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ObjectiveTurner Syndrome is associated with several phenotypic conditions associated with a higher risk of subsequent comorbidity. We aimed to evaluate the prevalence of congenital malformations and the occurrence of age-related comorbid conditions and to determine whether the frequencies of congenital and acquired conditions depend on X chromosome gene dosage, as a function of karyotype subgroup.Design and methodsThis national retrospective observational cohort study includes 1501 patients. We evaluated the prevalence of congenital malformations and the cumulative incidence of subsequent specific comorbidities at five-year intervals, from the ages of 10 to 30 years, with stratification by karyotype subgroup: 45,X (n = 549), 45,X/46,isoXq (n = 280), 46,X,r(X)/46,XX (n = 106), 45,X/46,XX (n = 221), presence of Y (n = 87).ResultsMedian age was 9.4 (3.7–13.7) years at first evaluation and 16.8 (11.2–21.4) years at last evaluation. Congenital heart (18.9%) malformations were more frequent in 45,X patients, and congenital renal (17.2%) malformations were more frequent in 45,X, 45,X/46,isoXq and 46,X,r(X)/46,XX patients than in those with 45,X/46,XX mosaicism or a Y chromosome (P ConclusionThese data suggest that X gene chromosome dosage, particularly for Xp genes, contributes to the risk of developing comorbidities.

Resume • Di@betomobile est une equipe mobile multi-professionnelle qui intervient en cooperation avec les services pediatriques des territoires nord et est de l’Ile-de-France afin de completer l’offre educative faite aux enfants diabetiques et leur entourage. • Elle propose une Education Therapeutique (ETP) de groupe au cours de programmes elabores a partir de l’analyse des besoins des equipes soignantes, des enfants et de leur famille. Les methodes d’apprentissage et les outils educatifs sont adaptes a l’evolution des jeunes patients ; les besoins sont reevalues regulierement, depuis le diagnostic jusqu’a la transition vers les services adultes.

Resume Les inhibiteurs selectifs de recapture de la serotonine (ISRS) ont deja ete associes chez les adultes a des effets secondaires osseux, mais leur impact sur la croissance osseuse a ete tres peu etudie chez les enfants, malgre des resultats d’etudes experimentales demontrant un role fonctionnel de la serotonine dans le metabolisme osseux. Nous avons effectue une revue de la litterature sur le lien entre serotonine et metabolisme osseux, en incluant les etudes experimentales et les etudes cliniques. Les donnees experimentales ont demontre que les ISRS affectent la croissance osseuse, a travers une reduction de la masse osseuse, une alteration de l’architecture osseuse et une diminution des proprietes mecaniques, par le biais de l’inhibition du transporteur serotoninergique, 5-HTT, present dans les cellules osseuses. Les donnees cliniques ont montre chez les hommes âges et les femmes en post-menopause une association entre les ISRS et une densite osseuse diminuee. Chez l’enfant, l’effet des ISRS sur la croissance osseuse est documente par des rapports de cas et des etudes transversales. Comme les ISRS sont prescrits en population pediatrique dans certaines indications necessitant des traitements au long cours, il est urgent de mieux etudier l’implication de ces molecules dans la croissance osseuse chez les enfants afin de proposer une surveillance et des modalites de prevention adaptees.

ObjectiveAdult height deficit seen in Turner syndrome (TS) originates, in part, from growth retardation in utero and throughout the first 3 years of life. Earlier diagnosis enables earlier therapeutic intervention, such as with recombinant human GH (r-hGH), which may help to prevent growth retardation. In this open-label, multicentre phase III study, we investigated efficacy and safety in r-hGH treatment in young girls with TS.Subjects and methodsGirls (n=61) aged n=51) comprising untreated, age- and height-matched girls with TS. The main outcome measure was change in height SDS (H-SDS). Other measures included changes in height velocity SDS, IGF1 levels and glucose metabolism.ResultsAfter 4 years, a gain in mean H-SDS of 1.0 SDS (from −2.33±0.73 to −1.35±0.86 SDS) was observed with r-hGH treatment, in contrast to the decrease in mean H-SDS of 0.3 SDS in the control group (from −2.09±0.81 to −2.44±0.73 SDS; PConclusionEarly treatment with r-hGH helps to prevent natural evolution towards short stature in most girls with TS. IGF1 levels and glucose metabolism should be monitored routinely during r-hGH therapy.

