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Management of the infant with atypical genital appearance (difference of sex development)

Management of the infant with atypical genital appearance (difference of sex development)
Literature review current through: Jan 2024.
This topic last updated: May 12, 2023.

INTRODUCTION — Individuals with a congenital discrepancy between the appearance of their external genitalia and gonadal and chromosomal sex are classified as having differences (or disorders) of sex development (DSD) [1,2]. Discrepancies sufficient to prompt evaluation (excluding uncomplicated cases of cryptorchidism and hypospadias) occur in approximately 1 in 4500 live births [3-6].

The birth of an infant with atypical genital appearance presents a unique set of challenging management issues. This is because psychosexual development is influenced by multiple factors, including the genes involved in sexual development, prenatal androgen exposure, societal and cultural factors, and family dynamics. In the past, decisions about sex of rearing were usually based on potential for reproduction and traditional sexual function and were often accompanied by complex genital surgery that can be difficult to reverse [7-9]. Long-term outcome data are now available to help predict gender identity for many infants with specific DSD diagnoses and provide insight into appropriate early management decisions [2,10-17]. Nonetheless, there is ongoing controversy about some aspects of management. The uncertainties about adult gender identity, optimal timing of surgery, and surgical outcomes including timing of surgery should be included in informed decision-making by the parents and patient (when age appropriate). Each child and family will have unique characteristics, so all decisions must be made on a case-by-case basis. Management at centers of excellence is associated with improved medical, surgical, and psychosexual outcomes.

The management of infants with clinically significant DSD will be discussed here. The evaluation of these infants and specific causes of DSD are discussed separately. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)" and "Causes of differences of sex development".)

TERMINOLOGY

Difference/disorder of sex development — The diagnostic category "disorders of sex development (DSD)" was proposed in a 2006 consensus conference, replacing potentially pejorative terms including "pseudohermaphrodite," "hermaphrodite," and "intersex" [1]. Since then, many groups have modified the term to "difference of sex development" in response to concerns that "disorder" is unnecessarily negative [6,18].

Concerns have been raised that DSD is an overly broad term that, with current nomenclature, is used to encompass conditions in which no issues with genital appearance or gender identity are expected (eg, complete androgen insensitivity syndrome [CAIS], Turner syndrome, Klinefelter syndrome, trisomy X); and also that a broad umbrella term like DSD lacks sufficient specificity to be helpful diagnostically and is therefore unnecessary. Many support and advocacy groups do not accept the DSD designation and feel that it should be abandoned by the medical community. We agree with the concept that each patient should be identified by a specific diagnosis and not the inexact umbrella DSD categorization.

Until a consensus is reached on this issue, we will use the term DSD but will employ it only in relation to those patients in whom there is altered physical sex differentiation (conditions previously captured by the term "intersex") and a diagnosis has not been established. Many of these individuals present as newborns with an atypical genital appearance, previously termed "ambiguous genitalia." We will not use the term to refer to conditions in which genital/gender discordance is not expected, such as Klinefelter syndrome, Turner syndrome, undescended testes, or isolated forms of hypospadias.

Glossary of other terms — The vocabulary used to describe features of DSD can be confusing and is sometimes inconsistently applied. A glossary of terms is provided (table 1).

TYPES OF DSD WITH ATYPICAL GENITAL APPEARANCE — Management depends on the type of DSD and degree of genital atypia. The initial management of the patient, including surveillance for adrenal crisis and family coping, occurs concurrently with the diagnostic process, which is described separately. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)

For the purposes of management, it is helpful to categorize these disorders into five major groups (table 2), listed here in decreasing order of frequency:

46,XX DSD – The most common form of DSD that presents with atypical genital appearance and a 46,XX karyotype in the newborn period is classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. This is a relatively homogenous group of patients, most of whom present in the newborn period with prenatal virilization and without palpable gonads. Extremely rarely, 46,XX individuals with CAH present with normal external male genitalia but without palpable gonads. Mandatory newborn screening in the United States allows for early detection of almost all cases of classic CAH due to 21-hydroxylase deficiency, usually within the first week of life. (See "Causes of differences of sex development", section on 'Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency'.)

Much less common 46,XX DSD include other forms of CAH and disorders caused by gonadal overproduction of androgens (eg, NR5A1 gene mutation) (table 3). (See "Causes of differences of sex development", section on 'Causes of XX differences of sex development'.)

45,X/46,XY mosaicism – The second most common category of DSD with atypical genital appearance is 45,X/46,XY mosaicism.

The phenotype of this condition is highly variable, ranging from phenotypically normal males (approximately 90 percent of patients, often undiagnosed), to males with atypical genital appearance/severe hypospadias, to those with female genitalia and Turner syndrome-like features. The specific presentation appears to be related to the degree of mosaicism in the gonad and its consequent hormonal function. (See "Clinical manifestations and diagnosis of Turner syndrome".)

Those with atypical genital appearance typically have hypospadias (often severe), a descended (but infertile) testis usually on the right side, and a streak gonad with retained remnants on the contralateral side (picture 1 and image 1); this phenotype is often described as "mixed gonadal dysgenesis" in the literature. It is unclear why the testicular tissue is usually found on the right side. (See "Causes of differences of sex development", section on 'Sex chromosome differences of sex development'.)

