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Dreuil-lès-Amiens, France

Fritez N.,Mohammed V University | Sobrier M.-L.,French Institute of Health and Medical Research | Sobrier M.-L.,Paris-Sorbonne University | Iraqi H.,Mohammed V University | And 14 more authors.
Clinical Endocrinology | Year: 2015

Background/Objectives Congenital hypopituitarism is a rare disease which, for most patients, has no identified molecular cause. We aimed to document the molecular basis of growth retardation in a Moroccan cohort. Design/Patients 80 index cases [54 with isolated growth hormone deficiency (IGHD), 26 with combined pituitary hormone deficiency (CPHD)] were screened for molecular defects in GH1 (including LCR-GH1), GHRHR, GHSR, GHRH, PROP1, POU1F1, HESX1, LHX3, LHX4 and SOX3. Results Five different deleterious mutations were identified in 14 patients from eight families. In the IGHD group, three genes were found to be involved: GH1, GHRHR and GHSR. In the CPHD group, PROP1 was the only mutated gene. In addition, two heterozygous variations whose deleterious effect remains to be demonstrated were identified (in GH1 and LHX4), and two polymorphisms (missense variations) were detected (in LHX3 and in GHSR). The prevalence of mutations in this Moroccan GHD cohort was 10% (8/80), 11·1% (6/54) in the IGHD group and 7·7% (2/26) in the CPHD group. Conclusion This is the first molecular screening of congenital GHD in a Moroccan population and, like other studies, mutations were preferentially identified in familial cases (75%); mutations in genes such as POU1F1, HESX1, SOX3, LHX3 and LHX4 are extremely rare. The p.R73C PROP1 mutation was the most frequent mutation in CPHD; this should be the first one to screen in this population. Our results should contribute to a better diagnosis and management of this heterogeneous disease condition. © 2014 John Wiley & Sons Ltd. Source

Even L.,Toulouse University Hospital Center | Bouali O.,Service de Chirurgie Pediatrique | Moscovici J.,Service de Chirurgie Pediatrique | Huyghe E.,Toulouse University Hospital Center | And 4 more authors.
Progres en Urologie | Year: 2015

Objective: To evaluate outcomes and long-term sexual quality of life after hypospadias surgery. Seventeen-years-old patients operated for a posterior hypospadias in childhood were included in a transversal study. Patients and methods: Fifteen patients, among the forty children treated since 1997, accepted to participate. These young men (mean age at the first surgery was 27.9. ±. 20. months) were clinically reviewed and responded to questionnaires (EUROQOL 5, IIEF15 and non-validated questionnaire). This study arises about 8.4. ±. 5. years after the last visit in paediatric department. Results: Mean study age was 21.2. ±. 4.7. years. One third of patients thought that global quality of life was distorted. Although 33% of the patients had erectile dysfunction, 80% were satisfied with their sexual quality of life. The most important complains were relative to the penile appearance. Number of procedures was not predictive of patient's satisfaction about penile function and appearance. Thirty-three percents of the patients would have been satisfied to have psychological and medical support. They would be interested in having contact with patients who suffered from the same congenital abnormality. Conclusion: These patients had functional and esthetical disturbances. This visit leads to a specific visit in 20% cases. In this study, medical follow-up does not seem to be counselling and had to be adapted. Adequate follow-up transition between paediatric and adult departments especially during adolescence seems to be necessary. © 2015 Elsevier Masson SAS. Source

Kalfa N.,Montpellier University Hospital Center | Meduri G.,Laboratoire Of Genetique Moleculaire | Philibert P.,Montpellier University Hospital Center | Patte C.,Institute Gustave Roussy | And 6 more authors.
Hormone Research in Paediatrics | Year: 2010

