Disorders of Sex Development/Intersex in Children and Adolescents

FOCUS | CLINICAL

A guide to differences/ disorders of sex development/intersex in children and adolescents

Komal A Vora, Shubha Srinivasan DIFFERENCES/DISORDERS of sex development consensus about nomenclature and (DSD) or ‘intersex’ encompass a wide optimal management. Promoting a range of conditions usually presenting non-binary view of sex and gender can be Background Differences/disorders of sex in the newborn period or adolescence. helpful to work towards common goals of development (DSD) or ‘intersex’ Most are relatively rare, and the overall optimal care. There is limited evidence encompass a broad range of congenital incidence depends on which conditions are to support and/or guide clinical decision variations in the complex pathways included; for example: making that involves the consideration involved in the development of sex • Klinefelter syndrome (47,XXY) – one in of medical, human rights, ethical and characteristics. Components of these 450 births of male infants1 legal aspects.5 Moreover, there has pathways include sex chromosomes, discordance between phenotypic been considerable debate regarding genes involved in gonadal development, • hormone production and action, and the and genotypic sex at birth – one in the indication and timing of surgical 2 development of internal and external 4500–5500 births interventions for minors with DSD. genital structures. Many variations are • congenital adrenal hyperplasia (CAH) – Clinical features and underlying rare, and some (eg congenital adrenal one in 14,000 births3 pathophysiology vary from one individual hyperplasia) are associated with urgent • complete XX or XY sex reversal – one in with a DSD to another. As a result, medical needs. People born with 20,000 births2 presentations can range from atypical variations in sex characteristics may ovotesticular DSD – one in 100,000 genitalia in infancy to atypical pubertal present in the neonatal period with • 2 atypical genitalia, during childhood births. development in adolescence to fertility and adolescence with atypical pubertal Terminology has been a source of concerns in adulthood. Throughout the development or in adulthood with dissatisfaction among many affected lifespan, there can be challenging and hormone imbalance, fertility issues individuals, with some peer support sensitive discussions and decisions, such and/or sexual health concerns. groups having a strong preference for as the appropriate sex of rearing, gender 4 Objective ‘intersex’ over ‘DSD’, while others identity, potential for future adult sexual An overview of DSD is presented in actively dissociate from the term functioning and fertility. Healthcare relation to presenting features and ‘intersex’. Clinicians generally avoid professionals may face pressure for management challenges in the either term when speaking with affected urgent diagnosis and management at paediatric population. individuals and their families, choosing presentation but also need to consider a Discussion to use terminology based on the diagnosis medium-term and long-term plan with the An experienced multidisciplinary team whenever possible (eg CAH, Klinefelter child/adolescent and family in the context that uses a shared decision-making syndrome). However, DSD/intersex can of the social and cultural environment. approach with a medical, surgical, be useful umbrella terms in the context Psychological support should be provided ethical, psychological and human rights of medical literature and policy. The throughout the patient journey. framework is required to maximise long- diverse clinical features, pathophysiology As a result of the rarity of many term positive outcomes for people born with variations in sex characteristics. and management challenges in DSD conditions, data on long-term outcomes have compounded efforts to reach are limited, and patient groups as well

© The Royal Australian College of General Practitioners 2020 REPRINTED FROM AJGP VOL. 49, NO. 7, JULY 2020 | 417 FOCUS | CLINICAL A GUIDE TO DIFFERENCES/DISORDERS OF SEX DEVELOPMENT/INTERSEX IN CHILDREN AND ADOLESCENTS

