Publications by authors named "Pierre Bougnères"

84 Publications

Exploring the risk of hypospadias in children born from mothers living close to a vineyard.

PLoS One 2021 15;16(4):e0249800. Epub 2021 Apr 15.

Inserm U1195, University Paris Saclay, Le Kremlin Bicêtre, France.

Hypospadias (H) is a common birth defect affecting the male urinary tract. It has been suggested that exposure to endocrine disrupting chemicals might increase the risk of H by altering urethral development. However, whether H risk is increased in places heavily exposed to agricultural pesticides, such as vineyards, remains debated and difficult to ascertain. The objective of the work is to test the possible association of H with residential proximity to vineyards. Residential address at birth of 8,766 H cases born 1980-2011 was taken from 17 specialized surgery centers. The geographical distribution of vineyards was obtained from the European Land Parcel Identification System (LPIS) and the distance of address to the nearest vineyard was computed. A first estimate of the variation of H relative risk with distance to vineyards was obtained using as controls 13,105 cryptorchidism (C) cases operated during the same period in the same centers. A separate estimate was obtained from a case-control study using "virtual controls" (VC) defined as points of the map sampled to match the demographic distribution of births within the recruitment territories of the study centers. Non-exposed patients were defined as those with a residence between 5,000 and 10,000 m from the closest vineyard. The residential distance to vineyard was smaller for H than for C cases (p<10-4). We found 42/8766 H cases (0.48%) and 50/13,105 C cases (0.38%) born to mothers living within 20 m of a vineyard. The odds ratios for H were 2.48 (CI: 1.0 to 5.1) and 2.4 (CI: 1.3 to 4.4), vs C or vs VC, respectively, when pregnant mothers lived 10-20 m from a vineyard. In conclusion, our study supports that children born to mothers living close to a vineyard have a two-fold increased risk of H. For environmental research, the use of VC provides an alternative to classical case control technique.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249800PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049337PMC
April 2021

Long-Term Follow-Up of Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.

Hum Gene Ther 2021 May 4. Epub 2021 May 4.

GeneWerk GmbH, Heidelberg, Germany.

In 2009, cerebral adrenoleukodystrophy (c-ALD) became the first brain disease to be treated with lentiviral (LV)-based hematopoietic stem cell gene therapy with the gene in four boys (P1-P4) who had demyelinating lesions expected to be lethal in the short term and no bone marrow donor. We report the clinical and magnetic resonance imaging (MRI) follow-up over a mean of 8.8 years posttransplant. In parallel, vector genome copies, expression of transgenic ALD protein (ALDP), and viral integration sites were determined in peripheral blood cells. Prior to transplant, the four patients had a normal or near normal neurocognitive status but gadolinium-enhanced demyelination in various brain regions. Gadolinium diffusion disappeared during the first year posttransplant. P3 kept a near normal status until 8.3 years of follow-up, but P1, P2, and P4 showed major cognitive degradation around 9, 28, and 60 months posttransplant. Neurological status and demyelination stabilized until last evaluation in P2, but deteriorated in both P1 at 10 years and P4 at 3 years posttransplant. The proportion of myeloid and lymphoid cells expressing transgenic ALDP decreased by half within 5 years then stabilized around 5% to 10%. Integration site analysis revealed a durable polyclonal distribution of genetically corrected hematopoietic cells. No adverse effects were observed. The long-term arrest of demyelination at MRI and persistence of transduced hematopoietic progenitors support that LV gene therapy may be a safe and durable treatment of c-ALD. However, the neurological degradation observed in three out of four patients mitigates the benefit of this therapy, calling for an earlier intervention, more potent vectors, and additional therapeutic strategies.
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http://dx.doi.org/10.1089/hum.2021.053DOI Listing
May 2021

Letter to the Editor: "A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness".

J Clin Endocrinol Metab 2021 Jan;106(1):e397-e398

Department of Pediatric Endocrinology, INSERM 1195, Kremlin Bicêtre 92, France.

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http://dx.doi.org/10.1210/clinem/dgaa734DOI Listing
January 2021

Low-dose IL-2 in children with recently diagnosed type 1 diabetes: a Phase I/II randomised, double-blind, placebo-controlled, dose-finding study.

Diabetologia 2020 09 1;63(9):1808-1821. Epub 2020 Jul 1.

Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department (i2B), AP-HP.Sorbonne Université, Pitié-Salpêtrière Hospital, 83 Bd de l'Hôpital, F-75013, Paris, France.

Aims/hypothesis: Low-dose IL-2 (ld-IL2) selectively activates and expands regulatory T cells (Tregs) and thus has the potential to skew the regulatory/effector T (Treg/Teff) cell balance towards improved regulation. We investigated which low doses of IL-2 would more effectively and safely activate Tregs during a 1 year treatment in children with recently diagnosed type 1 diabetes.

Methods: Dose Finding Study of IL-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes (DF-IL2-Child) was a multicentre, double-blinded, placebo-controlled, dose-finding Phase I/II clinical trial conducted in four centres at university hospitals in France: 24 children (7-14 years old) with type 1 diabetes diagnosed within the previous 3 months were randomly assigned 1:1:1:1 to treatment by a centralised randomisation system, leading to a 7/5/6/6 patient distribution of placebo or IL-2 at doses of 0.125, 0.250 or 0.500 million international units (MIU)/m, given daily for a 5 day course and then fortnightly for 1 year. A study number was attributed to patients by an investigator unaware of the randomisation list and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. The primary outcome was change in Tregs, expressed as a percentage of CD4 T cells at day 5. It pre-specified that a ≥60% increase in Tregs from baseline would identify Treg high responders.

Results: There were no serious adverse events. Non-serious adverse events (NSAEs) were transient and mild to moderate. In treated patients vs placebo, the commonest NSAE was injection site reaction (37.9% vs 3.4%), whereas other NSAEs were at the same level (23.3% vs 19.2%). ld-IL2 induced a dose-dependent increase in the mean proportion of Tregs, from 23.9% (95% CI -11.8, 59.6) at the lowest to 77.2% (44.7, 109.8) at the highest dose, which was significantly different from placebo for all dose groups. However, the individual Treg responses to IL-2 were variable and fluctuated over time. Seven patients, all among those treated with the 0.250 and 0.500 MIU m day doses, were Treg high responders. At baseline, they had lower Treg proportions in CD4 cells than Treg low responders, and serum soluble IL-2 receptor α (sIL-2RA) and vascular endothelial growth factor receptor 2 (VEGFR2) levels predicted the Treg response after the 5 day course. There was no significant change in glycaemic control in any of the dose groups compared with placebo. However, there was an improved maintenance of induced C-peptide production at 1 year in the seven Treg high responders as compared with low responders.