46,XY DSD – Several types of 46,XY DSD that are rare but reasonably well described are:

Disorders of androgen synthesis (eg, 17-beta-hydroxysteroid dehydrogenase [17-beta-HSD] deficiency and 5-alpha-reductase deficiency).

Androgen insensitivity syndrome is caused by androgen receptor or associated transcription factor gene mutations. Partial androgen insensitivity syndrome (PAIS) can be associated with atypical genital appearance, ranging from microphallus to severe hypospadias and undescended testes. (See 'Partial androgen insensitivity syndrome' below and "Causes of differences of sex development", section on 'Androgen insensitivity'.)

PAIS should not be confused with complete androgen insensitivity syndrome (CAIS), which is characterized by a 46,XY karyotype, typical female external genitalia, absent müllerian structures, and high likelihood of a female gender identity [19]. (See "Pathogenesis and clinical features of disorders of androgen action".)

Global defects in testicular function caused by mutations in genes involved in gonadal development (eg, NR5A1 [SF1], SRY, or WT1).

Other 46,XY DSD include additional disorders of androgen synthesis (eg, Leydig cell hypoplasia) and uncommon forms of CAH (table 4). (See "Causes of differences of sex development", section on 'Causes of XY differences of sex development'.)

46,XY DSD with severe genital anomalies that are not associated with presently identified gene or chromosome abnormalities. These include some children with micropenis, penile agenesis (aphallia), and cloacal exstrophy. These rare urogenital tract anomalies are typically cared for by the same multidisciplinary teams that manage the more common forms of DSD described above.

Ovotesticular DSD – Ovotesticular DSD (previously known as true hermaphroditism) refers to the presence of ovarian tissue with primordial follicles and testicular tissue with seminiferous tubules in the same individual. This can be either an ovary or testis on opposite sides or, more commonly, an ovotestis that is a gonad with both ovarian and testicular tissue intermixed. Most of these individuals have a 46,XX karyotype. (See "Causes of differences of sex development", section on 'Gonadal overproduction of androgens' and "Causes of differences of sex development", section on 'XY gonadal dysgenesis'.)

Management for some of these disorders is outlined below. (See 'Overview of decisions about sex of rearing' below.)

INITIAL STABILIZATION — The initial stabilization of infants with DSD presenting with atypical genital appearance requires attention to both medical and psychosocial issues, with the goal of making an accurate diagnosis to guide management and predict clinical and gender outcomes.

The most important medical concern is the possibility of life-threatening adrenal crisis in infants with salt-wasting congenital adrenal hyperplasia (CAH). Neonatal screening for CAH identifies most but not all affected infants before they develop an adrenal crisis. (See 'Risk of adrenal crisis' below.)

The main psychosocial concern during this period is the anxiety experienced by most parents whose child is born with an atypical genital appearance. Uncertainty about the sex of rearing can complicate or delay the traditional announcement of whether the child is a boy or girl to family members, friends, and community. This period of uncertainty is inevitable because of the time required to make an accurate diagnosis and develop a thoughtful treatment plan in collaboration with the child's parents. Supporting the family through this time period with information and reassurance is critical for the well-being of the family. (See 'Is it a boy or a girl? Family coping' below.)

Risk of adrenal crisis — CAH due to 21-hydroxylase (CYP21A2) deficiency (MIM #201910) is the most common cause of 46,XX DSD (virilization), and the more severe mutations carry a significant risk for a salt-wasting adrenal crisis (table 5). An adrenal crisis also may occur in some other types of CAH, including 11-beta hydroxylase deficiency. If salt-wasting CAH due to 21-hydroxylase deficiency is undiagnosed and not treated, vomiting, diarrhea, hypotension, and hypovolemic shock can occur, typically between 10 to 20 days of life. Other rare forms of salt-wasting CAH may manifest even earlier in both XX and XY infants.

Therefore, any infant with atypical genital appearance (and infants with a positive neonatal screen for CAH) should be presumed to have CAH and monitored for salt loss and adrenal crisis until the diagnosis is confirmed or excluded. Blood samples should be urgently obtained for steroid hormone precursors (most importantly, 17-hydroxyprogesterone) to evaluate for CAH due to 21-hydroxylase deficiency. Serum and urine electrolytes and plasma glucose should be monitored closely until CAH is definitively diagnosed or excluded.

Laboratory findings suggesting a salt-wasting crisis include hyperkalemia with or without hyponatremia, metabolic acidosis, and hypoglycemia [20]. A rapid overview guiding the recognition and treatment of adrenal crisis is shown in the accompanying table (table 6). (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Management in neonates'.)

Is it a boy or a girl? Family coping — An appropriate management plan can be developed only with the full participation of the parents after a careful and complete evaluation by an experienced team of endocrinologists, geneticists, and surgeons, aided by individuals capable of providing sophisticated psychosocial support [6,21,22]. The period of uncertainty before a specific diagnosis can be established is a particularly challenging time for parents. In the rarer forms of DSD presenting with atypical genital appearance, this can be an extended process because of the multiple diagnostic steps required and the complexity and time required for genomic testing and because less information is available about these diagnoses to reliably predict outcomes. Even with optimal education and support, parents and family may experience significant stress and difficulty in adjusting to the diagnosis before they are capable of making thoughtful and informed decisions about management.