as professionals have challenged aspects ovotestis as ovaries tend to remain in requires an individualised approach taking of clinical care that were previously pelvic position.9 DSD may also be part of into consideration prenatal androgen considered as standard. Through greater a multisystem disorder with coexistent exposure, fertility potential, quality of use of multidisciplinary teams (MDTs), metabolic abnormalities or dysmorphic sexual function, surgical options, gonadal development of patient registries and features. CAH is the most common pathology/malignancy risk and potential international collaboration, the evidence cause of genital ambiguity in infancy adult gender identity.2 Given the variation base for the best standards of care will and should be considered in any baby and complexity of different types of DSD, continue to develop. with genital ambiguity, shock and/or it may be difficult to extrapolate outcomes hyponatraemia and hyperkalaemia.10 It is for each individual. Research in DSD a potentially life-threatening condition and gender identity has only been done Classification and diagnosis of DSD and requires urgent treatment with in larger subgroups such as patients with The development of the 2006 consensus high-dose hydrocortisone to prevent an CAH and androgen insensitivity syndrome. guidelines6 was a turning point in the adrenal crisis. To date, evidence suggests sex of rearing classification of DSD, with three broad Initial investigations for genital ambiguity is an important but imperfect predictor categories: sex chromosomal DSD, include karyotype and/or rapid polymerase of gender identity, with some additional 46,XX DSD and 46,XY DSD (Box 1). chain reaction or fluorescence in situ contribution of prenatal androgen This resulted in the abandonment of hybridisation for Y material, glucose, exposure in male gender identity.11 misleading and pejorative terms such electrolytes, 17-hydroxyprogesterone as ‘hermaphrodite’. Diagnosis of DSD (17-OHP), gonadotropins, oestradiol generally involves a hormone profile and testosterone. Results should be Children and adolescents work-up, genetic testing and visualisation interpreted in the context of the baby’s Simple virilising CAH may present in of internal reproductive structures, gestational and chronological age. childhood with a rapid growth spurt, through either medical imaging or The paediatric endocrinologist may exaggerated signs of adrenarche (eg pubic laparoscopy. These investigations are request further testing including pelvic hair) and virilisation of the genitalia, with coordinated by a member of the MDT, ultrasonography, urine steroid profile, clitoromegaly or penile growth without often the paediatric endocrinologist.7 serum anti-Müllerian hormone, human testicular enlargement.10 A 17-OHP level, Throughout the diagnostic work-up and chorionic gonadotropin stimulation test synacthen test and genotyping are useful discussion of results and management and DSD gene panels. investigations for diagnosis. plans, it is paramount that there is an Sex assignment is a dilemma in a small Presenting features of DSD in an open and transparent discussion with percentage of patients with DSD and adolescent may include delayed puberty, parents and affected individuals at developmentally appropriate times. Box 1. Summary of classification of differences/disorders of sex development taken from the 2006 consensus statement6 Neonates 46,XY DSD Neonates who require diagnostic work-up • Disorders of testicular development, including partial and complete testicular dysgenesis, include those with ambiguous or atypical testicular regression and ovotesticular DSD genitalia or less obvious findings such as • Disorders of androgen biosynthesis (eg 5-alpha reductase deficiency) or action (CAIS, bilateral nonpalpable gonads, palpable PAIS, luteinising hormone receptor defects) gonads in labioscrotal folds, perineal • AMH disorders (eg persistent Müllerian duct syndrome) hypospadias, undervirilised phallus, • Other disorders, including severe hypospadias and cloacal exstrophy clitoromegaly or discordant genital 46,XX DSD appearance to prenatal genetic test. • Disorders of ovarian development, including ovarian dysgenesis as well as testicular The initial evaluation should include a or ovotesticular DSD thorough pregnancy and family history • Disorders of androgen excess of either fetal, fetoplacental or maternal origin and clinical examination. Physical • Other disorders, including cloacal exstrophy, MURCS and vaginal atresia examination should include evaluation Sex chromosome DSD of general health, hydration state, blood Disorders related to atypical arrangement of sex chromosomes, including: pressure and appearance of external • missing sex chromosome (eg 45,X, as seen with Turner syndrome) genitalia with regards to whether the • additional sex chromosome (eg 47,XXY, as seen with Klinefelter syndrome) labioscrotal folds are fused, the presence • more than one type of sex chromosome arrangement (eg 45,X/46,XY or 46,XX/46,XY) of palpable gonads, the location of the urethral meatus and the size of the AMH, anti-Müllerian hormone; CAIS, complete androgen insensitivity syndrome; DSD, differences/ phallus/clitoris.8 Palpable gonads are disorders of sex development; MURCS, Müllerian, renal, cervicothoracic somite abnormalities; PAIS, partial androgen insensitivity syndrome most commonly testes and occasionally