Conclusions/interpretation: The safety profile at all doses, the dose-dependent effects on Tregs and the observed variability of the Treg response to ld-IL2 in children with newly diagnosed type 1 diabetes call for use of the highest dose in future developments. The better preservation of insulin production in Treg high responders supports the potential of Tregs in regulating autoimmunity in type 1 diabetes, and warrants pursuing the investigation of ld-IL2 for its treatment and prevention.

Trial Registration: ClinicalTrials.gov NCT01862120.

Funding: Assistance Publique-Hôpitaux de Paris, Investissements d'Avenir programme (ANR-11-IDEX-0004-02, LabEx Transimmunom and ANR-16-RHUS-0001, RHU iMAP) and European Research Council Advanced Grant (FP7-IDEAS-ERC-322856, TRiPoD).
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http://dx.doi.org/10.1007/s00125-020-05200-wDOI Listing
September 2020

Laparoscopic Sleeve Gastrectomy for Adolescents Under 18 Years Old with Severe Obesity.

Obes Surg 2020 01;30(1):267-273

Department of Minimally Invasive Digestive Surgery, Antoine-Beclere Hospital, Assistance Publique - Hôpitaux de Paris, 92140, Clamart, France.

Introduction: Laparoscopic sleeve gastrectomy (LSG) is a widely accepted stand-alone bariatric operation. Data on adolescent patients undergoing LSG are limited. The aim of this study was to demonstrate that LSG is safe and effective for patients strictly under 18 years old with severe obesity.

Methods: Prospectively collected data from consecutive patients undergoing LSG were retrospectively analyzed. Patients with more than 1-year follow-up were included in the analysis for weight loss and comorbidity evaluation. Quality of life (QoL) was evaluated using the Short-Form 36 questionnaire.

Results: Eighty-four patients under 18 years old (range: 15-17 years) underwent LSG. Median weight was 128 kg and median body mass index (BMI) 43.7 kg/m. Median duration of surgery was 68.5 min. One major complication was recorded: a patient developed severe pneumonia that necessitated ventilatory support in intensive care unit and intravenous antibiotic treatment. Mortality was null. Median length of hospital stay was 4 days. Six, 12, and 24 months after LSG, median BMI decreased significantly to 34.3, 29.8, and 28.8 kg/m, respectively (p < 0.001), with a mean percentage of total body weight loss of 29.1% at 2 years. Obesity-related comorbidities improved at 1 year, while all SF-36 scale scores of QoL assessment improved significantly.

Conclusion: This study suggests that LSG is safe and effective for patients under 18 years old, resulting in significant weight loss, comorbidity remission, and QoL improvement. Careful patient selection after adequate risk versus benefit evaluation by an expert multidisciplinary team is essential.
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http://dx.doi.org/10.1007/s11695-019-04150-6DOI Listing
January 2020

Dynamic demethylation of the IL2RA promoter during in vitro CD4+ T cell activation in association with IL2RA expression.

Epigenetics 2018 10;13(5):459-472. Epub 2018 Aug 10.

a Institut National de la Santé et de la Recherche Médicale UMR1169 , Paris Sud University, Bicêtre Hospital , Le Kremlin-Bicêtre , France.

IL2RA, a subunit of the high affinity receptor for interleukin-2 (IL2), plays a crucial role in immune homeostasis. Notably, IL2RA expression is induced in CD4+ T cells in response to various stimuli and is constitutive in regulatory T cells (Tregs). We selected for our study 18 CpGs located within cognate regulatory regions of the IL2RA locus and characterized their methylation in naive, regulatory, and memory CD4+ T cells. We found that 5/18 CpGs (notably CpG + 3502) show dynamic, active demethylation during the in vitro activation of naive CD4+ T cells. Demethylation of these CpGs correlates with appearance of IL2RA protein at the cell surface. We found no influence of cis located SNP alleles upon CpG methylation. Treg cells show constitutive demethylation at all studied CpGs. Methylation of 9/18 CpGs, including CpG +3502, decreases with age. Our data thus identify CpG +3502 and a few other CpGs at the IL2RA locus as coordinated epigenetic regulators of IL2RA expression in CD4+ T cells. This may contribute to unravel how the IL2RA locus can be involved in immune physiology and pathology.
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http://dx.doi.org/10.1080/15592294.2018.1469893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140818PMC
February 2019

Correction to: Fetal growth is associated with CpG methylation in the P2 promoter of the gene.

Clin Epigenetics 2018 4;10:74. Epub 2018 Jun 4.

1Institut National de la Santé et de la Recherche Médicale U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France.

[This corrects the article DOI: 10.1186/s13148-018-0489-9.].
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http://dx.doi.org/10.1186/s13148-018-0506-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987394PMC
June 2018

Fetal growth is associated with CpG methylation in the P2 promoter of the IGF1 gene.

Clin Epigenetics 2018 19;10:57. Epub 2018 Apr 19.

1Institut National de la Santé et de la Recherche Médicale U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France.

Background: There are many reasons to think that epigenetics is a key determinant of fetal growth variability across the normal population. Since and genes are major determinants of intrauterine growth, we examined the methylation of selected CpGs located in the regulatory region of these two genes.

Methods: Cord blood was sampled in 159 newborns born to mothers prospectively followed during their pregnancy. A 142-item questionnaire was filled by mothers at inclusion, during the last trimester of the pregnancy and at the delivery. The methylation of selected CpGs located in the promoters of the and genes was measured in cord blood mononuclear cells collected at birth using bisulfite-PCR-pyrosequencing.

Results: Methylation at CpG-137 correlated negatively with birth length ( = 0.27,  = 3.5 × 10). The same effect size was found after adjustment for maternal age, parity, and smoking: a 10% increase in CpG-137 methylation was associated with a decrease of length by 0.23 SDS.

