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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 ().

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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 DSD while cancers were not (). Gonadal tumors such as germ taking into consideration etiology and sex of rearing cell tumors (GCTs) result from fetal germ cells and are and gender identity (). divided into two groups, seminoma (seminoma/ Finally, androgens are known to exert organiza- dysgerminoma) and nonseminoma (embryonal car- tional effects on brain structure and function (–); cinoma, yolk sac tumor, choriocarcinoma, and tera- however, how these hormones influence the devel- Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 toma) tumors (). Among GCTs, germ cell neoplasia opment and expression of specific psychiatric condi- in situ and gonadoblastoma (GB) are the most tions is unclear. Impaired androgen production or common noninvasive benign tumors that lead to the action is a feature of all types of ,XY DSD, with the development of invasive GCTs. Of note, germ cell exception of cloacal exstrophy, and people with these neoplasia in situ is a precursor of GB, but not every conditions may be more susceptible to diseases such as case will progress to GB (, ). Identified risk factors depression, addiction, and eating disorders. for GCT development include the presence of Y Compared with unaffected women, subjects with chromosome, especially the GBY region (TSPY) in the ,XY DSD due to CAIS and complete gonadal gonadal karyotype, abnormalities of gonadal devel- dysgenesis are more likely to report major depressive opment, incomplete differentiation of the gonad in episodes, somatization, antisocial personality, and individuals with ,XY or ,X/,XY, and delay or obsessive-compulsive disorders (). Women with block in maturation of germ cells (–). Addi- CAIS report self-harm and suicidal tendencies at tionally, gonadal location (abdominal or inguinal area) rates comparable to traumatized women with a his- is another risk factor, and individuals with isolated tory of physical or sexual abuse (). In a German cryptorchidism have higher risk for GCT development study, suicidal thoughts were frequently reported by than do controls (). Importantly, GCT risk in ,XY women with partial AIS (PAIS) or CAIS (). In DSD is mainly related to etiology. GCT risk is higher addition to potential hormonal influences on psy- (%to%) in conditions associated with gonadal chiatric comorbidities, lack of social support for dysgenesis compared with disorders of androgen DSD plays a role (). Additionally, parents of chil- synthesis or action (,%to%) in which testis dren with DSD sometimes report anxiety, depression, differentiation and development are normal (–). and posttraumatic stress that may contribute to When calculating GCT risk, a diagnosis of AIS re- the mental health of affected individuals (). Fi- quires special attention because the risk of GCTs also nally, variables associated with DSD beyond andro- relates to delays in germ cell maturation, and germ cell gens, including atypical genital anatomy, infertility, survival depends on androgen action (, ). surgical/medical interventions, and gender nonconfor- Overall mortality is similar between females with mity, likely contribute to increased distress reported by ,XY and controls, despite the higher risk of gonadal patients (). tumors in the former group. Although there is a lack of An investigation of a large number of men and evidence about long-term health outcomes for men women affected by ,XY DSD from Europe identi- with ,XY DSD, cardiovascular morbidity, impaired fied the presence of several somatic and psychiatric glucose tolerance, and osteoporosis have been re- comorbidities (). Receiving a DSD diagnosis early in ported in these men when hypogonadism is present life, as well as following a healthy lifestyle, were (, ). Notably, even mild impairment of Leydig cell associated with fewer mental and physical health function in otherwise healthy men with low-normal problems for these adults. Another investigation of androgens and elevated LH levels is associated with women with ,XY DSD from Denmark revealed no increased mortality and morbidity (). As men with increased morbidity or mortality compared with ,XY DSD may experience hypogonadism due to controls (). Although these initial results are en- irregular T replacement or androgen insensitivity, couraging, more studies are needed from populations careful monitoring of cardiometabolic health is war- both within and outside of Europe to determine ranted (). Multinational collaborations and the es- whether, and how, differences in health care delivery tablishment of patient registries are beginning to impact outcomes for people with ,XY DSD.

Diagnosing DSD is needed to determine whether other systems in addition to the reproductive system are involved. Signs of DSD can be detected during prenatal ultra- Such findings indicate the presence of potential sound (US), present as atypical genital development DSD-candidate genes. Complementary studies to the in newborns, bilateral inguinal hernias in children, physical examination such as hormonal, imaging, and atypical secondary sex characteristics in adolescents, or genetic investigations are often necessary to establish infertility in adults (–). An extensive examination an underlying diagnosis, excluding life-threatening

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Table 1. Main Features of the 46,XY DSD Conditions

Defects of Gonadal Development Defects of Androgen Production

Gonadal Dysgenesis LHCGR Defects 20,22- Smith–Lemli–Optiz Desmolase DSD Etiology 46,XY OT DSD Complete Form Partial FormSyndrome Complete Form Partial Form Deficiency StAR Deficiency

Inheritance Generally sporadic Autosomal recessive, X-linked; Autosomal Autosomal Autosomal Autosomal Autosomal Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 autosomal dominant, linked to recessive recessive recessive recessive recessive male sex (for both forms)

Most common sex Male Female Male/female Male Female, Male/female Female, Female, assignment male—mild male—mild male—mild form form form

Gender change Rare Rare Rare Rare Rare Rare Rare Rare

External genitalia Atypical Female Atypical Micropenis and/or Female micropenis Atypical to male Female Female micropenis hypospadias, hypoplasic (mild form) micropenis (mild form) or bifid scrotum; female (mild form)

Mullerian¨ duct Present Present Present or absent Rarely present Absent Absent Absent Absent derivatives

Wolffian duct Hypoplastic to Absent Present Absent to male Absent to hypoplastic Male Absent to Absent to derivatives normal hypoplastic hypoplastic

Gonads/ usual Ovary and testis/ Streak gonads/ Dysgenetic Testis/ inguinal or Testis/inguinal or Testis/scrotal or Testis/ inguinal, Testis/ inguinal, position intra- intra- gonads/ scrotal region intra-abdominal inguinal region intra- intra-abdominal abdominal, abdominal intra- abdominal or or scrotal region inguinal abdominal, scrotal region inguinal, or scrotal region

Associated clinical Syndromic Syndromic features related to genetic Mental retardation, None None Early adrenal Enlarged adrenal features features related cause (for both forms) syndromic features failure glands, Early to genetic adrenal failure cause

Puberty Virilization and Absence of Absent or partial Normal Absence of Partial virilization Absence of Absence of feminization spontaneous virilization spontaneous absence spontaneous spontaneous variable development development gynecomastia development development

Gene location Autosomal or Y Autosomal or X or Y chromosome (for 11q12-q13 2p21 2p21 15q24.1 8p11.2 chromosome both forms)

Molecular defect DMRT cluster Mutations in different genes (e.g., SRY, Inactivating mutations in Inactivating mutations Inactivating Mutations in Mutations in STAR deletion, NR5A1/SF1, MAP3K1.) (for both DHCR7 in LHCGR (complete mutations in CYP11A1 forms) inactivation) LHCGR (partial inactivation) mutation in SRY, Duplication of different genes (e.g., SOX9 WNT4, DAX1) (for both forms) (continued across on facing page)

conditions (adrenal or renal failure or Wilms tumors) spectrometry–based steroid hormone assays, liquid and inform the medical management plan (Fig. ) chromatography linked with tandem mass spec- (, ). trometry, and gas chromatography linked with tandem mass spectrometry allow for simultaneous Hormonal studies analyses of multiple hormones and their metabolites Hormonal analyses using blood and urine samples with high specificity in a small sample of serum (. are important for identifying diagnoses and for to . mL). Biochemical analyses by liquid chro- monitoring hormone replacement (Fig. ). Most matography linked with tandem mass spectrometry clinical laboratories use immunoassays that are are becoming increasingly common for routine limited by low specificity due to cross-reactivity with clinical use in some parts of the world; however, steroids and metabolites. Additionally, immunoas- assays continue to be unavailable in several countries says measure only one steroid at a time. Multiple (). hormonal analyses are often needed to diagnose ,XY DSD, requiring specialized laboratories ca- Imaging studies pable of interpreting results within the context of US of pelvic and inguinal/perineal regions, cystour- age- and sex-specific reference ranges (). Mass ethrography or genitography, and MRI are the imaging

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Table 1. Continued

Defects of Androgen Production

17a- Defects of Androgen Action 3b-HSD2 Hydroxylase 17,20-Lyase 17b-HSD3 5a-RD2 Defects in the Synthesis Deficiency Deficiency POR Deficiency Deficiency Deficiency Deficiency Complete Form Partial Form or Action of AMH