418 | REPRINTED FROM AJGP VOL. 49, NO. 7, JULY 2020 © The Royal Australian College of General Practitioners 2020 A GUIDE TO DIFFERENCES/DISORDERS OF SEX DEVELOPMENT/INTERSEX IN CHILDREN AND ADOLESCENTS FOCUS | CLINICAL

primary amenorrhea or virilisation of a (eg CAH) to historically low in 46,XY DSD. endocrinology, urology, gynaecology, phenotypic female.10 Non-classical CAH Targeted gene panels have improved the genetics, psychology, ethics and/or may have similar features to polycystic diagnostic yield to almost 50% of 46,XY hospital executive (Figure 1). With ovarian syndrome. Physical examination DSD.13 The reducing cost and greater the patient’s/parent’s consent to share of the external genitalia may be best accessibility of whole-exome sequencing information outside the hospital setting, deferred and only performed by an (WES) and whole-genome sequencing communication with the family’s primary experienced urologist or gynaecologist (WGS) may further increase the diagnostic care physician is important to nourish under an anaesthetic. Investigations yield of genetic testing. It is paramount the therapeutic relationship in primary include karyotype, serum electrolytes, that appropriate genetic counselling care, enable ongoing education of health pubertal hormone profile, androgens, be undertaken for all genetic testing professionals and provide a smoother pituitary hormone profile, adrenal and especially for potential unexpected transition to adult care. steroid profile and transabdominal pelvic findings from WES and WGS. In some centres, prospective, systematic ultrasonography. Magnetic resonance peer review of complex decision making imaging and ultrasonography of internal for patients with DSD has been formalised structures can be inaccurate, and internal Management through regular multidisciplinary meetings. structures ‘not visualised’ does not Multidisciplinary teams An audit of the DSD MDT meetings equate to absent structures or lack of A multidisciplinary approach to shared in Sydney (The Children’s Hospital at future function (eg a small uterus may be decision making is considered the Westmead, Sydney Children’s Hospital) due to lack of oestrogen effect). It may ‘crux of patient-centred care’14 and and Melbourne (Royal Children’s only be at genitoscopy and laparoscopy involves simultaneous, but independent, Hospital, Monash Children’s Hospital)15 that internal structures are confidently contributions of team members from two highlighted a number of areas discussed identified. The results from these or more disciplines.2 The core composition at the meetings (Box 2). The audit also investigations need careful interpretation of the team may vary according to the age showed that an active deferral of surgery in the context of other clinical features. of the child, DSD type and local resources, was the outcome in >20% of cases, For example, an adolescent with primary and may include a representative from surgery was only recommended for amenorrhoea who has normal breast development could have complete androgen insensitivity syndrome (CAIS) with a 46,XY karyotype, or Müllerian agenesis, also known as Mayer– Endocrinology Rokitansky–Küster–Hauser syndrome, with a 46,XX karyotype. An adolescent with primary amenorrhoea and little/no breast development and short stature could have Turner syndrome, while one Gynaecology Nursing with normal stature could have complete gonadal dysgenesis.

Genetic testing General Executive Young person Urology practitioner Many DSD are caused by variants in and family genes involved in genital and/or gonadal development or steroid hormone production. Recent advances in molecular genetics have enabled more accurate Genetics molecular diagnoses in many individuals, Psychology which can then provide guidance on prognosis and potential gonadal malignancy risk for some (eg CAIS).12 Furthermore, a genetic diagnosis is often Ethics helpful for individuals and families as they deal with uncertainty, potential stigma and blame. The yield from diagnostic gene testing varies from high in cases Figure 1. Multidisciplinary team model2 with a clear steroidogenic pathway defect

