Disorders of Sex Development/Intersex in Children and Adolescents
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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,