Autosomal Autosomal Autosomal recessive Autosomal recessive Autosomal Autosomal X-linked recessive X-linked recessive Autosomal recessive Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 recessive recessive recessive recessive

Male Female in most Male Female Female Female Female Female Male patients

Rare Rare Rare Rare Not so rare Frequent Rare Not so rare None

Atypical Female- like to Atypical Atypical Atypical, Atypical, Atypical Atypical, Male atypical frequently frequently frequently female-like female-like female-like at at birth at birth birth

Absent Absent Absent Absent Absent Absent Absent Absent Present

Male Hypoplastic to Hypoplastic to normal Normal Normal Normal Hypoplastic to Normal Normal normal normal

Testis/ inguinal, Testis/intra- Testis/intra-abdominal, Testis/intra- Testis/ inguinal Testis/inguinal Testis/inguinal Testis/inguinal Testis/ bilateral intra- abdominal or inguinal or scrotal abdominal inguinal or intra- or intra- or intra- or intra- cryptorchidism, unilateral abdominal or inguinal region or scrotal region abdominal abdominal abdominal abdominal cryptorchidism, hernia or scrotal region region region region region ectopic testis

Adrenal failure or Hypertension Antley–Bixler syndrome None None None None None None not (low renin)

Partial virilization, Absent or slight Partial virilization Poor virilization, Virilization, variable Virilization, Absence of Virilization, Virilization, absence of variable virilization, variable gynecomastia absence of virilization, gynecomastia gynecomastia gynecomastia variable gynecomastia gynecomastia gynecomastia gynecomastia

1p13.1 10q24.3 7q11.2 10q24.3 9q22 2p23 Xq12 Xq12 19p13.3 (AMH),

12q13 (AMHRII)

Mutations in Mutations in Mutations in POR Mutations in the Mutations in Mutations in Mutations in AR Mutations in AR Mutations in AMH HSD3B2 CYP17A1 redox partner HSD17B3 5RD5A2 (complete (partial or AMHRII binding site inactivation) inactivation) of CYP17A1 Abbreviations: LHCGR, LH/choriogonadotropin receptor; OT, ovotesticular; POR, cytochrome p450 oxidoreductase; StAR, steroidogenic acute regulatory protein.

techniques that aid clinical evaluation of individuals dependent on the evaluator’s expertise as well as the with ,XY DSD (–). Choice of technology is device used. Although genitography and MRI are also influenced by patient age, indication, and accuracy. For useful for visualizing internal anatomy, genitoscopy/ example, diagnostic US is used during pregnancy, as the cystoscopy performed during surgical procedures accuracy of sonographic fetal sex identification during are considered the gold standard for this purpose. gestation is well established (). The ability to identify Knowledge of internal anatomy, such as the presence fetal sex correctly improves with increasing gestational and length of the UGS, relationship of the UGS to the age (), and identification of atypical genital devel- urethra, and position of the external urethral sphincter opment can be detected early (). Prenatal diagnosis of are necessary for planning surgical strategies (, ). ,XY DSD allows for opportunities to educate families Genitography also reveals internal reproductive and health care personnel prior to the birth of the anatomy of young patients but may require confir- affected child. mation with cystoscopy. Owing to the invasive nature Goals for imaging after birth include verification of cystoscopy, this technique is used concomitantly of a uterus and vagina/urogenital sinus (UGS), as well with surgical procedures when these are desired. Low as localization of gonads, when such structures are CT resolution for evaluation of pelvic anatomy re- present. Imaging may also be needed to evaluate the stricts the use of this technique for investigating and kidneys, adrenals, and terminal spine (, ). US is staging tumors associated with ,XY DSD such as recommended as the initial imaging modality for Wilms tumors and GCTs (). The evaluation of clinical assessment because it is easily accessible and intrapelvic structures using MRI and US are consid- does not require sedation or contrast agents (). ered equally sensitive; however, MRI is better suited However, the quality of information provided by US is for visualizing gonads (). Streak gonads are difficult

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Figure 1. Flowchart for the evaluation of atypical genitalia.

+ Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019

to detect by MRI, and laparoscopy is the gold standard (contiguous genes syndrome) to small variations. for assessing these intra-abdominal tissues. Laparos- SNP array or aCGH should be used first when in- copy may also be used to visualize gonads in patients vestigating causes of ,XY DSD for patients with with ,XY ovotesticular DSD to retain gonadal tissue malformations or syndromic features, as their effec- that is congruent with sex or rearing as well as to assess tiveness to detect pathogenic CNVs is ~%(, , , tumor risk. Information obtained from laparoscopy –). However, careful interpretation of results is can guide biopsy, removal, or mobilization of the critical, as small genotype imbalances ( kb) are streak tissue or gonads (, ). commonly detected with uncertain clinical significance (). Genetic studies The introduction of next-generation sequencing PCR amplification of the SRY gene is the fastest methods has significantly improved the ability to method to disclose the presence of the Y chromosome identify molecular diagnoses underlying ,XY DSD in a newborn. The karyotype is often the first test (, –). As such, individual gene sequencing has ordered when trying to classify DSD (, ). Karyotype, been replaced by panels of DSD candidate genes and quantitative fluorescence PCR, fluorescence in situ whole-exome sequencing (WES)/whole-genome se- hybridization analysis, and array techniques [array- quencing (WGS) (Fig. ). WES and WGS allow for the comparative genomic hybridization (aCGH) and identification of novel genetic causes of ,XY DSD single-nucleotide polymorphism (SNP) array] are all (–) in addition to mutations in genes already capable of identifying sex chromosomes (Fig. ). Al- known to be associated with these conditions (, , though results from array techniques are obtained , , ). However, potentially inconclusive results faster than those from G-banding, arrays are less ef- such as identification of variants of unknown signif- fective at detecting sex chromosome mosaicism (). icance or a combination of pathogenic variants Several genes related to ,XY DSD have been shown identified in different genes (i.e., oligogenic disease) to exert a dose-dependent effect on sex differentiation may prevent a definitive diagnosis. Furthermore, re- and development, including duplications (DAX and sults from high-throughput DNA tests have revealed WNT) and deletions (ATRX, DMRT, EMX,and inconsistent associations between DSD phenotypes WT)(Fig.). Multiplex ligation-dependent probe and molecular findings, and thus the need for com- amplification, SNP array, and aCGH techniques plementary hormonal and imaging tests remains (, detect copy number variations (CNVs). Multiplex ). Finally, WES and WGS strategies are expensive, ligation-dependent probe amplification detects spe- thus limiting their application for first-line diagnostic cific target sites whereas the others examine the entire investigation in many clinical settings. As technical genome. Resulting CNVs range from several genes and bioinformatic advances continue, it is anticipated

1552 Wisniewski et al 46,XY DSD Management Endocrine Reviews, December 2019, 40(6):1547–1572 REVIEW that costs for these molecular tests will decrease. chromosome sequences such as SRY using quanti- Despite their limitations, molecular genetic tests tative fluorescent PCR in maternal blood from as play an increasingly important role in the man- early as  weeks of gestation (, ). In a large agement of DSD, as these allow for prognostic cohort of pregnant women screened for common predictions, genetic counseling, and individualized chromosomal abnormalities by NIPT, a genotype/ management (Fig. )(, ). In summary, only half phenotype discordance was identified in ~ in  of patients with nonsyndromic forms of ,XY DSD to  pregnancies (). The DSD diagnosis in cases Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 receive a genetic diagnosis. Although genetic eval- of incongruent NIPT (i.e., female genitalia in ,XY uation of patients can include a karyotype, chro- fetus) included vanishing twin (small Y chromosome mosomal microarray, single gene sequencing, gene signal), CAIS, mosaic monosomy (X/XY), and p slice panels, and WES, these options are rarely deletion syndrome (). exhausted owing to costs and unavailability. As NIPT is a safe procedure with high accuracy (%to next-generation sequencing becomes less expensive %) for identifying sex. Nonetheless, a diagnosis may and more efficient,perhapsmorepatientsworld- not be established if a fetal fraction is too small, as may wide will receive a genetic diagnosis associated with occur with maternal obesity, or if the sample is collected their DSD (, ). too early in gestation. Moreover, NIPT methodology in many commercial laboratories is not able to distinguish Prenatal diagnostics between fetal and maternal cell-free DNA. Another Suspicion of ,XY DSD prior to birth is influenced cause of an abnormal NIPT result is the presence of a by family history or atypical/discordant genital ap- vanishing twin (). In cases of genotype/phenotype pearance visualized by prenatal US (, ). Prenatal discordance, NIPT can be repeated or alternative testing diagnosis of DSD has increased as a result of the can be considered (). A detailed US to assess fetal frequent use of noninvasive prenatal testing (NIPT) genital phenotype is recommended to detect genital by cell-free DNA analysis of maternal blood to abnormalities and exclude potential causes of mis- screen for aneuploidy during the first trimester of diagnosis such as an empty second gestation sac or pregnancy (, , ). NIPT identifies Y demised twin (). When NIPT is unavailable,

Figure 2. Diagnostic approach for patients with 46,XY DSD based on hormonal analysis and imaging studies.

