Explorations Fonctionnelles Endocriniennes

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Explorations Fonctionnelles Endocriniennes

Paris, France
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Schluth-Bolard C.,University Claude Bernard Lyon 1 | Nadeau G.,Center Hospitalier Of Valence | Tevissen H.,Center Hospitalier Of Valence | Lesca G.,University Claude Bernard Lyon 1 | And 6 more authors.
Journal of Medical Genetics | Year: 2013

Background: Apparently balanced chromosomal rearrangements (ABCR) are associated with an abnormal phenotype in 6% of cases. This may be due to cryptic genomic imbalances or to the disruption of genes at the breakpoint. However, breakpoint cloning using conventional methods (ie, fluorescent in situ hybridisation (FISH), Southern blot) is often laborious and time consuming. In this work, we used next generation sequencing (NGS) to locate breakpoints at the molecular level in four patients with multiple congenital abnormalities and/or intellectual deficiency (MCA/ID) who were carrying ABCR (one translocation, one complex chromosomal rearrangement and two inversions), which corresponded to nine breakpoints. Methods: Genomic imbalance was previously excluded by array comparative genomic hybridisation (CGH) in all four patients. Whole genome paired-end protocol was used to identify breakpoints. The results were verified by FISH and by PCR with Sanger sequencing. Results: We were able to map all nine breakpoints. NGS revealed an additional breakpoint due to a cryptic inversion at a breakpoint junction in one patient. Nine of 10 breakpoints occurred in repetitive elements and five genes were disrupted in their intronic sequence (TCF4, SHANK2, PPFIA1, RAB19, KCNQ1). Conclusions: NGS is a powerful tool allowing rapid breakpoint cloning of ABCR at the molecular level. We showed that in three out of four patients, gene disruption could account for the phenotype, allowing adapted genetic counselling and stopping unnecessary investigations. We propose that patients carrying ABCR with an abnormal phenotype should be explored systematically by NGS once a genomic imbalance has been excluded by array CGH.


Dumoucel S.,University Pierre and Marie Curie | Gauthier-Villars M.,University Pierre and Marie Curie | Stoppa-Lyonnet D.,University Pierre and Marie Curie | Parisot P.,Hopital Necker | And 13 more authors.
Pediatric Blood and Cancer | Year: 2014

Background: Wilms Tumor (WT) can occur in association with tumor predisposition syndromes and/or with clinical malformations. These associations have not been fully characterized at a clinical and molecular genetic level. This study aims to describe clinical malformations, genetic abnormalities, and tumor predisposition syndromes in patients with WT and to propose guidelines regarding indications for clinical and molecular genetic explorations. Procedure: This retrospective study analyzed clinical abnormalities and predisposition syndromes among 295 patients treated for WT between 1986 and 2009 in a single pediatric oncological center. Results: Clinically identified malformations and predisposition syndromes were observed in 52/295 patients (17.6%). Genetically proven tumor predisposition syndromes (n=14) frequently observed were syndromes associated with alterations of the chromosome WT1 region such as WAGR (n=6) and Denys-Drash syndromes (n=3), syndromes associated with alterations of the WT2 region (Beckwith- Wiedeman syndrome, n=3), and Fanconi anemia (n=2). Hemihypertrophy and genito-urinary malformations (n=12 and n=16, respectively) were the most frequently identified malformations. Other different syndromes or malformations (n=10) were less frequent. Median age of WT diagnosis was significantly earlier for children with malformations than those without (27 months vs. 37 months, P=0.0009). There was no significant difference in terms of 5-year EFS and OS between WT patients without or with malformations. Conclusions: The frequency of malformations observed in patients with WT underline the need of genetic counseling and molecular genetic explorations for a better followup of these patients, with a frequently good outcome. A decisional tree, based on clinical observations of patients with WT, is proposed to guide clinicians for further molecular genetic explorations. © 2013 Wiley Periodicals, Inc.


