Publications by authors named "Sabine Baron"

26 Publications

  • Page 1 of 1

High Diagnostic Yield of Targeted Next-Generation Sequencing in a Cohort of Patients With Congenital Hypothyroidism Due to Dyshormonogenesis.

Front Endocrinol (Lausanne) 2020 22;11:545339. Epub 2021 Feb 22.

INSERM U1016, Cochin Institute, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Objective: To elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS).

Study Design: We studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature.

Results: TNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved , followed by , , and and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis.

Conclusions: In a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.
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http://dx.doi.org/10.3389/fendo.2020.545339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937947PMC
February 2021

Presenting features and molecular genetics of primary hyperparathyroidism in the paediatric population.

Eur J Endocrinol 2021 Feb;184(2):347-355

Paediatric Unit, Limoges University Hospital, Limoges, France.

Aim: To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population.

Methods: Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018.

Results: Compared to older children, infants were often asymptomatic (54% vs 15%, P = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, 'CaSR group'; 94% of infants with mutations) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, 'cell proliferation group'; 69% of children and adolescents with mutations). Although serum calcium levels did not differ between the two groups (P = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in 'cell proliferation group' patients compared to those in the 'CaSR group' (P = 0.001 and 0.028, respectively).

Conclusion: Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients.
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http://dx.doi.org/10.1530/EJE-20-1119DOI Listing
February 2021

Effects of advanced carbohydrate counting on glucose control and quality of life in children with type 1 diabetes.

Pediatr Diabetes 2020 11 3;21(7):1240-1248. Epub 2020 Aug 3.

Pediatric Diabetology, University Hospital, Angers, France.

Objective: The effect of advanced carbohydrate counting (ACC) on metabolic and quality of life (QOL) outcomes is uncertain in children with type 1 diabetes. Our aim was to determine whether ACC would improve HbA1c and QOL scores as compared with standard nutrition in this population.

Methods: We randomized 87 patients using pump and rapid-acting analogs in a 1 year randomized multicenter study (age 9.6 ± 3.5 years, diabetes duration 4.6 ± 2.7 years, HbA1c 7.8 ± 0.5% [62 ± 5 mmol/mol]). The ACC group received CC education and the control group received traditional dietary education. HbA1c was measured every 3 months. At 0 and 1 year, general, diabetes-specific, and diet-related QOL were respectively assessed by the KIDSCREEN and WHO-5 questionnaires, the diabetes-specific module of the DISABKIDS, and the diet restriction items of the DSQOLS.

Results: Mean HbA1c was lower in the ACC than the control group at 3 months (P < .05) and tended to be lower at 6 months (P = .10), 9 months (P = .10), but not at 12 months. The mean of individual average HbA1c during the one-year study period (from M3 to M12) was 7.63 ± 0.43 in the ACC vs 7.85 ± 0.47% in the control group (60 ± 5 vs 62 ± 5 mmol/mol)(P < .05). ACC was associated with significantly higher scores at 1 year on the KIDSCREEN children's psychological scale and the KIDSCREEN parents' physical scale, the DISABKIDS children's treatment scale, and the children's and parents' dietary restriction scales of the DSQOLS (indicating better QOL or lower perceived diet restriction).

Conclusions: ACC may be associated with small improvements in metabolic control and QOL scores in children.
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http://dx.doi.org/10.1111/pedi.13076DOI Listing
November 2020

[Knowledge, attitudes and practices of parents on vaccination against polio in Abeche-Tchad].

Pan Afr Med J 2018 4;31:219. Epub 2018 Dec 4.

Laboratoire de Santé Publique, EE1 EES, Université François Rabelais, Tours, France.

Introduction: in Chad, transmission of poliovirus has been interrupted in 2000, but imports from Nigeria and weakness of vaccination coverage are a major risk of disease reactivation. This study aims to investigate knowledge, attitudes and practices of parents of children aged 0 to 5 years on vaccination against polio in Chad.

Methods: this cross-sectional study was carried out in the six districts of Abéché. Only households who had children under 5 years of age were included. Data were collected through interviews with parents and guardians of eligible children using a tested and validated questionnaire.