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• Figure 3. Genetic approach to 46,XY DSD diagnosis. AIS includes both complete and partial forms. Sanger sequencing is recommended when the phenotype (clinical or hormonal patterns) is strongly indicative of diagnosis or to exclude 5a-RD2 in newborns. ¥Panel sequencing is first recommended except in conditions described under Sanger sequencing. *WES: Using family trio–based sequencing (affected person and parents) allows better discrimination of variant pathogenicity. LHCGR, LH/ choriogonadotropin receptor. Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019

karyotype or DSD candidate gene analyses can be In newborns ( to  hours after birth) mea- performed by chorionic villus biopsy or by amniotic surement of testicular hormone baseline levels fluid cells obtained from the th to th and th to provides information about the ability of the testes (if th weeks of gestation, respectively. Disadvantages of present) to secrete hormones such as T and anti- these tests compared with NIPT is that they are per- M¨ullerian hormone (AMH) (Fig. )(). During the formed later in the pregnancy and are associated with an period of spontaneous activation of hypothalamic– increased risk of miscarriage (.%to%) (, ). pituitary–gonadal axis (i.e., minipuberty, days  to  Finally, DSD is suspected when male- or female- after birth), these hormones should be (re)evaluated. typical genitalia are not visualized by US after  weeks Testicular hormone values obtained during mini- of gestation of prenatal life (, , ). A prenatal puberty can help to differentiate ,XY DSD secondary diagnosis of Smith–Lemli–Opitz syndrome () can be to (i) insufficient androgen production due to gonadal performed in a fetus with atypical genitalia by mea- dysgenesis or defective androgen synthesis, (ii) defects suring -dehydrocholesterol, in serum or other tissues, in target tissue responsiveness to androgens (androgen including cultured fibroblasts, amniocytes, or cho- insensitivity), or (iii) defects in T metabolism such as rionic villi, as well as in amniotic fluid (). a-RD deficiency. For example, low or undetectable T and AMH levels indicate complete testicular dys- Postnatal diagnostics function (Leydig and Sertoli cell dysfunction), and Partial virilization of the external genitalia is usually ,XY DSD due to gonadal dysgenesis should be identified during the neonatal period as a result of a suspected (–). This diagnosis is further con- medical examination or during routine care by the firmed by the identification of a uterus by pelvic US baby’s relatives. Complete absence of virilization may (, ). For patients with cloacal exstrophy, testicular be missed in some newborns presenting with a female hormone production during minipuberty should not phenotype. The identification of a Y chromosome differ from that observed in healthy boys. or its fragments is a fundamental step to direct Steroid precursors (progesterone, dehydroepian- the diagnosis of ,XY DSD () (Figs.  and ). The drosterone, androstenedione, a-hydroxyprogester- presence or absence of structures derived from the one, and a-hydroxypregnenolone) and DHT may M¨ullerian ducts, such as the uterus, can be visualized also be evaluated to search for enzymatic defects in with pelvic US to aid the diagnosis. adrenal and/or gonadal steroid synthesis and a-RD

1554 Wisniewski et al 46,XY DSD Management Endocrine Reviews, December 2019, 40(6):1547–1572 REVIEW deficiency, respectively (Fig. )(). Identification of of the genitalia (, , ). Such decisions are the accumulation of steroid precursors or low DHT based on the understanding that gender identity, or levels can guide genetic diagnostics, and a molecular the gender a person identifies with, does not always defect can be confirmed with individual gene se- align with a person’s genetic, gonadal, or anatomic quencing, panels of DSD-candidate genes, WES, or sex. Sexual attraction toward males, females, or both WGS (Fig. )(, , ). is likewise difficult to predict according to a person’s As just mentioned, a biochemical diagnosis of biological sex. Such discordance between sex, gender Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 a-RD deficiency can be based on an elevated serum identity, and sexual orientation illustrates the com- T/DHT ratio (, ). To analyze this ratio, T levels plexity physicians and caregivers face when deciding should be in the postpubertal range. After the first  to on a sex of rearing for a newborn with ,XY DSD. As  months of life, basal levels of T and gonadotropins older children recognize and reveal their gender are low and no longer informative, and therefore it is identity over time, decisions regarding sex of rearing necessary to stimulate endogenous T production with do not apply to them (). exogenous human chorionic gonadotropin or ad- Psychological support is a keystone for in- minister an injection of T ester in prepubertal patients terdisciplinary management (, , ), and every (, ). In newborns, a normal T/DHT ratio does parent caring for an affected child should be offered not exclude a-RD deficiency because transcription counseling by an experienced mental health spe- of the isoenzyme a-RD frequently occurs (, ). cialist. Ideally, this support should begin once a di- To determine the T/DHT ratio correctly, with the agnosis is suspected, and then continue throughout additional advantage of using a small serum sample childhood and beyond (, ). Unfortunately, no (. to . mL), DHT should be measured with evidence-based model for delivering mental health chromatography or mass spectrometry because care to people affected by ,XY DSD has yet to be commercial immunoassays present high cross- developed, and variability in access to mental health reactivity with T (). Metabolomics can also di- providers exists both within countries and cross- agnose a-RD deficiency (, ). For example, an culturally (). elevated ratio of b/a reduced steroid urinary me- Distress about the general health of their child, tabolites indicates a-RD deficiency prior to puberty coupled with the fear of stigma surrounding their and in orchidectomized adults (–). Considering child’s diagnosis, is often reported by parents. Thus, a “Sex steroid replacement is an the prevalence of normal T/DHT ratios in affected straightforward and comprehensive explanation about important component of newborns and the importance of a correct diagnosis to what to expect regarding their child’s future social management for some types ” plan for medical management, including male sex development, sexual function, fertility, and need for of 46,XY DSD. rearing, mutational analysis of SRDA is indicated as hormone replacement and/or surgery must be the first approach to a-RD deficiency diagnosis discussed with parents prior to their decisions re- when feasible (, ). garding sex of rearing for their child (, ). Patients with ,XY DSD due to CAIS and defects A special issue written by senior endocrinologists in LHCGR present similar phenotypes before puberty with a combined experience of . years in the but dissimilar hormonal profiles after puberty. The treatment of DSD offers guidance on decisions sur- hormonal profile for CAIS is characterized by elevated rounding sex of rearing for children with ,XY DSD LH and T levels, whereas that for LHCGR defects is residing in countries and cultures spanning four high LH and low T levels (). The phenotype of pa- continents (). For example, sufficient outcomes tients with PAIS is quite variable and overlaps with data exist to support female sex of rearing for new- many other conditions categorized as ,XY DSD. In borns affected by CAIS or complete ,XY gonadal these cases, a molecular diagnosis is helpful to define dysgenesis (–). For ,XY DSD secondary to etiology (, , , ). That said, a molecular di- steroid a-RD deficiency or b-hydroxysteroid agnosis occurs in only %to% of unselected cases dehydrogenase deficiency type , data are less clear; of ,XY DSD (). However, when subjects are however, female rearing is associated with a high selected by specific AIS characteristics such as normal likelihood of patient-initiated male reassignment later male basal and stimulated serum T levels and steroid in life (, , , ). Prior to the late th century, precursors coupled with gynecomastia at puberty, the decisions about sex of rearing were based on the molecular diagnosis is achieved in % of PAIS hypothesis of gender neutrality at birth (). Since subjects using AR exonic sequencing (). then, more knowledge has been obtained about the impact of prenatal androgens on psychosexual de- velopment (, , ). For instance, patients with Sex of Rearing ,XY DSD who are exposed to (and respond to) androgens during early development are more likely to Decisions regarding sex of rearing in newborns with develop a male gender than those with low/absent DSD are complex and can be especially challenging for prenatal androgen exposure, regardless of their degree those with a ,XY karyotype and severe undervirilization of virilization at birth (). Furthermore, prenatal