Conclusion: The current results suggest that the methylation of CpG-137 contributes to the individual variation of fetal growth by regulating expression in fetal tissues.
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http://dx.doi.org/10.1186/s13148-018-0489-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909239PMC
May 2019

Impact of social inequalities at birth on the longevity of children born 1914-1916: A cohort study.

PLoS One 2017 16;12(10):e0185848. Epub 2017 Oct 16.

INSERM U1169, Le Kremlin-Bicêtre, France.

Background: Testing whether familial socioeconomic status (SES) in childhood is a predictor of mortality has rarely been done on historical cohorts.

Methods: The birth certificates of 4,805 individuals born 1914-1916 in 16 districts of the Paris region were retrieved. The handwritten information provided the occupation of parents, the legitimacy status, life events (e.g. marriage, divorce), and the precise date of death when after 1945 (i.e. age 31 years (y) in the cohort). We used the median age at death (MAD) as a global measure of mortality, then studied separately survival to and after 31 y. Multivariate Imputation by Chained Equations (MICE), Generalized Additive Models (GAMs) and mixed effect Cox models were used.

Results: MAD showed large variations according to paternal occupation. The lowest MAD in both sexes was that of workers' children: it was 56.3 y (95% CI: [48.6-62.7]) in men and 67.4 y (95% CI: [60.8-72.7]) in women, respectively (95% CI: 13.4 y [5.7-21.3]) and 12.3 y (95% CI: [4.0-19.2]) below the highest MAD attained. MAD experienced by illegitimate children was 18.9 y (95% CI: [13.3-32.3]) shorter than of legitimate children. The multivariate analysis revealed that in both sexes survival to age 31 y was predicted independently by legitimacy and paternal occupation. Paternal occupation was found significantly associated with mortality after age 31 y in females only: accordingly difference in life expectancy at age 31 y was 4.4 y (95% CI: [1.2-7.6]) between upper class and workers' daughters.

Conclusions: Paternal occupation and legitimacy status were strong predictors of offspring longevity in this one-century historical cohort born during World War One.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185848PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643053PMC
October 2017

The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature.

Sci Adv 2017 06 16;3(6):e1602025. Epub 2017 Jun 16.

Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Although both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling were shown to regulate life span in lower organisms, the role of GH signaling in human longevity remains unclear. Because a GH receptor exon 3 deletion () appears to modulate GH sensitivity in humans, we hypothesized that this polymorphism could play a role in human longevity. We report a linear increased prevalence of homozygosity with age in four independent cohorts of long-lived individuals: 841 participants [567 of the Longevity Genes Project (LGP) (8% increase; = 0.01), 152 of the Old Order Amish (16% increase; = 0.02), 61 of the Cardiovascular Health Study (14.2% increase; = 0.14), and 61 of the French Long-Lived Study (23.5% increase; = 0.02)]. In addition, mega analysis of males in all cohorts resulted in a significant positive trend with age (26% increase; = 0.007), suggesting sexual dimorphism for GH action in longevity. Further, on average, LGP / homozygotes were 1 inch taller than the wild-type (WT) allele carriers ( = 0.05) and also showed lower serum IGF-1 levels ( = 0.003). Multivariate regression analysis indicated that the presence of / genotype adds approximately 10 years to life span. The LGP d3/ transformed lymphocytes exhibited superior growth and extracellular signal-regulated kinase activation, to GH treatment relative to WT GHR lymphocytes ( < 0.01), indicating a GH dose response. The variant is a common genetic polymorphism that modulates GH responsiveness throughout the life span and positively affects male longevity.
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http://dx.doi.org/10.1126/sciadv.1602025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473676PMC
June 2017

Genome-Wide Methylation Analysis Identifies Specific Epigenetic Marks In Severely Obese Children.

Sci Rep 2017 04 7;7:46311. Epub 2017 Apr 7.

INSERM U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France.

Obesity is a heterogeneous disease with many different subtypes. Epigenetics could contribute to these differences. The aim of this study was to investigate genome-wide DNA methylation searching for methylation marks associated with obesity in children and adolescents. We studied DNA methylation profiles in whole blood cells from 40 obese children and controls using Illumina Infinium HumanMethylation450 BeadChips. After correction for cell heterogeneity and multiple tests, we found that compared to lean controls, 31 CpGs are differentially methylated in obese patients. A greatest proportion of these CpGs is hypermethylated in obesity and located in CpG shores regions. We next focused on severely obese children and identified 151 differentially methylated CpGs among which 10 with a difference in methylation greater than 10%. The top pathways enriched among the identified CpGs included the "IRS1 target genes" and several pathways in cancer diseases. This study represents the first effort to search for differences in methylation in obesity and severe obesity, which may help understanding these different forms of obesity and their complications.
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http://dx.doi.org/10.1038/srep46311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384222PMC
April 2017

Prenatal loss of father during World War One is predictive of a reduced lifespan in adulthood.

Proc Natl Acad Sci U S A 2017 04 4;114(16):4201-4206. Epub 2017 Apr 4.

INSERM U1169, 94276 Le Kremlin-Bicêtre, France.

Although early-life stress is known to alter health, its long-term consequences on mortality remain largely unknown. Thanks to unique French legislation established in 1917 for war orphans and children of disabled soldiers, we were able to study the adult mortality of individuals born in 1914-1916 whose fathers were killed during World War 1. Vital information and socio-demographic characteristics were extracted manually from historical civil registers for 5,671 children born between 1 August 1914 and 31 December 1916 who were granted the status of "" (orphan of the Nation). We used a database comprising 1.4 million deceased soldiers to identify war orphans and collect information on their fathers and then paired each orphan with a nonorphan from the same birth register matched for date of birth, sex, and mother's age at the infant's birth. Mortality between ages 31 and 99 y was analyzed for 2,365 orphan/nonorphan pairs. The mean loss of adult lifespan of orphans who had lost their father before birth was 2.4 y (95% CI: 0.7, 3.9 y) and was the result of increased mortality before age 65 y. Adult lifespan was not reduced when the father's death occurred after the infant's birth. These results support the notion that intrauterine exposure to a major psychological maternal stress can affect human longevity.
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http://dx.doi.org/10.1073/pnas.1617911114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402438PMC
April 2017

Erratum to: A randomized pilot trial of growth hormone with anastrozole versus growth hormone alone, starting at the very end of puberty in adolescents with idiopathic short stature.