Results: we interviewed 210 households. No family had a vaccination record notebook of their children. However, 97% reported vaccinated children who had participated in mass vaccination campaigns. About 97% were aware of poliomyelitis disease and 98% knew vaccination campaign. The most cited channels of information were radio (98%) and vaccinators (72%). Only 3% of parents reported refusing vaccination. There was an association between the negative influence of the relatives and the non-vaccination of children (p = 0.005).

Conclusion: disease and vaccine knowledge is good in Chad despite the existence of rumours about, in particular, vaccine effects. The lack of immunization cards limited the analysis of survey results which were only declarative with a very high declared vaccination rate. Immunization cards are essential for eradication in association with prevention policy.
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http://dx.doi.org/10.11604/pamj.2018.31.219.12966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693789PMC
September 2019

Pycnodysostosis: Natural history and management guidelines from 27 French cases and a literature review.

Clin Genet 2019 10 25;96(4):309-316. Epub 2019 Jun 25.

Department of Medical Genetics, Reference Center for Skeletal Dysplasia and OSCAR Network, Paris Descartes-Sorbonne Paris Cité University, INSERM UMR 1163, Instititut Imagine, Hôpital Necker Enfants Malades, Paris, France.

Pycnodysostosis is a lysosomal autosomal recessive skeletal dysplasia characterized by osteosclerosis, short stature, acro-osteolysis, facial features and an increased risk of fractures. The clinical heterogeneity of the disease and its rarity make it difficult to provide patients an accurate prognosis, as well as appropriate care and follow-up. French physicians from the OSCAR network have been asked to fill out questionnaires collecting molecular and clinical data for 27 patients issued from 17 unrelated families. All patients showed short stature (mean = -3.5 SD) which was more severe in females (P = .006). The mean fracture rate was moderate (0.21 per year), with four fractures in total average. About 75% underwent at least one surgery, with an average number of 2.1 interventions per patient. About 50% required non-invasive assisted ventilation due to sleep apnea (67%). About 29% showed psychomotor difficulties and 33% needed a school assistant or adapted schooling. No patient had any psychological evaluation or follow-up. Molecular data were available for 14 families. Growth hormone administration was efficient on linear growth in 40% of cases. We propose several axis of management, such as systematic cerebral MRI for Chiari malformation screening at diagnosis and regular psychological follow-up.
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http://dx.doi.org/10.1111/cge.13591DOI Listing
October 2019

Should 45,X/46,XY boys with no or mild anomaly of external genitalia be investigated and followed up?

Eur J Endocrinol 2018 Sep 4;179(3):181-190. Epub 2018 Jul 4.

Pediatric Endocrinology Department, CHU Robert Debré, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Assistance-Publique Hôpitaux de Paris and Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

Objective: Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development.

Methods: Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France.

Results: Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. -2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% ( = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels).

Conclusion: This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.
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http://dx.doi.org/10.1530/EJE-18-0309DOI Listing
September 2018

Sex chromosome aneuploidies and copy-number variants: a further explanation for neurodevelopmental prognosis variability?

Eur J Hum Genet 2017 08 14;25(8):930-934. Epub 2017 Jun 14.

Service de Génétique Médicale, CHU Nantes, Nantes, France.

Sex chromosome aneuploidies (SCA) is a group of conditions in which individuals have an abnormal number of sex chromosomes. SCA, such as Klinefelter's syndrome, XYY syndrome, and Triple X syndrome are associated with a large range of neurological outcome. Another genetic event such as another cytogenetic abnormality may explain a part of this variable expressivity. In this study, we have recruited fourteen patients with intellectual disability or developmental delay carrying SCA associated with a copy-number variant (CNV). In our cohort (four patients 47,XXY, four patients 47,XXX, and six patients 47,XYY), seven patients were carrying a pathogenic CNV, two a likely pathogenic CNV and five a variant of uncertain significance. Our analysis suggests that CNV might be considered as an additional independent genetic factor for intellectual disability and developmental delay for patients with SCA and neurodevelopmental disorder.
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http://dx.doi.org/10.1038/ejhg.2017.93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567159PMC
August 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.

