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2025-06-29

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

Management of Gonads in Adults with Androgen Insensitivity: An International Survey.

Horm Res Paediatr. 2018 Oct 18:1-11. doi: 10.1159/000493645. [Epub ahead of print]

Management of Gonads in Adults with Androgen Insensitivity: An International Survey.

Tack LJW1, Maris E2, Looijenga LHJ3, Hannema SE4,5, Audi L6, Köhler B7, Holterhus PM8, Riedl S9,10, Wisniewski A11, Flück CE12, Davies JH13, T Apos Sjoen G14, Lucas-Herald AK15, Evliyaoglu O16, Krone N17, Iotova V18, Marginean O19, Balsamo A20, Verkauskas G21, Weintrob N22, Ellaithi M23, Nordenström A24, Verrijn Stuart A25, Kluivers KB26, Wolffenbuttel KP27, Ahmed SF28, Cools M1.

Author information EU全般

Abstract

BACKGROUND:

Complete and partial androgen insensitivity syndrome (CAIS, PAIS) are associated with an increased risk of gonadal germ cell cancer (GGCC). Recent guidelines recommend gonadectomy in women with CAIS in late adolescence. Nevertheless, many adult women prefer to retain their gonads.

AIMS:

This study aims to explore attitudes towards gonadectomy in AIS in centres around the world, estimate the proportion of adults with retained gonads and/or who developed GGCC, and explore reasons for declining gonadectomy.

METHODS:

A survey was performed among health care professionals who use the International DSD Registry (I-DSD).

RESULTS:

Data were provided from 22 centres in 16 countries on 166 women (CAIS) and 26 men (PAIS). In CAIS, gonadectomy was recommended in early adulthood in 67% of centres; 19/166 (11.4%) women refused gonadectomy. Among 142 women who had gonadectomy, evidence of germ cell neoplasm in situ (GCNIS), the precursor of GGCC, was reported in 2 (1.4%) out of 8 from whom pathology results were formally provided. Nine out of 26 men with PAIS (34.6%) had retained gonads; 11% of centres recommended routine gonadectomy in PAIS.

CONCLUSION:

Although development of GGCC seems rare, gonadectomy after puberty is broadly recommended in CAIS; in PAIS this is more variable. Overall, our data reflect the need for evidence-based guidelines regarding prophylactic gonadectomy in AIS.

© 2018 S. Karger AG, Basel.


KEYWORDS:

Complete androgen insensitivity syndrome; DSD management; Disorders of Sex Development (DSD); Germ cell cancer; International DSD Registry; Partial androgen insensitivity syndrome

2018-10-08

Malignant testicular germ cell tumors in postpubertal individuals with androgen insensitivity: prevalence, pathology and relevance of single nucleotide polymorphism-based susceptibility profiling.

Hum Reprod. 2017 Dec 1;32(12):2561-2573. doi: 10.1093/humrep/dex300.
https://academic.oup.com/humrep/article-abstract/32/12/2561/4600118:title=
Malignant testicular germ cell tumors in postpubertal individuals with androgen insensitivity: prevalence, pathology and relevance of single nucleotide polymorphism-based susceptibility profiling.]

Cools M1, Wolffenbuttel KP2, Hersmus R3, Mendonca BB4, Kaprová J3,5, Drop SLS6, Stoop H3, Gillis AJM3, Oosterhuis JW3, Costa EMF4, Domenice S4, Nishi MY4, Wunsch L7, Quigley CA8, T'Sjoen G9, Looijenga LHJ3.

Author information オランダ・ベルギー・ドイツ・アメリカ

Abstract

STUDY QUESTION:

What is the prevalence of malignant testicular germ cell tumors (TGCT) and its precursors, (pre-) germ cell neoplasia in situ (GCNIS), in late teenagers and adults who have androgen insensitivity syndrome (AIS) and the impact of an individual's genetic susceptibility to development of TGCT?

SUMMARY ANSWER:

No GCNIS or TGCT was diagnosed, but pre-GCNIS was identified in 14 and 10% of complete and partial AIS patients, respectively, and was associated with a higher genetic susceptibility score (GSS), with special attention for KITLG (rs995030) and ATFZIP (rs2900333).

WHAT IS KNOWN ALREADY:

Many adult women with AIS decline prophylactic gonadectomy, while data regarding the incidence, pathophysiology and outcomes of TGCT in postpubertal individuals with AIS are lacking. The relevance of genetic factors, such as single nucleotide polymorphisms (SNPs), in predisposing AIS individuals to TGCT is unknown.

