibility of susceptibility-based LIC quantification using a fat-referenced approach.Phantoms consisting of vials with increasing iron concentrations immersed between oil/water layers, and 27 subjects (9 controls/18 subjects with liver iron overload) were scanned. Ferriscan (1.5 T) provided R2-based reference LIC. Multiecho three-dimensional-SPGR (1.5 T/3 T) enabled fat-water, B0- and R2*-mapping. Phantom iron concentration (mg Fe L(-1)) was estimated from B0 differences (ΔB0) between vials and neighboring oil. Liver susceptibility and LIC (mg Fe g(-1) dry tissue) was estimated from ΔB0 between the lateral right lobe of the liver and adjacent subcutaneous adipose tissue.Estimated phantom iron concentrations had good correlation with true iron concentrations (1.5 T:slope = 0.86, intercept = 0.72, r(2) = 0.98; 3 T:slope = 0.85, intercept = 1.73, r(2) = 0.98). In liver, ΔB0 correlated strongly with R2* (1.5 T:r(2) = 0.86; 3 T:r(2) = 0.93) and B0-LIC had good agreement with Ferriscan-LIC (slopes/intercepts nearly 1.0/0.0, 1.5 T:r(2) = 0.67, slope = 0.93 ± 0.13, P ≈ 0.50, intercept = 1.93 ± 0.78, P ≈ 0.02; 3 T:r(2) = 0.84, slope = 1.01 ± 0.09, P ≈ 0.90, intercept = 0.23 ± 0.52, P ≈ 0.68).Fat-referenced, susceptibility-based LIC estimation is feasible at both field strengths. This approach may enable improved susceptibility mapping in the abdomen.

Mutations leading to hemophilia A by substitution of amino acids in coagulation factor VIII may provide important clues to the structure and function of this large and enigmatic protein. To efficiently find missense mutations, hemophiliacs with mild and moderately severe forms of the disease were surveyed. DNA samples from affected individuals were assayed for mutations by denaturing gradient gel electrophoresis following DNA amplification of target regions, which included all coding regions except for that of the dispensable B domain. Missense mutations were observed in 20 of the 34 patients examined, with identical mutations found in five pairs of patients. All mutations were found in the repetitive A and C domains. By aligning these domains in factor VIII with homologous domains in factor V, ceruloplasmin, and the mouse milk fat globule membrane protein, it was determined that most mutations change amino acids in areas of strong sequence conservation. Three additional mutations were detected, including a point mutation in an intron, a stop codon mutation, and a silent base change. Ten of the 18 different mutations discovered in this patient population are reported here for the first time. © 1992 Wiley-Liss, Inc.

Type 3 von Willebrand disease (VWD) is a rare bleeding disorder with markedly decreased or absent von Willebrand factor (VWF) protein, accompanied by a parallel decrease in VWF function and factor VIII (FVIII) activity. The goal of this study was to describe the population of patients enrolled in the USA Centers for Disease Control Universal Data Collection (UDC) study with type 3 VWD, defined as a VWF:Ag of

Health information technology (IT) has great potential to transform health care and inform population health goals in clinical research, quality measurement, and public safety. To fully realize the benefits of health IT for population health, we must focus on new models that maximize efficiency, encourage rapid learning, and protect patients’ privacy. In this paper we explore the advantages of a networked model for analyzing population health information, providing several examples. Although broadening the use of networked models is challenging, the societal benefits of a networked model merit continued exploration and the development of workable solutions.

As we move toward the creation of a networked health information environment, the potential of privacy intrusions increases, with potentially devastating impact on quality and access to healthcare. This paper describes the risks we face and proposes a framework to minimize those risks. In particular, it proposes nine principles to protect privacy in an information age.

For nationwide health information exchange to succeed, consumers must trust that their data are being managed responsibly. Regional and other networks that create the nationwide exchange should make consumer trust a priority that is factored into every decision they make. Connecting for Health's Common Framework offers a starting point.

Regional health information exchanges in California, Indiana, and Massachusetts have been collaborating on a prototype for a nationwide health information network, first under the auspices of the Markle Foundation's Connecting for Health program and now under contract to the Department of Health and Human Services' Office of the National Coordinator for Health Information Technology. Since mid-2004, this collaboration has evolved from a collection of regional efforts to a standards-driven cooperative and now to one of four prototype national networks fostered by federal efforts. This development reflects a maturing market for interoperability and integration in healthcare information technology, starting with RHIOs, and suggests one response to the industry's need for the type of plug-and-play information exchange available in other industries. The authors share their experiences and their views of how RHIOs and a Nationwide Health Information Network will further develop to make interoperable electronic health records a reality in coming years. The content of this article is solely the responsibility of the authors and does not necessarily represent the official view of the Office of the National Coordinator for Health Information Technology.