Authors:
F Balazard S Le Fur S Valtat A J Valleron P Bougnères Dominique Thevenieau Corinne Fourmy Chatel Rachel Desailloud Hélène Bony-Trifunovic Pierre-Henri Ducluzeau Régis Coutant Sophie Caudrelier Armelle Pambou Emmanuelle Dubosclard Florence Joubert Philippe Jan Estelle Marcoux Anne-Marie Bertrand Brigitte Mignot Alfred Penformis Chantal Stuckens Régis Piquemal Pascal Barat Vincent Rigalleau Chantal Stheneur Sylviane Fournier Véronique Kerlan Chantal Metz Anne Fargeot-Espaliat Yves Reznic Frédérique Olivier Iva Gueorguieva Arnaud Monier Catherine Radet Vincent Gajdos Daniel Terral Christine Vervel Djamel Bendifallah Candace Ben Signor Daniel Dervaux Abdelkader Benmahammed Guy-André Loeuille Françoise Popelard Agnès Guillou Pierre-Yves Benhamou Jamil Khoury Jean-Pierre Brossier Joachim Bassil Sylvaine Clavel Bernard Le Luyer Pierre Bougnères Françoise Labay Isabelle Guemas Jacques Weill Jean-Pierre Cappoen Sylvie Nadalon Anne Lienhardt-Roussie Anne Paoli Claudie Kerouedan Edwige Yollin Marc Nicolino Gilbert Simonin Jacques Cohen Catherine Atlan Agnès Tamboura Hervé Dubourg Marie-Laure Pignol Philippe Talon Stéphanie Jellimann Lucy Chaillous Sabine Baron Marie-Noëlle Bortoluzzi Elisabeth Baechler Randa Salet Ariane Zelinsky-Gurung Fabienne Dallavale Etienne Larger Marie Laloi-Michelin Jean-François Gautier Bénédicte Guérin Laure Oilleau Laetitia Pantalone Céline Lukas Isabelle Guilhem Marc De Kerdanet Marie-Claire Wielickzo Mélanie Priou-Guesdon Odile Richard François Kurtz Norbert Laisney Déborah Ancelle Guilhem Parlier Catherine Boniface Dominique Paris Bockel Denis Dufillot Berthe Razafimahefa Pierre Gourdy Pierre Lecomte Myriam Pepin-Donat Marie-Emmanuelle Combes-Moukhovsky Brigitte Zymmermann Marina Raoulx Anne Gourdin Et Catherine Dumont

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 patterns of patients with Noonan syndrome: correlation with age and genotype.

Eur J Endocrinol 2016 May 22;174(5):641-50. Epub 2016 Feb 22.

EndocrineBone Diseases, and Genetics Unit, Children's Hospital, Toulouse University Hospital, Toulouse, France INSERM UMR 1043Centre of Pathophysiology of Toulouse Purpan (CPTP), University of Toulouse Paul Sabatier, Toulouse, France

Background: Growth patterns of patients with Noonan syndrome (NS) were established before the involved genes were identified.

Objective: The goal of this study was to compare growth parameters according to genotype in patients with NS.

Subjects And Methods: The study population included 420 patients (176 females and 244 males) harboring mutations in the PTPN11, SOS1, RAF1, or KRAS genes. NS-associated PTPN11 mutations (NS-PTPN11) and NS with multiple lentigines-associated PTPN11 mutations (NSML-PTPN11) were distinguished. Birth measures and height and body mass index (BMI) measures at 2, 5, 10 years, and adulthood were compared with the general population and between genotypes.