STUDY DESIGN, SIZE, DURATION:

This multicenter collaborative study on prophylactically removed gonadal tissue was conducted in a pathology lab specialized in germ cell tumor biology.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Material from 52 postpubertal individuals with molecularly confirmed AIS (97 gonadal samples) was included; the median age at surgery was 17.5 (14-54) years. Immunohistochemical studies and high-throughput profiling of 14 TGCT-associated SNPs were performed. The main outcome measures were the prevalence of pre-GCNIS, GCNIS and TGCT, and its correlation with a GSS, developed based on the results of recent genome-wide association studies.

MAIN RESULTS AND ROLE OF CHANCE:

The earliest recognizable change preceding GCNIS, referred to as pre-GCNIS, was present in 14% of individuals with complete and 10% of those with partial AIS at a median age of 16 years. No GCNIS or invasive TGCT were found. The median GSS was significantly greater for those with, compared to those without, pre-GCNIS (P = 0.01), with an overlap between groups. Our data suggest important roles for risk alleles G at KITLG (rs995030) and C at ATFZIP (rs2900333), among the 14 studied TGCT-associated SNPs.

LARGE SCALE DATA:

N/A.

LIMITATIONS REASONS FOR CAUTION:

A limited number of cases were included.

WIDER IMPLICATIONS OF THE FINDINGS:

Our data suggest that the prevalence of pre-GCNIS in individuals with AIS beyond puberty is around 15%. Genetic susceptibility likely contributes to pre-GCNIS development in AIS but factors related to malignant progression remain unclear. Although data in older patients remain scarce, malignant progression appears to be a rare event, although the natural history of the premalignant lesion remains unknown. Therefore, the practice of routine prophylactic gonadectomy in adults with AIS appears questionable and the patient's preference, after having been fully informed, should be decisive in this matter.

STUDY FUNDING/COMPETING INTEREST(S):

This study was supported by research grants from the Research Foundation Flanders (FWO) (to M.C.), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq G0D6713N) (to B.B.M. and M.C.) and the European Society for Pediatric Endocrinology (ESPE), granted by Novo Nordisk AB (to J.K.). There are no competing interests.

© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

KEYWORDS:

androgen insensitivity syndrome; germ cell cancer; germ cell neoplasia in situ; non-seminoma; pathology; risk allele; seminoma; single nucleotide polymorphism; susceptibility; testis cancer

2018-07-19

Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis.

J Pediatr Urol. 2017 Oct;13(5):498.e1-498.e6. doi: 10.1016/j.jpurol.2017.02.013. Epub 2017 Mar 14.

Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis.

Chaudhry S1, Tadokoro-Cuccaro R2, Hannema SE3, Acerini CL1, Hughes IA1.

Author information

1Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
2Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
3Department of Paediatrics, Leiden University Medical Centre, Leiden, The Netherlands; Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Abstract

BACKGROUND:

Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive disorder of sex development (DSD) where affected individuals are phenotypically female, but have an XY karyotype and testes. The risk of gonadal tumour development in CAIS may increase with age; incidence rates have been reported to be 0.8-22% in patients who have retained their gonads into adulthood. Consequently, gonadectomy has been recommended either during childhood or after puberty is complete, although there is no consensus on the optimal timing for this procedure.

OBJECTIVE AND HYPOTHESES:

To establish the frequency of histological abnormalities in CAIS in relation to the age at gonadectomy.

METHOD:

Data were collected from the Cambridge DSD database on patients with CAIS (n = 225; age range 3-88 years) who had undergone gonadectomy, and their age of gonadectomy, gonadal histology and immunohistochemistry.

RESULTS:

Evaluable data were obtained from 133 patients. Median age at gonadectomy was 14.0 years (range: 18 days-68 years). Pubertal status was: prepuberty, n = 62; postpuberty, n = 68. Thirteen cases were aged >20 years at gonadectomy. The pattern of histology is summarised in the Summary table.

DISCUSSION:

In this large case series of CAIS patients who had undergone gonadectomy, while the combined malignant and premalignant gonadal histology prevalence was 6.0%, the findings confirm the low occurrence of gonadal malignancy in CAIS, with a frequency of 1.5%. The two cases of malignancy were postpubertal. Germ cell neoplasia in situ (GCNIS) was observed in six cases, of which one occurred prepuberty and five postpuberty. The study highlighted difficulties in diagnosis of GCNIS and the need for histological analysis in expert centres.

CONCLUSION:

The results support the current recommendation that gonads in CAIS can be retained until early adulthood. The small number of individuals with gonadectomy after age 20 years do not allow firm conclusion regarding later adulthood. Therefore, it is recommended that the option of gonadectomy be discussed in adulthood. Some form of regular surveillance of the gonads is then recommended, although none of the available options are ideal.

Copyright © 2017 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.


KEYWORDS:

Androgen insensitivity syndrome; Carcinoma in situ (CIS); Germ cell neoplasia in situ (GCNIS); Gonadal tumour; Gonadectomy

2018-06-29

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;`)。