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2025-07-18

Participation of adults with disorders/differences of sex development (DSD) in the clinical study dsd-LIFE: design, methodology, recruitment, data quality and study population

BMC Endocr Disord. 2017; 17: 52.
Published online 2017 Aug 18. doi: 10.1186/s12902-017-0198-y

Participation of adults with disorders/differences of sex development (DSD) in the clinical study dsd-LIFE: design, methodology, recruitment, data quality and study population

Robert Röhle,1 Katharina Gehrmann,2 Maria Szarras-Czapnik,8 Hedi Claahsen-van der Grinten,4 Catherine Pienkowski,7 Claire Bouvattier,3 Peggy Cohen-Kettenis,5 Anna Nordenström,6 Ute Thyen,9 Birgit Köhler,corresponding author2 and on behalf of the dsd-LIFE group

Abstract

Background

dsd-LIFE is a comprehensive cross-sectional clinical outcome study of individuals with disorders/differences of sex development (DSD). This study focuses on various rare genetic conditions characterized by impaired gonadal or adrenal functionality.

Methods/Design

The study aims to assess quality of life (QoL) as a measure of psychosocial adaptation, psychosexual and mental health aspects as major outcomes. Health status and functioning, medical and surgical therapies, participants’ views on health care, psychological and social support, sociodemographic factors and their interrelations will be investigated as factors associated with the outcomes. In addition, ethical considerations in the field of DSD are addressed and previous experiences with health care were gathered. One thousand and forty participants with different DSD conditions were recruited by 14 study centres in 6 European countries (France, Germany, the Netherlands, Poland, Sweden and the United Kingdom) from February 2014 until September 2015. The conditions included were: Turner syndrome (n = 301); 45,X0/46,XY conditions (n = 45); Klinefelter syndrome (n = 218); 47,XYY (n = 1); 46,XY gonadal dysgenesis/ovotestes (n = 63); complete androgen insensitivity (CAIS) (n = 71); partial androgen insensitivity (PAIS) (n = 35) and androgen synthesis disorders (n = 20); severe hypospadias (n = 25); other or non-classified 46,XY DSD (n = 8); 46,XX congenital adrenal hyperplasia (CAH) (n = 226); 46,XX gonadal dysgenesis/ovotestis (n = 21); and 46,XX in males (n = 6). For an add-on study, 121 46,XY male-assigned individuals with CAH due to 21-hydroxylase deficiency were recruited. Mean age of participants’ was 32.4 (+/− 13.6 years).

Discussion

Participation was high in conditions not commonly described as DSD, such as Turner and Klinefelter syndromes or CAH. Recruitment of individuals with XY DSD conditions proved to be more difficult. The data collection of PROs resulted in high data quality. Within medical and physical examination data, more missings and/or inaccurate data were found than expected. The European dsd-LIFE study recruited and evaluated the largest cross-sectional sample of individuals with different conditions classified under the term DSD. The data from this large sample will provide a sufficient basis for evidence-based recommendations for improvement of clinical care of individuals affected by a DSD condition.

Trial registration
German Clinical Trials Register DRKS00006072.

Keywords: Disorders of sex development, Differences of sex development, DSD, Sexual differentiation, Interdisciplinary care, European network

2025-06-29

Involving Individuals with Disorders of Sex Development and Their Parents in Exploring New Models of Shared Learning: Proceedings from a DSDnet COST Action Workshop.

Sex Dev. 2018 Jun 23.

Involving Individuals with Disorders of Sex Development and Their Parents in Exploring New Models of Shared Learning: Proceedings from a DSDnet COST Action Workshop.

Sanders C, Hall J, Sanders C, Dessens A, Bryce J, Callens N, Cools M, Kourime M, Kyriakou A, Springer A, Audi L, Balsamo A, Iotova V, Mladenov V, Krawczynski M, Nordenskjöld A, Rozas M, Claahsen-van der Grinten H, Hiort O, Riedl S, Ahmed SF.