Results: Patients with NS were shorter at birth (mean birth length standard deviation score (SDS): -1.0 ± 1.4; P < 0.001) and throughout childhood than the healthy population, with height SDS being -2.1 ± 1.3 at 2 years, and -2.1 ± 1.2 at 5 and 10 years and adulthood (P < 0.001). At birth, patients with NS-PTPN11 were significantly shorter and thinner than patients with NSML-PTPN11, SOS1, or KRAS. Growth retardation was significantly less severe and less frequent at 2 years in patients with NSML-PTPN11 and SOS1 than in patients with NS-PTPN11 (P < 0.001 and P = 0.002 respectively). Patients with NS had lower BMI at 10 years (P < 0.001). No difference between genotypes was demonstrated.

Conclusion: Determining the growth patterns of patients with NS according to genotype should better inform clinicians about the natural course of growth in NS so that they can optimize the follow-up and management of these patients.
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http://dx.doi.org/10.1530/EJE-15-0922DOI Listing
May 2016

Support for the usefulness of passive postdischarge surveillance in surgical site infection.

Am J Infect Control 2015 09 29;43(9):1023-4. Epub 2015 Jul 29.

Centre de coordination pour la lutte contre les infections associées aux soins (C-CLIN), Paris, France.

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http://dx.doi.org/10.1016/j.ajic.2015.05.048DOI Listing
September 2015

Surgical site infection after primary hip and knee arthroplasty: a cohort study using a hospital database.

Infect Control Hosp Epidemiol 2015 Oct 8;36(10):1198-207. Epub 2015 Jul 8.

5Ecole des Hautes Etudes en Santé Publique & Centre de coordination pour la lutte contre les infections associées aux soins,Paris,France.

Background: Hip or knee arthroplasty infection (HKAI) leads to heavy medical consequences even if rare.

Objective: To assess the routine use of a hospital discharge detection algorithm of prosthetic joint infection as a novel additional tool for surveillance.

Methods: A historic 5-year cohort study was built using a hospital database of people undergoing a first hip or knee arthroplasty in 1 French region (2.5 million inhabitants, 39 private and public hospitals): 32,678 patients with arthroplasty code plus corresponding prosthetic material code were tagged. HKAI occurrence was then tracked in the follow-up on the basis of a previously validated algorithm using International Statistical Classification of Disease, Tenth Revision, codes as well as the surgical procedures coded. HKAI density incidence was estimated during the follow-up (up to 4 years after surgery); risk factors were analyzed using Cox regression.

Results: A total of 604 HKAI patients were identified: 1-year HKAI incidence was1.31%, and density incidence was 2.2/100 person-years in hip and 2.5/100 person-years in knee. HKAI occurred within the first 30 days after surgery for 30% but more than 1 year after replacement for 29%. Patients aged 75 years or older, male, or having liver diseases, alcohol abuse, or ulcer sore had higher risk of infection. The inpatient case fatality in HKAI patients was 11.4%.

Conclusions: The hospital database method used to measure occurrence and risk factors of prosthetic joint infection helped to survey HKAI and could optimize healthcare delivery.
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http://dx.doi.org/10.1017/ice.2015.148DOI Listing
October 2015

Clinical and economic outcomes of infective endocarditis.

Infect Dis (Lond) 2015 Feb 26;47(2):80-7. Epub 2014 Nov 26.

From the Service de Médecine Interne et Maladies Infectieuses , CHRU de Tours, Tours , France.

Background: In France, the estimated annual incidence of infective endocarditis (IE) is 33.8 cases per million residents. Valvular surgery is frequently undergone. We report an epidemiological and economic study of IE for 2007-2009 in a French region, using the hospital discharge database (HDD).

Methods: The population studied concerned all the patients living in Centre region, France, hospitalized for IE. We extracted hospital stay data for IE from the regional HDD, with a definition based on IE-related diagnosis codes. The predictive positive value (PPV) and sensitivity (Se) of the definition were 87.4% and 90%, respectively, according to the Duke criteria (definite IE frequency 74.4%). Hospitalization costs were estimated, taking into account the fixed hospital charges of the diagnosis-related group (DRG) and supplementary charges due to intensive care unit (ICU) stay.