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androgen exposure is a better predictor of male gender surgical treatment of patients (, ). Finally, any development than androgen exposure later in life decision about rearing should respect parents’ cultural (). This increased understanding of endocrine and religious beliefs about what is best for their child, influences on psychosexual development has trans- including postponing or opting out of genital surgery lated to changes in clinical practice. For example, a completely (, , ). retrospective evaluation of  patient charts in the DSD European Registry revealed that prior to  Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 only % of patients with a ,XY karyotype and Hormone Treatment Across Development atypical genitalia were raised male. After , most (%) young children with ,XY DSD including Sex steroid replacement is an important component atypical genitalia were raised male (). of management for some types of ,XY DSD (, Despite the association between early androgen ). The goals of replacement include induction and exposure and male identification, for most patients maintenance of secondary sex characteristics as well with ,XY DSD, sex of rearing continues to be the as other aspects of pubertal development, including best predictor of gender development (), and growth. Bone mineral optimization and promotion patient-initiated reassignment observed in ~%of of uterine development may also be helped by patients studies retrospectively is the exception rather treatment with sex steroids for some patients. Hor- than the rule (). Factors in addition to androgens mone replacement can also impact psychosocial and impact psychosexual development in ways that may be psychosexual development, as well as general well- unique to different etiologies underlying ,XY DSD. being, in positive ways for some people (–). This potentially condition-specific sensitivity to in- Induction and maintenance of pubertal development fluences on gender development underscores the is necessary in most patients affected by ,XY DSD importance of establishing a molecular diagnosis prior regardless of male or female rearing; however, specific to deciding on a sex of rearing for young patients (, indications depend on the underlying etiology of the , ). condition. At the hospital nursery, it is important to discuss what is known about gender development with par- Androgen replacement ents and give them the opportunity to discuss their Most individuals affected by ,XY DSD have a de- concerns for their child (). The incongruence ficiency in either androgen production or action as between karyotype and sex of rearing may cause part of their condition (, ). For those raised male, distress, and an explanation that karyotype does not T replacement should strive to mimic masculine define gender is recommended. Sharing prevalence pubertal induction between  and  years of age, estimates that  out of , men possesses a ,XX provided the child’s projected height and growth are karyotype and  out of , women has a Y normal and he indicates a desire and readiness for chromosome is helpful to illustrate the independence puberty (). Intramuscular, short-acting injections of of the karyotype from psychosexual development T esters are the most suitable formulation to induce (, ). male puberty, although other options include oral T Parents often want guidance about how to explain undecanoate and transdermal preparations (, ). their child’s diagnosis to family and friends. Instruct The initial dose of short-acting T esters is  to  mg/ parents to use simple explanations such as the baby mo intramuscularly, with further increments of  mg had an alteration in genital development and some every  to  months thereafter. After reaching a tests are necessary to guide sex assignment. Of note, replacement dose of  to  mg/mo, the delivery parents’ concerns about discussing their child’s DSD interval can decrease to every  weeks. were noted at the first Disorders of Sex Development An adult dose of  to  mg every  weeks (short- (DSD) Consensus meeting in Chicago in  (). In acting T esters),  mg every  to  weeks (long- summary, it is important to inform parents that ev- acting T esters), or  to  mg for T gel or other idence supports female rearing in newborns with transdermal preparations applied topically are effective CAIS or complete gonadal dysgenesis (, , ). to maintain male secondary sex characteristics (Table ) The opposite is recommended for individuals with (, ). Monitoring of T levels should be performed on a-RD and b-hydroxysteroid dehydrogenase type the day preceding the next hormone administration, III (b-HSD)deficiencies (, ). For other types and serum levels should fall just above the lower limit of of DSD, condition-specific outcomes related to psy- the normal range for eugonadal men. Transdermal chosexual development, anatomy, fertility potential, preparations should be started at % of an adult re- and the need for subsequent medical and surgical placement dose (). treatment must be considered when deciding on sex of For patients with a-RD deficiency or PAIS, rearing (, , , , ). Data support male higher doses of intramuscular T preparations or rearing in all patients with ,XY with micropenis, as topical DHT can be used to optimize virilization this option optimizes fertility potential and requires no (, –). For boys and men with PAIS, T esters

1556 Wisniewski et al 46,XY DSD Management Endocrine Reviews, December 2019, 40(6):1547–1572 REVIEW

Table 2. Doses, Advantages, and Disadvantages of Available Testosterone (T) Formulations for Clinical Use Formulation Dose Advantages Disadvantages

Short-acting T esters (enanthate, • Initial dose: 25–50 mg/mo • Low cost • Does not mimic the circadian rhythm cypionate, or mixed esters); • – – • – • intramuscular After 6 12 mo: 50 100 mg/mo One dose every 2 3 weeks Provides supraphysiological levels of T within the first days after injection Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019

• Adult dose: 250 mg • Suitable for low doses • Fluctuation in mood or libido every 2–3wk • Erythrocytosis

Long-acting T (undecanoate); • Adult dose: 1000 mg/12 wk • Four injections per year • High cost intramuscular • Does not provide supraphysiological • Not suitable for low doses levels of T • Pain at injection site

• Risks of pulmonary oil microembolism

Transdermal patch • Adult dose: 5 mg/d • Mimics the circadian rhythm • Daily use

• Moderate cost • Often causes skin irritation at the site

• Leads to physiological levels • High cost of T • No data available for low doses

Transdermal gel Adult dose: 50-100 • Quick and efficient absorption • Daily use mg/d • Maintains satisfactory levels • High cost of T

• Unusual skin irritation at the site • No data available for low doses

• Potential risk for T transfer to partner or another person who is in close contact

Subcutaneous implants • Adult dose: 600 mg/4–6mo • Leads to stable and • Possibility of extrusion and local infection physiological T levels

• One implant every 6 mo • Not suitable for low doses

T undecanoate oral tablets • Adult dose: 80–160 mg/d • The only effective and safe oral • Daily use two to four daily doses T ester

• Does not cause hepatotoxicity • Variability of absorption according to meals

• Unstable T serum levels

• No data available for low doses

Buccal patch • Adult dose: 30 mg/ • Mimics the circadian rhythm • Twice daily 12 h • Leads to physiological levels • High cost of T

• Does not seem to cause • Short experience of clinical use mucosal irritation • Not suitable for low doses

• Alterations in taste and irritation gum

( to  mg once or twice a week) can increase androgen replacement doses. Standard replacement DHT levels to promote penile growth in addition to regimens should be reinstituted after that period of male secondary characteristics (–). Similarly, time (, ). Importantly, DHT treatment in- percutaneous administration of DHT results in creases penile length without the unwanted side phallic growth for infants and children with a-RD effects of gynecomastia or influencing bone matura- deficiency (). Maximum penile length is ob- tion (). Although these results from increased tained in patients  months after starting higher androgen replacement are promising, clinical trials

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designed to test the effectiveness and safety of high- every  to  months to an additional  mg/kg daily dose T and/or DHT replacement in the promotion until an adult dose of  to  mg daily is achieved of virilization for undervirilized boys and men are (). In case of transdermal replacement, the initial needed. recommended dose for the b-estradiol patch is . to . mg/ h overnight (one-eight to one-fourth of Estrogen replacement the  mg/ h patch). Transdermal doses can in- Estrogen replacement is recommended for girls with crease . to . mg/ hevery months until an Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 ,XY DSD using low doses of hormone starting adult dose of  to  mg/ h twice a week is around  to  years of age (Table ). Low doses (one- achieved (). Once breast development is com- sixth to one-fourth of an adult dose) are used to avoid plete, an adult dose can be maintained continuously. excessive bone maturation. Estrogen replacement For patients who do not possess a uterus, estrogen should be titrated every  months according to the alone is indicated (, ). Progesterone is needed clinical response (i.e., breast Tanner stage, bone age). to induce endometrial cycling and menses in pa- This strategy ensures gradual feminization with full tients with a uterus. For the latter group, medrox- pubertal maturation reached within  to  years of yprogesterone acetate ( to  mg/d) and micronized starting replacement. For females with unwanted tall progesterone ( mg/d from the st to the th day stature, the initial replacement dose can be the same as of each month) are appropriate to maintain uterine that used for adult women. health. There are several options available for estrogen Some females with CAIS report decreased replacement as well as different combinations and psychological well-being and sexual dissatisfaction doses of progestins (, , ); however, following bilateral gonadectomy and subsequent b-estradiol (oral or transdermal) is preferred. estrogen replacement (, ). T treatment has Transdermal delivery is thought best to replace with a been proposed as an alternative to estrogen for bioidentical hormone, and transdermal delivery avoids hormone replacement in these women, and such hepatic first-pass metabolism, resulting in less treatment improves sexual desire (). Long-term thrombogenicity and more neutral effects on lipids follow-up studies on the impact of T replacement (–). It is also easier to administer small doses on additional psychological measures, as well as on of estrogen by cutting up a patch or by using a bone metabolism and cardiovascular outcomes, are metered-dose gel dispenser. An initial recommended needed (). Summaries of the available prepara- dose of oral b-estradiol is  mg/kg daily, titrated tions of androgen and estrogen replacement for

