Neurodegenerative ( ND ) complications in Langerhans cell histiocytosis ( LCH ) are a late‐onset but dramatic sequelae for which incidence and risk factors are not well defined. Based on a national prospective registry of paediatric LCH patients, we determined the incidence rate of clinical ND LCH ( cND ‐ LCH ) and analysed risk factors, taking into account disease extent and molecular characteristics. Among 1897 LCH patients, 36 (1·9%) were diagnosed with a cND ‐ LCH . The 10‐year cumulative incidence of cND ‐ LCH was 4·1%. cND ‐ LCH typically affected patients previously treated for a multisystem, risk organ–negative LCH , represented in 69·4% of cND ‐ LCH cases. Pituitary gland, skin and base skull/orbit bone lesions were more frequent ( P < 0·001) in cND ‐ LCH patients compared to those without cND ‐ LCH (respectively 86·1% vs. 12·2%, 75·0% vs. 34·2%, and 63·9% vs. 28·4%). The ‘ cND susceptible patients’ ( n = 671) i.e., children who had experienced LCH disease with pituitary or skull base or orbit bone involvement, had a 10‐year cND risk of 7·8% vs. 0% for patients who did not meet these criteria. Finally, BRAF V 600E status added important information among these cND susceptible patients, with the 10‐year cND risk of 33·1% if a BRAF V 600E mutation was present compared to 2·9% if it was absent ( P = 0·002).

Osteosarcoma is the most common malignant bone tumor in adolescents and young adults. Most osteosarcomas are sporadic but the risk of osteosarcoma is also increased by germline variants in TP53, RB1 and RECQL4 genes. ATRX germline variations are responsible for the rare genetic disorder X-linked alpha-thalassemia mental retardation (ATR-X) syndrome characterized by severe developmental delay and alpha-thalassemia but no obvious increased risk of cancer. Here we report two children with ATR-X syndrome who developed osteosarcoma. Notably, one of the children developed two osteosarcomas separated by 10 years. Those two cases raise the possibility that ATRX germline variant could be associated with an increased risk of osteosarcoma.

Objective: To determine whether changing antiretroviral therapy (ART) during pregnancy because of concern about fetal risks led to poorer virological outcomes. Methods: All pregnancies in women with HIV-1 infection enrolled in the national multicenter prospective French Perinatal cohort at 14 week gestation or more were included between January 2005 and December 2015, if the mother was on ART at conception with a plasma viral load,50 copies/mL. The reasons for a change in the ART were analyzed according to treatment guidelines at the time of the pregnancy and defined as for safety concerns in the absence of reported maternal intolerance. Virological and pregnancy outcomes were studied by survival analysis and logistic regression adjusted for a propensity score established for each patient according to baseline characteristics. Results: Of 7079 pregnancies in the overall cohort, 1797 had ART at conception with a viral load,50 copies/mL before 14 week gestation. Of these, 22 changed regimens in the first trimester for intolerance, and 411 of the remaining 1775 (23%) solely for safety concerns. The proportion of change was higher when the initial treatment was not recommended in the national guidelines (OR adjusted: 23.1 [14.0-38.2]), than when it was an alternative option (ORa: 2.2 [1.3-3.7]), as compared to recommended first-line regimens. Treatment changes for safety concerns did not lead to poorer virological control, compared with pregnancies without such changes (19.3% vs. 15.6%, HRa: 1.0 [0.7-1.4]). Conclusions: Changing ART early in pregnancy to regimens considered safer for pregnancy, and neonatal health did not have a destabilizing effect on viral suppression.

The BRAFV600E mutation is reported in half of patients with Langerhans cell histiocytosis (LCH). This study investigated the detection of the BRAFV600E allele in circulating cell-free (ccf) DNA in a paediatric LCH cohort. Children with BRAFV600E -mutated LCH were investigated to detect ccf BRAFV600E at diagnosis (n = 48) and during follow-up (n = 17) using a picolitre-droplet digital PCR assay. At diagnosis, ccf BRAFV600E was positive in 15/15 (100%) patients with risk-organ positive multisystem (RO+ MS) LCH, 5/12 (42%) of patients with RO- MS LCH and 3/21 (14%) patients with single-system (SS) LCH (P < 0·001, Fisher's exact test). The positive BRAFV600E load was higher for RO+ patients (mean, 2·90%; range, 0·04-11·4%) than for RO- patients (mean, 0·16%; range, 0·01-0·39) (P = 0·003, Mann-Whitney U test). After first-line vinblastine-steroid induction therapy, 7/7 (100%) of the non-responders remained positive for ccf BRAFV600E compared to 2/4 (50%) of the partial-responders and 0/4 of the complete responders (P = 0·002, Fisher's exact test). Six children treated with vemurafenib showed a clinical response that was associated with a decrease in the ccf BRAFV600E load at day 15. Thus, ccf BRAFV600E is a promising biomarker for monitoring the response to therapy for children with RO+ MS LCH or RO- LCH resistant to first-line chemotherapy.