Int J Pediatr Endocrinol 2017 27;2017. Epub 2017 Feb 27.

Department of Pediatric Endocrinology, Bicêtre Hospital, Pôle I3E, AP-HP, Paris Sud University, 94275 Le Kremlin Bicêtre, France.

[This corrects the article DOI: 10.1186/1687-9856-2015-4.].
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http://dx.doi.org/10.1186/s13633-017-0043-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5327564PMC
February 2017

Using spatio-temporal surveillance data to test the infectious environment of children before type 1 diabetes diagnosis.

PLoS One 2017 2;12(2):e0170658. Epub 2017 Feb 2.

Inserm U1169, Paris Sud University, Le Kremlin Bicêtre, France.

The "hygiene hypothesis" postulates that reduced exposure to infections favours the development of autoimmunity and childhood type 1 diabetes (T1D). But on the other side, viruses, notably enteroviruses, are suspected to trigger T1D. The assessment of the possible relationships between infections and T1D still defies the classical tools of epidemiology. We report the methods and results of a geographical approach that maps the addresses of patients to a communicable diseases surveillance database. We mapped the addresses of patients at birth, infancy and T1D diagnosis to the weekly estimates of the regional incidences of 5 frequent communicable diseases routinely collected since 1984 by the French Sentinel network. The pre-diagnostic infectious environment of 3548 patients with T1D diagnosed between 0.5 and 15 years was compared to those of 100 series of age-matched "virtual controls" drawn randomly on the map. Associations were classified as "suggestive" (summer diarrhea, SD, and varicella, V) when p< 0.05, or "significant" (influenza-like infections, ILI) when they passed the Bonferroni correction for FDR. Exposure to ILI and SD were associated with T1D risk, while V seemed protective. In the subset of 2521 patients for which we had genome wide data, we used a case-only approach to search for interactions between SNPs and the infectious environment as defined by the Sentinel database. Two SNPs, rs116624278 and rs77232854, showed significant interaction with exposure to V between 1 and 3 years of life. The infectious associations found should be taken as possible markers of patients' environment, not as direct causative factors of T1D. They require replication in other populations. The increasing public availability of geographical environmental databases will expand the present approach to map thousands of environmental factors to the lifeline of patients affected by various diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170658PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289461PMC
September 2017

Deferring surgical treatment of ambiguous genitalia into adolescence in girls with 21-hydroxylase deficiency: a feasibility study.

Int J Pediatr Endocrinol 2017 28;2017. Epub 2017 Jan 28.

First Department of Obstetrics and Gynaecology, University of Athens, Alexandra Hospital, Athens, Greece.

Background: Genital surgery in Disorders of Sex Development (DSD) has been an area of debate over the past 20 years. Emerging scientific evidence in the late 1990s defied the then routine practice to surgically align genitalia to the sex of rearing, as early as possible. However, despite multitude of data showing detrimental effects to genital sensation and sexuality, few patients born with ambiguous genitalia have remained unoperated into adolescence.

Methods: We followed up girls with 21 hydroxylase deficiency (21- OHD) in genital morphology during childhood and acceptability among patients and parents of such an approach.

Results: Preliminary results from 7 children, aged 1-8 years (median 4.5 years), suggest that it is acceptable among patients and families to defer genital operation in 21-OHD. All patients had a Prader stage III and above. Median clitoral length at birth was 24 mm (20-28 mm) and had diminished to a median of 9 mm (5-15 mm) at their last visit. Height and weight have remained strictly normal in all patients. So far girls and their parents have not expressed significant concerns regarding genital ambiguity.

Conclusions: With this encouraging data at hand, we propose to formally address levels of anxiety, adaptation and quality of life during childhood, with an ultimate goal to assess long term satisfaction and effects on sexuality through deferring genital surgery for adolescence.
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http://dx.doi.org/10.1186/s13633-016-0040-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5273823PMC
January 2017

Knock-In of the Recurrent R368X Mutation of PRKAR1A that Represses cAMP-Dependent Protein Kinase A Activation: A Model of Type 1 Acrodysostosis.

J Bone Miner Res 2017 Feb 24;32(2):333-346. Epub 2016 Oct 24.

INSERM U1169, University Paris Sud, Hôpital Bicêtre, Le Kremlin Bicêtre, France.

In humans, activating mutations in the PRKAR1A gene cause acrodysostosis 1 (ACRDYS1). These mutations result in a reduction in PKA activation caused by an impaired ability of cAMP to dissociate mutant PRKAR1A from catalytic PKA subunits. Two striking features of this rare developmental disease are renal resistance to PTH and chondrodysplasia resulting from the constitutive inhibition of PTHR1/Gsa/AC/cAMP/PKA signaling. We developed a knock-in of the recurrent ACRDYS1 R368X PRKAR1A mutation in the mouse. No litters were obtained from [R368X]/[+] females (thus no homozygous [R368X]/[R368X] mice). In [R368X]/[+] mice, Western blot analysis confirmed mutant allele heterozygous expression. Growth retardation, peripheral acrodysostosis (including brachydactyly affecting all digits), and facial dysostosis were shown in [R368X]/[+] mice by weight curves and skeletal measurements (μCT scan) as a function of time. [R368X]/[+] male and female mice were similarly affected. Unexpected, however, whole-mount skeletal preparations revealed a striking delay in mineralization in newborn mutant mice, accompanied by a decrease in the height of terminal hypertrophic chondrocyte layer, an increase in the height of columnar proliferative prehypertrophic chondrocyte layer, and changes in the number and spatial arrangement of proliferating cell nuclear antigen (PCNA)-positive chondrocytes. Plasma PTH and basal urinary cAMP were significantly higher in [R368X]/[+] compared to WT mice. PTH injection increased urinary cAMP similarly in [R368X]/[+] and WT mice. PRKACA expression was regulated in a tissue (kidney not bone and liver) manner. This model, the first describing the germline expression of a PRKAR1A mutation causing dominant repression of cAMP-dependent PKA, reproduced the main features of ACRDYS1 in humans. It should help decipher the specificity of the cAMP/PKA signaling pathway, crucial for numerous stimuli. In addition, our results indicate that PRKAR1A, by tempering intracellular cAMP levels, is a molecular switch at the crossroads of signaling pathways regulating chondrocyte proliferation and differentiation. © 2016 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.2987DOI Listing
February 2017

Association of environmental markers with childhood type 1 diabetes mellitus revealed by a long questionnaire on early life exposures and lifestyle in a case-control study.