Although only 39% of patients with wrist trauma have sustained a fracture, the majority of patients is routinely referred for radiography. The purpose of this study was to derive and externally validate a clinical decision rule that selects patients with acute wrist trauma in the Emergency Department (ED) for radiography. This multicenter prospective study consisted of three components: (1) derivation of a clinical prediction model for detecting wrist fractures in patients following wrist trauma; (2) external validation of this model; and (3) design of a clinical decision rule. The study was conducted in the EDs of five Dutch hospitals: one academic hospital (derivation cohort) and four regional hospitals (external validation cohort). We included all adult patients with acute wrist trauma. The main outcome was fracture of the wrist (distal radius, distal ulna or carpal bones) diagnosed on conventional X-rays. A total of 882 patients were analyzed; 487 in the derivation cohort and 395 in the validation cohort. We derived a clinical prediction model with eight variables: age; sex, swelling of the wrist; swelling of the anatomical snuffbox, visible deformation; distal radius tender to palpation; pain on radial deviation and painful axial compression of the thumb. The Area Under the Curve at external validation of this model was 0.81 (95% CI: 0.77-0.85). The sensitivity and specificity of the Amsterdam Wrist Rules (AWR) in the external validation cohort were 98% (95% CI: 95-99%) and 21% (95% CI: 15%-28). The negative predictive value was 90% (95% CI: 81-99%). The Amsterdam Wrist Rules is a clinical prediction rule with a high sensitivity and negative predictive value for fractures of the wrist. Although external validation showed low specificity and 100 % sensitivity could not be achieved, the Amsterdam Wrist Rules can provide physicians in the Emergency Department with a useful screening tool to select patients with acute wrist trauma for radiography. The upcoming implementation study will further reveal the impact of the Amsterdam Wrist Rules on the anticipated reduction of X-rays requested, missed fractures, Emergency Department waiting times and health care costs

Gender dysphoria, originally called gender identity disorder, is characterized by the dissociation between one's expressed gender and the gender of rearing as assigned at birth, which generates significant clinical distress and social, academic, and other important forms of isolation. This state is also known as transgender or transsexualism and is recognized as a medical disease. Adults with gender dysphoria can benefit from psychological, medical, and surgical care. However, gender dysphoria rarely occurs in adulthood but rather emerges in childhood or adolescence, generating deep social and academic difficulties, especially at puberty. For the last 10years, the management of gender dysphoria in children and adolescents has developed in several countries, specifically in Europe, but remains under-recognized in France. Since 2013, several pediatric psychiatry and endocrinology departments have initiated a multidisciplinary evaluation and management approach for these patients. This article reviews the clinical criteria helping diagnose gender dysphoria and presents the different steps in the assessment and management of these patients in accordance with international guidelines.

Editors' Note: WriteClick this week centers on controversy over the recent article, “Growth hormone treatment for childhood short stature and risk of stroke in early adulthood.” Drs. Linglart et al. and Drs. Geffner et al. argue strongly for caution in warning patients of short stature treated with growth hormone of a possible increased stroke risk based on the study's findings, the former group pointing to previous false alarms and issues of bias, and the latter group questioning the study's data collection and analysis. Both cast doubt on the appropriateness of the study's chosen control population. Authors Coste et al. defend their methodology and assert that all available information regarding risks and benefits should be communicated to patients. —Megan Alcauskas, MD, and Robert C. Griggs, MD We read with interest the article by Poidvin et al.1 In 2012, an article from the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) study group warned of cancer and mortality in growth hormone (GH)–treated patients that turned out to be flawed due to inappropriate controls of normal height.2 The largest SAGhE cohort did not detect any increase in mortality or cerebrovascular events, a report agreed and cosigned by the French team.3 Given this deplorable experience, Poidvin et al.1 …

La puberte precoce se definit comme l’apparition des signes cliniques de la puberte, avant l’âge de 8 ans chez la fille et de 9,5 ans chez le garcon. Cependant, le debut de la puberte, et donc la definition de la puberte precoce peuvent varier en fonction de variations environnementales (seculaire, adoption, absence du pere), nutritionnelles (indice de masse corporelle), constitionnelles (genetique, ethnie) [1–3].