In these discussions, the emphasis should be on helping the parents understand that the atypical genital appearance, although uncommon, is biologically understandable in almost all children [23]. The genitalia can be described to the parents as "not being fully formed" or being "overly developed." It may be helpful to summarize the embryology of genital development, including the presence of indeterminate external genitalia in the early stages of fetal development, followed by subsequent maturation toward male- or female-typical genitalia. This discussion should be tailored to the educational background and emotional state of the family, and special needs caused by the family's cultural or religious background should be identified and addressed.

We generally suggest to the families that they consider postponing birth announcements describing the sex of the infant until more information is known about the cause of the atypical genital appearance because some DSD are associated with fairly predictable gender identity, while others have less predictable gender identity outcomes (see 'Overview of decisions about sex of rearing' below). Similarly, the birth certificate in most of the United States now has a gender-neutral option that can be adjusted over time, when a diagnosis has been determined and/or gender identity has clearly evolved. If the diagnosis is clear (eg, minimal virilization in an XX infant with 21-hydroxylase deficiency), then a family can comfortably announce the sex. When the diagnosis will be delayed several days or months until diagnostic testing is complete, or delayed indefinitely when a diagnosis remains elusive, the family will require counseling and support to be able to postpone the birth announcement about the baby's sex [1]. Gender-neutral names may be a useful family option in this scenario.

Many families, even those with strong health literacy, feel guilty that they are in some way responsible for the genital malformation. This must be discussed openly; the discussion will differ depending upon the nature of the disorder. If the child is known to have a gene variant, the variant and its manifestations must be described so that the family can learn about and cope with the disorder as it is understood, with full disclosure regarding the degree of uncertainty in outcome associated with the specific diagnosis.

Families of children with atypical genital appearance often wish to discuss issues of long-term reproductive function and sexuality early in the evaluation. These issues should be frankly discussed.

Further evaluation

Specific DSD diagnosis – After initial stabilization, infants with DSD should be thoroughly evaluated to establish an accurate diagnosis, including a molecular genetic diagnosis whenever possible, because this information is an important guide to management. The types of DSD and steps in the evaluation are discussed in detail separately. The infant should also be evaluated for other non-genital abnormalities that might suggest a syndromic form of DSD. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)

Care setting – Because of the complexity of DSD diagnoses and the infrequency with which they are seen, affected infants should be evaluated and managed at centers with experienced interdisciplinary DSD teams, if possible [21]. If it is not possible to transfer the infant to a DSD center for evaluation, consultation should be sought with a DSD team to help organize and facilitate management. In response to the consensus conference on the management of DSD in 2006 [1], several groups published useful information on the development of collaborative management teams in Western Europe and in North America [24-27]. DSD centers are generally different from centers that manage children and adults with gender dysphoria, although members of both teams often have similar expertise.

OVERVIEW OF DECISIONS ABOUT SEX OF REARING — Gender identity is thought to be primarily innate rather than a consequence of the sex of rearing. Nonetheless, in most societies, it is helpful to the family to have a provisional plan for sex of rearing, provided that they also understand that the child will determine their own gender expression as they grow older.

Factors to consider – Guidance given to families about sex of rearing should be based on:

The most probable adult gender identity, based on the clinical outcomes for the specific DSD type (when available)

Potential for adult psychosocial and psychosexual function, including fertility potential

Degree of virilization as a marker of prenatal androgen exposure

The family's preferences and expectations, which may be influenced by their sociocultural background

The relevance of these factors is supported by an increasing number of studies examining gender identity in individuals with DSD [28-32]. All of these factors must be assessed in every patient, regardless of the type of DSD. Unfortunately, even the best outcome data available suffer from problems with sampling bias and often small sample size. Large-scale, long-term follow-up, which will be available through several large national and international consortia, will undoubtedly improve the reliability of such outcome data even for relatively rare disorders.

Concept of evolving gender identity – Children with or without DSD will define their own gender identities over time. In some cases, the child's gender role behavior and gender identity may not be fixed until early adulthood or even later. Gender identity in individuals with or without DSD may be male, female, or neither (nonbinary) [2]. Because of these uncertainties, a watch-and-wait approach may be particularly beneficial for most children with DSD. Long-term outcomes should be judged by psychosexual and psychosocial well-being and an ability to positively contribute to society, rather than by conformity to social gender norms [33,34].

Predictors of gender identity – The child's probable gender identity depends in part on the type of DSD and may reflect the degree of prenatal androgen exposure [32].

For some DSD, including the most common type (46,XX congenital adrenal hyperplasia [CAH] due to 21-hydroxylase deficiency with mild or moderate virilization), gender identity is mostly predictable (table 2). For these children, decisions about sex of rearing are fairly straightforward. Nonetheless, the family should be counseled that, in rare cases, there can be uncertainty about the child's long-term gender identity. (See 'Clinical approach to 46,XX congenital adrenal hyperplasia' below.)