Results: The analysis included 578 patients. The annual average incidence was 45.4 cases per million residents. Valvular surgery was performed in 19.4% of cases. The hospital mortality was 17.6%. Multivariate analysis identified as risk factors for mortality an age ≥ 70 years (odds ratio (OR) = 3.03, 95% confidence interval (CI) = 1.78-5.18), staphylococcal IE (OR = 3.3, 95% CI = 1.9-5.7), chronic renal insufficiency (OR = 2.04, 95% CI = 1.00-4.15), ischemic stroke (OR = 2.55, 95% CI = 1.19-5.47), and hemorrhagic stroke (OR = 5.7, 95% CI = 1.9-17.3). The average cost per episode was $20 103 (€15 281).

Conclusions: We report a higher incidence of IE than described by the French national study of 2008. Valvular surgery was considerably less frequent than in the published data, whereas mortality was similar. IE generates substantial costs.
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http://dx.doi.org/10.3109/00365548.2014.968608DOI Listing
February 2015

Quality assessment of hospital discharge database for routine surveillance of hip and knee arthroplasty-related infections.

Infect Control Hosp Epidemiol 2014 Jun 22;35(6):646-51. Epub 2014 Apr 22.

Université Pierre et Marie Curie, Paris, France.

Objective: Surgical site infection (SSI) surveillance represents a key method of nosocomial infection control programs worldwide. However, most SSI surveillance systems are considered to be poorly cost effective regarding human and economic resources required for data collection and patient follow up. This study aims to assess the efficacy of using hospital discharge databases (HDDs) as a routine surveillance system for detecting hip or knee arthroplasty-related infections (HKAIs).

Methods: A case-control study was conducted among patients hospitalized in the Centre region of France between 2008 and 2010. HKAI cases were extracted from the HDD with various algorithms based on the International Classification of Diseases, Tenth Revision, and procedure codes. The control subjects were patients with hip or knee arthroplasty (HKA) without infection selected at random from the HDD during the study period. The gold standard was medical chart review. Sensitivity (Se), specificity (Spe), positive predictive value (PPV), and negative predictive value (NPV) were calculated to evaluate the efficacy of the surveillance system.

Results: Among 18,265 hospital stays for HKA, corresponding to 17,388 patients, medical reports were checked for 1,010 hospital stays (989 patients). We identified 530 cases in total (incidence rate, 1% [95% confidence interval (CI), 0.4%-1.6%), and 333 cases were detected by routine surveillance. As compared with 480 controls, Se was 98%, Spe was 71%, PPV was 63%, and NPV was 99%. Using a more specific case definition, based on a sample of 681 hospital stays, Se was 97%, Spe was 95%, PPV was 87%, and NPV was 98%.

Conclusions: This study demonstrates the potential of HDD as a tool for routine SSI surveillance after low-risk surgery, under conditions of having an appropriate algorithm for selecting infections.
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http://dx.doi.org/10.1086/676423DOI Listing
June 2014

Constitutional telomeric association (Y;7) in a patient with a female phenotype.

Am J Med Genet A 2013 Jun 23;161A(6):1436-41. Epub 2013 Apr 23.

CHU Nantes, Service de Génétique Médicale, Nantes, France.

Telomeric associations (TAs) are fusions between two telomeres of two different chromosomes without visible loss of chromosomal material. Constitutional telomeric associations are rare chromosomal anomalies. We report on the cytogenetic and molecular analyses of a TA involving chromosomes Y and 7 in a child with a female phenotype. Prenatal cytogenetic analysis showed a 45,X chromosome complement in all cells. No fetal abnormality was identified at ultrasound examinations and the pregnancy went to term. During childhood, the proband had gonadal dysgenesis but no other phenotypic manifestations of Turner syndrome. Molecular genetic analyses showed the presence of genomic DNA of the SRY gene without any mutation. Karyotyping and fluorescent in situ hybridization (FISH) analyses on blood showed two cell lines: one cell line with a TA involving chromosomes Y and 7 [46,X,tas(Y;7)(p11.32;q36.3)] and a second cell line with a 45,X pattern. A human pantelomeric repeat TTAGGG probe hybridized to the junction of the TA within the derivative chromosome. FISH and array comparative genomic hybridization (aCGH) analyses demonstrated that tas(Y;7) occurred without detectable loss of any sequence at the derivative chromosome. SNP array analysis excluded an uniparental isodisomy of chromosome 7. Knowing more about TAs will help geneticists to deliver accurate genetic counseling.
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http://dx.doi.org/10.1002/ajmg.a.35889DOI Listing
June 2013

Adrenal rest tissue in gonads of patients with classical congenital adrenal hyperplasia: multicenter study of 45 French male patients.