Abstract

The level of connection between health care professionals and people who experience a condition that affects sex development is variable. These people and associated support groups need to be included in discussions about research and healthcare delivery. The aim of this study was to understand the experiences of individuals with disorders of sexual development (DSD), their parents, health care providers, and support groups. Workshop planning, preparation, delivery, and evaluation involved members of working groups from the COST Action DSDnet. A coordinator, in collaboration with a support group representative, led the workshop design and delivery. Our successful, facilitated workshop involved 33 attendees from 8 EU countries. The workshop provided individuals with DSD, parents, advisory groups, and professionals with an opportunity for shared learning. Outputs focused on 7 key areas, including diagnosis, childhood, and transition to adult care as well as fostering discussion around registries, future research topics, consent processes, and information needs across the life course. The importance of trustworthy and knowledgeable providers, time to understand such rare conditions, and the place support groups have in a life course approach were valuable learning points for all attendees. In conclusion, workshops can be designed and delivered in meaningful ways for all those involved in care of individuals with rare conditions.

EURすごいなあ・・・。

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

EXPERT CONSENSUS DOCUMENT

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

Martine Cools, Anna Nordenstrom, Ralitsa Robeva, Joanne Hall, Puck Westerveld, Christa Fluck, Birgit Kohler, Marta Berra, Alexander Springer, Katinka Schweizer & Vickie Pasterski on behalf of the COST Action BM1303 working group 1

Nature Reviews Endocrinology volume 14, (2018)

Abstract

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.

最強やっと出た・・・(´;ω;`)。

2018-10-21

Long-term healthcare of people with disorders of sex development: Predictors of pubertal outcomes of partial androgen insensitivity syndrome.

EBioMedicine. 2018 Oct 15. pii: S2352-3964(18)30438-9. doi: 10.1016/j.ebiom.2018.10.026. [Epub ahead of print]

Long-term healthcare of people with disorders of sex development: Predictors of pubertal outcomes of partial androgen insensitivity syndrome.

Fukami M1.

Author information 日本

1Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan. Electronic address: fukami-m@ncchd.go.jp.

Abstract

Partial androgen insensitivity syndrome (PAIS) is a relatively common type of 46, XY disorders of sex development (DSD) caused by hypomorphic mutations in the androgen receptor gene (AR) [6]. Patients with PAIS typically present with hypomasculinized external genitalia at birth [6]. The median external masculinization score (EMS) of neonates with PAIS is around 5–7 (typical female- and male-type genitalia correspond to scores 0 and 12, respectively) [5], causing difficulties in sex assignment of many cases.


Partial androgen insensitivity syndrome (PAIS) is a relatively common type of 46, XY disorders of sex development (DSD) caused by hypomorphic mutations in the androgen receptor gene (AR) [6]. Patients with PAIS typically present with hypomasculinized external genitalia at birth [6]. The median external masculinization score (EMS) of neonates with PAIS is around 5–7 (typical female- and male-type genitalia correspond to scores 0 and 12, respectively) [5], causing difficulties in sex assignment of many cases. Moreover, PAIS tends to be associated with poor clinical outcomes: PAIS patients more frequently require multiple surgeries and exhibit insufficient masculinization in adulthood than patients with similar genital abnormalities at birth but no AR mutations [5]. Since degrees of pre- and post-natal masculinization are highly variable among PAIS patients [5,6], personalized management is necessary for each case. In this regard, outcome prediction for children with PAIS is essential for the decision-making of clinicians and patients' parents; however, no reliable biomarkers for long-term outcomes of PAIS have been documented.