© The Royal Australian College of General Practitioners 2020 REPRINTED FROM AJGP VOL. 49, NO. 7, JULY 2020 | 419 FOCUS | CLINICAL A GUIDE TO DIFFERENCES/DISORDERS OF SEX DEVELOPMENT/INTERSEX IN CHILDREN AND ADOLESCENTS

therapeutic indications, and >90% of the parents and patients may require repeated on the presence of gonadoblastoma gonadectomies performed had abnormal explanation about the condition because on Y chromosome (GBY) material in features on histology.15 information retention can be an issue, the karyotype, anatomical localisation especially during the stressful period of a and degree of maturation of the Psychological support new diagnosis. It is also important to bear gonad. The highest risk is in patients Parents of newborns with DSD should in mind that the focus of explanation and with undifferentiated gonadal tissue, be provided with psychological support, the issues of discussion change over the dysgenetic testes and intra-abdominal ideally by someone with experience in time. Information disclosure can present testes in undervirilisation syndromes.21,22 DSD. The clinical psychologist is able further challenges for culturally and Gonadoblastoma and invasive GCTs occur to provide support at times of medical/ linguistically diverse patients, as concepts at a much younger age when compared surgical discussions and interventions, about sexuality and gender roles may vary with germ cell neoplasia in situ, which gender identity assessments of the young between different cultures.18 A systematic occurs mainly after the exposure to person, and transition to adult services. approach to medical record keeping also puberty hormones.21 The psychologist can aid in assessing the helps with future disclosure of the basis on Delaying surgery for functional gonads parents’ and young person’s understanding which management decisions were made. allows time for exploration of gender of information discussed and provide family identity, which may differ from assigned support in a culturally sensitive manner. Surgical decisions sex; however, it is important to bear The psychologist can also liaise with the Surgical decisions remain the most in mind the lack of robust surveillance general practitioner and guide individuals challenging and controversial area methods to predict malignancy risk if and families to appropriate peer support in DSD, especially if the surgery is dysgenetic gonads are left in situ. The groups and resources. Unfortunately, considered irreversible. Functionality, use of gonadotropin-releasing hormone access to psychological support is limited malignancy prevention and cosmetic agonist therapy can also be considered to in Australia and around the world,16 appearance are all taken into account extend the decision-making timeframe for and these roles may be undertaken to when considering surgical procedures.19 the patient temporarily where endogenous a variable degree by doctors, nurses, There is currently no consensus in hormone production is incongruent with genetics counsellors and other health team relation to the need for, or optimal timing gender identity. members. Parent and peer support groups of, many surgical interventions. Over can be helpful for many families (Table 1). time, recommendations for surgery Ethics and human rights issues It is important that any information have evolved for reasons including: A major consideration in paediatric disclosure is done in a sensitive manner, • a cessation of the standard practice to decision making is respecting parental with language that is appropriate for the remove gonads solely to align with sex views/wishes and the impact on the patient’s developmental age and parental of rearing individual as they become more aware of capacity to understand.17 There may • advances in immunohistochemistry and their diagnosis and involved in decision be uncertainty about outcomes, and genetics that have improved tumour risk making.23 Some patient groups advocate stratification a complete moratorium on any genital/ • patient advocate requests for deferral of gonadal surgery until the individual is Box 2. Common issues discussed non-therapeutic surgery, despite a lack able to give informed consent.24 This at multidisciplinary team meetings of universal interpretation of ‘medically questions the parents’ ability to act in the necessary surgery’. best interest of the child and whether • Complex differences/disorders of sex development cases with diagnostic There is a paucity of longitudinal and the best interest of the child is identical 25 dilemmas systematic studies on the impact of surgery to that of the future adult while giving • Sex of rearing versus deferral of surgery to guide optimal due consideration to the universal human • Timing and/or indication for genital management. DSD MDT meeting reviews rights of non-discrimination and equality tract surgeries consider these factors and may result in in any decision-making process. Each • Timing and/or indication for hormone active deferral of surgical intervention. individual case should be discussed on its treatment Concerns about the appropriateness of own merit, with due consideration given • Risk of gonadoblastoma surgery were the subject of an Australian to available evidence on benefits versus • Timing and/or indication for Senate Inquiry in 201320 and a recent risks for a particular procedure as well gonadectomy Australian Human Rights Commission as psychosocial, cultural and personal • Discordance between the parents’ view review on protecting the human rights circumstances.26 Six key ethical principles and the members of the multidisciplinary of people born with variations in sex in the management of DSD were proposed team, conflicts of opinion within the team characteristics (report awaited). by Gillam et al27 and later adopted by the • Psychosocial wellbeing of the young 2 person and family Predicting the risk of germ cell tumour consensus DSD guidelines to guide the • Referral to peer support groups (GCT) development in DSD is an area of decision-making process for DSD MDTs. ongoing research and varies depending However, striking a balance between