Background: Hyperandrogenism is a rare symptom of juvenile ovarian granulosa cell- tumors (JGCTO). This study aimed to determine whether hyperandrogenism was related to overexpression of SOX9, decreased expression of FOXL2 or absent aromatase expression in tumor with particular scheme of expression of P450scc and P450c17α. Methods: Through a nationwide study including the French Society of Pediatric Oncology, 6/30 patients with JGCTO presented with clinical hyperandrogenism and high plasma testosterone. Tumor specimens underwent immunofluorescence (SOX9, FOXL2) and immunochemistry (aromatase, P450scc, P450c17α). Results were compared with patients without hyperandrogenism. Results: SOX9 was expressed in the granulosa cell nucleus in 2/6 cases but also in 9/24 tumors without hyperandrogenism (p = n.s.). FOXL2 was absent or decreased in 3/6 cases of JGCTO with hyperandrogenism with no statistical difference from the group without this symptom. In 6/6 patients, the intratumoral expression of aromatase was absent (n = 5) or dramatically reduced (n = 1). In contrast, 15/24 patients without virilization exhibited conserved aromatase expression in their tumor (p < 0.05). A variable number of tumoral cells expressed P450scc while some interstitial cells were focally immunopositive for P450c17α. Conclusion: Unusual virilization in girls with JGCTO is not explained by a dysregulation in SOX9 or FOXL2 expression, but is related to a localized defect of aromatase expression in granulosa cells and to the ability of interstitial cells to produce testosterone. © 2010 S. Karger AG. Source

Brioude F.,University Paris Est Creteil | Bouvattier C.-E.,Service dendocrinologie pediatrique | Lombes M.,French Institute of Health and Medical Research
Annales d'Endocrinologie | Year: 2010

Hypogonadotropic hypogonadism (HH) is defined by the absence of sex steroid synthesis associated with the lack of appropriate gonadotrophin secretion. This leads to a variable degree of impuberism, often diagnosed during childhood or adolescence. Genetics of HH involve many genes. However, molecular defects have been identified in only 30 % of patients. Kallmann syndrome (KS) is defined by the association of HH and anosmia. Six genes are involved in KS (KAL1, FGFR1, FGF8, PROK2, PROKR2 and CHD7). However, genetics of KS is complex, because of the variability of the phenotype for a similar molecular defect. Otherwise, heterozygous anomalies are frequently described. Identification in the same patient of several mutations in some of these genes (digenism) could account for this variability. Autosomal recessive transmission is frequently observed in familial cases of HH without anosmia. Molecular alterations have been identified for several neuropeptides or their corresponding receptors, which are involved in the physiology of the gonadotropic axis: GNRHR, KISS1R/. GPR54, neurokinin B (TAC3), TACR3 and GNRH1 (and PROK2, PROKR2 and CHD7). Anomalies of leptin or its receptor are also involved in HH cases. A new negative regulating element has been recently identified in humans: RFRP3, which is ortholog of the avian GnIH (gonadotrophin inhibitory hormone). Recent progress about these neuropeptides leads to a new model of comprehension of the gonadotropic axis physiology, from a linear model to a network model, which regulates the central element of regulation of the gonadotropic axis, represented by the GnRH neurons. © 2010 Elsevier Masson SAS. Source

Demars J.,Heart Health | Rossignol S.,French Institute of Health and Medical Research | Netchine I.,French Institute of Health and Medical Research | Lee K.S.,Heart Health | And 12 more authors.
Human Mutation | Year: 2011

The imprinted 11p15 region is organized in two domains, each of them under the control of its own imprinting control region (ICR1 for the IGF2/H19 domain and ICR2 for the KCNQ1OT1/CDKN1C domain). Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes. Various 11p15 genetic and epigenetic defects have been demonstrated in BWS and SRS. Among them, isolated DNA methylation defects account for approximately 60% of patients. To investigate whether cryptic copy number variations (CNVs) involving only part of one of the two imprinted domains account for 11p15 isolated DNA methylation defects, we designed a single nucleotide polymorphism array covering the whole 11p15 imprinted region and genotyped 185 SRS or BWS cases with loss or gain of DNA methylation at either ICR1 or ICR2. We describe herein novel small gain and loss CNVs in six BWS or SRS patients, including maternally inherited cis-duplications involving only part of one of the two imprinted domains. We also show that ICR2 deletions do not account for BWS with ICR2 loss of methylation and that uniparental isodisomy involving only one of the two imprinted domains is not a mechanism for SRS or BWS. © 2011 Wiley-Liss, Inc. Source

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