Ann Endocrinol (Paris) 2012 Dec 3;73(6):515-22. Epub 2012 Nov 3.

Adult Endocrinology Unit, University Hospital of Tours, 2, boulevard Tonnelé, 37044 Tours cedex 9, France.

Objectives: Several cases of testicular adrenal rest tumours have been reported in men with congenital adrenal hyperplasia (CAH) due to the classical form of 21-hydroxylase deficiency but the prevalence has not been established. The aims of this report were to evaluate the frequency of testicular adrenal rest tissue in this population in a retrospective multicentre study involving eight endocrinology centres, and to determine whether treatment or genetic background had an impact on the occurrence of adrenal rest tissue.

Material And Methods: Testicular adrenal rest tissue (TART) was sought clinically and with ultrasound examination in forty-five males with CAH due to the classical form of 21-hydroxylase deficiency. When the diagnosis of testicular adrenal rest tumours was sought, good observance of treatment was judged on biological concentrations of 17-hydroxyprogesterone (17OHP), delta4-androstenedione, active renin and testosterone. The results of affected and non-affected subjects were compared.

Results: TART was detected in none of the 18 subjects aged 1 to 15years but was detected in 14 of the 27 subjects aged more than 15years. Five patients with an abnormal echography result had no clinical signs. Therapeutic control evaluated at diagnosis of TART seemed less effective when diagnosis was made in patients with adrenal rest tissue compared to TART-free subjects. Various genotypes were observed in patients with or without TART.

Conclusion: Due to the high prevalence of TART in classical CAH and the delayed clinical diagnosis, testicular ultrasonography must be performed before puberty and thereafter regularly during adulthood even if the clinical examination is normal.
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http://dx.doi.org/10.1016/j.ando.2012.09.005DOI Listing
December 2012

Clinical utility gene card for: Leri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD).

Eur J Hum Genet 2012 Aug 18;20(8). Epub 2012 Apr 18.

CHU Nantes Hôtel-Dieu, Institut de Biologie, Service de Génétique Médicale, Laboratoire de Génétique Moléculaire, Nantes, France.

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http://dx.doi.org/10.1038/ejhg.2012.64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400739PMC
August 2012

GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus.

N Engl J Med 2012 Feb;366(5):433-42

Division of Pediatrics, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.

Background: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.

Methods: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.

Results: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences.

Conclusions: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).
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http://dx.doi.org/10.1056/NEJMoa1107096DOI Listing
February 2012

Impaired puberty, fertility, and final stature in 45,X/46,XY mixed gonadal dysgenetic patients raised as boys.

Eur J Endocrinol 2012 Apr 11;166(4):687-94. Epub 2012 Jan 11.

Pediatric Endocrinology Department, Bicêtre Hospital, 78 Rue du Général Leclerc, Le Kremlin Bicêtre, France.

Context: Gender assignment followed by surgery and hormonal therapy is a difficult decision in the management of 45,X/46,XY patients with abnormal external genitalia at birth considering the paucity of studies evaluating pubertal development and fertility outcome, most notably for patients raised as boys.

Objective: The purpose of this study was to describe the pubertal course of 20 45,X/46,XY patients born with ambiguous genitalia and raised as boys.

Methods: This is a multicenter retrospective study.