Table 3. Doses, Advantages, and Disadvantages of Available Estrogen Formulations for Clinical Use Formulation Dose Advantages Disadvantages

17b-Estradiol oral • Initial dose: 5 mg/kg/d • Natural estrogen, preferable to synthetic • Low doses are not available in all countries tablets estrogens • Every 6–12 mo: increase to 10 mg/kg/d, then 15 mg/kg and then 20 mg/kg/d

• Adult dose: 1–2 mg daily

17b-Estradiol • Initial dose: 3.1–6.2 mg/24 h (one-eighth to • Avoid hepatic first-pass metabolism • Potential skin irritation at the site transdermal one-fourth of 25 mg/24 h patch) (potentially better for IGF1 synthesis) patch • Lower thrombogenicity

• Every 6 mo: increase to 3.1–6.2 mg/24 h • Neutral effect on lipids

• Adult dose: 50–100 mg/24 h twice a week • Suitable to administer low doses

17b-Estradiol • Adult dose: 1–2 mg daily • Same advantages as those of transdermal • No dosage-equivalent data between patches transdermal gel patches • Not suitable for low doses

• Potential risk transfer to partner or another person who is in close contact

Estradiol valerate • Adult dose: 1–2 mg daily • Synthetic estrogen (not physiological) oral tablets • Increased risk of venous tromboembolism

• Not suitable for low doses

1558 Wisniewski et al 46,XY DSD Management Endocrine Reviews, December 2019, 40(6):1547–1572 REVIEW patients with ,XY DSD are displayed in Tables  (). Despite favorable reports of using T to im- and . prove urethroplasty outcomes, there is a lack of guidance on how best to do so. Glucocorticoid replacement Orthophallopasty is achieved by degloving the It is necessary for ,XY DSD patients with classical penis either with or without sectioning the urethral forms of congenital lipoid adrenal hyperplasia, plate, depending on the degree of curvature of the b-hydroxysteroid dehydrogenase type II (b-HSD), phallus. If the curvature is mild (,°), correction Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 and a-hydroxylase/,-lyase deficiency to receive can be achieved with one to three nonabsorbable glucocorticoid replacement for adrenal insufficiency as stitches in the midline of the dorsal aspect of the well as hypertension management (, ). Min- penis without sectioning the urethral plate (). If eralocorticoid replacement is also required for patients the curvature is .°, the urethral plate must be with ,XY DSD who are salt-losing (). initially sectioned and the ventral chordee is either resected or incised with multiple corporotomies (). Surgical Considerations A number of urethroplasty techniques exist, with no agreement on which is best (). Urethroplasty Preoperative evaluation and goals for can be performed by tubularization of the preserved surgical intervention urethral plate, with or without an onlay preputial The physical examination to prepare for genital surgery flap. If the plate has to be sectioned, then a preputial focuses on length and diameter of the phallus, location tubularized flap can act as a substitute for the urethra of the urethral meatus, and presence of an orifice that and this can be achieved with a one-stage procedure. reveals a potential vaginal cavity (, ). When a Forpatientswithimportantcurvature,whorequired single perineal opening is observed, a UGS is suspected. sectioning of the original urethral plate with a long Depending on the degree of undervirilization, patients gap, urethroplasty can be performed as a planned, can present with a normally formed scrotum, hemi- two-stage procedure after preparing the urethral bed scrotum, separated labioscrotal folds, or some degree of with preputial flapsorgraftsduringorthophallo- penoscrotal transposition. Careful palpation is required plasty (, ). As just alluded to, both one-stage to identify gonads in the inguinal region, labioscrotal (i.e., simultaneous orthophalloplasty and urethroplasty) folds, or scrotum. and two-stage (i.e., orthophalloplasty first, followed Because congenital malformations of the external by urethroplasty  to  months later) procedures are genitalia associated with ,XY DSD do not affect used; however, the two-stage approach typically results micturition, surgical intervention is not typically in better cosmetic outcomes and fewer postoperative required during the neonatal period. For some complications for patients with severe hypospadias families, the atypical appearance of the patient’s and significant chordee (, , –). genitalia causes distress and may result in subsequent Depending on the degree of undervirilization, distress for the patient as well. Furthermore, atypical scrotoplasty can consist of simple or complex mobi- genital anatomy may impact long-term urinary and lization and suturing of scrotal flaps to the mid- reproductive function. Thus, the aims of surgical line followed by covering the urethra. This procedure intervention in the context of ,XY DSD are to alter can be performed simultaneously with urethroplasty. genital appearance to better correspond with sex of However, when there are concerns about the vascular rearing, reconstruct anatomy to allow for future supply to the skin pedicles used in the hypospadias sexual activity and optimize fertility potential, and repair, scrotoplasty can be performed separately. For prevent the development of urinary and genital tract patients with undescended testes, simultaneous orchid- complications such as infections and gonadal ma- opexy may be performed (). lignancy (–). The surgical treatment of gonads of patients with ,XY DSD aims to preserve testicular function Masculinizing procedures (production of T and sperm) and prevent malig- Surgical procedures for patients with ,XY DSD nancy (, , ). For patients with partial gonadal raised male can include correction of hypospadias dysgenesis, PAIS, or disorders of T or DHT bio- and scrotal abnormalities, relocation of the testes to synthesis, orchidopexy can be performed (, , , the scrotum or removal when dysgenetic, and re- , ). section of M¨ullerian remnants (, ). Correction For patients with ovotesticular DSD, conservative of hypospadias includes correction of phallic cur- gonadal surgery guided by intraoperative histological vature (orthophalloplasty) and construction of a analysis in frozen sections of gonadal tissues is in- urethra to the tip of the glans (urethroplasty). For dicated to define the margins between ovarian and patients with a small penis (), preoperative ad- testicular components, with preservation of gonadal ministration of T may increase penile length and tissue that is concordant with the gender identity improve resilience of tissue to surgical handling ().

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Finally, gonadectomy is recommended for patients into the UGS, vaginal cavity, and inferior urinary tract at risk for neoplastic transformation of germ cells (GBs can be visualized with intraoperative genitoscopy or and/or invasive GCTs) in dysgenetic gonads (). The MRI when such structures exist. Endoscopic evalua- risk for GCTs is also increased in patients with un- tion during surgery confirms the location of vaginal descended testes, including all other ,XY DSD insertion and allows for vaginal catheterization to syndromes. Although data are limited, in AIS the risk improve identification and mobilization of the vaginal seems to be higher in the partial form than in the channel (). When imaging studies are unable to Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 complete form, and tumor prevalence in this condition identify the presence of intra-abdominal gonads, increases after puberty. laparoscopy is recommended to identify whether Current guidelines of the American Urological gonadal tissues are present (). Feminizing genito- Association recommend that orchidopexy be per- plasty includes reduction of phallic size when enlarged, formed between  and  months of age for patients opening the UGS to separate the urethra from the with undescended testes (). Both orchidopexy and vaginal introitus, and constructing labioscrotal folds. gonadectomy can be performed with open or lapa- Similar to masculinizing genitoplasty, a number of roscopic approaches (, ). Testes relocated to the procedures have been developed to reconstruct female scrotum in young patients should undergo periodic genitalia in patients affected by ,XY DSD. Femi- surveillance by physical examination (). After nizing techniques have evolved over time to achieve puberty, repositioned testes should be evaluated an- better cosmetic outcomes (, ); however, func- nually with US or eventual biopsy. When gonadec- tional outcomes and patient satisfaction with surgical tomy is recommended, patients may then choose to care remain to be documented after newer surgical have testicular prostheses placed in the scrotum (, approaches (). Many techniques have been pro- ). posed over the years to separate the urethra from the vaginal introitus and bring both to the surface of the Mullerian¨ remnants perineum. For example, an inverted U-shaped perineal M¨ullerian structures are rudimentary in some patients skin flap was first proposed to expose and enlarge and present as a cystic prostatic utricle. These utricles the introitus, and this technique continues to be may be left in situ when asymptomatic, but in cases of widely used today (). An alternative to the skin recurrent urinary tract infection, stones, or significant flap approach to vaginoplasty is the “pull-through” postvoid urethral dribbling due to urinary pooling, for patients with a high vaginal insertion. However, they can be removed either laparoscopically or through pull-through vaginoplasty is limited by unsatisfactory a sagittal posterior incision of the perineum (, ). cosmetic outcomes associated with this procedure With either approach, great care must be taken to (, ). Yet another vaginoplasty technique for prevent injury to the vas deferens, seminal vesicles, patients with high vaginal insertion is known as the and pelvic nerves so as to avoid subsequent infer- Passerini–Glazel procedure. This technique uses UGS tility, erectile dysfunction, and urinary incontinence tissue to create the anterior wall of the vagina in (, , ). combination with phallic skin flaps to create the distal Late evaluation of patients with ,XY DSD vagina and introitus (). Although the Passerini– operated in childhood due to proximal hypospadias Glazel procedure results in good cosmetic outcomes, reveals that many felt that their genitals had an complications such as vaginal stenosis and a short unusual appearance or presented some degree of vagina are common (). Sexual function and genital urinary or sexual dysfunction (, , ). Ob- sensitivity in women who received Passerini–Glazel jectively, most patients with DSD have a penile genitoplasty revealed reduced clitoral sensitivity (). length below the 2. SD (. 6 . cm) (, , As a result of these unsatisfactory outcomes, variations ). in the Passerini–Glazel procedure have been proposed Dysfunctional voiding and lower urinary tract to maintain satisfactory cosmetic outcomes while symptoms are also more frequent in these patients optimizing functional results. One such variation is the than in controls (, ). However, between .% total urogenital sinus mobilization (TUM) technique and % of these patients were satisfied with their initially developed for patients with cloacal anomalies overall sexual function after genitoplasty, when con- (). Good results have been reported with TUM sidering sexual contacts, libido, erections, orgasm, as (), although there is a risk of urinary incontinence well as size of the penis and volume of ejaculation (, with this procedure (, ). , , , , ). As feminizing genitoplasty continued to evolve, partial UGS mobilization was proposed. Partial UGS Feminizing procedures mobilization was thought to be superior to TUM in The presence of a UGS requires an accurate un- that it kept the anterior dissection of the UGS distal to derstanding of the patient’s internal anatomy to plan the pubourethral ligaments, thus decreasing the risk of an appropriate surgical approach to achieve femini- incontinence (). Another surgical access to high zation (, , ). The location of vaginal insertion vaginal insertion is an anterior sagittal transrectal