Purpose Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF V600E mutation occurs frequently, but clinical significance remains to be determined. Patients and Methods BRAF V600E mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. Results Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAF V600E mutation. Patients with BRAF V600E manifested more severe disease than did those with wild-type BRAF. Patients with BRAF V600E comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAF V600E mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAF V600E more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). Conclusion In children with LCH, BRAF V600E mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.

Summary The French national cohort of children with Langerhans cell histiocytosis ( LCH ) has included 1478 patients since it was established in 1983. LCH therapeutic strategies substantially changed in 1998, so we have divided the cohort into two 15‐year periods. Starting in 1998, therapy duration increased from 6 to 12 months, repeated induction therapy was performed in cases showing a poor response to the first induction with vinblastine and steroids, and refractory disease in a risk organ ( RO +) was treated with cladribine and cytarabine. A total of 483 (33%) patients were enrolled before 1998, and 995 (67%) after 1998. Five‐year survival was 96·6% (95% confidence interval: 95·4–97·5%) overall, improving from 92% pre‐1998 to 99% post‐1998 ( P < 0·001 adjusted to disease extent). This change was supported by an increase in 5‐year survival from 60% to 92% in the RO + group. Survival was particularly associated with cladribine and cytarabine among refractory RO + patients. Disease reactivation was slightly less frequent after 1998, due to better enrolment of single‐system patients, extended therapy duration, and more efficient second‐line therapy. The crude rates of endocrine and neurological sequelae (the most frequent sequelae) appeared to improve over time, but this difference was not observed when the analysis was stratified by disease extent.

Background Germline non‐polyalanine repeat expansion mutations in PHOX2B ( PHOX2B NPARM) predispose to peripheral neuroblastic tumors (PNT), frequently in association with other neurocristopathies: Hirschsprung disease (HSCR) or congenital central hypoventilation syndrome (CCHS). Although PHOX2B polyalanine repeat expansions predispose to a low incidence of benign PNTs, the oncologic phenotype associated with PHOX2B NPARM is still not known in detail. Methods We analyzed prognostic factors, treatment toxicity, and outcome of patients with PNT and PHOX2B NPARM. Results Thirteen patients were identified, six of whom also had CCHS and/or HSCR, one also had late‐onset hypoventilation with hypothalamic dysfunction (LO‐CHS/HD), and six had no other neurocristopathy. Four tumours were “poorly differentiated,” and nine were differentiated, including five ganglioneuromas, three ganglioneuroblastomas, and one differentiating neuroblastoma, hence illustrating that PHOX2B NPARM are predominantly associated with differentiating tumors. Nevertheless, three patients had stage 4 and one patient had stage 3 disease. Segmental chromosomal alterations, correlating with poor prognosis, were found in all the six tumors analyzed by array‐comparative genomic hybridization. One patient died of tumor progression, one is on palliative care, one died of hypoventilation, and 10 patients are still alive, with median follow‐up of 5 years. Conclusions Based on histological phenotype, our series suggests that heterozygous PHOX2B NPARM do not fully preclude ganglion cell differentiation in tumors. However, this tumor predisposition syndrome may also be associated with poorly differentiated tumors with unfavorable genomic profiles and clinically aggressive behaviors. The intrafamilial variability and the unpredictable tumor prognosis should be considered in genetic counseling. Pediatr Blood Cancer 2015; 9999:XX–XX © 2015 Wiley Periodicals, Inc.

Langerhans cell histiocytosis (LCH) is a multisystemic disease of childhood characterized by abnormal clonal proliferation of Langerhans cells, with skin lesions often involving flexural areas. We report 2 cases of eruptive nevi seen in skin folds of children with LCH.