Results: Mean age at study was 25.6±2.4 years. Eighty-five percent of the patients presented a 'classical' mixed gonadal dysgenetic phenotype at birth. Puberty was initially spontaneous in all but three boys, although in six other patients, testosterone therapy was subsequently necessary for completion of puberty. Sixty-seven percent of the remaining patients presented signs of declined testicular function at the end of puberty (increased levels of FSH and low levels of testosterone and/or inhibin B). Moreover, an abnormal structure of the Y chromosome, known to alter fertility, was found in 10 out of 16 (63%) patients. Two patients developed testicular cancer. Half of the patients have adult penile length of <80 mm. Mean adult height is 156.9±2 cm, regardless of GH treatment.

Conclusions: In summary, 45,X/46,XY children born with ambiguous genitalia and raised as boys have an altered pubertal course and impaired fertility associated with adult short stature, which should, therefore, be taken into consideration for the management of these patients.
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http://dx.doi.org/10.1530/EJE-11-0756DOI Listing
April 2012

Axial spondylometaphyseal dysplasia: Confirmation and further delineation of a new SMD with retinal dystrophy.

Am J Med Genet A 2010 Jun;152A(6):1550-4

Clinical Genetic Department, Nantes University Hospital, Nantes Cedex, France.

This report describes two unrelated boys presenting with short stature, femoral metaphyseal abnormalities, platyspondyly, and retinitis pigmentosa. Patients share similar findings with cases described by Ehara et al. [Ehara et al. (1997); Eur J Pediatr 156:627-630] described as axial spondylometaphyseal dysplasia. The presence of consanguinity in one of our patients further supports an autosomal recessive mode of inheritance of what, we believe, constitutes a separate and distinct entity.
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http://dx.doi.org/10.1002/ajmg.a.33397DOI Listing
June 2010

46,XY pure gonadal dysgenesis: clinical presentations and management of the tumor risk.

J Pediatr Urol 2011 Feb 11;7(1):72-5. Epub 2010 Feb 11.

Department of pediatric surgery, Hopital Mère-Enfant, Nantes, France.

Patients: Eleven patients with 46,XY PGD were divided into two groups. Six symptomatic girls (group 1) were referred for amenorrhea (n = 3), gonadal tumor (n = 2) or campomelic dysplasia (n = 1). Five asymptomatic screened patients (group 2) were diagnosed as 46,XY PGD after familial investigation of the two probands with gonadal tumor. Bilateral gonadectomy was performed in all patients.

Results: In group 1, pathologic examination revealed an association of dysgerminoma with gonadoblastoma (n = 2), bilateral gonadoblastoma (n = 2) and streak gonads (n = 2). Prophylactic gonadectomy in asymptomatic patients (group 2) also showed asymptomatic dysgerminoma with gonadoblastoma (n = 1), bilateral gonadoblastoma (n = 2) and streak gonads (n = 2).

Conclusions: A gonadal tumor arising in a girl with pubertal delay may be related to dysgenesis of the gonad. Primary amenorrhea or diagnosis of dysgerminoma should warrant karyotype, and familial study if 46,XY PGD is found. Considering the high incidence of gonadoblastoma and the early occurrence of dysgerminoma, early bilateral gonadectomy is recommended.
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http://dx.doi.org/10.1016/j.jpurol.2010.01.010DOI Listing
February 2011

Deletion of the CUL4B gene in a boy with mental retardation, minor facial anomalies, short stature, hypogonadism, and ataxia.

Am J Med Genet A 2010 Jan;152A(1):175-80

Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes 7, Quai Moncousu, 44000 Nantes Cedex, France.

The CUL4B gene encodes a member of Cullin-RING ubiquitin ligase complex. Point mutations in CUL4B were identified recently in patients with syndromic X-linked mental retardation (XLMR). Here, using oligoarray-based comparative genomic hybridization (array CGH), we identified a de novo deletion of the CUL4B gene in a boy with syndromic mental retardation, minor facial anomalies, short stature, delayed puberty, hypogonadism, relative macrocephaly, gait ataxia, and pes cavus, all manifestations described previously in patients with CUL4B point mutations. Interestingly, our patient also presented with aortic valvular "dysplasia" and vertebral anomalies similar to those seen in Scheuermann disease, both of which may also be part of this syndrome. This report further suggests that point mutations and deletions of the CUL4B gene lead to a recognizable phenotype. The association of facial anomalies, short stature, hypogonadism, and gait ataxia in a mentally retarded boy should prompt molecular analyses of the CUL4B gene.
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http://dx.doi.org/10.1002/ajmg.a.33152DOI Listing
January 2010

Familial frameshift SRY mutation inherited from a mosaic father with testicular dysgenesis syndrome.