1560 Wisniewski et al 46,XY DSD Management Endocrine Reviews, December 2019, 40(6):1547–1572 REVIEW approach (ASTRA). With ASTRA, a posterior longi- Timing of surgery tudinal incision is made in the midline of the perineal Appropriate surgical management for DSD has been a surface, opening the anterior wall of the rectum to topic of discussion since the first guidelines were allow for a better surgical approach in cases of high published in the s(). Historically, a female vaginal insertion (, ). A promising study of appearance of the external genitalia in a newborn with women who received ASTRA reported a low fre- palpable gonads resulted in female sex of rearing, quency of complications (). If the UGS persists, because it was thought that learning, or “nurture,” Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 complications such as urinary infections, postvoid had a greater influence in gender identity development dribbling, and difficulties with sexual intercourse can than biology or “nature” (, ). Additionally, occur (, ). For this group of women, additional unsatisfactory cosmetic and functional outcomes as- surgical techniques can be used to mobilize a posterior sociated with masculinizing surgeries, coupled with vagina, including buccal mucosa grafts and perineal the need for multiple procedures to achieve male skin flaps (). The large number of vaginoplasty appearance and function, supported the idea that techniques developed over time reveals the challenging female rearing was optimal for these newborns. nature of such procedures. As postoperative compli- Feminizing surgical procedures were performed in the cations and the need for additional surgeries to correct past when both knowledge about underlying etiologies these are common with even the most advanced and long-term outcome information about patients approaches, surgeons continue to strive to improve with ,XY DSD were unavailable. As the passage of upon vaginoplasty techniques to optimize outcomes time allowed for molecular diagnoses and behavioral for their patients. Finally, for women with ,XY DSD studies to be conducted, several patients with ,XY who possess a short vagina and wish to engage in DSD reared female exhibited gender dysphoria and vaginal intercourse, dilation with acrylic molds results presented phenotypes compatible with a-RD de- in adequate vaginal length without surgical in- ficiency, the diagnosis most likely associated with tervention. Success is usually achieved with  months gender dysphoria among those affected by ,XY DSD of dilation (). Vaginal lubricant may be required for (). sexual intercourse. Since the publication of the more recent DSD Clitoridectomy, or removal of the entire clitoris, consensus, aspects of care including timing of surgery was the first surgical procedure used to reduce phallic and decisions about sex of rearing have been ques- “Fertility potential varies size in girls with DSD (). This technique is no tioned. While both the American Academy of Pedi- depending on the underlying longer used, as it is now understood that clitoral atrics and the original Consensus recommended etiology od 46,XY DSD as well ” function is important for satisfactory sexual function genital surgery in children with DSD to occur early in as the severity of the condition. (, , ). The resulting technique of resecting life (i.e.,upto months of age) (, ), members of the clitoral body while preserving the neurovascular human rights organizations, ethicists, patient advo- bundle was developed (). With a better un- cates, and some health care providers strongly oppose derstanding of clitoral anatomy came further ad- such practices (, , ). The experiences of late- vances in clitoroplasty procedures, such as reducing treated patients from a large Brazilian cohort illustrate the glans of the clitoris ventrally to avoid damage to the complexities surrounding timing of treatment of the dorsal neurovascular bundle (). Kogan et al. atypical genital anatomy (). () further described preserving the neurovascular It has been reported that some parents and sur- bundle attached to the dorsal portion of the tunica geons prefer early surgery, as younger patients are albuginea to protect the nerves and blood supply. thought to heal better from such procedures and However, despite attempts to preserve nerves and escape stigma associated with living with atypical blood supply during clitoroplasty, atrophy and ne- anatomy (, , , ). While studies comparing crosis of clitoral tissue can occur in severely virilized outcomes of early (before age  months) vs late individuals (). For some patients, labia minora can genital surgery exist (, ), controversy con- be created using redundant clitoral skin obtained cerning timing of genitoplasty persists. Results from during clitoroplasty. This skin is divided longitudi- a multi-institutional study on contemporary genito- nally and then sutured along either side of the vagina. plasty procedures performed in young children When necessary, the reduction of labioscrotal folds is with moderate to severe atypical genitalia reported performed to create the labia majora, often using a good cosmetic outcomes, although minor and major Y-V plasty technique (). complications occurred (). Opposition to early For girls with CAIS the risk for GCTs is low, and surgery is based on retrospective studies that report therefore the gonads can be retained in these patients poor cosmetic and functional outcomes coupled with until complete pubertal maturation (, , ). the irreversibility of these procedures for patients too However, data on safety to retained gonads are in- young to provide informed consent. Thus, more complete in many of the ,XY DSD conditions. For outcome data on current genitoplasty procedures are patients who retain their gonads, careful monitoring needed. Until such data are available to parents and including US or MRI is suggested (). physicians, the best time to perform genital surgery in