BMC Public Health 2016 Sep 29;16(1):1021. Epub 2016 Sep 29.

INSERM U1169, Hôpital Bicêtre, Université Paris-Sud, Kremlin-Bicêtre, France.

Background: The incidence of childhood type 1 diabetes (T1D) incidence is rising in many countries, supposedly because of changing environmental factors, which are yet largely unknown. The purpose of the study was to unravel environmental markers associated with T1D.

Methods: Cases were children with T1D from the French Isis-Diab cohort. Controls were schoolmates or friends of the patients. Parents were asked to fill a 845-item questionnaire investigating the child's environment before diagnosis. The analysis took into account the matching between cases and controls. A second analysis used propensity score methods.

Results: We found a negative association of several lifestyle variables, gastroenteritis episodes, dental hygiene, hazelnut cocoa spread consumption, wasp and bee stings with T1D, consumption of vegetables from a farm and death of a pet by old age.

Conclusions: The found statistical association of new environmental markers with T1D calls for replication in other cohorts and investigation of new environmental areas.

Trial Registration: Clinical-Trial.gov NCT02212522 . Registered August 6, 2014.
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http://dx.doi.org/10.1186/s12889-016-3690-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041527PMC
September 2016

Growth and descent of the testes in infants with hypogonadotropic hypogonadism receiving subcutaneous gonadotropin infusion.

Int J Pediatr Endocrinol 2016 4;2016:13. Epub 2016 Jul 4.

Department of Pediatric Endocrinology, Pôle I3E, Hôpital Bicêtre, Assistance Publique des Hôpitaux de Paris, Paris Sud University, Le Kremlin-Bicetre, France.

Background: One third of infants with congenital hypogonadotropic hypogonadism (CHH) are said to have micropenis and/or bilateral or unilateral cryptorchidism leading many of them to orchiopexy. Our previous study in two patients suggests that prolonged subcutaneous infusion of large doses of gonadotropins might normalize testicular function and growth.

Case Presentation: To confirm the effects of early and prolonged subcutaneous infusion of large doses of gonadotropins on growth and descent of the testes. Eight boys with CHH, aged 0.25-11 months. Testes were non-palpable in 5 or in high scrotal position in 3. CHH was isolated in 5 infants and part of a syndrome of combined pituitary hormonal deficits in the 3 others. In response to gonadotropin infusion, mean levels of testicular hormones were normalized. Complete testis descent occurred in 6 patients. Partial descent occurred in 2. Testes re-ascended in 1 patient. Testes and penis gained normal dimensions in all cases.

Conclusion: Subcutaneous gonadotropin infusion seems able to induce testis descent in a large proportion of infants with CHH. If confirmed, this may allow patients to avoid testes surgery but studies in larger series are needed to evaluate the benefits of this treatment versus traditional orchiopexy.
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http://dx.doi.org/10.1186/s13633-016-0031-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931699PMC
July 2016

Role of DNA methylation at the placental RTL1 gene locus in type 1 diabetes.

Pediatr Diabetes 2017 05 13;18(3):178-187. Epub 2016 May 13.

INSERM U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France.

Genome-wide association studies (GWAS) have identified more than 40 T1D loci associated with type 1 diabetes (T1D). How these polymorphisms interact with environmental factors to trigger T1D is unknown, but recent evidence suggests that epigenetic mechanisms could play a role. To begin to explore the contribution of epigenetics to T1D, we have examined DNA methylation in a pilot study of whole blood cells DNA from 10 young T1D patients and 10 young controls. Through the study of >900 000 CG loci across a diverse set of functionally relevant genomic regions using a custom DNA methylation array, we identified 250 T1D-differentially methylated region (DMR) at p < 0.05 and 1 DMR using next a permutation-based multiple testing correction method. This DMR is located in an imprinted region previously associated with T1D on the chromosome 14 that encompasses RTL1 gene and 2 miRNAs (miR136 and miR432). Using pyrosequencing-based bisulfite PCR, we replicated this association in a different and larger set of T1D patients and controls. DNA methylation at this DMR was inversely correlated with RTL1 gene expression and positively correlated with miR136 expression in human placentas. The DMR identified in this study presents suggestive evidence for altered methylation site in T1D and provide a promising new candidate gene. RTL1 is essential for placental permeability function in the mid-to-late fetal stages. We suggest that hypo-methylation could increase the fetal exposure to environmental factors in T1D susceptibility.
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http://dx.doi.org/10.1111/pedi.12387DOI Listing
May 2017

Higher methylation of the IGF1 P2 promoter is associated with idiopathic short stature.

Clin Endocrinol (Oxf) 2016 Feb 3;84(2):216-221. Epub 2015 Sep 3.

Institut National de la Santé et de la Recherche Médicale U986, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France.

Background: Idiopathic short stature (ISS) has a strong familial component, but genetics explains only part of it. Indeed, environmental factors act on human growth either directly or through epigenetic factors that remain to be determined. Given the importance of the GH/IGF1 axis for child growth, we suspected that such epigenetic factors could involve the CG methylation at the IGF1 gene P2 promoter, which was recently shown to be a transcriptional regulator for IGF1 gene and a major contributor to GH sensitivity.

Objective: Explore whether the methylation of the two IGF1 low-CG-rich promoters (P1 and P2) is associated with ISS.

Subjects And Methods: A total of 94 children with ISS were compared with 119 age-matched children of normal height for the methylation of CGs located within the IGF1 promoters measured with bisulphite PCR pyrosequencing.

Results: The methylation of 5 CGs of the P2 promoter was higher in ISS children, notably CG-137 (49 ± 4% in ISS vs 46 ± 4 % in control children, P = 9 × 10 ). This was also true for CG-611 of the P1 promoter (93 ± 3% vs 91 ± 3% P = 10 ). The CG methylation of the IGF1 promoters thus takes place among the multifactorial factors that are associated with ISS.
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http://dx.doi.org/10.1111/cen.12867DOI Listing
February 2016

Primordial Influence of Post-operative Compliance on Weight Loss After Adolescent Laparoscopic Adjustable Gastric Banding.