Cholesteryl ester storage disease (CESD) and Wolman disease (WD) are both autosomal recessive disorders associated with reduced activity and genetic defects of lysosomal acid lipase (LAL). The strikingly more severe course of WD is caused by genetic defects of LAL that leave no residual enzymatic activity. Mutations at the exon 8/intron 8 transition of the LAL gene have been identified in several CESD and WD patients and are responsible for the manifestation of the disease. We have determined the genetic defect in a 3-month-old boy of African origin affected by WD. No enzymatic activity of the lysosomal acid lipase was detectable in white blood cells and cultured fibroblasts. Analysis of his LAL cDNA and genomic DNA revealed that he was homozygous for a mutation at position -3 of the exon 8 splice donor site. A C-->T transition leads to a nonsense codon and to a premature termination of the LAL protein at amino acid 277. Due to this mutation, a shorter LAL mRNA species was also generated that lacked exon 8 and was deficient of the nonsense codon. As a consequence, the protein synthesis proceeded to the natural termination codon, but the enzyme generated had an internal deletion of 24 amino acids (254-277) and was also inactive. These findings, together with our previous observations when analyzing the mutations in WD and CESD patients lead to the conclusion that the more severe WD is due to mutations that absolutely abolish lysosomal acid lipase (LAL) enzyme activity and the cholesteryl ester storage disease phenotype is due to mutations that allow some residual LAL activity to be manifested.

Immediate total body computed tomography (CT) scanning has become important in the early diagnostic phase of trauma care because of its high diagnostic accuracy. However, literature provides limited evidence whether immediate total body CT leads to better clinical outcome then conventional radiographic imaging supplemented with selective CT scanning in trauma patients. The aim of the REACT-2 trial is to determine the value of immediate total body CT scanning in trauma patients.The REACT-2 trial is an international, multicenter randomized clinical trial.All participating trauma centers have a multi-slice CT scanner located in the trauma room or at the Emergency Department (ED). All adult, non-pregnant, severely injured trauma patients according to predefined criteria will be included. The intervention group will receive a contrast-enhanced total body CT scan (head to pelvis) during the primary survey. The control group will be evaluated according to local conventional trauma imaging protocols (based on ATLS guidelines) supplemented with selective CT scanning. Primary outcome will be in-hospital mortality. Secondary outcomes are differences in mortality and morbidity during the first year post trauma, several trauma work-up time intervals, radiation exposure, general health and quality of life at 6 and 12 months post trauma and cost-effectiveness.The REACT-2 trial is the first multicenter randomized clinical trial that will provide evidence on the value of immediate total body CT scanning during the primary survey of severely injured trauma patients.

Immediate total body computed tomography (CT) scanning has become important in the early diagnostic phase of trauma care because of its high diagnostic accuracy. However, literature provides limited evidence whether immediate total body CT leads to better clinical outcome then conventional radiographic imaging supplemented with selective CT scanning in trauma patients. The aim of the REACT-2 trial is to determine the value of immediate total body CT scanning in trauma patients. The REACT-2 trial is an international, multicenter randomized clinical trial. All participating trauma centers have a multi-slice CT scanner located in the trauma room or at the Emergency Department (ED). All adult, non-pregnant, severely injured trauma patients according to predefined criteria will be included. The intervention group will receive a contrast-enhanced total body CT scan (head to pelvis) during the primary survey. The control group will be evaluated according to local conventional trauma imaging protocols (based on ATLS guidelines) supplemented with selective CT scanning. Primary outcome will be in-hospital mortality. Secondary outcomes are differences in mortality and morbidity during the first year post trauma, several trauma work-up time intervals, radiation exposure, general health and quality of life at 6 and 12 months post trauma and cost-effectiveness. The REACT-2 trial is the first multicenter randomized clinical trial that will provide evidence on the value of immediate total body CT scanning during the primary survey of severely injured trauma patients

