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  • Abstract: Adrenal x
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  • Abstract: Catecholamines x
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  • Abstract: Cushings x
  • Abstract: Glucocorticoids x
  • Abstract: Medulla x
  • Paediatric Endocrinology x
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Muriel Houang Laboratoire des Explorations Fonctionnelles Endocriniennes, Hôpital Armand Trousseau, AP-HP Sorbonne Université, Paris, France

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Thao Nguyen-Khoa Centre Régional de Dépistage Néonatal-Ile de France, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France

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Thibaut Eguether Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
Département de Métabolomique Clinique, Hôpital Saint-Antoine, AP-HP Sorbonne Université, Paris, France

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Bettina Ribault Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
Département de Métabolomique Clinique, Hôpital Saint-Antoine, AP-HP Sorbonne Université, Paris, France

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Séverine Brabant Laboratoire d’Explorations Fonctionnelles, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France

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Michel Polak Centre Régional de Dépistage Néonatal-Ile de France, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France
Université de Paris, INSERM, Institut IMAGINE, Hôpital Necker-Enfants Malades, AP-HP, Paris, France

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Irène Netchine Laboratoire des Explorations Fonctionnelles Endocriniennes, Hôpital Armand Trousseau, AP-HP Sorbonne Université, Paris, France
Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
Hôpital Armand Trousseau, AP-HP Sorbonne Université, Paris, France

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Antonin Lamazière Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
Département de Métabolomique Clinique, Hôpital Saint-Antoine, AP-HP Sorbonne Université, Paris, France

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Neonatal screening for congenital adrenal hyperplasia (CAH) faces many specific challenges. It must be done using a performant analytical approach that combines sensitivity and specificity to capture the potential causes of mortality during the first week of life, such as salt wasting and glucocorticoid deficiency. Here, we confirm that maternal inhaled corticosteroid intake during pregnancy is a possible cause of missed CAH diagnosis. Thanks to liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis, we were able to quantify endogenous steroid metabolites and also detect the presence of exogenous steroids in the dried blood spot of a newborn. Adding LC-MS/MS analysis as second-tier test, especially one that includes both 17-hydroxyprogesterone and 21-deoxycortisol measurements, would probably improve CAH diagnosis. In familial neonatal screening one could also look for maternal corticosteroid therapies that are hidden to prevent false-negative tests.

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Martijn J J Finken Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

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Aleid J G Wirix Department of Public and Occupational Health, EMGO Institute for Health and Care Research, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

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Ines A von Rosenstiel-Jadoul Department of Pediatrics, Rijnstate Hospital, Arnhem, The Netherlands

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Bibian van der Voorn Department of Pediatric Endocrinology and Obesity Center CGG, Erasmus MC Sophia Children’s Hospital, Rotterdam, The Netherlands

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Mai J M Chinapaw Department of Public and Occupational Health, EMGO Institute for Health and Care Research, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

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Michaela F Hartmann Steroid Research and Mass Spectrometry Unit, Laboratory for Translational Hormone Analytics, Department of Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany

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Joana E Kist-van Holthe Department of Public and Occupational Health, EMGO Institute for Health and Care Research, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

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Stefan A Wudy Steroid Research and Mass Spectrometry Unit, Laboratory for Translational Hormone Analytics, Department of Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany

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Joost Rotteveel Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

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Objective

Childhood obesity is associated with alterations in hypothalamus–pituitary–adrenal axis activity. We tested the hypothesis that multiple alterations in the metabolism of glucocorticoids are required for the development of hypertension in children who become overweight.

Methods

Spot urine for targeted gas chromatography-mass spectrometry steroid metabolome analysis was collected from (1) overweight/hypertensive children (n  = 38), (2) overweight/non-hypertensive children (n  = 83), and (3) non-overweight/non-hypertensive children (n  = 56).

Results

The mean (± s.d.) age of participants was 10.4 ± 3.4 years, and 53% of them were male. Group 1 and group 2 had higher excretion rates of cortisol and corticosterone metabolites than group 3 (869 (interquartile range: 631–1352) vs 839 (609–1123) vs 608 (439–834) μg/mmol creatinine × m2 body surface area, P < 0.01, for the sum of cortisol metabolites), and group 1 had a higher excretion rate of naive cortisol than group 3. Furthermore, groups differed in cortisol metabolism, in particular in the activities of 11β-hydroxysteroid dehydrogenases, as assessed from the ratio of cortisol:cortisone metabolites (group 2 < group 3), 5α-reductase (group 1 > group 2 or 3), and CYP3A4 activity (group 1 < group 2 or 3).

Discussion

The sequence of events leading to obesity-associated hypertension in children may involve an increase in the production of glucocorticoids, downregulation of 11β-hydroxysteroid dehydrogenase type 1 activity, and upregulation of 5α-reductase activity, along with a decrease in CYP3A4 activity and an increase in bioavailable cortisol.