Obes Surg 2016 Jan;26(1):98-104

AP-HP, Hôpital Necker-Enfants Malades, Service de Chirurgie Pédiatrique Viscérale, 149 rue de Sevres, 75015, Paris, France.

Background: Accumulating evidence suggests that the benefits seen in adult bariatric surgery can be reproduced in adolescents. In contrast with North America, bariatric surgery in adolescents is still not well accepted in Europe and indications and protocols have still to be formulated.

Methods: This prospective study tested the gastric banding procedure in 49 patients operated in a single French institution since 2008. The mean age at surgery was 16.2 ± 0.9 years with a weight of 118.8 ± 22.3 kg and body mass index of 42.5 ± 5.9 kg/m(2).

Results: At 6, 12 and 24 months after surgery, weight was 103.7 ± 20.8 kg, 98.7 ± 21 kg and 93.6 ± 19.3 kg, respectively (p < 0.001), corresponding to excess weight loss (EWL) of 31.6 ± 17.2 %, 41.8 ± 21.4 % and 59.1 ± 24.9 % (p < 0.001), respectively. Multivariate analysis showed that the number of consultations per year was the only variable significantly associated to weight loss. Metabolic disorders were corrected, with a decreased prevalence of insulin resistance from 100 to 17 % and normalisation of homeostasis model assessment-insulin resistance (HOMA-IR) at 24 months (2.09 ± 0.95). Band-related complications were five slippages, one psychological intolerance and two ports repositioning. Six patients (12 %) had the device explanted. The death of a patient was an exceptionally severe adverse event.

Conclusion: Given frequent follow-up support by a multidisciplinary team, laparoscopic adjustable gastric banding (LAGB) surgery in adolescent results in sustained weight loss. However, even exceptional, potentially serious complications are possible and long-term follow-up is needed to evaluate the risk/benefit ratio at 5 or 10 years after LAGB surgery.
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http://dx.doi.org/10.1007/s11695-015-1725-4DOI Listing
January 2016

A randomized pilot trial of growth hormone with anastrozole versus growth hormone alone, starting at the very end of puberty in adolescents with idiopathic short stature.

Int J Pediatr Endocrinol 2015 16;2015(1). Epub 2015 Feb 16.

Department of Pediatric Endocrinology, Bicêtre Hospital, Pôle I3E, AP-HP, Paris Sud University, 94275 Le Kremlin Bicêtre, France.

Background: When given during the course of puberty, anastrozole (A), an aromatase inhibitor, has been shown to increase the predicted adult height (PAH) of GH-deficient (GHD) boys treated with recombinant human growth hormone (rhGH). Our study questioned whether this treatment could retain some of its effects in non-GHD adolescent boys if started only at the very end of puberty, a time when rhGH treatment is denied to short adolescents who have almost reached their final height.

Objective: To explore the effect on adult height of a combination of rhGH and A, compared with rhGH alone, at the end of puberty in boys with idiopatic short stature (ISS).

Methods: A prospective randomized study comparing rhGH + A and rhGH was conducted in 24 healthy adolescent boys aged 15.2 ± 1.2 yrs with serum testosterone at adult levels and a faltering growth velocity <3.5 cm/yr leading to a predicted adult height (PAH) <2.5 SDS. Treatments were stopped when growth velocity became <10 mm in 6 months or when height was close to 170 cm. A historical group of ISS adolescents (N = 17) matched for puberty and growth was used for comparison.

Results: IGF1 levels remained within normal limits in all treated patients. Mean treatment duration was 19 months in the rhGH + A group and 11.5 months in the rhGH group (P = 6.10(-4)). Adult height reached 168.4 ± 2.6 cm in the rhGH + A group and 164.2 ± 5.6 cm in the rhGH group (P < 0.02). Adult height was 160.1 ± 2.8 cm in the historical controls.

Conclusion: A combination of rhGH and A, started at the very end of puberty, seems to allow boys with ISS to reach a greater adult height than rhGH alone. Larger trials are needed to confirm this preliminary observation.
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http://dx.doi.org/10.1186/1687-9856-2015-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429943PMC
May 2015

Global epidemiology of type 1 diabetes in young adults and adults: a systematic review.

BMC Public Health 2015 Mar 17;15:255. Epub 2015 Mar 17.

Background: Although type 1 diabetes (T1D) can affect patients of all ages, most epidemiological studies of T1D focus on disease forms with clinical diagnosis during childhood and adolescence. Clinically, adult T1D is difficult to discriminate from certain forms of Type 2 Diabetes (T2D) and from Latent Autoimmune Diabetes in Adults (LADA).

Methods: A systematic review of the literature was performed to retrieve original papers in English, French and Spanish published up to November 6, 2014, reporting the incidence of T1D among individuals aged over 15 years. The study was carried out according to the PRISMA recommendations.

Results: We retrieved information reporting incidence of T1D among individuals aged more than 15 years in 35 countries, and published in 70 articles between 1982 and 2014. Specific anti-beta-cell proteins or C-peptide detection were performed in 14 of 70 articles (20%). The most frequent diagnostic criteria used were clinical symptoms and immediate insulin therapy. Country-to-country variations of incidence in those aged >15 years paralleled those of children in all age groups. T1D incidence was larger in males than in females in 44 of the 54 (81%) studies reporting incidence by sex in people >15 years of age. The overall mean male-to-female ratio in the review was 1.47 (95% CI = 1.33-1.60, SD = 0.49, n = 54, p = <0.0001). Overall, T1D incidence decreased in adulthood, after the age of 14 years.

Conclusions: Few studies on epidemiology of T1D in adults are available worldwide, as compared to those reporting on children with T1D. The geographical variations of T1D incidence in adults parallel those reported in children. As opposed to what is known in children, the incidence is generally larger in males than in females. There is an unmet need to evaluate the incidence of autoimmune T1D in adults, using specific autoantibody detection, and to better analyze epidemiological specificities - if any - of adult T1D.