Turner syndrome is a rare genetic disorder, affecting approximately one in 2500 live-born female, due to total or partial absence of the X chromosome. Typical clinical features are short stature and premature ovarian failure and less constantly phenotypic particularities such as congenital malformations, acquired cardiovascular, otological (hearing impairment), autoimmune and metabolic pathologies. The phenotype is highly variable with slight or even normal phenotype. Several studies have shown that growth hormone treatment improves adult height. The possibility of pregnancies after oocyte donation highlights the high risk of these pregnancies requiring a careful follow-up, especially in terms of cardiovascular issues. Although the quality of life seems similar to the normal population, the presence of cardiovascular and otological diseases, and delayed feminisation are associated with an impaired quality of life. Early diagnosis and regular screening for potentials associated complications are essential in the medical follow-up of these patients. The recent publication of recommendations should lead to an optimization and harmonisation of the medical practices and follow-up from paediatric age to adulthood, a lowering morbidity and self-esteem improvement. The interest of ovarian cryopreservation at an early age in these patients is under investigation.

We have created a new transgenic model in which the human Epstein-Barr virus receptor, CR2 (CD21), has been expressed in pancreatic beta-cells. Mice derived from three transgenic founders bred into H-2b (C57BL/6) or H-2k (CBA) genetic backgrounds did not become spontaneously diabetic. After transplantation of CR2-expressing islets under the kidney capsule of genetically matched recipients, a histologic picture of peri-insulitis was found. However, animals did not manifest cellular invasion of the islets, destruction of the islets, or diabetes for at least 230 days. Significant numbers of both T and B lymphocytes were found in the cell population surrounding the islets. A pronounced serologic response to CR2 was also present and appeared to precede the onset of peri-insulitis. Thus, in this model, we have separated the process of diabetes induction into at least two phases. One is associated with peri-islet infiltration and an antibody response. However, at least one second signal is likely necessary for the process of islet destruction to follow.

Le syndrome de Turner a un retentissement sur differents aspects de la croissance, du developpement, de la puberte et de la fertilite, entrainant des consequences sur le vecu psychosocial. La qualite de vie est un concept difficile a mesurer, mais important a formaliser pour l’evaluer de facon structuree. Cette evaluation permet en effet d’essayer de mieux cerner les aspects prioritaires a prendre en compte pour ameliorer la qualite de vie des femmes ayant un syndrome de Turner, et de mesurer l’impact de la prise en charge medicale, notamment le traitement par hormone de croissance et l’induction pubertaire.

We stably expressed human complement receptor 2 ([CR2] CD21 C3d/Epstein-Barr virus [EBV] receptor) on the rat insulinoma cell line RINm5F with a recombinant retroviral vector. CR2-expressing RINm5F cells secreted 78–33% less insulin than parental cells or cells transduced with an antisense vector and could be infected with high-titer EBV. We tested whether human CR2 expression on RINm5F cells would affect tumorigenesis after transplantation to syngeneic New England Deaconess Hospital rats. Non-CR2–expressing antisense-transduced RINm5F cells rapidly grew tumors and caused hypoglycemia, hyperinsulinemia, and the death of the animals after 15.7 ± 0.7 days. CR2-expressing RINm5F cells were infiltrated by mononuclear cells at an early stage and eventually caused noninfiltrated tumors and the death of the animals after 33.0 ± 0.4 days. These tumors were CR2− and are believed to have arisen from a minor CR2− population of tumor cells. The pancreatic islets were histologically normal at all time points. We conclude that expression of a xenoantigen on a rat insulinoma cell line induces an immune response in syngeneic rats but does not result in breakage of tolerance to parental or revertant cells.