The fragmentation of our health care system, our need to accommodate the diversity of existing health information exchanges, the lack of consistent implementation of clinical information standards, and the need to protect patients' privacy and maintain trust are all challenges to overcome in achieving broad-scale interoperable health information exchange. We propose several steps to coordinate information sharing among regional and other networks through universal adherence to a basic framework of policies and standards. The critical policy action is the identification of a "common framework" of standards and policies, maintained by a new Standards and Policy Entity that reflects both public- and private-sector participation.

We report on a 4-year-old boy adopted from Paraguay who presented with an acute onset of thigh pain. Initial clinical, imaging, and histopathologic findings suggested florid osteomyelitis. However, the development of pancytopenia on intravenous antibiotics prompted further investigation and the ultimate diagnosis of Gaucher disease. In retrospect, characteristic changes on conventional radiographic and MR images, as well as growth of a contaminant organism, pointed to the diagnosis of pseudo-osteomyelitis rather than osteomyelitis.

Abstract 707FN2 Bernard-Soulier syndrome (BSS) is an extremely rare inherited bleeding disorder characterized by a defect of the GPIb/IX/V complex, which is essential for hemostasis, as the GPIbα subunit binds to subendothelial von Willebrand factor. Since the identification of the first mutation in 1990, almost one hundred cases carrying mutations in the GP1BA, GP1BB, and GP9 genes have been described. Most of the mutations prevent the coordinated association of the complex or binding to the von Willebrand factor. BSS is usually transmitted as a recessive trait with giant platelets and severe bleeding tendency. However, there are families with a dominant mild form, in which the affected individuals have only moderate macrothrombocytopenia and bleeding tendency. A correct definition of the clinical and laboratory features, together with accurate genotype/ phenotype correlation studies, remains essential for understanding the molecular basis of the disease and managing patients appropriately. Moreover, it is important to understand the variability of clinical manifestations. Since BSS is rare with an estimated prevalence of 1:1,000,000, an International Consortium has recently been established to collect a large series of cases and families worldwide. At present, the Consortium has been compiling data from 165 unrelated families, of which 50% have not been previously described. In this cohort, the molecular genetic testing reveals more than 30 novel mutations, confirming the wide spectrum of alterations responsible for the disease. Data from 65 unrelated families (69 patients) mainly from France, Italy and Japan show that 23 have mutations in GP9 and 29 in GP1BB. In the remaining 13 families, the defective gene is GP1BA. In agreement with the view that BSS is an extremely rare disease, 53 probands carried homozygous mutations, 10 are compound heterozygous, and 2 hemizygous because of a 22q11 deletion of the DiGeorge syndrome. The mean age of patients at diagnosis was 18 years (range 0–75 years) of which 27 were males and 38 females. Misdiagnosis of autoimmune thrombocytopenia was frequent and 26 patients were previously treated with steroids, intravenous immunoglobulins and/or splenectomy. Except two Japanese cases without any bleeding manifestations, patients presented with a variable bleeding diathesis measured by the World health Organization bleeding scale: grades 1, 2, 3 and 4 in 9, 18, 19 and 10 patients, respectively. The mean platelet count was 64×109/L (range 24–130) as determined by microscopy. In contrast, using a cell counter, thrombocytopenia was more severe (45×109/L; range 5–125). The mean platelet mean diameter was larger than in controls and varied from 2.9 to 7.5 mm. Ristocetin-induced platelet agglutination was absent or lower than 22% of normal response in all patients. Flow cytometry revealed a defective expression of the GPIb/IX/V expression in all patients. Correlating between expression data and gene affected, we found that the expression of GP1ba was often undetectable in patients with GP1BA mutations whereas it was higher, 8% and 17%, in patients with mutations of GP1BB and GP9, respectively. Instead, the GPIX mean level was 14%, 8% and 25% in patients with GP9, GP1BB and GP1BA mutations. The expression of GPV was higher than that of the other subunits, being more than 30% regardless of which gene was mutated. This is the largest cohort of BSS patients characterized to date. These patients together with the other 100 cases not yet included in the BSS database will enable correlations of the molecular genetic defects, receptor expression and clinical manifestations observed in BSS patients. Disclosures: Zieger: CSL Behring Hattersheim: Research Funding.