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Yijun Tang
Yijun Tang
Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Yao Chen
Yao Chen
Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Jiayi Wang
Jiayi Wang
Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Qianwen Zhang
Qianwen Zhang
Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Yirou Wang
Yirou Wang
Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Yufei Xu
Yufei Xu
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Xin Li
Xin Li
Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Jian Wang
Jian Wang
International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Xiumin Wang
Xiumin Wang
Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Introduction Disorder of sex development (DSD) is a general term for diseases with inconsistencies between chromosomal karyotypes, external genitalia, and gonadal development ( 1 ). According to the DSD etiology classification defined in the
Luca Persani
Luca Persani
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
Department of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
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Department of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
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Martine Cools
Martine Cools
Departments of Internal Medicine and Paediatrics and of Paediatric Endocrinology, Ghent University Hospital, Ghent, Belgium
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Stamatina Ioakim
Stamatina Ioakim
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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S Faisal Ahmed
S Faisal Ahmed
Developmental Endocrinology Research Group, School of Medicine, Dentistry & Nursing, University of Glasgow, Glasgow, United Kingdom
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Silvia Andonova
Silvia Andonova
National Genetic Laboratory, UHOG “Maichin dom", Medical University, Sofia, Bulgaria
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Magdalena Avbelj-Stefanija
Magdalena Avbelj-Stefanija
Department for Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
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Federico Baronio
Federico Baronio
Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Jerome Bouligand
Jerome Bouligand
Université Paris-Saclay, Inserm UMRS1185 & Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpital Bicêtre, France
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Hennie T Bruggenwirth
Hennie T Bruggenwirth
Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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Justin H Davies
Justin H Davies
Faculty of Medicine, University of Southampton, Southampton, United Kingdom
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Elfride De Baere
Elfride De Baere
Departments of Internal Medicine and Paediatrics and of Paediatric Endocrinology, Ghent University Hospital, Ghent, Belgium
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Iveta Dzivite-Krisane
Iveta Dzivite-Krisane
Children’s University Hospital, Riga, Latvia
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Paula Fernandez-Alvarez
Paula Fernandez-Alvarez
Department of Clinical and Molecular Genetics, Vall d'Hebron University Hospital, Barcelona, Spain
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Alexander Gheldof
Alexander Gheldof
Center for Medical Genetics, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Brussels, Belgium
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Claudia Giavoli
Claudia Giavoli
Unit of Endocrinology, Fondazione IRCCS Ospedale Maggiore Policlinico, Milano, Italy
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
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Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
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Claus H Gravholt
Claus H Gravholt
Departments of Endocrinology, of Clinical Medicine and of Molecular Medicine, Aarhus University, Aarhus, Denmark
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Olaf Hiort
Olaf Hiort
University Hospital Schleswig-Holstein, Campus Lübeck, and University of Lübeck, Lübeck, Germany
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Paul-Martin Holterhus
Paul-Martin Holterhus
University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
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Anders Juul
Anders Juul
Departments of Growth and Reproduction and of Clinical Medicine, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
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Csilla Krausz
Csilla Krausz
Endocrinology and Andrology Units, University Hospital of Careggi and Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
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Kristina Lagerstedt-Robinson
Kristina Lagerstedt-Robinson
Department of Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
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Ruth McGowan
Ruth McGowan
Developmental Endocrinology Research Group, School of Medicine, Dentistry & Nursing, University of Glasgow, Glasgow, United Kingdom
West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, United Kingdom
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West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, United Kingdom
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Uta Neumann
Uta Neumann
Charité Medicine University, Berlin, Germany
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Antonio Novelli
Antonio Novelli
Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
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Xavier Peyrassol
Xavier Peyrassol
Universitè Libre di Bruxelles, Brussels, Belgium
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Leonidas A Phylactou
Leonidas A Phylactou
Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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Julia Rohayem
Julia Rohayem
University Hospital Münster, Munster, Germany
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Philippe Touraine
Philippe Touraine
Center for Rare Endocrine and Gynecological Disorders, Department of endocrinology and reproductive Medicine, Hospital Pitié Salpêtrière, Paris, France
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Dineke Westra
Dineke Westra
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
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Valeria Vezzoli
Valeria Vezzoli
Department of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
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Raffaella Rossetti
Raffaella Rossetti
Department of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
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Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate classification of underlying molecular conditions, and next-generation sequencing (NGS) should represent the most appropriate approach. Therefore, we conducted a survey dedicated to the use and potential outcomes of NGS for SDM disorders diagnosis among the 53 health care providers (HCP) of the European Reference Network for rare endocrine conditions. The response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except 1, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with differences of sex development (DSD), including 811 unexplained primary ovarian insufficiency, and 2956 (44%) with congenital hypogonadotropic hypogonadism (CHH). The approaches varied from targeted analysis of custom gene panels (range: 11–490 genes) in 81.5% of cases or whole exome sequencing with the extraction of a virtual panel in the remaining cases. These analyses were performed for diagnostic purposes in 21 HCPs, supported by the National Health Systems in 16 cases. The likelihood of finding a variant ranged between 7 and 60%, mainly depending upon the number of analysed genes or criteria used for reporting, most HCPs also reporting variants of uncertain significance. These data illustrate the status of genetic diagnosis of DSD and CHH across Europe. In most countries, these analyses are performed for diagnostic purposes, yielding highly variable results, thus suggesting the need for harmonization and general improvements of NGS approaches.