For rarer forms of DSD, the child's ultimate gender identity is more difficult to predict. In such cases, management decisions remain challenging for providers and family. Adult gender identity may be variable and difficult to predict. When counseling the families of these children, we discuss the concept of an evolving gender identity, which recognizes that future gender identity is not entirely predictable at birth and can evolve as the child grows. We explain that "we just do not know yet" and encourage parents or caregivers to assume a supportive role regarding their child's gender identity, with flexibility to permit the child to manifest changes in gender identity with maturation. This approach remains untested prospectively in the management of children with DSD.

We recognize that the family will bear the major burden of rearing a child with atypical genital appearance. For this reason, we respect the family's right and responsibility to make the decisions regarding sex of rearing. After providing detailed and sensitive counseling, we support the parents or caregivers in their decisions. Considerations and available evidence to guide decisions are outlined for some forms of DSD below.

CLINICAL APPROACH TO 46,XX CONGENITAL ADRENAL HYPERPLASIA — 46,XX congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common cause of atypical genital appearance. As a result, much of the clinical experience and evidence about long-term outcomes are based on this population [35,36]. Nonetheless, the surgical considerations described below may apply to children with other forms of DSD who will be raised as female.

Surgical considerations are different for children with DSD who will be raised as male, and these approaches are considered later in this review. (See 'Approach to other differences/disorders of sex development' below.)

Gender identity expectations

Mild or moderate virilization – Among individuals with 46,XX CAH with Prader II to IV virilization (figure 1A-B and picture 2), approximately 90 percent have female gender identity as adults and psychosocial outcomes are generally positive [35]. For infants with this diagnosis, the expectation of female gender identity can be communicated to the family and decisions about sex of rearing are relatively straightforward. The female gender role is also consistent with the individual's internal anatomy, and fertility may be possible. This perspective is consistent with an international consensus statement [37]. However, clinicians and family members should also recognize that gender dysphoria is experienced by 5 to 10 percent of 46,XX CAH patients and that some of these individuals may later develop a male or nonbinary gender identity [28-30,37,38].

Severe virilization – Individuals with 46,XX CAH and severe virilization (Prader V genitalia) are rare, representing <3 percent of all patients with CAH. Decisions about sex of rearing are more complex for these individuals, in part because of relatively high frequency of gender dysphoria, as discussed below. (See '46,XX congenital adrenal hyperplasia, Prader V' below.)

Genital surgery

Surgical procedures — Patients with 46,XX CAH have a normal vagina, cervix, uterus, and ovaries. Those with virilization will have a common urogenital sinus (ie, one common opening located in the introitus below the clitoris, with the confluence of the urethra and vagina internally) and varying degrees of clitoral hypertrophy. Surgery to restore female anatomy includes:

Separation of the urinary tract and vagina – Detachment of the vagina from the confluence of the common urogenital sinus allows the common urogenital channel to function as the urethra. The separated vagina is then brought out as a separate opening below the urethra (vaginoplasty).

The most common complication is vaginal stenosis, which may require additional surgery, typically as a teenager [39]. In a meta-analysis of 29 observational studies, approximately one half of patients who engaged in penetrative sexual activity reported discomfort and one-third had vaginal stenosis requiring either dilatation or repeated surgeries [38]. Less common complications included fistulas, urinary incontinence, and recurrent urinary tract infection.

Labioplasty – Reconstruction of the labia minora and labia majora so that they have a typical appearance and position, next to the opening of the reconstructed vagina (introitoplasty).

Clitoroplasty – Clitoroplasty (reduction of the size of the clitoris) is generally considered only for the rare patient with severe virilization (Prader IV or V) and not for those with milder clitoromegaly [40]. The general consensus is to defer clitoroplasty until patients are old enough to specifically request surgery.

A possible complication of clitoroplasty is impaired clitoral sensitivity. This has been reported in one retrospective study, yet other studies have not documented any impairment in sexual function compared with that of age-matched, healthy controls [41-44]. Newer techniques (ventral nerve-sparing approach) are designed to preserve sensation and sexual function, but no long-term data are available on the functional capacity of the clitoris after surgery, including in patients who received the newer nerve-sparing procedures [36]. If clitoral surgery is performed at any age, a major focus should be on preserving the innervation and erectile tissue to optimize sexual function, rather than focusing on cosmetic appearance [45].

Timing and extent of surgery — Decisions about timing of surgery require shared decision-making with the family, as reflected in an international consensus statement [37]. The statement also suggests avoiding feminizing surgery during infancy for those with mild virilization but supports its consideration for those with severe virilization (figure 1A-B); decisions also include factors other than the degree of virilization. We present two approaches to this question; provide available evidence for each approach; and suggest discussing the options, risks, and benefits with the family [38].

Advantages of early surgical intervention – Some clinicians and parent advocacy groups support the option of early reconstructive surgery for children with CAH, if this is desired by the parents after fully informed, collaborative decision-making [35,36,46].