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patients with ,XY DSD, if ever, remains debatable. Women with ,XY DSD who are virilized at birth Until this controversy concerning surgical timing is are more likely to report dissatisfaction with their resolved, parents and physicians are left to make vaginal length and overall sexual function compared surgical decisions for affected children on a case-by- with women with ,XY with a female genital phe- case basis with input from other members of the health notype. Regardless of their genital phenotype, most care delivery team. (%) of the affected women who reported sexual difficulties attributed these to their DSD. Finally, ~% Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 Sexual Function, Intimate Partner of affected women with a female phenotype live with Involvement, and Fertility an intimate partner, similar to rates reported by un- affected control women. In contrast, only %of Whereas some adults with ,XY DSD report dis- women with DSD including virilization report satisfaction with their sexual lives and intimate having a partner (, ). The increased sexual relationships, others do not. Stigma, compromised dysfunction reported by the latter group of women self-esteem, negative body image, social anxieties, and most assuredly impacts their decreased likelihood of traumatic sexual experiences contribute to dissatis- having an intimate partner. Most women with ,XY factionwhenitexists(, , , , ), as do DSD report a female heterosexual orientation re- suboptimal mental health, endocrine, and surgical gardless of the degree of virilization of their genitalia at interventions. Owing to both the rarity and het- birth; however, attraction to females as well as bi- erogeneity of ,XY DSD, studies of sexual function sexuality are reported by a significant minority (). and involvement with intimate partners frequently Finally, women with DSD who are virilized often enroll patients affected by different etiologies and received genital surgery as children. Although the treatment histories, thus making it difficult to con- number of surgical procedures received was not found cludehowthesevariablesimpact sexual relationships. to be related to sexual functioning (), certain types Furthermore, such studies are conducted in a range of procedures caused dysfunction. For example, of countries, where cultural differences in expecta- women who received a total clitoridectomy in child- tions for romance and sexual function exist hood were less likely to achieve orgasm than were (–). These challenges likely explain the dis- those who received clitoral reduction (, ). crepant results from studies pertaining to these im- portant aspects of life for people with ,XY DSD (, Male sexual function and intimate partner , , ). Sparse literature exists regarding sexual function of men with ,XY DSD. There is a high likelihood Sexual function of dissatisfaction with penile length (%) and lack of ejaculation (%) (), and men with DSD are also Women sexual function and intimate partner likely to report a fear of sexual contact (%), problems Some studies reveal that most women with ,XY DSD with erection (%), and precocious ejaculation (%). are involved in sexual relationships (, ), whereas Despite these problems, men with DSD are more others do not (). For instance, one-third of affected satisfied than women with their surgical outcomes and women from Europe reported having a steady intimate sexual function (, ). Men with ,XY DSD are partner (), whereas a more inclusive review of typically attracted to females; however, both homo- international patients estimated that two-thirds are sexuality and bisexuality are reported in studies of involved in such relationships (). Two factors that patients raised male (). influence intimacy and sexual involvement in DSD are When specific etiologies underlying DSD are ex- atypical genital anatomy and history of genital surgery amined, men with partial gonadal dysgenesis report (, , , ). To better understand these in- both sexual experiences with partners () and sat- fluences, sexual function was assessed in women with isfaction with their sexual function (). In contrast, ,XY DSD who were evaluated according to their (i) men with PAIS are unlikely to do so (). Although degree of responsivity to androgens, as inferred by there is a need to understand how men affected by their degree of genital virilization at birth, and (ii) different forms of DSD function sexually, insufficient genital surgical history (). A significant minority data exist to inform patients and health care providers (.%) of women reported overall dissatisfaction with about this topic. their sexual function, and all participants reported For both men and women with ,XY DSD, quality sexual anxiety. Patients with no virilization reported of sexual life is lower compared with unaffected adults low sexual desire and arousal, as well as dyspareunia. (). Specifically, those with DSD were less likely to These problems were more frequently reported by have a sexual partner, more likely to report sexual women with CAIS compared with those with com- insecurities and problems, and less satisfied with plete gonadal dysgenesis (). Thus, escaping genital overall quality of sexual life. People with ,XY DSD virilization does not preclude women with DSD from tend to engage in sexual activity at later ages than do experiencing difficulties with sexual function. controls, and a considerable number of affected

1562 Wisniewski et al 46,XY DSD Management Endocrine Reviews, December 2019, 40(6):1547–1572 REVIEW individuals report never engaging in sexual activity M¨ullerian structures currently prevents carrying a with a partner (, , ). Patients report greater pregnancy for people with CAIS or PAIS; however, sexual dysfunction than does the general population advances in uterine transplants may change this in the (, ), and an inability to achieve orgasm and low future (, ). Finally, biological fertility is possible arousal are the most frequently reported problems for men with defects in the synthesis or action of (, , ). AMH, but infertility is common due to azoospermia or other ductal abnormalities (). Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 Fertility Individuals with ,XY DSD often face infertility. This Quality of life may be due to abnormal gonadal development and Quality of life (QoL) is defined as “an individual’s progressive gonadal failure, prophylactic gonadectomy perception of their position in life in the context of for malignancy risk, abnormal hormone production culture and value systems in which they live, and in that impairs gamete formation, or anatomic barriers relation to their goals, expectations, standards and such as lack of a uterine structure (). For clarity, we concerns” (). In DSD, several factors related to use the term “biological fertility” to refer to having a gender and sexuality decrease QoL (, , ). child with one’s own genetic material, whereas “fer- Similar to sexual function and relationships, too few tility” refers to carrying a child who does not share a studies have investigated QoL in people with ,XY parent’s genetic material. Fertility is important to most DSD. Among the studies that have been conducted, affected individuals, and patients and parents desire weaknesses such as small sample sizes, lack of stan- discussion of this topic with their health care providers dardized tools for assessment, and inclusion of par- (, ). Careful counseling about fertility chances ticipants with various ,XY conditions exist—the and discussing valuable alternatives such as adoption same weaknesses associated with studies of sexual are fundamental (). When considering fertility function and relationships. potential, it is also important not to assume hetero- In the s, the QoL group of the World Health sexual orientation and to be open-minded about the Organization (WHOQOL) developed a generic in- many ways in which fertility can be achieved for in- strument for assessing QoL in both healthy people and dividuals or partners. those affected by illness and disease (WHOQOL-) Fertility potential varies depending on the un- (). A short version of this questionnaire “Information sharing in DSD is derlying etiology of ,XY DSD as well as the se- (WHOQOL-BREF) was developed to measure QoL in essential for a comprehensive verity of the condition. For example, individuals people across cultures (). The WHOQOL-BREF understanding by parents and ” with complete gonadal dysgenesis lack gonadal has been used to study people with ,XY DSD in patients. development and gametes and thus do not have Brazil, China, and several European nations biological fertility potential; however, they may (–). Generally speaking, people with a DSD possess a uterus, and women with this condition score lower in the area of social relationships () and have successfully carried pregnancies via oocyte men with ,XY DSD report better QoL than do donation (, ). affected women (). Questions regarding sexual In comparison, patients with partial gonadal dys- function and relationships are included in the social genesis have varying degrees of testicular and internal relationship’s domain of the WHOQOL-BREF and reproductive development, an thus some experience likely contribute to the low scores. However, some azoospermia whereas others are fertile (). Similar to studies report similar or better QoL in people with the variable fertility outcomes observed in patients DSD compared with unaffected men and women with gonadal dysgenesis, those with androgen bio- (). In an investigation including a large number of synthetic defects also experience a range of outcomes. men and women affected by ,XY DSD from Europe, To illustrate, infertility is common in individuals with most perceived their health to range from fair to very a-RD deficiency due to oligospermia, low semen good despite the presence of many somatic and volume, and increased viscosity, but biological fertility psychiatric comorbidities (). Perhaps these dis- is possible (, –). Biological fertility has also crepancies reflect cultural differences in the burden of been documented in those with nonclassical congeni- being affected by these conditions. tal lipoid adrenal hyperplasia, b-HSD deficiency, and LHCG receptor defect (). There are no reported cases of biological fertility in individuals with classic Delivery of Care congenital lipoid adrenal hyperplasia, cytochrome p oxidoreductase deficiency, complete CYPA defi- Guidelines for delivery of care to patients with DSD ciency, or b-HSD deficiency (, ). have changed a great deal since the mid-th century There are also no reported cases of biological and continue to evolve as knowledge about DSD fertility in CAIS. Biological fertility is reported in accrues (, ). What remains constant since the patients with PAIS, both spontaneously and with  Consensus is the recommendation for open, assisted reproductive technology (). Absence of complete communication about DSD with patients

