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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;`)。

2019-01-25

Sexual Identity Disorder and Psychosis in Klinefelter Syndrome: A Synthesis of Literature and a Case Report.

J Nerv Ment Dis. 2019 Jan 21. doi: 10.1097/NMD.0000000000000930. [Epub ahead of print]

Sexual Identity Disorder and Psychosis in Klinefelter Syndrome: A Synthesis of Literature and a Case Report.

Maillefer A1, Sabe M1, Coste C1, Bartolomei J1, Jaafar J2, Sentissi O1.

Author information スイス


Abstract

Klinefelter syndrome (KS) 47, XXY is the most frequent chromosomal abnormality causing hypogonadism in humans. This chromosomal abnormality of number in its classical form called homogeneous (supernumerary X) is generally the result of a meiosis accident. Several studies have suggested that individuals with KS are at greater risk of developing various psychiatric disorders, including depression and schizophrenia. The diagnosis is made based on subnormal testosterone with high pituitary gonadotropins and confirmed by determining the karyotype on a blood simple. We did a literature review using an electronic search in three databases: Pubmed/MEDLINE, Google Scholar, and PsychInfo. We found that since 1989, seven case reports with KS and mental disorders with similar and different characteristics of our case illustration of a patient with KS and psychosis were published.

2019-01-21

Testosterone replacement in androgen insensitivity: is there an advantage?

Ann Transl Med. 2018 Nov;6(Suppl 1):S85. doi: 10.21037/atm.2018.10.73.

Testosterone replacement in androgen insensitivity: is there an advantage?

Batista RL1, Mendonca BB1.

Author information ブラジル

Androgen insensitivity syndrome (AIS) is the most common etiology of 46,XY disorders of sex development (DSD) (1). In the complete phenotype (CAIS), affected individuals present typically female external genitalia at birth, are assigned as female and present psychosexual development in agreement with sex assignment (2). In CAIS, bilateral gonadectomy is necessary either due to inguinal hernia at childhood or to avoid germ cell tumor development (3). The consequence of bilateral gonadectomy is the need of oestrogen replacement as expected for matched-age women. However, despite an adequate hormonal replacement with estrogens, some CAIS women complained about reduced psychological wellbeing and sexual satisfaction after bilateral gonadectomy (4,5).

Birnbaum et al. designed a clinical trial to answer the question: is testosterone able to improve wellbeing and sexual functioning in patients with CAIS? That question was based on evidence that some sexual behavior brain activation is independent of a functioning androgen receptor and depends on the conversion of testosterone into estrogen by aromatase (6,7).

The effectiveness and safety of testosterone replacement on wellbeing and sexuality in patients with CAIS were evaluated in a national, multicenter, double blind, randomized crossover trial conduced in Germany at three university centers and three specialized treatment institutions (8). The authors enrolled 26 patients with CAIS (aged 18–54 years), with molecular diagnosis of AIS and previous gonadectomy (at least 1 year). They were treated with estradiol 1.5 mg/day during a 2-month run-in phase. After this phase, they were divided into two groups (14 in sequence A and 12 in sequence B), in a random manner to receive: oestradiol (1.5 mg/day or testosterone 50 mg/day for 6 months (sequence A). Gel preparations for both hormonal replacements via transdermal application were used daily. After that period, there was a cross over and the groups changed from the previous hormone-replacement therapy to the other one, in a double-blinded manner for more 6 months (sequence B).

The primary endpoint was mental health and secondary endpoints were psychological wellbeing and sexual functioning. Safety parameters were also analyzed, and possible side effects were reported and classified according to severity into three categories: mild, moderate, and intense.

The health-related quality of life (HRQoL) and mental HRQoL (MHRQoL) were measured with the standardized SF-36 German version, a multipurpose and validated short-form survey which measure eight health domains (physical functioning, vitality, social functioning, role-physical, role-emotional, bodily pain, mental health, general health) and psychometrical physical and mental health summary measures. The Brief Symptom Inventory (BSI), which is an instrument that evaluates psychological distress and psychiatric disorders covering nine symptom dimensions, was used to assess psychological wellbeing. Sexual functioning was measured with a German version of the Female Sexual Function Index (FSFI), a multidimensional self-report instrument for assessing the key dimensions of sexual function in women. This questionnaire provides scores on six domains of sexual function (desire, arousal, lubrication, orgasm, satisfaction, and pain) as well as a total score.

Testosterone, estradiol, LH, FSH and urinary steroid metabolites were measured at baseline, after the run-in phase and during the treatment, both for treatment monitoring and for compliance estimative.

There was no significant difference in the effect of oestradiol and testosterone on mental health scores or physical summary scores. The MHRQoL and physical HRQoL scores did not differ significantly from baseline either for testosterone or oestradiol replacement. Wellbeing evaluated by BSI scores showed that the patients enrolled had psychological distress at beginning of the trial. Nevertheless, there’s no significant difference regarding BSI scores for psychological wellbeing between two groups.