For families contemplating early surgical intervention, the components of surgery can be considered separately:

Repair of the urogenital sinus, vaginoplasty, and labioplasty (without clitoroplasty) – For patients with a low urogenital confluence of the vagina and urethra, proponents of early surgery generally recommend performing these steps during infancy or as soon as the family is fully informed and feels ready [36]. No randomized studies have evaluated either the best age or the best methods for restoring functional female anatomy with a separate urethra and vaginal opening. However, proponents of early surgery argue that functional outcomes are good when performed by highly experienced surgeons using modern techniques that focus on preserving neurologic innervation of the vagina and clitoris [41,46-50]. They argue that the relatively poor outcomes described in some reports reflect surgery performed more than two decades ago, using older techniques. In addition, early restoration of typical female anatomy helps to avoid potential complications of a confluent vagina and urethra, such as the risk for urinary tract infections (rare) and obstruction of menstrual flow at puberty. A possible advantage for infants with severe virilization is that performing early complete reconstruction allows the surgeon to use the excess common urogenital sinus tissue to reconstruct the anterior vaginal wall [51].

For individuals with a high urogenital confluence, the surgery is more complex and outcomes of early surgery are less certain. These individuals may have higher risk for vaginal stenosis, but this is unproven and retrospective studies report that early surgery using modern surgical methods has good long-term success with respect to sexual function compared with normal controls [41,46-49].

Clitoroplasty – Clitoral reduction is the most controversial area of management [36,52]. Most authorities agree that it should not be performed for infants with mild to moderate virilization (Prader II and III) [53]. For those with more advanced virilization (Prader IV and V), decisions should be individualized [42,49,54]; the family should be encouraged to consider delaying any clitoral surgery until the patient can understand and consent to clitoral reconstructive procedures, typically in late adolescence or later [53]. Reasons for avoiding clitoral surgery during early childhood are possible loss of clitoral sensitivity, uncertainty about the child's gender identity and preferences, and possible varying preferences regarding clitoral size.

Advantages of avoiding early surgical intervention – A contrasting perspective supported by numerous patient advocacy groups is to avoid all reconstructive surgery during infancy and childhood, ie, not to perform repair of the common urogenital sinus and vaginoplasty or clitoroplasty [55].

The rationale for this noninterventional approach is:

Uncertain gender identity – Decisions about early urogenital surgery may not be consistent with the child's ultimate gender identity, sexual orientation or desire for penetrative sexual activity, fertility desires, and personal preferences. In a large meta-analysis, approximately 10 percent of individuals with CAH do not identify as females as adults and approximately 25 percent of those with female gender identity experienced sexual attraction to women, which might influence their preferences and decisions about their genital appearance and function as they reach adolescence and adulthood [38]. The incidence of gender-fluid or nonbinary gender identities in this population is unknown because most studies have not collected those data.

For individuals who are not diagnosed and treated for CAH in infancy (eg, those living in low-resource countries), female gender identity is even less common. This may be due to exposure to high concentrations of androgens in utero and during childhood, the effect of male sex of rearing in this setting, and, possibly, the higher social position of males in some societies [56].

Surgical complications – Feminizing surgery can have lifelong complications, including vaginal stenosis and loss of clitoral sensitivity. The risk of long-term complications is not well known and likely depends on individual patient characteristics as well as the methods and experience of the surgical team, but complications can occur even with optimal surgical management. (See 'Surgical procedures' above.)

Clitoral surgery may not be necessary – An enlarged clitoris observed in the newborn may decrease in prominence over time with glucocorticoid treatment. Moreover, the individual may not be concerned about the clitoromegaly, depending on their ultimate gender identity, personal preferences, and sociocultural norms. Moreover, the opinions of the clinician(s) and parent/caregiver(s) about the cosmetic appearance of the newborn clitoris may depend on their own gender and cultural assumptions [57].

Limited evidence on outcomes – The effects of early versus late genital surgery on psychosocial or psychosexual development or quality of life are unknown [37,58,59]. Therefore, a noninterventional approach is appropriate.

Social supports for patients who defer surgery – Living with atypical genital appearance may be acceptable to the child and family because of changing social norms and the availability of excellent professional and peer support.

Despite these considerations, we recognize that the perspectives above are based primarily upon the wishes of advocates and limited outcome data about adult gender roles and therefore represent a form of social experimentation. Whether a shift away from early reconstructive surgery will lead to an improved quality of life for most children with differences in genital appearance is not yet known and will require careful follow-up.

46,XX congenital adrenal hyperplasia, Prader V — A few children (approximately <3 percent) with 46,XX CAH have severe virilization, with a complete penile urethra (Prader V genitalia). Historically, in such cases, the child was often identified as male at birth and the DSD was not recognized until late childhood. However, with the implementation of newborn screening, most cases in resource-abundant settings are identified soon after birth. Management of these children presents a complex and difficult problem because of uncertainties about gender identity and surgical challenges:

Gender identity – For children diagnosed with this DSD early in life, uncertainty of the child's gender identity and the fertility implications must be openly and completely discussed with the family [37]. Gender identity is particularly uncertain for those individuals who are diagnosed later in life, when a male sex of rearing is already established.

Many practitioners advise a female sex of rearing when the diagnosis is made in the neonatal period. This perspective is extrapolated from the experience with patients with CAH and milder virilization, who have a reasonable likelihood of female gender identity and the potential for normal ovarian function and fertility in adulthood. However, it is suspected but not proven that gender dysphoria may be more common among those with severe virilization; adequately sized studies are lacking [30,53,60]. (See 'Gender identity expectations' above.)