420 | REPRINTED FROM AJGP VOL. 49, NO. 7, JULY 2020 © The Royal Australian College of General Practitioners 2020 A GUIDE TO DIFFERENCES/DISORDERS OF SEX DEVELOPMENT/INTERSEX IN CHILDREN AND ADOLESCENTS FOCUS | CLINICAL

ethical principles can be challenging as handover from the paediatric MDT to provide a framework and opportunity respecting one principle may result in specialists can be difficult to navigate. for interactive discussion between compromise of another. The primary care physician has a vital representatives from several specialities In Australia, the child is unable to role, together with the paediatric team, to and help create local expertise within consent to a surgical procedure until they work through a transition checklist and the team. The primary care physician reach the developmental age at which link individuals with DSD to appropriate plays a key part in multidisciplinary they can understand the procedure and its services throughout the lifespan.29 care by providing holistic support to consequences. Until then, parents or legal Building rapport and having sensitive the individual and their family. Because guardians are responsible to give consent discussions relating to phenotypic, of the rarity of DSD, national and provided they are fully informed and make anatomical and hormonal variations, international collaboration is necessary the decision in child’s best interest.28 DSD gender identity and sexual health can to carry out meaningful research. It is MDT meetings may enable the deferral of be complex and take time. essential that management practices are surgical procedures that are not deemed continually evaluated and new advances medically necessary until the age at which are embraced as more outcome data the child can consent, and may provide a Conclusion become available from scientific research. viable alternative to involvement of legal Individuals with DSD may present in the agencies in the management of DSD. newborn period with atypical genitalia, during adolescence with atypical Authors Komal A Vora MBBS, FRACP, Paediatric Transition to adult care pubertal development, or in adulthood Endocrinologist, John Hunter Children’s Hospital, People born with variations in sex with fertility issues. Management NSW; Cojoint Lecturer, School of Medicine and Public Health, Faculty of Health and Medicine, characteristics often require individualised of DSD requires highly specialised University of Newcastle, NSW long-term hormone replacement, fertility multidisciplinary care encompassing Shubha Srinivasan BSc (Med), MBBS, PhD, management, sexual health counselling medical, surgical, psychosocial, MRCP (UK), FRACP, Senior Staff Specialist, Institute of Endocrinology and Diabetes, The and ongoing psychological support. psychosexual and human rights/ethical Children’s Hospital at Westmead, NSW; Clinical Adult MDTs for DSD are rare; therefore, aspects. Formal DSD MDT meetings Senior Lecturer, Sydney Medical School, Faculty

Table 1. List of support groups and online resources for parents and health professionals

General information about differences/ dsdfamilies – information and support for families, www.dsdfamilies.org disorders of sex development (DSD) dsdteens – information for young people with DSD, www.dsdteens.org DSD genetics, http://dsdgenetics.org/index.php

Patient advocacy/human rights Intersex Human Rights Australia (IHRA), https://ihra.org.au

Congenital adrenal hyperplasia (CAH) Congenital Adrenal Hyperplasia Support Group Australia (CAHSGA), www.cah.org.au Australasia Paediatric Endocrine Group, https://apeg.org.au/patient-resources/hormones- me-booklet-series CARES Foundation (USA based), www.caresfoundation.org CAH IS US (UK based), www.cahisus.co.uk/index.htm