A Bergougnoux
A Bergougnoux
Service de Génétique Moléculaire et de Cytogénétique, Centre Hospitalier Universitaire de Montpellier, Université de Montpellier, Montpellier, France
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L Gaspari
L Gaspari
Département d'Endocrinologie et de Gynécologie Pédiatrique, Hôpital Arnaud de Villeneuve, Université de Montpellier, Montpellier, France
INSERM Unité 1203 (DEFE), Université de Montpellier, Montpellier, France
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INSERM Unité 1203 (DEFE), Université de Montpellier, Montpellier, France
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M Soleirol
M Soleirol
Département de Pediatrie, CHU Nîmes, France, Université de Montpellier Faculté de Médecine Montpellier-Nîmes, Montpellier, France
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N Servant
N Servant
Service de Génétique Moléculaire et de Cytogénétique, Centre Hospitalier Universitaire de Montpellier, Université de Montpellier, Montpellier, France
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S Soskin
S Soskin
Département de Pédiatrie, Centre Hospitalier Universitaire Hautepierre de Strasbourg, Strasbourg, France
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S Rossignol
S Rossignol
Département de Pédiatrie, Centre Hospitalier Universitaire Hautepierre de Strasbourg, Strasbourg, France
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K Wagner-Mahler
K Wagner-Mahler
Département de Pédiatrie, CHU Nice, Hôpitaux Pédiatriques de Nice CHU-Lenval, Nice, France
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J Bertherat
J Bertherat
Department of Endocrinology, French Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Université Paris Cité, Institut Cochin, Assitance Publique-Hôpitaux de Paris, Paris, France
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C Sultan
C Sultan
Département d'Endocrinologie et de Gynécologie Pédiatrique, Hôpital Arnaud de Villeneuve, Université de Montpellier, Montpellier, France
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N Kalfa
N Kalfa
Department of Pediatric Urological Surgery, French Reference Center for abnormalities of Genital Development (DevGen), CHU Lapeyronie, Montpellier University, Montpellier, France
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F Paris
F Paris
Service de Génétique Moléculaire et de Cytogénétique, Centre Hospitalier Universitaire de Montpellier, Université de Montpellier, Montpellier, France
Département d'Endocrinologie et de Gynécologie Pédiatrique, Hôpital Arnaud de Villeneuve, Université de Montpellier, Montpellier, France
INSERM Unité 1203 (DEFE), Université de Montpellier, Montpellier, France
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Département d'Endocrinologie et de Gynécologie Pédiatrique, Hôpital Arnaud de Villeneuve, Université de Montpellier, Montpellier, France
INSERM Unité 1203 (DEFE), Université de Montpellier, Montpellier, France
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are useful to identify the hyperandrogenism cause. Independently of the presence or not of Müllerian structures, karyotyping must also be performed to exclude a 46,XY disorder of sex development (DSD) resulting in sex reversal. Indeed, in the absence
Marie Lindhardt Ljubicic
Marie Lindhardt Ljubicic
Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Trine Holm Johannsen
Trine Holm Johannsen
Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Margit Bistrup Fischer
Margit Bistrup Fischer
Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Emmie N Upners
Emmie N Upners
Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Alexander S Busch
Alexander S Busch
Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Katharina M Main
Katharina M Main
Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Anna-Maria Andersson
Anna-Maria Andersson
Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Casper P Hagen
Casper P Hagen
Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Anders Juul
Anders Juul
Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Nordenström A Houk CP Ahmed SF Auchus R Baratz A Baratz Dalke K Liao LM Lin-Su K Looijenga LHJ Global disorders of sex development update since 2006: perceptions, approach and care . Hormone Research in Paediatrics 2016 85 158 – 180