A male sex of rearing is also reasonable for these severely virilized children, especially if the diagnosis is made after the neonatal period. Reports describe successful outcomes in patients raised as males, especially those who are diagnosed after infancy [53,60-63]. However, in one report, approximately 10 percent of those who were reared as males experienced severe gender dysphoria [30]. Uncommonly, these individuals may later self-identify as female and choose to have feminizing surgery [64]. Lifelong medical treatment with glucocorticoids and mineralocorticoids would still be required, and supplemental testosterone may be required to support male secondary sexual characteristics. Height outcomes for male patients may be less than mid-parental height, similar to that reported in other individuals with CAH.

Surgical considerations – Surgical feminization is especially challenging in patients with extreme virilization. These patients typically have a high insertion of the vagina close to the bladder neck (image 2). When surgery is deemed necessary, the separation of the high common urogenital channel should only be attempted by an experienced surgeon. Robotic and laparoscopic abdominal approaches to the high urogenital sinus have avoided the need for a temporary diverting colostomy and/or the anterior sagittal transrectal approach (ASTRA) procedure. These surgeries are complex and require a combined perineal abdominal approach [46,65-67].

When these severely virilized patients are raised as males, they may undergo "hypospadias repair" in infancy. If the child accepts the male gender identity, he will ultimately require a hysterectomy and removal of the internal gonads (ovaries). The gonadectomy should be done before puberty to prevent gender-incongruent body development (menstruation and breast development). Alternatively, treatment with a gonadotropin-releasing hormone (GnRH) analog can be initiated before puberty and the surgery deferred until later in adolescence or early adulthood, when the patient can affirm their gender identity and participate in the decisions about further surgery. It is important that the family and/or patient understand that this type of surgery is irreversible and precludes female fertility. It is not necessary to remove the vagina, although its presence may increase the risk for urinary tract infection, similar to the risk seen in patients with an enlarged prostatic utricle.

APPROACH TO OTHER DIFFERENCES/DISORDERS OF SEX DEVELOPMENT — Key characteristics and information about projected gender identity for several other common DSD are outlined in the table (table 2).

Mixed gonadal dysgenesis (45,X/46,XY mosaicism)

Gender identity – Most individuals with mixed gonadal dysgenesis (45,X/46,XY mosaicism) will have a male gender identity. This is consistent with the moderate level of genital virilization, the presence of a Y chromosome, and the in utero exposure to higher levels of androgen. Infertility is likely, and the adult phallus size can be inadequate if it is poorly responsive to androgen [68,69].

Surgical considerations – Hypospadias surgery is performed at 6 to 15 months of age [70]. Patients with 45,X/46,XY DSD are more likely to require preoperative androgen treatment to stimulate penile growth before the repair compared with infants with hypospadias and a normal karyotype (see "Hypospadias: Pathogenesis, diagnosis, and evaluation"). The scrotal gonad (testis), which is typically on the right, requires careful follow-up because it is dysplastic and has an increased tumor risk [71]. A biopsy of the scrotal testis is recommended after puberty to rule out the presence of carcinoma in situ, a premalignant condition [68]. The streak gonad is typically removed because of tumor risk and lack of function [72]. The müllerian remnant (hemiuterus) is typically removed at the same time as the streak gonad (image 1). (See 'Gonads' below.)

In the rare patient with minimal virilization, it is prudent to defer feminizing surgery until a female gender identity is confirmed. Suboptimal outcomes have been reported in the past with early feminizing surgery in these patients. The vagina/müllerian cavity is typically more narrow and rigid than in patients with congenital adrenal hyperplasia (CAH). As a result, the outcome of vaginal surgery may be less than ideal in this form of DSD and typically requires postsurgical dilation and/or revision. When feminizing surgery is performed, discordant testes and/or streak gonads should be removed because of the risk of malignancy.

46,XY 17-beta-HSD and 5-alpha-reductase deficiencies

Gender identity – Individuals with 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD) type 3 (MIM 605573) or 5-alpha-reductase type 2 (MIM 607306) deficiencies usually develop male gender identity [37,73]. These individuals have impaired androgen synthesis but respond to androgens and can virilize during spontaneous puberty or with androgen treatment. Modern molecular diagnostic techniques permit an early and accurate diagnosis of both of these enzymatic defects. (See "Causes of differences of sex development", section on 'Reduced androgen synthesis'.)

Men with 5-alpha-reductase type 2 deficiency often have problems with fertility; this and other details of management are discussed further in a separate topic review. (See "Steroid 5-alpha-reductase 2 deficiency", section on 'Gender role change at puberty' and "Steroid 5-alpha-reductase 2 deficiency", section on 'Management'.)

In the past, patients with 17-beta-HSD type 3 or 5-alpha-reductase type 2 often underwent early feminizing surgery (including gonadectomy) and were raised as females. This approach was used because they appeared phenotypically closer to females and feminizing surgery was considered less complicated than surgical reconstruction of male anatomy. Case series and other studies suggest that female gender of rearing in these children is often problematic [74,75], perhaps as a result of fetal androgen exposure and virilization at puberty (in those with intact testes). Among those raised as females, at least 50 percent develop male gender identity, especially around puberty and if the gonads have been left intact [31,37,75].