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and parents, coupled with access to interdisciplinary by a lack of evidence-based information about who care for affected families (). In this section we describe benefits from, and how best to administer, psycho- recommendations for family-centered, interdisciplinary logical support (). Although research is beginning to care, including education for physicians, patients, and identify psychosocial screening tools for assessing caregivers. patients and families within DSD clinics, tested pro- Information sharing in DSD is essential for a tocols for the delivery of developmentally appropriate comprehensive understanding by parents and patients. mental health care are not yet available. Low satis- Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 A qualitative analysis of communication skills of faction with overall medical care reported by patients fellows undergoing training in pediatric endocrinology would presumably improve if providers had access to showed large variation in completeness, quality of such protocols as part of their interdisciplinary toolkit wording, and evidence of empathy. Several relevant (). As mental health support is increasingly viewed aspects of competent clinical communication were not as an alternative to early genitoplasty for protection mentioned or were inadequate among these trainees. from stigma associated with genital ambiguity (), Training of physicians who care for patients with DSD and as parents are increasingly called to take part in is necessary to avoid inadequate delivery of in- shared decision-making with health care teams for formation to patients and their families. Guidelines for planning and implementing their child’s treatment the assessment of communication between health (), identifying and ameliorating distress in patients professionals and individuals with DSD and their and parents is a research priority. In reality, the receipt parents are starting to be developed (). of family-centered, interdisciplinary care remains elusive to many people with DSD throughout the Family-centered, interdisciplinary care world (, , ). Barriers are geographic, as DSD Family-centered care acknowledges that family is the teams are unavailable in many countries, as well as major source of strength and support to children, and economic, as it is expensive to provide comprehensive, that patient and family perspectives should inform interdisciplinary care to patients and their families clinical decision-making (). Family-centered care (). improves knowledge and enhances quality of life for patients, and decreases distress for caregivers (). Educating affected people and their loved ones Interdisciplinary care is provided by a team of spe- Historically, both patients and parents were either cialists who work together to provide health care totally uninformed or inadequately informed about for patients and families. In the context of DSD, in- DSD and related treatment options (, ). More terdisciplinary care includes nursing, medical spe- recently, patients and parents report increased cialists, surgical specialists, and mental health, social knowledge in these areas; however, there remains work, and peer-to-peer support (). Optimally, the room for improvement. A key principle of family- team works with a family as soon as DSD is suspected centered care is the ongoing provision of complete and to provide appropriate information during the medical unbiased information to patients and families (). evaluation (). A shared decision-making model Assisting patients and parents with strategies to requires an emphasis on effective communication to discuss DSD with family members and loved ones is normalize the family’s experience, understand and needed (–). However, such strategies remain address the family’s knowledge, background, and difficult, as concerns about stigma (, , , ) concerns, educate the family about sex differentiation and the desire to protect privacy (, ) can result and development, and facilitate support networks in avoidance of information sharing. For example, (). Discussions conducted with an interdisciplinary parents report increased stigma with raising a child team allow team members to provide their expertise whose genetic sex is atypical or incongruent with their while maintaining a cohesive message for the patient sex of rearing, as well as raising a child with a history and family. of a delayed decision about sex of rearing (). Thus, Patients with DSD, particularly those with an parents with these experiences would benefit from atypical genital phenotype, are prone to stigmatization situation-specific instruction on how to share such that can be harmful for psychosocial well-being. This is information with others. particularly true when the medical condition is not In addition to the challenge of protecting privacy understood by the patient, the parents, and members while providing information about DSD to others, of the community, as well as when patients cannot parents also recognize that such communication make their own decisions regarding clinical man- evolves over time (). For example, parents’ desire to agement. Accessible, culturally sensitive education understand for themselves a particular diagnosis fol- about DSD for patients, families, and the community lowing the birth of an infant with DSD is later replaced improves social acceptance of DSD (). Mental by the need for language and skills to effectively health and peer support are thus foundations of care communicate this information to maturing children (, , ). However, delivery of mental health and adolescents. Thus, education for parents is both services for those affected by ,XY DSD is hampered ongoing and dynamic ().

1564 Wisniewski et al 46,XY DSD Management Endocrine Reviews, December 2019, 40(6):1547–1572 REVIEW

As mentioned earlier, discordance between genetic her gender to discuss biological fertility potential (, sex and sex of rearing is perceived as stigmatizing by , ). some parents (). Women with ,XY DSD report less knowledge about their medical history than do Evidence-based care affected men (), and women with ,XY DSD For patients and parents who opt for genital surgery report dissatisfaction with how they received educa- (masculinizing or feminizing) as part of a DSD tion about their sex chromosome complement and treatment plan, there remains a need for objective Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019 gonadal sex (). Additionally, many parents are information regarding optimal timing for, as well as hesitant to discuss aspects of DSD seen as potentially risks and benefits associated with, various surgical stigmatizing with family and friends (). Peer support approaches currently in use (). Such studies should can provide practical and credible advice on how to include measures of cosmetic outcomes, urethral and discuss such sensitive topics while minimizing stigma sexual function, overall QoL, and patient satisfaction and maximizing transparency (). Many parents and with treatment. Similar research is also needed in patients desire such support (, ), and the most people with DSD who do not receive genital surgery to recent update on the diagnosis and care of people with determine the risks and benefits of this choice (, DSD includes a discussion of the importance of peer ). Studies of current surgical techniques are nec- support for delivering care and providing education essary because most literature available to inform (). patients, parents, and physicians about surgical treatment choices is based on dated procedures (). Perhaps this explains reports of adverse (, )as Future Research well as satisfactory outcomes (, , , ). Additionally, although providers agree that mental Advances of reproductive endocrinology health support is essential for patients and families, Advancing technology and innovative thinking may there is limited understanding of who would benefit enable future fertility for individuals with DSD cur- from this support and how to deliver it. rently considered to be infertile. Initial data indicate In summary, improvement in clinical and surgical that germ cells are present in gonads of many in- practice for treating patients with ,XY DSD resulted dividuals with DSD, particularly at younger ages (). from the original Consensus meeting. Stemming from Thus, experimental techniques pioneered in onco- that meeting is the recognition of the importance of fertility, including prepubertal gonadal cryopreservation, interdisciplinary teams to provide care to patients and may be useful for those with DSD (). This raises their families, the value of molecular diagnostics, and many ethical issues, including those of consent and the need for collaborations to study ways to optimize assent, experimental treatment causing false hope, cost outcomes for affected people. What remains to be and distributive justice, and potential transmission of improved is understanding how to talk about DSD, as DSD to offspring (). Notably, it should not be as- well as developing evidence-based mental health care, sumed that an individual’s gametes must match his or surgical interventions, and fertility optimization.

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Current models of care for from the Conselho Nacional de Desenvolvimento Cient´ıfico 2015 — velopment. BioMed Res Int. 2015; :342420. disorders of sex development results from an e Tecnologico´ (CNPq, Grants 305743/2011-2 and 303002/ ’ 257. D Alberton F, Assante MT, Foresti M, Balsamo A, international survey of specialist centres. Orphanet J 2016-6) and by the Fundação de Amparo a` Pesquisa do 11 Bertelloni S, Dati E, Nardi L, Bacchi ML, Mazzanti L. Rare Dis. 2016; (1):155. Estado de São Paulo (FAPESP, Grants 05/04726-0, 07/512156, Quality of life and psychological adjustment of 269. Pasterski V, Prentice P, Hughes IA. Impact of the 10/51102-0, 2013/02162-8, and 2014/50137-5). women living with 46,XY differences of sex devel- consensus statement and the new DSD classifica- opment. J Sex Med. 2015;12(6):1440–1449. tion system. Best Pract Res Clin Endocrinol Metab. 258. Cassia Amaral R, Inacio M, Brito VN, Bachega TA, 2010;24(2):187–195. Additional Information Oliveira AA Jr, Domenice S, Denes FT, Sircili MH, 270. Migeon CJ, Wisniewski AB, Brown TR, Rock JA, Correspondence and Reprint Requests: Berenice B. Arnhold IJ, Madureira G, Gomes L, Costa EM, Meyer-Bahlburg HF, Money J, Berkovitz GD. 46,XY Mendonca, MD, Hospital das Cl´ınicas, Faculdade de Mendonca BB. Quality of life in a large cohort of intersex individuals: phenotypic and etiologic classi- Medicina da Universidade de São Paulo, Disciplina de adult Brazilian patients with 46,XX and 46,XY fication, knowledge of condition, and satisfaction Endocrinologia e Metabologia, Avenida Dr. En´eas de

doi: 10.1210/er.2019-00049 https://academic.oup.com/edrv 1571 REVIEW

Carvalho Aguiar, 155, 2° Andar, Bloco 6, 05403-900 São Paulo, Abbreviations insensitivity syndrome; CNV, copy number variation; DSD, differ- SP, Brazil. E-mail: [email protected]. 3b-HSD2, 3b-hydroxysteroid dehydrogenase type II; 5a-RD2, ences/disorders of sex development; GB, gonadoblastoma; GCT, Disclosure Summary: The authors have nothing to 5a-reductase type 2 deficiency; 17b-HSD3, 17b-hydrox- germ cell tumor; NIPT, noninvasive prenatal testing; PAIS, partial disclose. ysteroid dehydrogenase type III; aCGH, array-comparative androgen insensitivity syndrome; QoL, quality of life; SNP, single- Data Availability: Data sharing is not applicable to this genomic hybridization; AIS, androgen insensitivity syndrome; nucleotide polymorphism; T, testosterone; TUM, total urogenital article as no datasets were generated or analyzed during the AMH, anti-Mullerian¨ hormone; ASTRA, anterior sagittal transrectal sinus mobilization; UGS, urogenital sinus; US, ultrasound; WES, current study. approach; BMD, bone mineral density; CAIS, complete androgen whole-exome sequencing; WGS, whole-genome sequencing.. Downloaded from https://academic.oup.com/edrv/article-abstract/40/6/1547/5540927 by Bibliotheque Mathematique Orsay user on 03 November 2019

1572 Wisniewski et al 46,XY DSD Management Endocrine Reviews, December 2019, 40(6):1547–1572