Bruno C.,University of Burgundy | Bruno C.,Center Hospitalier University | Carmignac V.,University of Burgundy | Netchine I.,Explorations fonctionnelles endocriniennes | And 13 more authors.
Human Molecular Genetics | Year: 2015

Like genetic mutations, DNA methylation anomalies or epimutations can disrupt gene expression and lead to human diseases. However, unlike genetic mutations, epimutations can in theory be reverted through developmental epigenetic reprograming, which should limit their transmission across generations. Following the request for a parental project of a patient diagnosed with Silver-Russell syndrome (SRS), and the availability of both somatic and spermatozoaDNAfromthe proband and his father, we had the exceptional opportunity to evaluate the question of inheritance of an epimutation.We provide here for the first time evidence for efficient reversion of a constitutive epimutation in the spermatozoa of an SRS patient, which has important implication for genetic counseling. © The Author 2015. Published by Oxford University Press. All rights reserved.


PubMed | Explorations Fonctionnelles Endocriniennes, University of Leipzig, University Medicine, Mediclinic City Hospital and 3 more.
Type: | Journal: Medical devices (Auckland, N.Z.) | Year: 2016

A questionnaire-based survey was conducted to assess attitudes toward a reusable self-injection system (SurePal) among pediatric patients with growth disturbances who were prescribed treatment with Omnitrope() within routine clinical practice.This was a multicenter, observational study, incorporated into the noninterventional PAtients TReated with Omnitrope() (PATRO) Children study. Included subjects, or their caregivers, completed a questionnaire on the following five main areas: attractiveness of SurePal, training received, using the device, the low drug wastage system, and experience versus other devices used previously (pretreated patients). Responses were based on a 5-point scale, with 2 being the best possible outcome and -2 the worst possible outcome.In total, 550 patients were included in this study (338 from France, 169 from Germany, and 43 from the UK). The mean age standard deviation of participants was 10.83.5 years; the majority (57%) were male and growth hormone treatment nave (88%). Almost half (49.8%) of children prepared their SurePal for injection themselves and 45.5% performed injections themselves. As patients progressed into their teens, the majority (75%) favored preparing SurePal and performing injections themselves, rather than seeking assistance. The attractiveness of SurePal was rated as excellent/good by 84.7% of patients overall; this rating was similarly high (79%) across countries and age-groups. Preparing (88.8%) and using (83.3%) SurePal were rated as very easy/easy by most patients; these ratings were similarly high, irrespective of country or age-group. The dose-memory function was rated as very helpful/helpful by 66.2% of patients. Among 246 patients who reported using the low drug-waste feature, 87.4% found it helpful. Among pretreated patients (n=64), 78.2% reported that SurePal was much better/better than their previous device.These data confirm the ease of use and patient preference for SurePal among pediatric patients with growth disturbances.


Schnabel D.,University Medicine | Partsch C.-J.,Endokrinologikum Hamburg | Houang M.,Explorations Fonctionnelles Endocriniennes | Ehtisham S.,Mediclinic City Hospital | And 3 more authors.
Medical Devices: Evidence and Research | Year: 2016

Background: A questionnaire-based survey was conducted to assess attitudes toward a reusable self-injection system (SurePal™) among pediatric patients with growth disturbances who were prescribed treatment with Omnitrope® within routine clinical practice. Methods: This was a multicenter, observational study, incorporated into the noninterventional PAtients TReated with Omnitrope® (PATRO) Children study. Included subjects, or their caregivers, completed a questionnaire on the following five main areas: attractiveness of SurePal™, training received, using the device, the low drug wastage system, and experience versus other devices used previously (pretreated patients). Responses were based on a 5-point scale, with 2 being the best possible outcome and −2 the worst possible outcome. Results: In total, 550 patients were included in this study (338 from France, 169 from Germany, and 43 from the UK). The mean age ± standard deviation of participants was 10.8±3.5 years; the majority (57%) were male and growth hormone treatment naïve (88%). Almost half (49.8%) of children prepared their SurePal™ for injection themselves and 45.5% performed injections themselves. As patients progressed into their teens, the majority (≥75%) favored preparing SurePal™ and performing injections themselves, rather than seeking assistance. The attractiveness of SurePal™ was rated as excellent/good by 84.7% of patients overall; this rating was similarly high (≥79%) across countries and age-groups. Preparing (88.8%) and using (83.3%) SurePal™ were rated as very easy/easy by most patients; these ratings were similarly high, irrespective of country or age-group. The dose-memory function was rated as very helpful/helpful by 66.2% of patients. Among 246 patients who reported using the low drug-waste feature, 87.4% found it helpful. Among pretreated patients (n=64), 78.2% reported that SurePal™ was much better/ better than their previous device. Conclusion: These data confirm the ease of use and patient preference for SurePal™ among pediatric patients with growth disturbances. © 2016 Schnabel et al.