In EBioMedicine, Lek and colleagues introduce their findings about outcome predictors of PAIS [4]. The authors performed a prospective long-term follow-up study on 27 patients with molecularly confirmed PAIS. The authors also investigated the residual activity of each mutant AR protein by in vitro assays. The results suggested that the pubertal outcomes of PAIS patients do not parallel to the predicted activities of the mutant proteins. Instead, the outcomes were correlated with EMS at birth. Specifically, all patients with EMS ≥ 5 at birth subsequently exhibited spontaneous puberty and frequently developed normal adult male-type external genitalia, while 33% and 83% of patients with EMS < 5 at birth did not show spontaneous puberty and satisfactory adult genitalia, respectively. These results highlighted the usefulness of EMS as clinical parameters of PAIS. Since EMS can be easily obtained from all neonates suspected to have PAIS, these findings would facilitate decision-making in clinical practice. From the viewpoint of basic research, the paper revealed limitations of current in vitro methods in the functional assessment of hypomorphic mutations in AR.

In their paper, Lek et al. also pointed out two unsolved issues that need to be addressed in future studies. First, it remains unknown whether blood hormone values can be used as biomarkers for pubertal outcomes of PAIS. In this regard, previous studies have shown that PAIS occasionally underlies testicular dysfunction, in addition to androgen resistance in peripheral tissues [5]. Indeed, elevated blood levels of FSH and/or blunted responses of testosterone to human chorionic gonadotropin stimulation have been reported in multiple patients with PAIS [5]. Testicular dysfunction of these patients was assumed to result from maldescent of the testis or insufficient androgen action in the developing testis [5]. Since testicular dysfunction further attenuates suboptimal masculinization caused by androgen resistance, hormonal evaluation of children with PAIS may provide information about future phenotypes. Second, Lek et al. did not examine somatic mosaicism of AR mutations, which has previously been reported in multiple patients with PAIS [3]. The lack of genotype-phenotype correlation in this cohort may be ascribed to somatic mosaicism, because mosaicism can modify phenotypic severities of the patients. Furthermore, Lek et al. mentioned that current in vitro assays may not be sensitive enough to detect mild functional impairment of AR mutations. In this regard, novel methods for the functional assessment of AR mutants, such as quantification of APOD mRNA in genital skin fibroblasts, have recently been developed [2]. In future studies, detection of mosaicism and the use of novel assay methods would help to clarify precise genotype-phenotype correlation of PAIS.

An important issue that also needs to be addressed is psychological outcomes of PAIS patients. Currently, there are no parameters to predict long-term gender identity in children with DSD including PAIS [1]. The lack of reliable predictors for gender development raises difficulty in sex-assignment of neonates. Indeed, PAIS patients have a risk of gender incongruousness in adulthood. In addition, PAIS has been linked to a relatively high risk of gynecomastia, cardiovascular diseases, glucose intolerance, and osteoporosis [5]. Thus, biomarkers for these complications also need to be established.

Altogether, the study by Lek et al. [4] provided useful information for the long-term healthcare of DSD. Yet, further studies are necessary to determine reliable predictors of various health issues of PAIS. To this end, international registries and study groups for DSD have been launched recently (for example, I-DSD registry, https://www.i-dsd.org/) [1]. Such research networks enable scientists to collect longitudinal data of a large number of patients, and are therefore expected to promote personalized management for patients with DSD including PAIS.

2018-09-02

Psychosocial and psychosexual aspects of disorders of sex development.

Best Pract Res Clin Endocrinol Metab. 2010 Apr;24(2):325-34. doi: 10.1016/j.beem.2009.11.005.

Psychosocial and psychosexual aspects of disorders of sex development.

Cohen-Kettenis PT

Author information
Department of Medical Psychology, VU University, PO Box 7057, 1007 MB Amsterdam, The Netherlands. pt.cohen-kettenis@vumc.nl

Abstract

Psychosocial aspects of the treatment of disorders of sex development (DSDs) concern gender assignment, information management and communication, timing of medical interventions, consequences of surgery, and sexuality. Although outcome is often satisfactory, a variety of medical and psychosocial factors may jeopardise the psychological development of children with DSDs. This sometimes results in the desire to change gender later in life. The clinical management of gender dysphoria in individuals with DSD may profit from methods and insights that have been developed for gender dysphoric individuals without DSD. In DSD care, clinical decisions are often made with long-lasting effects on quality of life and should be based on empirical evidence. Yet, such evidence (e.g., regarding gender assignment, information management and timing of surgery) is largely non-existent. DSD-specific protocols and educational materials need to be developed to standardise and evaluate interventions in order to facilitate decision making of professionals and individuals with DSD and enhance psychosocial care in this area.