Prospero Registration Number: CRD42012002369.
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http://dx.doi.org/10.1186/s12889-015-1591-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381393PMC
March 2015

Genetic and Epigenetic Modulation of Growth Hormone Sensitivity Studied With the IGF-1 Generation Test.

J Clin Endocrinol Metab 2015 Jun 2;100(6):E919-25. Epub 2015 Apr 2.

Institut National de la Santé et de la Recherche Médicale Unité 986 (M.O., A.-L.C., A.L., P.B.) and Department of Pediatric Endocrinology and Diabetes (A.-L.C., A.L., P.B.), Paris Sud University, Bicêtre Hospital, 94275 Le Kremlin-Bicêtre, France.

Context: Like all hormones, GH has variable physiological effects across people. Many of these effects initiated by the binding of GH to its receptor (GHR) in target tissues are mediated by the expression of the IGF1 gene. Genetic as well as epigenetic variation is known to contribute to the individual diversity of GH-dependent phenotypes through two mechanisms. The first one is the genetic polymorphism of the GHR gene due to the common deletion of exon 3. The second, more recently reported, is the epigenetic variation in the methylation of a cluster of CGs dinucleotides located within the proximal part of the P2 promoter of the IGF-1 (IGF1) gene, notably CG-137.

Objective: The current study evaluates the relative contribution of these two factors controlling individual GH sensitivity by measuring the response of serum IGF-1 to a GH injection (IGF-1 generation test) in a sample of 72 children with idiopathic short stature.

Results: Although the d3 polymorphism of the GHR contributed 19% to the variance of the IGF-1 response, CG-137 methylation in the IGF-1 promoter contributed 30%, the combined contribution of the two factors totaling 43%.

Conclusion: Our observation indicates that genetic and epigenetic variation at the GHR and IGF-1 loci play a major role as independent modulators of individual GH sensitivity.
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http://dx.doi.org/10.1210/jc.2015-1413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454803PMC
June 2015

The IGF1 P2 promoter is an epigenetic QTL for circulating IGF1 and human growth.

Clin Epigenetics 2015 13;7:22. Epub 2015 Mar 13.

Institut National de la Santé et de la Recherche Médicale U986, Bicêtre Hospital, Paris Sud University, 80 rue du Général Leclerc Le Kremlin-Bicêtre, Paris, 94276 France ; Department of Pediatric Endocrinology and Diabetes, I3E Pole, Bicêtre Hospital, Paris Sud University, rue du Général Leclerc Le Kremlin-Bicêtre, Paris, 94276 France.

Background: Even if genetics play an important role, individual variation in stature remains unexplained at the molecular level. Indeed, genome-wide association study (GWAS) have revealed hundreds of variants that contribute to the variability of height but could explain only a limited part of it, and no single variant accounts for more than 0.3% of height variance. At the interface of genetics and environment, epigenetics contributes to phenotypic diversity. Quantifying the impact of epigenetic variation on quantitative traits, an emerging challenge in humans, has not been attempted for height. Since insulin-like growth factor 1 (IGF1) controls postnatal growth, we tested whether the CG methylation of the two promoters (P1 and P2) of the IGF1 gene is a potential epigenetic contributor to the individual variation in circulating IGF1 and stature in growing children.

Results: Child height was closely correlated with serum IGF1. The methylation of a cluster of six CGs located within the proximal part of the IGF1 P2 promoter showed a strong negative association with serum IGF1 and growth. The highest association was for CG-137 methylation, which contributed 13% to the variance of height and 10% to serum IGF1. CG methylation (studied in children undergoing surgery) was approximately 50% lower in liver and growth plates, indicating that the IGF1 promoters are tissue-differentially methylated regions (t-DMR). CG methylation was inversely correlated with the transcriptional activity of the P2 promoter in mononuclear blood cells and in transfection experiments, suggesting that the observed association of methylation with the studied traits reflects true biological causality.

Conclusions: Our observations introduce epigenetics among the individual determinants of child growth and serum IGF1. The P2 promoter of the IGF1 gene is the first epigenetic quantitative trait locus (QTL(epi)) reported in humans. The CG methylation of the P2 promoter takes place among the multifactorial factors explaining the variation in human stature.
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http://dx.doi.org/10.1186/s13148-015-0062-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363053PMC
March 2015

Covariation of the incidence of type 1 diabetes with country characteristics available in public databases.

PLoS One 2015 23;10(2):e0118298. Epub 2015 Feb 23.

Institut National de la Santé et de la Recherche Médicale, Inserm Unité-1169, F-94276, Le Kremlin Bicêtre, France; Université Pierre et Marie Curie-Paris 6, Ecole Doctorale 393, F-75012, Paris, France.

Background: The incidence of Type 1 Diabetes (T1D) in children varies dramatically between countries. Part of the explanation must be sought in environmental factors. Increasingly, public databases provide information on country-to-country environmental differences.

Methods: Information on the incidence of T1D and country characteristics were searched for in the 194 World Health Organization (WHO) member countries. T1D incidence was extracted from a systematic literature review of all papers published between 1975 and 2014, including the 2013 update from the International Diabetes Federation. The information on country characteristics was searched in public databases. We considered all indicators with a plausible relation with T1D and those previously reported as correlated with T1D, and for which there was less than 5% missing values. This yielded 77 indicators. Four domains were explored: Climate and environment, Demography, Economy, and Health Conditions. Bonferroni correction to correct false discovery rate (FDR) was used in bivariate analyses. Stepwise multiple regressions, served to identify independent predictors of the geographical variation of T1D.

Findings: T1D incidence was estimated for 80 WHO countries. Forty-one significant correlations between T1D and the selected indicators were found. Stepwise Multiple Linear Regressions performed in the four explored domains indicated that the percentages of variance explained by the indicators were respectively 35% for Climate and environment, 33% for Demography, 45% for Economy, and 46% for Health conditions, and 51% in the Final model, where all variables selected by domain were considered. Significant environmental predictors of the country-to-country variation of T1D incidence included UV radiation, number of mobile cellular subscriptions in the country, health expenditure per capita, hepatitis B immunization and mean body mass index (BMI).