Surgical considerations – Once the diagnosis of either of these types of DSD is confirmed, we initiate androgen treatment to stimulate penile growth before proceeding to surgical reconstruction of the hypospadias, which is typically performed between 6 and 15 months of age [70] (see "Hypospadias: Pathogenesis, diagnosis, and evaluation"). In patients with undescended testes, orchiopexies should be performed to allow for testicular self-examination. The risk of testicular cancer appears to be similar to that of patients with cryptorchidism.

In the rare patient who develops a female gender identity, surgical reconstruction needs to take into account the benefit of gonadectomy to prevent virilization at puberty [73].

If gender identity is fluid or inconsistent with the sex of rearing, a gonadotropin-releasing hormone (GnRH) agonist can be used to prevent virilization at puberty until gender identity is confirmed and the patient can make an informed decision about surgery and hormonal therapy.

Partial androgen insensitivity syndrome — Patients with partial androgen insensitivity syndrome (PAIS) present with a range of phenotypes from predominantly male to predominantly female with mild virilization. (See "Pathogenesis and clinical features of disorders of androgen action", section on 'Partial androgen insensitivity (PAIS)'.)

Gender identity – Gender identity is uncertain in individuals with PAIS. Case series suggest that 5 to 15 percent of children raised in either sex role will experience gender dysphoria [76,77]. Historically, many patients with PAIS underwent feminizing reconstruction even if they had a predominantly male phenotype [73]. This practice is now questioned because many of these individuals will have a male gender identity. Therefore, we generally advise the parents about the concept of a fluid gender identity, which recognizes that gender identity may evolve as the child grows. (See 'Overview of decisions about sex of rearing' above.)

One approach is to make suggestions concerning sex of rearing based upon the response of the phallus to testosterone therapy, as outlined in a consensus statement [37]. Female sex of rearing is likely appropriate for those with no evidence of androgen effect, and a male sex of rearing is likely appropriate for those who do respond to testosterone. Among patients who respond to testosterone, phallus size is usually within 2 standard deviations of the mean both before and after androgen therapy. (See "Diagnosis and treatment of disorders of the androgen receptor", section on 'Management'.)

PAIS should not be confused with complete androgen insensitivity syndrome (CAIS), which is characterized by a 46,XY karyotype, typical external female genitalia, absent müllerian structures, and strong female gender identity [19]. (See "Pathogenesis and clinical features of disorders of androgen action", section on 'Complete androgen insensitivity (CAIS)'.)

Surgical considerations – If a male sex of rearing is planned, surgical reconstruction of the hypospadias follows the same protocol as for patients with severe hypospadias [78]. The response of the phallus to androgen stimulation is important in determining the optimal timing for surgery and, perhaps, in decision-making about appropriate sex of rearing. Orchiopexy should also be performed to facilitate testicular self-examination and ultrasound surveillance because these patients are at increased risk (approximately 7 percent) for developing testicular cancer in adulthood [79-82].

If a female sex of rearing is planned, we encourage the family to postpone surgery until the child is old enough to affirm gender identity and make an informed decision about surgery, typically during adolescence. Feminizing surgery typically involves vaginal dilation, removal of the gonads, and, sometimes, clitoral recession.

Ovotesticular differences/disorders of sex development — Individuals with ovotesticular DSD (previously known as "true" hermaphroditism) present particularly complex management decisions. This is an extremely rare form of DSD in which both male and female gonadal tissue (testis, ovary, or ovotestis) as well as male and female internal and external structures coexist. The testes are most often found on the right side and can be inguinal or scrotal. Ovaries are most often found on the left side, and ovotestes can occur on either side. The diagnosis requires surgical biopsy of the gonadal tissue for pathologic confirmation of both ovarian follicular and testicular tubular tissue, demonstrated by the finding of primordial follicles and seminiferous tubules, respectively.

Gender identity – Data from small case series suggest that patients reared in either sex can be satisfied with their sex assignment [83,84] but that gender dysphoria also may occur [37]. Overall, there are insufficient data to reliably predict gender outcomes for this group of patients. Most individuals are infertile, but pregnancy has been described in patients raised as female [85].

Surgical considerations – Surgical decisions for patients with ovotesticular DSD remain complex [79-81]. Fertility is rare, partly because of the close proximity of the male and female internal genitalia, which makes it difficult to separate ductal structures. The risk for gonadal tumors is low in the dysgenetic testicular tissue and is estimated at approximately 2.6 percent [1,86].

If a male sex of rearing is assigned, surgery involves the removal of the discordant ovarian tissue and retention of the testicular tissue, as well as masculinizing genitoplasty. Conversely, for those assigned a female sex of rearing, the testicular tissue is removed. There may not be a clear separation of ovarian from testicular tissue in an ovotestis, and, consequently, gonadectomy may be necessary to prevent discordant secondary sex characteristics from developing at puberty.

46,XY with severe genital anomalies

Gender identity – 46,XY individuals with cloacal exstrophy (picture 3), micropenis, or penile agenesis have normal sex hormone production and signaling. Testicular function and male fertility potential are normal, although patients will require assisted reproductive techniques. Accordingly, the practice is to suggest a male sex of rearing, despite the technical challenges of phallic reconstruction (when and if it is desired by the patient).