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2018-07-08

Quality of health care in adolescents and adults with disorders/differences of sex development (DSD) in six European countries (dsd-LIFE).

BMC Health Serv Res. 2018 Jul 5;18(1):527. doi: 10.1186/s12913-018-3342-0.

Quality of health care in adolescents and adults with disorders/differences of sex development (DSD) in six European countries (dsd-LIFE).

Thyen U1, Ittermann T2, Flessa S3, Muehlan H4, Birnbaum W5, Rapp M6, Marshall L5, Szarras-Capnik M7, Bouvattier C8, Kreukels BPC9, Nordenstroem A10, Roehle R11, Koehler B12; dsd-LIFE group.


Author information

1Klinik fur Kinder- und Jugendmedizin, Universitat zu Lubeck, Ratzeburger Allee 160, 23538, Lubeck, Germany. ute.thyen@uksh.de.
2Institute for Community Medicine - SHIP-KEF, Ernst-Moritz-Arndt University Greifswald, Walther-Rathenau-Str. 48, 17487, Greifswald, Germany.
3Department of Health Care Management, University of Greifswald, 17487, Greifswald, Germany.
4Institute of Psychology, Department Health & Prevention, Ernst-Moritz-Arndt University Greifswald, Robert-Blum-Str. 13, 17487, Greifswald, Germany.
5Klinik fur Kinder- und Jugendmedizin, Sektion Padiatrische Endokrinologie, Universitat zu Lubeck, Ratzeburger Allee 160, 23538, Lubeck, Germany.
6Klinik fur Kinder- und Jugendmedizin, Universitat zu Lubeck, Ratzeburger Allee 160, 23538, Lubeck, Germany.
7Department of Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland.
8Endocrinologie pediatrique, Centre de reference des maladies rares du developpement sexuel, Hopital Bicetre, Universite Paris-Sud, 78 rue du General Leclerc, 94270, Paris, Le Kremlin Bicetre, France.
9Medische Psychologie en Medisch Maatschappelijk Werk, VU Medisch Centrum, PO Box 7057, 1007, MB, Amsterdam, the Netherlands.
10Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, 171 76, Stockholm, Sweden.
11Koordinierungszentrum fur Klinische Studien (KKS) Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
12Klinik für Padiatrische Endokrinologie und Diabetologie, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Abstract

BACKGROUND:
To investigate the association between the structural quality of care and patient satisfaction with care in individuals with disorders/ differences of sex development (DSD).

METHODS:
A multicenter cross-sectional comparative study was conducted in 14 clinics in six European countries. We assessed the level of structural quality of care in each center using a self-constructed measure (Center Score) and the level of participant satisfaction with care using the customer satisfaction questionnaire (CSQ-4) and an adopted version of the Youth Health Care - Satisfaction, Utilization & Needs (YHC-SUN-SF). Data were obtained from individuals with Turner Syndrome (261), Klinefelter Syndrome (173), 46, XX congenital adrenal hyperplasia (190) and XY-DSD (257).

RESULTS:
We found large variations between the scores for structural quality of care both within a diagnostic group and within a country; the overall association between participant satisfaction with the center score was significant.

CONCLUSIONS:
Comparative effectiveness research across Europe can lead to more insight on beneficial structures and processes and the overall strategy to care for people with rare diseases in general and specific conditions such as disorders/ differences of sex development. Appreciation of higher levels of structural quality of the centers in this study supports the concept of comprehensive care.

TRIAL REGISTRATION:
German Clinical Trials Register: Registration identification number: DRKS00006072 , date of registration April 17th, 2014. DRKS00006072 (German Clinical Trials Register).


KEYWORDS:
Disorders/differences of sex development; Multidisciplinary care; Patient satisfaction