Le Bouc Y.,Explorations fonctionnelles endocriniennes | Le Bouc Y.,French Institute of Health and Medical Research | Rossignol S.,Explorations fonctionnelles endocriniennes | Rossignol S.,French Institute of Health and Medical Research | And 5 more authors.
Annales d'Endocrinologie | Year: 2010

Epigenetic mechanisms play a key role in regulating gene expression. One hallmark of these modifications is DNA methylation at cytosine residues of CpG dinucleotides in gene promoters, transposons and imprinting control regions. Genomic imprinting refers to an epigenetic marking of genes that results in monoallelic expression depending on their parental origin. There are two critical time periods in epigenetic reprogramming: gametogenesis and early preimplantation development. Major reprogramming takes place in primordial germ cells in which parental imprints are erased and totipotency is restored [1]. Imprint marks are then and re-established during spermatogenesis or oogenesis, depending on sex [1-3]. Upon fertilization, genome-wide demethylation occurs followed by a wave of de novo methylation, both of which are resisted by imprinted loci [4]. Epigenetic patterns are usually faithfully maintained during development. However, this maintenance sometimes fails, resulting in the disturbance of epigenetic patterns and human disorders. For example, two fetal growth disorders, the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes with opposite phenotypes, are caused by abnormal DNA methylation at the 11p15 imprinted locus [5-7]: respectively loss of methylation at the Imprinting Region Center (ICR2) or gain of methylation at ICR1 in BWS and loss of methylation at ICR1 in SRS. Early embryogenesis is a critical time for epigenetic regulation, and this process is sensitive to environmental factors. The use of assisted reproductive technology (ART) has been shown to induce epigenetic alterations and to affect fetal growth and development [8-11]. In humans, several imprinting disorders, including BWS, occur at significantly higher frequencies in children conceived with the use of ART than in children conceived spontaneously [12,13]. The cause of these epigenetic imprinting disorders (following ART, unfertility causes, hormonal hyperstimulation, in vitro fertilization-IVF, Intracytoplasmic sperm injection-ICSI, micro-manipulation of gametes, exposure to culture medium, in vitro ovocyte maturation, time of transfer) remains unclear. However, recent data have shown that in patients with BWS or SRS, including those born following the use of ART, the DNA methylation defect involves imprinted loci other than 11p15 [14,15] (11p15 region: CTCF binding sites at ICR1, H19 and IGF2 DMRs, KCNQ1OT1 [ICR2], SNRPN [chromosome 15 q11-13], PEG/MEST1 [chromosome 7q31], IGF type2 receptor and ZAC1 [chromosome 6q26 et 6q24 respectively], DLK1/GTL2-IG-DMR [chromosome 14q32] and GNAS locus [chromosome 20q13.3]). This suggests that unfaithful maintenance of DNA methylation marks following fertilization involves the dysregulation of a trans-acting regulatory factor that could be altered by ART. © 2010.


Arpin S.,Groupe Hospitalier Pitie Salpetriere | Arpin S.,Center Olympe Of Gouges | Arpin S.,University of Tours | Afenjar A.,Groupe Hospitalier Pitie Salpetriere | And 5 more authors.
Clinical Dysmorphology | Year: 2012

Floating-Harbor Syndrome is a growth retardation syndrome with delayed bone age, typical facial features, and retarded speech development of unknown etiology. Very few familial cases have been reported. We report on the fourth case in a mother and daughter, suggesting autosomal dominant inheritance. © 2011 Wolters Kluwer Health|Lippincott Williams & Wilkins.