The predicted amino acid sequence of human complement receptor 2 (CR2, CD21, C3d,g/Epstein-Barr virus receptor) and its genetic murine homologue are approximately 70% identical. The sequence of each consists of a linear array of 60-70 amino acid repeats designated short consensus repeats (SCRs). Although they share significant sequence identity, a major difference in the activities of these two proteins has been believed to be the ability of human, but not mouse, CR2 to mediate Epstein-Barr virus (EBV) infection of B lymphocytes. In order to formally address this question and to directly compare the activities of the CR2 protein of each species, we have expressed recombinant mouse CR2 (rMCR2) in a human K562 erythroleukemia cell line background. We have found that rMCR2 reacts with two previously described rat anti-MCR2 monoclonal antibodies (mAbs), 7G6 and 7E9, but not mAb 8C12, which recognizes only mouse complement receptor 1. rMCR2 rosettes with erythrocytes bearing mouse and human C3d,g and binds glutaraldehyde cross-linked human C3d,g with a similar Kd as human CR2 (HCR2). rMCR2 does not bind EBV. By using this observation and constructing chimeras bearing portions of MCR2 on a HCR2 background, we have been able to define unique sequences in HCR2 SCRs 1 and 2 important in the interaction with both mAb OKB7, which blocks EBV binding and infection, and with EBV. In addition, by using blocking peptides derived from HCR2 sequence, we have identified a second distinct region in SCR2 important in EBV binding. Therefore, within the first two SCRs of HCR2 are multiple distinct sites of interaction with EBV and with mAb OKB7.

The relationships between functional, biochemical, and genetic homologues of human and mouse C receptors 1 (CR1) and 2 (CR2) are incompletely understood. We have isolated and characterized a partial mouse CR2 cDNA clone and determined the exon-intron organization of the gene encoding it. Together they predict a form of mouse CR2 highly identical to the 15 short consensus repeat form of human CR2. Strong similarities in genomic organization and exon-intron junctions indicate that this mouse gene and human CR2 are evolutionary homologues. A polyclonal rabbit anti-mouse CR2 fusion protein, BRN-1, was prepared. BRN-1 immunoprecipitates bands of 155 to 160 kDa under nonreducing conditions in mouse CR2 expressing B cell lines. In mouse spleen a doublet of 155 kDa and 190 kDa under nonreducing and 165 and 205 kDa under reducing conditions is recognized by immunoprecipitation and Western blot analysis. Staphylococcus aureus V8 protease maps of these two proteins show many shared bands. Crossed immunoprecipitation using BRN-1 and 7E9, a previously described mAb reported to identify the 190-kDa mouse CR1 and a smaller 150-kDa protein, indicates that both antibodies react with the same proteins. Therefore, by using BRN-1 we have now linked the genetic mouse CR2 to its functional, biochemically characterized gene product. The observation that BRN-1 also recognizes a second 190-kDa mouse protein defined functionally as a homologue of human CR1, and that these proteins have very similar peptide maps, provides strong evidence that these two proteins are expressed by a single mouse CR2/CR1 transcription unit.

The structure of CR2, the human C3d,g/EBV receptor (CR2/CD21) consists of 15 or 16 60-70 amino acid repeats called short consensus repeats (SCRs) followed by a transmembrane and a 34-amino acid intracytoplasmic domain. Functions of CR2 include binding the human complement component C3d,g when it is covalently attached to targets or cross-linked in the fluid phase. In addition, CR2 binds the Epstein-Barr virus (EBV) and mediates internalization of EBV and subsequent infection of cells. In order to explore functional roles of the repetitive extracytoplasmic SCR structure and the intracytoplasmic domain of CR2, we have created truncated CR2 (rCR2) mutants bearing serial deletions of extracytoplasmic SCRs and also the intracytoplasmic tail. We then stably transfected these rCR2 mutants into two cell lines, murine fibroblast L cells and human erythroleukemic K562 cells. Phenotypic analysis of these expressed mutants revealed that 1) The C3d,g- and EBV-binding sites are found in the two amino-terminal SCRs of CR2, 2) expression of SCRs 3 and 4 is further required for high affinity binding to soluble cross-linked C3d,g, 3) the intracytoplasmic domain of CR2 is not required for binding C3d,g or EBV but is necessary for internalization of cross-linked C3d,g as well as for EBV infection of cells, 4) monoclonal anti-CR2 antibodies with similar activities react with single widely separated epitopes, and 5) no functional roles can yet be clearly assigned to SCRs 5-15, as rCR2 mutants not containing these SCRs show no major differences from wild-type rCR2 in binding or internalizing cross-linked C3d,g or mediating EBV binding and infection.

