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      Changes in the clinical management of 5α-reductase type 2 and 17β-hydroxysteroid dehydrogenase type 3 deficiencies in France

      research-article
      1 , 2 , 3 , 4 , , 2 , 5 , 2 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 2 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 18 , 26 , 2 , 27 , , 1 , 2 , 28 , 29 , 1 , 2 , 29 , 2 , 19 , 29 , 2 , 19 , 1 , 2
      Endocrine Connections
      Bioscientifica Ltd
      5α-reductase type 2 deficiency, 17β-hydroxysteroid dehydrogenase type 3 deficiency, 46,XY disorders of sex development, sex assignment, change in practices

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          Abstract

          Objectives

          To examine the changes in diagnostic practices and clinical management of patients with 5α-reductase type 2 (SRD5A2) or 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency since molecular diagnoses became available.

          Methods

          Clinical, laboratory, and therapeutic data were retrieved from the medical records of 52 patients with a molecular diagnosis of SRD5A2 ( n = 31) or HSD17B3 ( n = 21) deficiency. Temporal trends regarding age at assessment and initial sex assignment over 1994–2020 were qualitatively analyzed. Age at molecular diagnosis was compared between two subgroups of patients according to their year of birth.

          Results

          Fifty-eight percent ( n = 30) patients were diagnosed during the perinatal period, 33% ( n = 17) during infancy, and 9% ( n = 5) during adolescence or adulthood. Over the studied period, the patients’ age at initial assessment and diagnosis frankly decreased. The median (range) age at diagnostic confirmation was 10.5 (0–53.2) years for patients born before 2007 and 0.4 (0–9.3) years for those born in 2007 or later ( P = 0.029). Genetic testing identified 27 different variants for the SRD5A2 gene (30% novel, n = 8) and 18 for the HSD17B3 gene (44% novel, n = 8). Before 2002, most patients were initially assigned as females (95%, n = 19), but this proportion dropped for those born later (44%, n = 14; P < 0.001). The influence of initial genital appearance on these decisions seemingly decreased in the most recent years. Therapeutic interventions differed according to the sex of rearing. Ten percent ( n = 2) patients requested female-to-male reassignment during adulthood.

          Conclusion

          This study showed, over the past two decades, a clear trend toward earlier diagnosis and assignment of affected newborns as males.

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          Most cited references43

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          Consensus statement on management of intersex disorders.

          I A Hughes (2005)
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            Is Open Access

            Caring for individuals with a difference of sex development (DSD): a Consensus Statement

            The term differences of sex development (DSDs; also known as disorders of sex development) refers to a heterogeneous group of congenital conditions affecting human sex determination and differentiation. Several reports highlighting suboptimal physical and psychosexual outcomes in individuals who have a DSD led to a radical revision of nomenclature and management a decade ago. Whereas the resulting recommendations for holistic, multidisciplinary care seem to have been implemented rapidly in specialized paediatric services around the world, adolescents often experience difficulties in finding access to expert adult care and gradually or abruptly cease medical follow-up. Many adults with a DSD have health-related questions that remain unanswered owing to a lack of evidence pertaining to the natural evolution of the various conditions in later life stages. This Consensus Statement, developed by a European multidisciplinary group of experts, including patient representatives, summarizes evidence-based and experience-based recommendations for lifelong care and data collection in individuals with a DSD across ages and highlights clinical research priorities. By doing so, we hope to contribute to improving understanding and management of these conditions by involved medical professionals. In addition, we hope to give impetus to multicentre studies that will shed light on outcomes and comorbidities of DSD conditions across the lifespan.
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              Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency.

              Individuals with 5alpha-reductase-2 deficiency (5alpha-RD-2) and 17beta-hydroxysteroid dehydrogenase-3 deficiency (17beta-HSD-3) are often raised as girls. Over the past number of years, this policy has been challenged because many individuals with these conditions develop a male gender identity and make a gender role change after puberty. The findings also raised doubts regarding the hypothesis that children are psychosexually neutral at birth and emphasized the potential role of prenatal brain exposure to androgens in gender development. If prenatal exposure to androgens is a major contributor to gender identity development, one would expect that all, or nearly all, affected individuals, even when raised as girls, would develop a male gender identity and make a gender role switch later in life. However, an estimation of the prevalence of gender role changes, based on the current literature, shows that gender role changes occur frequently, but not invariably. Gender role changes were reported in 56-63% of cases with 5alpha-RD-2 and 39-64% of cases with 17beta-HSD-3 who were raised as girls. The changes were usually made in adolescence and early adulthood. In these two syndromes, the degree of external genital masculinization at birth does not seem to be related to gender role changes in a systematic way.