Backeljauw P.,University of Cincinnati | Bang P.,Karolinska University Hospital | Dunger D.B.,University of Cambridge | Juul A.,Copenhagen University | And 2 more authors.
Journal of Pediatric Endocrinology and Metabolism | Year: 2010

Deficiency of insulin-like growth factor-I (IGF-I) results in growth failure. A variety of molecular defects have been found to underlie severe primary IGF-I deficiency (IGFD), in which serum IGF-I concentrations are substantially decreased and fail to respond to GH therapy. Identification of more patients with primary or secondary IGFD is likely with investigative and diagnostic progress, particularly in the assessment of | children with idiopathic short stature. Diagnosis of IGFD requires accurate and reliable IGF-I assays, adequate normative data for reference, and knowledge of IGF-I physiology for proper interpretation of data. Recombinant human IGF-I (rhIGF-I) treatment improves stature in patients with severe primary IGFD, and has also been shown to improve glycaemic control and insulin sensitivity in patients with severe insulin resistance. Ongoing studies of patients receiving rhIGF-I will allow further evaluation of the clinical utility of this treatment, with concurrent increase in our understanding of IGF-I and conditions of IGFD. © Freund Publishing House Ltd.,.


PubMed | Explorations fonctionnelles endocriniennes
Type: Journal Article | Journal: Annales d'endocrinologie | Year: 2010

Epigenetic mechanisms play a key role in regulating gene expression. One hallmark of these modifications is DNA methylation at cytosine residues of CpG dinucleotides in gene promoters, transposons and imprinting control regions. Genomic imprinting refers to an epigenetic marking of genes that results in monoallelic expression depending on their parental origin. There are two critical time periods in epigenetic reprogramming: gametogenesis and early preimplantation development. Major reprogramming takes place in primordial germ cells in which parental imprints are erased and totipotency is restored [1]. Imprint marks are then and re-established during spermatogenesis or oogenesis, depending on sex [1-3]. Upon fertilization, genome-wide demethylation occurs followed by a wave of de novo methylation, both of which are resisted by imprinted loci [4]. Epigenetic patterns are usually faithfully maintained during development. However, this maintenance sometimes fails, resulting in the disturbance of epigenetic patterns and human disorders. For example, two fetal growth disorders, the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes with opposite phenotypes, are caused by abnormal DNA methylation at the 11p15 imprinted locus [5-7]: respectively loss of methylation at the Imprinting Region Center (ICR2) or gain of methylation at ICR1 in BWS and loss of methylation at ICR1 in SRS. Early embryogenesis is a critical time for epigenetic regulation, and this process is sensitive to environmental factors. The use of assisted reproductive technology (ART) has been shown to induce epigenetic alterations and to affect fetal growth and development [8-11]. In humans, several imprinting disorders, including BWS, occur at significantly higher frequencies in children conceived with the use of ART than in children conceived spontaneously [12,13]. The cause of these epigenetic imprinting disorders (following ART, unfertility causes, hormonal hyperstimulation, in vitro fertilization-IVF, Intracytoplasmic sperm injection-ICSI, micro-manipulation of gametes, exposure to culture medium, in vitro ovocyte maturation, time of transfer) remains unclear. However, recent data have shown that in patients with BWS or SRS, including those born following the use of ART, the DNA methylation defect involves imprinted loci other than 11p15 [14,15] (11p15 region: CTCF binding sites at ICR1, H19 and IGF2 DMRs, KCNQ1OT1 [ICR2], SNRPN [chromosome 15 q11-13], PEG/MEST1 [chromosome 7q31], IGF type2 receptor and ZAC1 [chromosome 6q26 et 6q24 respectively], DLK1/GTL2-IG-DMR [chromosome 14q32] and GNAS locus [chromosome 20q13.3]). This suggests that unfaithful maintenance of DNA methylation marks following fertilization involves the dysregulation of a trans-acting regulatory factor that could be altered by ART.

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