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Claire L Wood Department of Paediatric Endocrinology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

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Kieren G Hollingsworth Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

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Edrina Bokaie Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

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Eric Hughes Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

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Robert Muni-Lofra Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

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Anna Mayhew Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

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Rod T Mitchell MRC Centre for Reproductive Health, The University of Edinburgh, Queens Medical Research Institute, Edinburgh, UK

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Michela Guglieri Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

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Joseph McElvaney Department of Paediatric Endocrinology, Royal Victoria Infirmary, Newcastle upon Tyne, UK

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Timothy D Cheetham Department of Paediatric Endocrinology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

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Volker Straub Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

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Glucocorticoids (GCs) reduce inflammation and preserve muscle function in boys with Duchenne muscular dystrophy (DMD) but cause pubertal delay. Pubertal induction with testosterone is recommended but longer-term outcome is unknown.

Objective

To assess hypothalamic–pituitary–gonadal axis, muscle volume and function 5 years after pubertal induction.

Methods

A prospective observational follow-up of a clinical study was conducted. 15 GC-treated males with DMD were treated with incremental testosterone for 2 years (end of regimen +2 years) then evaluated at +2.5 years and +5 years (final follow-up ~3 years after last injection). Data collected included testicular volume (TV), gonadotrophin, testosterone, inhibin B, muscle function, and limb muscle MRI.

Results

Participants were 18.7 years (s.d. 1.6) at the final follow-up and had been on GC for 11.2 years (s.d. 2.2). Testosterone levels were similar at +2.5 years (8.6 nmol/L (s.d. 3.4) and 5 years (11.0 nmol/L (s.d. 6.1). TV increased from 2.8 mL (s.d. 0.9) at +2 years to 7.1 mL (s.d. 1.8) then 10.6 mL (s.d. 3.5) at +2.5 years and +5.0 years (P < 0.001). Inhibin B levels increased from 55.6 pg/mL (s.d. 47.0) at baseline to 158.2 pg/mL (s.d.87.6), P =0.004 at 5 years but remained lower than reference values (mean 305 pg/mL). Muscle contractile bulk decreased.

Interpretation

Pubertal induction with testosterone in DMD is associated with HPG axis activation and ongoing increases in inhibin B, TV, and testosterone concentrations. Some patients have normal levels which is promising regarding future fertility. Given the beneficial impact of testosterone on bone health, muscle, and well-being, monitoring testosterone levels in this population and supplementation of sub-optimal levels is important.

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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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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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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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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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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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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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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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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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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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The ratio between luteinizing hormone (LH) and follicle-stimulating hormone (FSH) has previously been described as an excellent marker of sex in healthy infants. However, LH/FSH remains not fully described in patients with differences of sex development (DSD). The aim was therefore to describe LH/FSH in infants with DSD. This was a retrospective study of DSD patients, all aged 0–1.2 years. In total, 87 infants with DSD and at least one serum sample per infant were included. Longitudinal samples from single patients were included whenever possible. Serum LH/FSH ratios in these patients were plotted against recently published age-related and sex-dimorphic cutoffs. Overall, LH/FSH sometimes corresponded to assigned sex without any obvious pattern in terms of diagnoses. LH/FSH corresponded to the biological sex in all patients with Turner or Klinefelter syndrome. In patients with 46,XX or 46,XY DSD (except congenital adrenal hyperplasia (CAH)), the ratios did not correspond to the assigned sex in all cases and were interchangeably within the male and female range. In patients with CAH, the ratio corresponded to biological sex (based on sex chromosomes) in some cases but also ranged across the cutoffs. In the 15 patients with 45,X/46,XY mosaicism, the LH/FSH ratios corresponded to the assigned sex in all cases (12 were raised as males, 3 as females) and at all time points in cases with multiple sampling. While this study describes LH/FSH in infants with DSD, the exact clinical role of the ratio in the management of these patients remains to be further elucidated.

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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 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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M Soleirol Département de Pediatrie, CHU Nîmes, France, Université de Montpellier Faculté de Médecine Montpellier-Nîmes, Montpellier, France

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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 Département de Pédiatrie, Centre Hospitalier Universitaire Hautepierre de Strasbourg, Strasbourg, France

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S Rossignol Département de Pédiatrie, Centre Hospitalier Universitaire Hautepierre de Strasbourg, Strasbourg, France

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K Wagner-Mahler Département de Pédiatrie, CHU Nice, Hôpitaux Pédiatriques de Nice CHU-Lenval, Nice, France

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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 Département d'Endocrinologie et de Gynécologie Pédiatrique, Hôpital Arnaud de Villeneuve, Université de Montpellier, Montpellier, France