J Clin Endocrinol Metab 2009 Sep 16;94(9):3467-71. Epub 2009 Jun 16.

Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, 9 Quai Moncousu, 44093 Nantes Cedex 1, France.

Context: The SRY gene encodes a transcription factor responsible for initiating testis differentiation. Mutations in SRY almost always result in XY sex reversal with pure gonadal dysgenesis and an increased risk of gonadal tumor. Most of these mutations are de novo, affecting only one individual in a family. Only a small subset of mutations is shared between a phenotypically normal father and one or more of his affected children. Incomplete penetrance and somatic mosaicism are two hypotheses that may explain a normal phenotype in a father carrying a SRY mutation.

Patients And Results: We describe a family with two sisters with XY sex reversal and pure gonadal dysgenesis and a phenotypically normal brother. A novel constitutional frameshift SRY mutation was identified in both sisters and was absent in the brother. The single base pair deletion (c.71delA) led to a premature stop codon in position 60 of the protein, removing entirely the high-mobility group domain and the DNA-binding domain of SRY. The father of the three children presented with hypospadias; cryptorchidism; testicular seminoma and oligoasthenozoospermia, an association termed testicular dysgenesis syndrome (TDS); and the SRY mutation in a mosaic state in the peripheral blood and the tumor.

Conclusions: This observation of somatic and germinal mosaicism for a SRY mutation may explain the variable penetrance in some familial gonadal dysgenesis. Importantly, the present report is the first one describing the association of SRY mutation in a male with TDS. This suggests that mutations in a sex-determining gene may contribute to the pathogenesis of TDS.
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http://dx.doi.org/10.1210/jc.2009-0226DOI Listing
September 2009

Cone-rod dystrophy, growth hormone deficiency and spondyloepiphyseal dysplasia: report of a new case without nephronophtisis.

Am J Med Genet A 2009 Feb;149A(4):788-92

Clinical Genetic Department, Nantes University Hospital, Nantes, France.

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http://dx.doi.org/10.1002/ajmg.a.32343DOI Listing
February 2009

46,XY gonadal dysgenesis: evidence for autosomal dominant transmission in a large kindred.

Am J Med Genet A 2003 Jan;116A(1):37-43

Service de Génétique Médicale, Centre Hospitalo-Universitaire, Nantes, France.

46,XY gonadal dysgenesis is characterized by abnormal testicular determination. We describe a large kindred in which various disorders of sexual development were observed, ranging from completely female phenotype without ambiguities of the external genitalia (five cases) to men with isolated penile or perineal hypospadias (four cases), including two cases with moderate virilization and one case with ambiguity of the external genitalia. Histologic examination of gonadal tissue was performed on seven subjects. These findings were suggestive of complete gonadal dysgenesis in one patient, partial gonadal dysgenesis in three patients, and mixed gonadal dysgenesis in three patients. Four patients developed gonadal tumors (two gonadoblastoma, two dysgerminoma, and one immature teratoma, i.e., one patient had a dysgerminoma with some areas of gonadoblastoma). All affected subjects had no other congenital anomalies or dysmorphic features. Analysis of families with several affected individuals with 46,XY gonadal dysgenesis implied an X-linked mode of inheritance because of the apparent absence of male-to-male transmission. However, a sex-limited autosomal dominant mode of inheritance affecting only XY individuals could not be ruled out. Analysis of the pedigree we report indicated an autosomal dominant mode of inheritance because of male-to-male transmission. This kindred supports the involvement of at least one autosomal gene in non-syndromic 46,XY gonadal dysgenesis.
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http://dx.doi.org/10.1002/ajmg.a.10820DOI Listing
January 2003