With regard to sexual functioning, the mean value of FSFI score at baseline was 15.78, which is consistent with a low prevalence of satisfactory sexual functioning among those CAIS individuals before treatment. Both hormone-replacement therapies increase the FSFI score from baseline to 19.3 (under oestradiol) and to 21.5 (under testosterone). These increments in FSFI scores were significant from basal FSFI score but it was not significant between each other. The mean FSFI total scores for sexual functioning were higher for testosterone than oestradiol treatment in all sexual domains (except by sexual satisfaction) but statistical significance only occurred in the desire domain (P=0.018).

Regarding safety, three patients dropped out because of adverse events. One patient had fibrous mastopathy receiving oestradiol during run in phase (classified as a serious adverse event). The other two side effects (episodes of depression and hot flush symptoms) occurred in patients receiving testosterone.

In summary, at the end of the study the difference of FSFI total score between both groups was not significant. Although, testosterone was superior to oestradiol in the improvement of sexual desire in the FSFI sub analysis (analysis of each domain) there were no differences on safety between both treatments.

The authors concluded that testosterone was well tolerated and safety as estradiol and it could be an alternative hormone-replacement therapy for patients with CAIS, especially when sexual desire is reduced.

It has been demonstrated that sexual life of 46,XY DSD people is affected for many reasons. However, the results of studies on quality of sexual life are inconsistent, in part either due to the lack of questionnaire on sexual life specific for DSD and for the heterogeneity of the DSD etiologies enrolled in previous studies (5,9,10).

The Birnbaum et al. clinical trial is very interesting because it is the first clinical trial designed for disorders of sexual development individuals. In addition to contributing results of efficacy, this study expands knowledge about the role of androgens in human sexuality. However, it is necessary to pay attention to some points: the sexual improvement by testosterone seems to be related to sexual desire, which was not enough to improve sexual satisfaction. The benefits of steroid replacement in bone integrity and cardiovascular protection are well-established with estrogen replacement but it is unknown regarding testosterone. The shorter period of therapy (6 months) preclude the conclusion of long-term safety.

Although testosterone could be an alternative hormone therapy for patients with CAIS, long term follow-up, assessment of impact on other psychological issues and on bone metabolism and cardiovascular protection are necessary to consider testosterone replacement in CAIS in clinical practice.

2019-01-19

The Association of Motor Skills and Adaptive Functioning in XXY/Klinefelter and XXYY Syndromes.

Phys Occup Ther Pediatr. 2018 Dec 28:1-14. doi: 10.1080/01942638.2018.1541040. [Epub ahead of print]

The Association of Motor Skills and Adaptive Functioning in XXY/Klinefelter and XXYY Syndromes.

Martin S1,2, Cordeiro L3, Richardson P2, Davis S3, Tartaglia N1,3.

Author information アメリカ


Abstract

AIMS:

Klinefelter (XXY) and XXYY syndromes are genetic disorders in males characterized by additional sex chromosomes compared to the typical male karyotype of 46, XY. Both conditions have been previously associated with motor delays and motor skills deficits. We aimed to describe and compare motor skills in males with XXY and XXYY syndromes, and to analyze associations with age, cognitive abilities, and adaptive functioning.

METHODS:

Sixty-four males with XXY and 46 males with XXYY, ages 4-20 were evaluated using the Beery Test of Visual Motor Integration and the Bruininks-Oseretsky Test of Motor Proficiency - 2nd Edition assessments, Vineland-2 adaptive scales, and cognitive testing.

RESULTS:

Motor coordination impairments were found in 39% of the males with XXY and 73% of the males with XXYY. Both groups showed strengths in visual perceptual skills. Males with XXYY had lower mean scores compared to males with XXY across all assessments. Fine motor dexterity and coordination deficits were common. There was a positive correlation between VMI scores and adaptive functioning.

CONCLUSION:

Occupational and physical therapists should be aware of the motor phenotype in XXY and XXYY both to aid in diagnosis of unidentified cases and to guide intervention.


KEYWORDS:

47; Klinefelter syndrome; activities of daily living; motor skills; occupational therapy; physical therapy; visual motor integration; xxy; xxyy

Is genetic fatherhood within reach for all azoospermic Klinefelter men?

PLoS One. 2018 Jul 25;13(7):e0200300. doi: 10.1371/journal.pone.0200300. eCollection 2018.

Is genetic fatherhood within reach for all azoospermic Klinefelter men?

Vloeberghs V1, Verheyen G1, Santos-Ribeiro S1, Staessen C2, Verpoest W1, Gies I3, Tournaye H1.

Author information ベルギー

Abstract

BACKGROUND:

Multidisciplinary management of Klinefelter cases is now considered good clinical practice in order to ensure optimal quality of life. Reproductive performance of Klinefelter men is an important issue however literature in this domain is limited and prone to bias.