Androgen insensitivity syndrome (AIS) and/or Intersex Peer Support Australia (IPSA), https://isupport.org.au other intersex/DSD conditions AIS-DSD Support Group (USA based), http://aisdsd.org Accord Alliance, www.accordalliance.org

Turner syndrome Turner Syndrome Association of Australia, www.turnersyndrome.org.au

Klinefelter syndrome and variants Australian X & Y Spectrum Support (AXYS), https://genetic.org Klinefelter Syndrome Australia Inc., https://klinefelter.org.au XYY Syndrome Association of Australia Inc., https://xyyaustralia.org Triple X & Trisomy X Support Group Australia (closed Facebook support group), www.facebook.com/groups/TrXAUS

Hypospadias, bladder/cloacal exstrophy Bladder Exstrophy, Epispadias, Cloacal Exstrophy, Hypospadias, Australian Community (BEECHAC), www.beechac.com/about-us.html

Mayer–Rokitansky–Küster–Hauser (MRKH) Sisters for Love MRKH Foundation, www.sistersforlove.org/home.html syndrome/Müllerian agenesis

© The Royal Australian College of General Practitioners 2020 REPRINTED FROM AJGP VOL. 49, NO. 7, JULY 2020 | 421 FOCUS | CLINICAL A GUIDE TO DIFFERENCES/DISORDERS OF SEX DEVELOPMENT/INTERSEX IN CHILDREN AND ADOLESCENTS