Lipoblastoma is a rare benign adipocytic tumor that occurs usually in children. It can be difficult to distinguish a lipoblastoma from other lipogenic tumors. In such cases, the detection of a rearrangement of the PLAG1 gene by fluorescence in situ hybridization analysis is useful for characterizing a lipoblastoma. We present here a novel case of morphological infantile lipoblastoma showing a rearrangement of HMGA2 instead of the classical PLAG1 alteration. HMGA2 is the main target of clonal aberrations encountered in lipomas. This result supports the hypothesis that benign lipomatous tumors harboring PLAG1 or HMGA2 rearrangement could constitute a unique pathogenetic entity. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.

e20006 Background: When a child suffers from a cancer, parents worry about a probable hereditary cause. If a cancer occurs in the context of a genetic mutation, this can worsen the situation and make it more complicated. On the other hand, when the hereditary cause is rejected, the reinsurance for the family is clear. Methods: A partnership has been set between the Oncogenetics department in Centre Antoine Lacassagne Hospital in Nice and the Archet hospital in Nice (CHU) who takes in charge the children suffering from a cancer. Fifty little patients are seen every year in the paediatric oncology service at the Archet hospital (CHU). A consultation in oncogenetics is suggested to each family and insistently when a known syndrome is suspected. This consultation is also about to provide an other kind of care, in an other hospital, focused on the family with the aim to free of guilt the parents. Psychological care for families is in backdrop as they can express freely their questioning. Results: Twenty one families have been seen and fifteen different types of cancers recorded: mostly haematological cancers and neurological cancers. For each family, a pedigree was drawn. Data concerning the child’s disease and familial data were gathered. Most of the time, these information led to reassure the families. Therefore two Li and Fraumeni syndrome have been evoked. The first child suffered from a plexus choroid carcinoma and the second one had two distinct cancers: a nephroblastoma and a medulloblastoma. On the other hand, 2 children had had a LAL within a family with history of malignant haemopaties. Interestingly, 3 children with isolated LAL in the family where suggested to contribute to a research trial. Conclusions: This oncogenetic pediatric consultation allows to detect known hereditary predisposition syndromes and to contribute to researches in paediatric oncology. Above all, this strong bound between the oncogentics department and the pediatric oncology service permitted to reach an objective: offering families a specialised consultation with psychological support with a gap from disease.

Progressive liver toxicity is a concern in HIV-infected patients. Although liver biopsy remains the gold standard for liver assessment, its invasiveness, sampling errors, variability in interpretation and expense do not make it an ideal routine follow-up exam. During the last decade, new non-invasive tools have been developed for the assessment of hepatic fibrosis in HCV and HIV/HCV co-infected patients.

OBJECTIVES:: Progressive liver injury is a concern in HIV-infected children exposed to long-term antiretroviral drugs and to the cytopathic effect of HIV. Yet liver biopsy is usually considered too invasive to be repeated in these patients. The aims of this study are to evaluate the feasibility of noninvasive hepatic investigations in HIV-1-infected children, assess the prevalence of signs of liver affection, and analyse the influence of the HIV disease severity and the exposure to antiretroviral therapy.MATERIALS AND METHODS:: A cross-sectional study conducted in 26 HIV-1 vertically infected children ages 8 to 18 years old. Liver function was assessed with standard serum biochemical markers, FibroTest, ActiTest, SteatoTest, Forns index, aspartate aminotransferase to platelet ratio index, ultrasound, and Fibroscan.RESULTS:: Nineteen (>60%) children had signs of liver affection on at least 1 of the test results: 13 (50%) had elevated liver enzymes, 15 (63%), 8 (33%), 5 (21%), and 5 (21%) had abnormal FibroTest, ActiTest, Forns index, and aspartate aminotransferase to platelet ratio index results, respectively. Four children (17%) had mild liver steatosis on ultrasound. Fibroscan measures were significantly higher in patients than in age-matched healthy children. Patients with elevated Fibroscan measures also had significantly higher FibroTest results. Age, HIV stage N in the Centers for Disease Control and Prevention classification and exposure duration to nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor drugs were the main risk factors for hepatotoxicity.CONCLUSIONS:: More than half of our population of HIV-infected children had biological and/or radiological signs of liver affection. Regular follow-up of liver function is necessary in these patients, which is now possible with noninvasive procedures.