                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                05 January 2023
                01 March 2023
                : 12
                : 3
                : e220227
                Affiliations
                [1 ]Hospices Civils de Lyon , Hôpital Femme-Mère-Enfant, Service d’endocrinologie pédiatrique, Bron, France
                [2 ]Centre National de Référence Maladies Rares du développement génital du fœtus à l’adulte DEV-GEN , Hospices Civils de Lyon, Bron, France
                [3 ]Hospices Civils de Lyon , Hôpital Femme-Mère-Enfant, Service de psychopathologie du développement, Bron, France
                [4 ]Centre national de la recherche scientifique UMR 5317 , Ecole Normale Supérieure de Lyon, Institut d’Histoire des Représentations et des Idées dans les Modernités, Lyon, France
                [5 ]Hospices Civils de Lyon , Hôpital Femme-Mère-Enfant, Centre de biologie et pathologie Est, Service d’hormonologie, d’endocrinologie moléculaire et des maladies rares, Bron, France
                [6 ]Hospices Civils de Lyon , Hôpital Femme-Mère-Enfant, Service Endocrinologie Moléculaire et Maladies Rares, Bron, France
                [7 ]Centre Hospitalier Universitaire AP-HP , Hôpital Bicêtre, Service d’endocrinologie pédiatrique Centre National de Référence Maladies Rares du développement génital du fœtus à l’adulte DEV-GEN Université Paris Saclay, Le Kremlin-Bicêtre, France
                [8 ]Centre Hospitalier Régional Universitaire Lille , Hôpital Jeanne de Flandre, Unité d’Endocrinologie pédiatrique Centre National de Référence Maladies Rares du développement génital du fœtus à l’adulte DEV-GEN, Lille, France
                [9 ]Centre Hospitalier Universitaire AP-HP , Hôpital Robert Debré, Service d’Endocrinologie pédiatrique Centre de Référence des Maladies Rares Endocriniennes de la Croissance et du Développement – CRMERC Université de Paris, Paris, France
                [10 ]Centre Hospitalier Universitaire AP-HP , Hôpital universitaire Necker Enfants malades, Endocrinologie gynécologie diabétologie pédiatriques Centre de référence des maladies endocriniennes rares de la croissance et du développement Inserm U1016, institut Imagine, Paris, France
                [11 ]Centre Hospitalier Universitaire AP-HP , Hôpital Pitié Salpêtrière, Department of Endocrinology and Reproductive Medicine Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement Centre de Référence des pathologies gynécologiques rares IE3M, Paris, France
                [12 ]Centre Hospitalier Universitaire Dijon-Bourgogne , Hôpital d’Enfants, Service de Pédiatrie Multidisciplinaire, Dijon, France
                [13 ]Centre Hospitalier universitaire de Nantes , Hôpital Mère-Enfant, Service de Pédiatrie, Nantes, France
                [14 ]Centre Hospitalier Universitaire AP-HP , Hôpital Armand Trousseau, Service d'Explorations Fonctionnelles Endocriniennes, Paris, France
                [15 ]Hôpitaux Universitaires de Strasbourg , CHU Hautepierre, Service de Pédiatrie 1, Strasbourg, France
                [16 ]Centre hospitalier universitaire Limoges , Hôpital de la Mère et de l’enfant, Service de Pédiatrie, Limoges, France
                [17 ]Groupement Hospitalier Universitaire de Paris , AP-HP, Hôpital Cochin, Service d'Endocrinologie, Paris, France
                [18 ]Centre Hospitalier Universitaire de Montpellier , Hôpital Lapeyronie, Service de Néphrologie et Endocrinologie Pédiatrique Centre National de Référence Maladies Rares du développement génital du fœtus à l’adulte DEV-GEN, Montpellier, France
                [19 ]Hospices Civils de Lyon , Hôpital Femme-Mère-Enfant, Service de chirurgie Uro-viscérale et de Transplantation de l’Enfant, Bron, France
                [20 ]AP-HP , Hôpital Bicêtre, Unité de gynécologie de l’adolescente Centre National de Référence Maladies Rares du développement génital du fœtus à l’adulte DEV-GEN Université Paris Saclay, Le Kremlin-Bicêtre, France
                [21 ]Centre Hospitalier Régional Universitaire Lille , Hôpital Jeanne de Flandre, Service de chirurgie pédiatrique Centre National de Référence Maladies Rares du développement génital du fœtus à l’adulte DEV-GEN, Lille, France
                [22 ]Centre Hospitalier Universitaire AP-HP Robert Debré , Service de Chirurgie Viscérale et Urologie pédiatrique Centre de Référence des Maladies Endocriniennes de la croissance et du développement – CRMERC Université de Paris, Paris, France
                [23 ]Centre Hospitalier Universitaire AP-HP , Hôpital Necker Enfants malades, Endocrinologie gynécologie diabétologie pédiatriques Centre de référence des maladies endocriniennes rares de la croissance et du développement, Paris, France
                [24 ]Hospitaux Universitaires de Strasbourg , CHU Hautepierre, Service de chirurgie pédiatrique, Strasbourg, France
                [25 ]Centre Hospitalier Universitaire de Montpellier , Hôpital Lapeyronie, Service de Chirurgie Viscérale et Urologie Pédiatrique Centre National de Référence Maladies Rares du Développement Génital Constitutif Sud Institut Debrest de Santé Publique IDESP, UMR INSERM, Université de Montpellier, Montpellier, France
                [26 ]Centre Hospitalier Régional Universitaire Lille , Hôpital Jeanne de Flandre, Service de psychiatrie de l’enfant et de l’adolescent Centre National de Référence Maladies Rares du développement génital du fœtus à l’adulte DEV-GEN, Lille, France
                [27 ]Hospices Civils de Lyon , Groupement Hospitalier Est, Service d’endocrinologie, Bron, France
                [28 ]Hospices Civils de Lyon , Hôpital Femme-Mère-Enfant, Service de médecine de la reproduction, Bron, France
                [29 ]Université Claude Bernard , Lyon, France
                Author notes
                Correspondence should be addressed to A Brac de la Perrière or M Winter: aude.brac@ 123456chu-lyon.fr or mathias.winter@ 123456chu-lyon.fr

                *(E Bonnet and M Winter contributed equally to this work)

                Author information
                http://orcid.org/0000-0001-5990-810X
                http://orcid.org/0000-0001-6453-8326
                Article
                EC-22-0227
                10.1530/EC-22-0227
                9986397
                36606580
                778e66a8-fbe9-4f59-beb7-c8085e179844
                © The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                : 18 October 2022
                : 05 January 2023
                Categories
                Research

                5α-reductase type 2 deficiency,17β-hydroxysteroid dehydrogenase type 3 deficiency,46,xy disorders of sex development,sex assignment,change in practices

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