of Medicine and Health, University of Sydney, 15. Komal A, Vora CH, Philip Bergman, et al. NSW. [email protected] Multidisciplinary team (MDT) review of Competing interests: None. management decisions in disorders/differences of sex development (DSD): Experience of two Funding: None. paediatric tertiary hospital networks. Australasian Provenance and peer review: Commissioned, Paediatric Endocrine Group Annual Scientific externally peer reviewed. Meeting – APEG 2016; 14–17 August 2016; Alice Springs, NT: Alice Springs Convention Centre. References 16. Ernst MM, Liao L-M, Baratz AB, Sandberg DE. Disorders of sex development/intersex: Gaps 1. Herlihy AS, Halliday J, Cock M, McLachlan RI. in psychosocial care for children. Pediatrics The prevalence and diagnosis rates of Klinefelter 2018;142(2):e20174045. doi: 10.1542/peds.2017- syndrome: An Australian comparison. Med J Aust 4045. 2011;194(1):24–28. doi: 10.5694/j.1326-5377.2011. tb04141.x. 17. Cohen-Kettenis PT. Psychosocial and psychosexual aspects of disorders of sex 2. Lee PA, Nordenström A, Houk CP, et al. development. Best Pract Res Clin Endocrinol Global disorders of sex development update Metab 2010;24(2):325–34. doi: 10.1016/j. since 2006: Perceptions, approach and beem.2009.11.005. care. Horm Res Paediatr 2016;85(3):158–80. doi: 10.1159/000442975. 18. Lang C, Kuhnle U. Intersexuality and alternative gender categories in non-Western cultures. Horm 3. Pang SY, Wallace MA, Hofman L, et al. Res 2008;69(4):240–50. doi: 10.1159/000113025. Worldwide experience in newborn screening for classical congenital adrenal hyperplasia 19. Lee P, Schober J, Nordenström A, et al. Review due to 21-hydroxylase deficiency. Pediatrics of recent outcome data of disorders of sex 1988;81(6):866–74. development (DSD): Emphasis on surgical and sexual outcomes. J Pediatr Urol 2012;8(6):611–15. 4. Australia and Aotearoa/New Zealand intersex doi: 10.1016/j.jpurol.2012.10.017. community organisations and independent 20. Community Affairs References Committee. advocates. Darlington Statement: Joint Involuntary or coerced sterilisation of intersex consensus statement from the intersex people in Australia. Canberra, ACT: Senate community retreat in Darlington, March 2017. Community Affairs Committee Secretariat, 2013. IHRA and IPSA/AISSGA, 2017. 21. Cools M, Looijenga LH, Wolffenbuttel KP, 5. health.vic. Decision-making principles for the T’Sjoen G. Managing the risk of germ cell care of infants, children and adolescents with tumourigenesis in disorders of sex development intersex conditions. Melbourne, Vic: Victorian patients. Endocr Dev 2014;27:185–96. Government, 2013. doi: 10.1159/000363642. 6. Lee PA, Houk CP, Ahmed SF, et al. Consensus 22. Pyle LC, Nathanson KL. A practical guide for statement on management of intersex disorders. evaluating gonadal germ cell tumor predisposition International consensus conference on intersex. in differences of sex development. Am J Med Pediatrics 2006;118(2):e488–500. doi: 10.1542/ Genet C Semin Med Genet 2017;175(2):304–14. peds.2006-0738. doi: 10.1002/ajmg.c.31562. 7. Cools M, Nordenström A, Robeva R, et al. Caring 23. Karkazis K. Fixing sex: Intersex, medical for individuals with a difference of sex development authority, and lived experience. Durham, NC: (DSD): A consensus statement. Nat Rev Endocrinol Duke University Press, 2008. Women’s Studies 2018;14(7):415–29. doi: 10.1038/s41574-018-0010-8. 2009;38(4):486–89. 8. Ahmed SF, Achermann JC, Arlt W, et al. Society 24. Diamond M, Garland J. Evidence regarding for Endocrinology UK guidance on the initial cosmetic and medically unnecessary surgery on evaluation of an infant or an adolescent with a infants. J Pediatr Urol 2014;10(1):2–6. doi: 10.1016/j. suspected disorder of sex development (Revised jpurol.2013.10.021. 2015). Clin Endocrinol (Oxf) 2016;84(5):771–88. doi: 10.1111/cen.12857. 25. Wiesemann C, Ude-Koeller S, Sinnecker GHG, Thyen U. Ethical principles and recommendations 9. Ahmed SF, Rodie M. Investigation and initial for the medical management of differences of management of ambiguous genitalia. Best Pract sex development (DSD)/intersex in children and Res Clin Endocrinol Metab 2010;24(2):197–218. adolescents. Eur J Pediatr 2010;169(6):671–79. doi: 10.1016/j.beem.2009.12.001. doi: 10.1007/s00431-009-1086-x. 10. Speiser PW, Arlt W, Auchus RJ, et al. Congenital 26. Australian Human Rights Commission. Surgery on adrenal hyperplasia due to steroid 21-hydroxylase intersex infants and human rights. Sydney, NSW: deficiency: An Endocrine Society clinical Australian Human Rights Commission, 2009. practice guideline. J Clin Endocrinol Metab 2018;103(11):4043–88. doi: 10.1210/jc.2018-01865. 27. Gillam LH, Hewitt JK, Warne GL. Ethical principles for the management of infants with 11. Berenbaum SA. Psychological outcome in children disorders of sex development. Horm Res Paediatr with disorders of sex development: Implications 2010;74(6):412–18. doi: 10.1159/000316940. for treatment and understanding typical development. Annu Rev Sex Res 2006;17(1):1–38. 28. Funder K. Citizen child: Australian law and children’s rights. Melbourne, Vic: Australian 12. Cools M, Looijenga L. Update on the Institute of Family Studies, 1996. pathophysiology and risk factors for the development of malignant testicular germ cell 29. Hullmann SE, Chalmers LJ, Wisniewski AB. tumors in complete androgen insensitivity Transition from pediatric to adult care for syndrome. Sex Dev 2017;11(4):175–81. adolescents and young adults with a disorder doi: 10.1159/000477921. of sex development. J Pediatr Adolesc Gynecol 13. Eggers S, Sadedin S, van den Bergen JA, et al. 2012;25(2):155–57. doi: 10.1016/j.jpag.2011.11.003. Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort. Genome Biol 2016;17(1):243. doi: 10.1186/s13059-016-1105-y. 14. Weston WW. Informed and shared decision- making: The crux of patient-centered care. CMAJ 2001;165(4):438–39. correspondence [email protected]