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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 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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Although hyperandrogenism is a frequent cause of consultation in adolescent girls, more severe forms with virilization must lead to suspicion of an adrenal or ovarian tumor. However, they may also reveal a 46,XY disorder of sexual development (DSD). Here, we describe four adolescent girls referred for pubertal virilization and in whom we diagnosed a 46,XY DSD. We performed gene mutation screening by Sanger sequencing (all patients) and by next-generation sequencing (NGS) in patient #4. We identified new heterozygous NR5A1 gene variants in patients #1 and #2 and a homozygous SRD5A2 gene deletion in patient #3. Patient #4 received a diagnosis of complete androgen insensitivity in childhood; however, due the unusual pubertal virilization, we completed the gene analysis by NGS that revealed two heterozygous HSD17B3 variants. This work underlines the importance of considering the hypothesis of 46,XY DSD in adolescent girls with unexplained virilization at puberty.

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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 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 Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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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 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 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 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 International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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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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Diagnosis and management strategy of disorders of sex development (DSD) are difficult and various due to heterogeneous phenotype and genotype. Under widespread use of genomic sequencing technologies, multiple genes and mechanisms have been identified and proposed as genetic causes of 46,XY DSD. In this study, 178 46,XY DSD patients were enrolled and underwent gene sequencing (either whole-exome sequencing or targeted panel gene sequencing). Detailed clinical phenotype and genotype information were summarized which showed that the most common clinical manifestations were micropenis (56.74%, 101/178), cryptorchidism (34.27%, 61/178), and hypospadias (17.42%, 31/178). Androgen synthesis/action disorders and idiopathic hypogonadotropic hypogonadism were the most frequent clinical diagnoses, accounting, respectively, for 40.90 and 21.59%. From all next-generation sequencing results, 103 candidate variants distributed across 32 genes were identified in 88 patients. The overall molecular detection rate was 49.44% (88/178), including 35.96% (64/178) pathogenic/likely pathogenic variants and 13.48% (24/178) variants of uncertain significance. Of all, 19.42% (20/103) variants were first reported in 46,XY DSD patients. Mutation c.680G>A (p.R227Q) on SRD5A2 (steroid 5-alpha-reductase 2) (36.67%, 11/30) was a hotspot mutation in the Chinese population. Novel candidate genes related to DSD (GHR (growth hormone receptor) and PHIP (pleckstrin homology domain-interacting protein)) were identified. Overall, this was a large cohort of 46,XY DSD patients with a common clinical classification and phenotype spectrum of Chinese patients. Targeted gene panel sequencing covered most of the genes contributing to DSD, whereas whole-exome sequencing detected more candidate genes.

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Christine Poitou Assistance Publique-Hôpitaux de Paris, Centre de référence Maladies Rares (PRADORT, Syndrome de Prader-Willi et autres formes rares d’obésité avec troubles du comportement alimentaire), Service de Nutrition, Hôpital Pitié-Salpêtrière, Paris, France

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Anthony Holland Department of Psychiatry, University of Cambridge, UK

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Charlotte Höybye Department of Endocrinology and Department of Molecular Medicine and Surgery, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden

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Laura C G de Graaff Center for Adults with Rare Genetic Syndromes, Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands

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Sandrine Bottius Assistance Publique-Hôpitaux de Paris, Centre de référence Maladies Rares (PRADORT, Syndrome de Prader-Willi et autres formes rares d’obésité avec troubles du comportement alimentaire), Service de Nutrition, Hôpital Pitié-Salpêtrière, Paris, France

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Berit Otterlei Landsforeningen for Prader-Willis Syndrom Hiltonåsen, Slependen, Norway

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Maithé Tauber Centre de référence Maladies Rares (PRADORT, Syndrome de Prader-Willi et autres formes rares d’obésité avec troubles du comportement alimentaire), Service d’Endocrinologie, Obésités, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants, Toulouse, France

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Prader–Willi syndrome (PWS), the most common form of syndromic obesity, is a complex neurodevelopmental genetic disorder including obesity with hyperphagia, endocrine and metabolic disorders and also psychiatric disorders. The most frequent endocrine disturbances include hypogonadism and growth hormone (GH) deficiency. Hypothyroidism and central adrenal insufficiency can also be observed but are less frequent. The transition of individuals with PWS from adolescence to adult life is challenging because of multiple comorbidities and complex disabilities. Individuals and caregivers face psychological, medical and social issues. This period of profound changes is thus prone to disruptions, and the main risks being the worsening of the medical situation and loss to follow-up of the individuals. Medical care may be poorly adapted to the needs of individuals because of a lack of knowledge concerning the syndrome and also lack of the necessary specific skills. A multidisciplinary panel composed of several experts in PWS met in November 2021 during an European Reference Network on Rare Endocrine Conditions (Endo-ERN) webinar. They presented complementary aspects of PWS from the perspective of the transition including psychiatric, pediatric and adult endocrinological and parent’s and patient’s points of view and shed light on the best way to approach this pivotal period.

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