Natural selection is a major force behind the shaping of patterns of human genome variability. Inferences concerning the action of selection in the human genome provide a powerful tool for predicting regions of the genome of major functional importance. Genetic variants influencing human susceptibility to disease are likely to affect the fitness of the organism, unless the disease concerned begins late in the life. There is therefore an intimate relationship between disease and selection that can be exploited for the identification of candidate disease loci. To date, some of the strongest evidence for selection in the human genome has been obtained for genes involved in the immune response or host-pathogen interactions. Indeed, before the advent of antibiotics and vaccines, infectious diseases have been paramount among the threats to health and survival for most of human evolutionary history. I will review our most recent studies searching for the footprints of natural selection in the human genome. These studies, which go from global genomewide scans to more fine-tuned analyses in specific genes, highlight how the identification of selected loci or variants may provide insight into host genes or pathways playing an important role in pathogen resistance. For example, we have shown that natural selection has significantly driven the processes of population differentiation in modern human populations. Specifically, we have identified a number of genes under strong geographicallyrestricted positive selection, some of them involved in hostpathogen interactions. In addition, I will present our most recent data on the Toll-like receptor (TLR) signalling pathway. Our evolutionary data indicate that the different members of TLR family differ in their ecological relevance and increase our understanding of how variation in these genes results in different contributions to the outcome of infectious diseases. More generally, I will show how the identification of the extent and type of selection acting upon human genes involved in hostpathogen interactions make it possible to define the redundant and non-redundant functions of individual immunity-related genes in the natural setting. L2 Perspectives on pathogenesis and prevention of congenital herpes virus infection Mark R Schleiss Pediatric Infectious Diseases, University of Minnesota Medical School and Center for Infectious Diseases and Microbiology Translational Research, Minneapolis, MN, USA

Today, bone scintigraphy still remains a mainstay imaging modality for the baseline work-up, the follow-up and the diagnosis of recurrence by osteomedullary metastases in Ewing's sarcoma (ES). We describe the case of a 13-year-old teenager diagnosed with an Ewing's sarcoma of mandible associated to a right sixth rib metastasis. Initial bone scintigraphy displayed a mandibular hot spot related to the tumour. Initial therapy consisted of chemotherapy according to EURO EWING combining chemotherapy, autologous stem cells transplantation and surgery. Clinical and imaging proved normal for the two first years of follow-up. Then, the patient reported a sternal pain at night which pointed to recurrence and triggered a new imaging work-up. The bone scintigraphy only showed a solitary sternal cold spot. However, thoracic CT and MRI evidenced an extended osteolytic space-occupying lesion of sternal manubrium with cortical rupture. Moreover, cross-sectional imaging disclosed numerous lesions in spine. In order to complete the discrepant work-up, the patient benefited from a FDG-(18F) PET/CT exam. PET/CT displayed multiple osteomedullary metastases scattered over sternum, humeral diaphyses, thoracolumbar spine, sacrum and right femur. There was no associated visceral spread. This case report exemplifies PET/CT lesion-based sensitivity of osteomedullary metastases surpassing bone scintigraphy in ES. This difference likely stems from a medullary intertrabecular proliferation, igniting only limited cortical osteoblastic reaction. These features explain the nickname of pass through walls conferred to ES by pathologists. (C) 2009 Elsevier Masson SAS. All rights reserved.

First described in HIV-infected patients who recently initiated highly active antiretroviral therapy, the immune reconstitution inflammatory syndrome (IRIS) is best characterized as a collection of inflammatory disorders triggered by rapid resolution of immunosuppression. Treatment of IRIS is a clinical challenge due to the variety of clinical presentations and the presence of multiple pathogens capable of causing the syndrome. Hepatosplenic candidiasis, an uncommon form of invasive Candida species infection, was recently suggested to belong to the spectrum of fungus-related IRIS. We report 2 cases of probable hepatosplenic candidiasis according to the guidelines of the European Organization for Research and Treatment of Cancer and the Mycosis Study Group, occurring in pediatric patients with acute leukemia during rapid neutrophil recovery after cytotoxic chemotherapy. In both cases, abdominal computed tomography scan revealed multiple hepatic micronodules, and liver biopsy showed nonspecific granulomatous lesions. Hepatosplenic candidiasis symptoms (fever, nausea and vomiting, abdominal pain) resolved within 2 days after adjunction of corticosteroid therapy to antifungal treatment. Inflammatory markers and related radiologic abnormalities decreased or disappeared within 1 month. Recovery of neutrophil count in a context of hepatosplenic candidiasis may result in a heightened inflammatory response. Corticosteroid therapy in this setting is associated with prompt resolution of the symptoms.

We present one case of bone-Langerhans' cell histiocytosis in a three-year-old male child presenting osseous lesions in the skull and the femur, which are very frequent localisations in histiocytosis. Bone scintigraphy is useful for both initial staging and follow-up associated with other imaging modalities. (c) 2008 Elsevier Masson SAS. All rights reserved.