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Management of 46,XY Differences/Disorders of Sex Development (DSD) Throughout Life

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Management of 46,XY Differences/Disorders of Sex Development (DSD) Throughout Life REVIEW Management of 46,XY Differences/Disorders of Sex Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 Development (DSD) Throughout Life Amy B. Wisniewski,1 Rafael L. Batista,2 Elaine M. F. Costa,2 Courtney Finlayson,3 Maria Helena Palma Sircili,2 Francisco Tibor Denes,´ 4 Sorahia Domenice,2 and Berenice B. Mendonca2 1Psychology Department, Oklahoma State University, Stillwater, Oklahoma 74078; 2Division of Endocrinology, Department of Internal Medicine, University of São Paulo Medical School, University of São Paulo, 05403-000 São Paulo, Brazil; 3Division of Endocrinology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; and 4Division of Urology, Department of Surgery, University of São Paulo Medical School, University of São Paulo, 05403-000 São Paulo, Brazil ORCiD numbers: 0000-0003-1762-1084 (B. B. Mendonca). ABSTRACT Differences/disorders of sex development (DSD) are a heterogeneous group of congenital conditions that result in discordance between an individual’s sex chromosomes, gonads, and/or anatomic sex. Advances in the clinical care of patients and families affected by 46,XY DSD have been achieved since publication of the original Consensus meeting in 2006. The aims of this paper are to review what is known about morbidity and mortality, diagnostic tools and timing, sex of rearing, endocrine and surgical treatment, fertility and sexual function, and quality of life in people with 46,XY DSD. The role for interdisciplinary health care teams, importance of establishing a molecular diagnosis, and need for research collaborations using patient registries to better understand long-term outcomes of specific medical and surgical interventions are acknowledged and accepted. Topics that require further study include prevalence and incidence, understanding morbidity and mortality as these relate to specific etiologies underlying 46,XY DSD, appropriate and optimal options for genitoplasty, long-term quality of life, sexual function, involvement with intimate partners, and optimizing fertility potential. (Endocrine Reviews 40: 1547 – 1572, 2019) ifferences/disorders of sex development (DSD) results in female-typical external genitalia, and di- D are a heterogeneous group of congenital con- agnoses in this group may be delayed until puberty or ditions that result in discordance between an individual’s later when a lack of breast development and/or sex chromosomes, gonads, and/or anatomic sex (). primary amenorrhea is observed (). Partial virili- Although the term “disorders of sex development” is zation is often noted at birth when atypical external widely used in recent medical literature, it is not uni- genital anatomy is noted (–). Regardless of the versally accepted by patients and advocates. Alternatives extent of undervirilization, the underlying cause for describing such conditions include the terms “vari- of ,XY DSD can be attributed to (i) decreased ations in sex development” or “differences,” which is production of androgens such as testosterone (T) or implemented in this review. DHT during fetal sex differentiation, or (ii) impaired Some people with DSD possess a ,XY chro- androgen action at target tissues throughout life – mosome complement, collectively referred to as ,XY ( , )(Table ). ISSN Print: 0163-769X DSD ( , ). People with ,XY DSD can present with Owing to both the complexity and heterogeneity of ISSN Online: 1945-7189 variable degrees of virilization of their external geni- conditions labeled ,XY DSD, optimal management Printed: in USA talia, along with variable degrees of development of for patients merits an interdisciplinary team approach Copyright © 2019 structures derived from the Wolffian and M¨ullerian with the goal of providing holistic care throughout the Endocrine Society ducts (–). Testes are identified in many, but not lifespan (, ). Data pertaining to the long-term Received: 12 February 2019 Accepted: 23 July 2019 all, affected individuals regardless of their degree outcomes of people with ,XY DSD are beginning to First Published Online: of undervirilization ( , ). Complete absence of virilization inform medical teams about optimizing management; 31 July 2019 doi: 10.1210/er.2019-00049 https://academic.oup.com/edrv 1547 REVIEW ESSENTIAL POINTS · Due to the complexity and heterogeneity of conditions under the 46,XY DSD umbrella, interdisciplinary health care teams are best suited to provide care to patients and their families · Optimal laboratory measurements followed by the molecular diagnosis are strongly recommended before sex assignment · Several factors influence decisions regarding sex of rearing for 46,XY DSD newborns, including etiology-specific Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 information related to gender development, genital appearance and surgical options, hormone replacement, fertility potential, family preferences, and cultural considerations · Looking forward, further research in large worldwide samples is needed to explore the influence of hormone exposure, genetic etiology, type and timing of genital surgery, aspects of romantic life, and sexual function · Counseling patients on their fertility options, as well as discussing parenthood alternatives, is essential · Patients and parents should have access to mental health support and receive complete and unbiased education about DSD, including treatment options specific to their particular condition · Mental health providers and peer support should encourage patients and their families to discuss DSD with others in a way that respects privacy while eliminating shame and secrecy however, much remains to be learned. The aims of is that the Danish cohort mainly included patients this proposal are to review what is known about with AIS ( out cases of ,XY DSD) and prevalence, incidence, morbidity, diagnostic tools and gonadal dysgenesis ( of cases). Although the timing, sex of rearing, endocrine and surgical treat- Danish sample may not generalize to other areas of ment, fertility and sexual function, and behavioral the world, the number of cases of AIS and gonadal development in affected people. dysgenesis allows for estimates of prevalence (. per , live-born females) and incidence (. per Prevalence and incidence , live-born females). Data on the incidence and prevalence of ,XY DSD are sparse, and estimates vary widely because Morbidity DSD etiology is heterogeneous. Whereas some types To optimize health care for people affected by any of DSD are monogenic conditions, others result medical condition, broader knowledge about mor- from several gene mutations, making a molecular bidity and mortality is essential (). There are many diagnosis difficult to perform (, ). Addition- reasons why people with ,XY DSD may present high ally, some etiologies are observed worldwide [i.e., morbidity, including hypogonadism, irregular sex androgen insensitivity syndrome (AIS)] whereas hormone replacement, genital surgery, and gonadec- others occur in geographic clusters [i.e., a-reductase tomy. To access epidemiological data relevant to type deficiency (a-RD)] (Table )(–). people with ,XY DSD, morbidity and mortality for Therefore, accurate estimates of prevalence and in- females with ,XY DSD were compared with , cidence of many presentations of ,XY DSD are female and , male controls (). The overall unavailable. morbidity of females with ,XY was increased in AIS is thought to be the most common ,XY comparison with unaffected people. For example, DSD etiology followed by gonadal dysgenesis (). women with complete AIS (CAIS) who received a The incidence of AIS and gonadal dysgenesis is gonadectomy experienced reduced bone mineral reported to be one to five per , births and one density (BMD), although BMD was less affected in per , births, respectively (–). For other women with this condition who retained their types of ,XY DSD, epidemiologic studies are testes (, ). Women with ,XY DSD with partial lacking due to their rarity. To estimate the incidence virilization due to gonadal dysgenesis have a normal and prevalence of ,XY DSD, a nationwide cohort BMD (). was conducted in Denmark and the prevalence was Increased prevalence of obesity, insulin resistance, . per , live-born females whereas the in- and lipid abnormalities have been reported in women cidence was . permillionfemales(). To compare with CAIS, and these are attributed to the loss of their results with the literature, the authors pooled androgen receptor signaling (). However, the data from large cytogenetic survey studies and prevalence of metabolic syndrome is not well defined calculated a prevalence of four cases of ,XY DSD in patients with other types of ,XY DSD. Overall, per , female births. Why prevalence in the females with ,XY had no increased occurrence of Danish population was higher than the pooled circulatory system diseases, including ischemic heart prevalence is not clear, but possible bias from pooled disease, arteriosclerosis, hypertension, and cerebro- results could be an explanation. Another possibility vascular disease (). 1548 Wisniewski et al 46,XY DSD Management Endocrine Reviews, December 2019, 40(6):1547–1572 REVIEW Regarding cause-specific morbidity, gonadal cancer ameliorate the lack of knowledge about long-term was increased in females with ,XY whereas other health outcomes for people with ,XY
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