Conclusions: The increasing availability of public databases providing information in all global environmental domains should allow new analyses to identify further geographical, behavioral, social and economic factors, or indicators that point to latent causal factors of T1D.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118298PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338253PMC
December 2015

A pilot study of growth hormone administration in boys with predicted adult short stature and near-ending growth.

Growth Horm IGF Res 2015 Apr 26;25(2):96-102. Epub 2015 Jan 26.

AP-HP, Department of Pediatric Endocrinology, Bicêtre Hospital, Paris Sud University, 94275 Le Kremlin Bicêtre, France; Biomathematics Team, InsermU986, Pincus Building, Bicêtre Hospital, Paris Sud University, 94275 Le Kremlin Bicêtre, France. Electronic address:

Context: The growth-promoting effect of starting recombinant human growth hormone (rhGH) at the time of near-ending growth has not been studied in sexually mature boys who will have idiopathic short stature (ISS) as adults because it is believed that such an advanced stage of puberty would preclude favorable results.

Objectives: 1) To explore the effects of starting rhGH administration at time of near-ending growth in boys with ISS. 2) To search for predictors of response to rhGH.

Subjects: Fifteen boys aged 15.5 ± 1 years terminating puberty were growing at a rate < 2 cm/6 months towards a predicted adult height (PAH) <-2.5 SDS.

Methods: Participants received 0.50 ± 0.06 mg/kg · wk of rhGH according to a target-to-treat protocol. When growth became less than 0.5 cm in 3 months or when height has reached 169 cm, rhGH was ceased. Testosterone, growth velocity (GV), height, serum IGF-1, bone age (BA) at hand-wrist and knee score were measured at onset; IGF-1 and height were monitored every 3 months. A formula for PAH was developed. Height increment (HI, adult height-starting height) and height gain (HG, adult height-PAH) were calculated.

Results: Following rhGH administration for 11.1 ± 4.8 months, GV-SDS increased from -2.5 ± 1.7 to 3.5 ± 4.3 (P = 2 × 10(-4)), HI = 8.5 ± 3.7 cm, HG = 6.8 ± 4.8 cm and adult height was -1.8 ± 0.9 SDS, compared to a PAH of -2.9 ± 0.6 SDS (P = 4 × 10(-4)). Knee score (P = 2 × 10(-3)), GV at rhGH onset (P = 8 × 10(-3)) and rhGH dose (P = 8 × 10(-3)) were identified as predictors of HI and HG, but BA was not.

Conclusions: Our study suggests that 1) a short period of rhGH administration can increase true adult height significantly in boys with ISS at time of near-ending growth; and 2) knee score rather than BA should be used to identify rhGH responders. These preliminary observations await confirmation by larger randomized trials.
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http://dx.doi.org/10.1016/j.ghir.2015.01.002DOI Listing
April 2015

Comparison of a French pediatric type 1 diabetes cohort's responders and non-responders to an environmental questionnaire.

BMC Public Health 2014 Dec 3;14:1241. Epub 2014 Dec 3.

Institut National de la Santé et de la Recherche Médicale (U986), Paris Sud University, Le Kremlin Bicêtre, France.

Background: Type 1 diabetes (T1D) incidence has doubled since the 1980's for children aged <5 years old, potentially relevant environmental factors having thus to be sought early in the patient's life. The identification of environmental factors that can explain the changing epidemiology of T1D requires comprehensive environmental inquiries. However, a limitation is the willingness of patients and families to complete these environmental questionnaires. Our objective was to identify patients' personal and social characteristics predictive of the return, time to the return and completeness of a comprehensive environmental questionnaire.

Methods: The parents of 2832 T1D patients aged <15 years old enrolled in the French Isis cohort were sent a 1379-item environmental questionnaire. A geographic information system was used to collect information on patients' socioeconomic environment. Multivariate statistical analyses were conducted to identify predictors of questionnaire return, time to its return and its completeness.

Results: Within 6 months, 867 (30.6%) questionnaires were returned. Socioeconomic environment was strongly associated with the probability of response, with fewer responses from cities with high Townsend deprivation index (p =2 × 10-7), high unemployment (p =0.005), blue-collar workers' rate (p =0.0002) and household overcrowding (p =0.02). Response rates were similar for male and female patients, but were higher for less severely affected patients (p =0.006) and younger patients (p =5 × 10-5). When returned, completeness was high with a mean of 96%.

Conclusion: Identification of personal or socioeconomic characteristics differing between questionnaire responders and non-responders may help target future environmental investigations on those patients who will more likely return the information, and reduce bias using these variables to stratify the analyses.
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http://dx.doi.org/10.1186/1471-2458-14-1241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326427PMC
December 2014

Short-term results of single-port sleeve gastrectomy in adolescents with severe obesity.

Surg Obes Relat Dis 2015 Jan-Feb;11(1):65-9. Epub 2014 Jun 3.

Service d'Endocrinologie et Diabétologie Pédiatrique & Médecine des Adolescents, Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

Background: Dietary and lifestyle modifications, which are commonly proposed to overweight or obese youth, lack efficacy in individuals who are severely obese. Early results with bariatric procedures in obese adolescents suggest that weight loss and safety are comparable or better than seen in adults. One of these procedures, laparoscopic sleeve gastrectomy, is commonly performed using multiple ports.

Methods: We selected single-port sleeve gastrectomy (SPSG) as a minimally invasive surgery to be tested in severely obese adolescents. Prospective clinical and biochemical data were collected from 16 young severely obese patients who underwent SPSG. The setting was a university hospital.

Results: The mean age of the cohort was 17.8 years (12 girls, 4 boys). The individuals' average weight was 125.5 kg and their average body mass index was 45.3 kg/m(2). All patients were insulin-resistant and 6 showed hypertriglyceridemia. The median operating time was 66 minutes, and there were no intraoperative complications. No conversion to open surgery was required. No patient required additional trocars and no patient had postoperative complications. The median hospital stay was 3 days. After a one-year follow-up, the average weight decrease was 40.3 kg, resulting in a decrease in excess weight loss by 70.61%. Insulin-resistance decreased in 16/16 patients and hypertriglyceridemia decreased in 5/6 patients.

Conclusion: SPSG seems safe and effective in the short term in severely obese adolescents.
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http://dx.doi.org/10.1016/j.soard.2014.05.029DOI Listing
January 2016