Objectives: The objective of this work is to provide updated guidelines for the evaluation and treatment of girls and women with Turner syndrome (TS). Participants: The Turner Syndrome Consensus Study Group is a multidisciplinary panel of experts with relevant clinical and research experience with TS that met in Bethesda, Maryland, April 2006. The meeting was supported by the National Institute of Child Health and unrestricted educational grants from pharmaceutical companies. Evidence: The study group used peer-reviewed published information to form its principal recommendations. Expert opinion was used where good evidence was lacking. Consensus: The study group met for 3 d to discuss key issues. Breakout groups focused on genetic, cardiological, auxological, psychological, gynecological, and general medical concerns and drafted recommendations for presentation to the whole group. Draft reports were available for additional comment on the meeting web site. Synthesis of the section reports and final revisions were reviewed by e-mail and approved by whole-group consensus. Conclusions:Wesuggest that parents receiving a prenatal diagnosis of TS be advised of the broad phenotypic spectrum and the good quality of life observed in TS in recent years. We recommend that magnetic resonance angiography be used in addition to echocardiography to evaluate the cardiovascular system and suggest that patients with defined cardiovascular defects be cautioned in regard to pregnancy and certain types of exercise. We recommend that puberty should not be delayed to promote statural growth. We suggest a comprehensive educational evaluation in early childhood to identify potential attention-deficit or nonverbal learning disorders. We suggest that caregivers address the prospect of premature ovarian failure in an open and sensitive manner and emphasize the critical importance of estrogen treatment for feminization and for bone health during the adult years. All individuals with TS require continued monitoring of hearing and thyroid function throughout the lifespan. We suggest that adults with TS be monitored for aortic enlargement, hypertension, diabetes, and dyslipidemia. (J Clin Endocrinol Metab 92: 10–25, 2007) TURNER SYNDROME (TS) affects approximately one in 2500 live-born females (1). This disorder presents the clinician with a challenging array of genetic, developmental, endocrine, cardiovascular, psychosocial, and reproductive issues. There have been important advances in each of these arenas since publication of the previous recommendations for the care of girls and women with TS (2). This paper is based on the proceedings of a multidisciplinary international conference sponsored by the National Institute of Child Health and Human Development (NICHD) in April 2006. Discussions at this conference and the ensuing recommendations have been based upon recent, peer-reviewed scientific publications. However, there are very few TS studies that would qualify as guidance for evidence-based recommendations, and hence

Type 1 diabetes is characterized by the infiltration of inflammatory cells into pancreatic islets of Langerhans, followed by the selective and progressive destruction of insulin-secreting beta cells. Islet-infiltrating leukocytes secrete cytokines such as IL-1β and IFN-γ, which contribute to beta cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-κB is an important component of the signal triggering beta cell apoptosis. To study the in vivo role of NF-κB in beta cell death, we generated a transgenic mouse line expressing a degradation-resistant NF-κB protein inhibitor (ΔNIκBα), acting specifically in beta cells, in an inducible and reversible manner, by using the tet-on regulation system. In vitro , islets expressing the ΔNIκBα protein were resistant to the deleterious effects of IL-1β and IFN-γ, as assessed by reduced NO production and beta-cell apoptosis. This effect was even more striking in vivo , where nearly complete protection against multiple low-dose streptozocin-induced diabetes was observed, with reduced intraislet lymphocytic infiltration. Our results show in vivo that beta cell-specific activation of NF-κB is a key event in the progressive loss of beta cells in diabetes. Inhibition of this process could be a potential effective strategy for beta-cell protection.

The Authors report two cases of APECED syndrome (Auto-immune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy) revealed by hyponatremia due to isolated mineralocorticoids deficiency. Such cases illustrate the variable endocrine features revealing the syndrome. The mechanisms underlying the auto-immune destruction of the adrenals are discussed.