STUDY DESIGN:

This was a retrospective longitudinal cohort study performed at a tertiary referral University Centre for Reproductive Medicine and Genetics. One hundred thirty-eight non-mosaic azoospermic Klinefelter patients undergoing their first testicular biopsy (TESE) between 1994 and 2013, followed by intracytoplasmic sperm injection (ICSI) with fresh or frozen-thawed testicular sperm in the female partner, were followed-up longitudinally. The main outcome measure was cumulative live birth rate per Klinefelter patient embarking on TESE-ICSI.

FINDINGS:

In forty-eight men (48/138) sperm were successfully retrieved at the first TESE (34.8%). The mean age of the patients was 32.4 years. Younger age at first TESE was associated with a higher sperm retrieval rate (p<0.001). Overall 39 couples underwent 62 ICSI cycles and 13 frozen embryo transfer cycles resulting in in 20 pregnancies and 14 live birth deliveries (16 children). The mean age of the female partner was 28.1 years. The crude cumulative delivery rate after four ICSI cycles was 35.9%. Per intention-to-treat however, only 10.1% (14/138) of the Klinefelter men starting treatment succeeded in having their biologically own child(ren).

CONCLUSION:

Non-mosaic Klinefelter patients with azoospermia seeking treatment by TESE-ICSI should be counseled that by intention-to-treat the chance of retrieving sperm is fair, however only a minority will eventually father genetically own children.

High-level language competencies and Theory of Mind in a group of children with Klinefelter syndrome.

Am J Med Genet A. 2019 Jan 8. doi: 10.1002/ajmg.a.12. [Epub ahead of print]

High-level language competencies and Theory of Mind in a group of children with Klinefelter syndrome.

Melogno S1,2, Pinto MA1, Badolato F3, Sist E1, Esposito A3, Orsolini M1, Tarani L3.

Author information イタリア


Abstract

Klinefelter syndrome (KS) is a genetic anomaly involving the presence of one or more supernumerary X chromosomes in male individuals. In the cognitive profile of these individuals, strengths are found in nonverbal abilities, whereas weaknesses are observed in executive function, language, and academic performance. Our study is based on a comparison between eight children diagnosed with KS (47,XXY) (age range: 9-13 years; IQ range: 80-123), with no delay in language development, and eight typically developing (TD) controls. We explored a range of high-level language competencies and Theory of Mind (ToM) in addition to basic language competency. High-level language competencies were assessed by a battery that measures pragmatic language skills and a metaphor comprehension test (MCT). To assess ToM, we administered the corresponding subtest of the NEPSY II. Basic language competence was assessed by the NEPSY II Comprehension of Instructions subtest. Although basic language performance did not differentiate the individuals with KS from the TD controls, relevant differences appeared in some of the high-level language competencies as well as in the ToM task. All tasks in which the individuals with KS performed less well were characterized by complex inferential processes. Some possible clinical and educational implications are discussed.

© 2019 Wiley Periodicals, Inc.


KEYWORDS:

High-level language competencies; Klinefelter syndrome; Theory of Mind; Verbal inferential processes; metaphor comprehension

The incidence of anxiety symptoms in boys with 47,XXY (Klinefelter syndrome) and the possible impact of timing of diagnosis and hormonal replacement therapy.

Am J Med Genet A. 2019 Jan 13. doi: 10.1002/ajmg.a.61038. [Epub ahead of print]

The incidence of anxiety symptoms in boys with 47,XXY (Klinefelter syndrome) and the possible impact of timing of diagnosis and hormonal replacement therapy.

Samango-Sprouse C1,2,3,4, Lasutschinkow P4, Powell S1, Sadeghin T4, Gropman A1,2.

Author information アメリカ

Abstract

47,XXY (Klinefelter syndrome) is the most common X and Y chromosomal variation (1:660 males). The incidence of anxiety disorders and the impact of hormonal replacement therapy (HRT) is not well understood. Child Behavior Checklist and Screen for Childhood Anxiety Related Emotional Disorders were completed by parents of 80 boys with 47,XXY. Forty received HRT prior to 10 years of age while 40 did not. HRT (22.5%) received early hormonal treatment prior to 18 months. About 32.5% received hormone booster treatment between 5 and 10 years. The remaining 42.5% received both. There were fewer reported social (p = .015), thought (p = .012), and affective problems (p = .048) in treated boys when compared to untreated. Boys with both treatments demonstrated fewer symptoms on anxious/depressed scale (p = .001) compared to those with early treatment only. Within the treated group, prenatally diagnosed showed fewer indications of anxiety problems (p = .02) than their postnatal counterparts. This comparative, cross-sectional study expands previous findings on the possible positive effect of HRT in boys with 47,XXY. Anxiety disorders appear to be a penetrant aspect of the 47,XXY phenotype. Further investigation is warranted to explore the relationship between biological treatment and individual responses to HRT to develop more personalized and precise medicine.

© 2019 Wiley Periodicals, Inc.


KEYWORDS:

47,XXY; Klinefelter syndrome; X and Y chromosomal variations; anxiety disorders; hormonal replacement therapy; sex chromosome abnormalities and aneuploidies