Historically, 46,XY patients with severe genital anomalies were often raised as females from birth with feminizing reconstruction and removal of normal testes. However, gender dysphoria has been reported in approximately one-third of patients with a female sex of rearing [87-89]. This may be due to exposure to normal male levels of testosterone in utero and during infancy, as well as the presence of putative gender-determining genes [74,87,88,90]. If a female sex of rearing is contemplated, it is essential that the parents understand that it is difficult to predict gender identity and that feminizing surgery is irreversible. It is prudent to delay surgery until gender identity is confirmed and the patient can participate in decisions about surgery.

46,XX individuals with cloacal exstrophy should be raised as females and offered reconstructive surgery as appropriate. (See "Body stalk anomaly and cloacal exstrophy: Prenatal diagnosis and management".)

Surgical considerations – For patients with cloacal exstrophy, surgical reconstruction often requires a permanent colostomy. These patents often have associated anomalies such as a tethered spinal cord. Renal anomalies such as a solitary or blocked kidney are common, as well as müllerian abnormalities such as duplication of the vagina. In males, surgical reconstruction may include phalloplasty, depending on the degree of the penile atypia, which can range from hypospadias to a split penis. (See "Body stalk anomaly and cloacal exstrophy: Prenatal diagnosis and management".)

46,XY patients with penile agenesis can be offered cosmetic phallic reconstruction. Short-term results have been promising for phalloplasty performed in the neonatal period or early childhood [91]. Patients will typically require further phallic reconstruction after puberty to create an adult-sized phallus [92]. Erectile function is not expected.

LONG-TERM MANAGEMENT — The long-term care of children born with DSD requires attention to both psychosexual and medical concerns. Transition to adult care at the appropriate age is often problematic, and a coordinated program for such transition is important, as it is in other chronic illnesses [93].

Psychosexual issues — Psychosexual identity cannot be "assigned." However, to the extent that it is possible, sex of rearing should be congruent with anticipated gender identity [23]. This strategy is in the best interest of the child, given the cultural constraints of raising a child with atypical genital appearance and an undefined gender.

Children with atypical genital appearance who do not undergo early surgical correction and their parents require ongoing consultation and support to address management issues that arise over time. Once a decision has been made about sex of rearing, the child should be raised in the predicted sex, although the parents should be encouraged to be accepting if the child conveys a different gender identity, either verbally or through behaviors. Parents should be aware of this possibility and reminded of it as the child gets older and has a better understanding of their condition. A multidisciplinary team specializing in DSD can facilitate the child's participation in any decision-making process, as appropriate to the child's age [6,21].

For both the child and parents, long-term follow-up with mental health specialists with expertise in this area is critical [22]. Counseling should be multistaged and take place at birth, sometime after two years of age, at school entry, before and during pubertal changes, and at least annually during adolescence [23]. Counseling should be detailed and forthright. Pubertal development, the likelihood (or not) of menses and fertility, and sexual function should be addressed.

Psychological gender must be monitored by skilled professionals during childhood, adolescence, and adulthood so that if the patient's gender identity is inconsistent with the sex of rearing, the patient can receive full psychological, medical, and surgical support [76].

Medical concerns — Ongoing medical concerns in children with DSD include the potential for malignancy in gonadal tissue, effects of altered levels of sex steroid exposure, and decreased bone mineral density. Several DSD diagnoses are associated with variable risks for gonadal malignancy, as discussed in the next section. In addition, individuals with XY chromosomes and gonadal dysgenesis caused by Wilms tumor 1 (WT1) gene mutations may have Denys-Drash syndrome, which includes progressive renal disease and Wilms tumor.

Gonads — The gonadal tissue of infants who have DSD may require specific management to decrease the risk of long-term complications such as cancer, torsion, and infertility.

Surgical decisions — Abdominal gonads bearing Y chromosomal material should be either brought into the scrotum or placed in a fixed anatomic position where they can be monitored by ultrasound or removed surgically. The risk for gonadal malignancy and optimal age for performing the surgery varies with the diagnosis and is summarized in the 2006 Consensus Statement and in several review articles [1,37,82,94,95]. For patients who undergo gonadectomy, experimental cryopreservation of gonadal tissue can be performed in an attempt to preserve fertility if germ cells are present in the gonad; a protocol has been described but is not widely available, and long-term success remains to be confirmed [96]. (See "Fertility preservation: Cryopreservation options".)

DSD with an increased risk for gonadal tumors (in addition to atypical genital appearance) are listed below and in the table (table 2):

Mixed gonadal dysgenesis (45,X/46,XY mosaic) – This disorder is associated with substantially increased risk of gonadal malignancy (>30 percent in some series) [1]. The increased tumor risk is present in both the streak gonad (which is typically on the left) and the abnormal testis (which is typically on the right side and descended) (picture 1 and image 1). Removal of the streak gonad should be performed within the first decade of life [97-99]. Many experts advocate biopsy of the scrotal testis because of the tumor risk, especially after puberty [64]. (See 'Mixed gonadal dysgenesis (45,X/46,XY mosaicism)' above and "Anatomy and pathology of testicular tumors", section on 'Gonadoblastoma'.)

Partial androgen insensitivity syndrome (PAIS) – For those raised male, the risk for gonadal tumors is minimal until late puberty [82,98,99]. Bilateral orchiopexies are performed during infancy to bring the testes into the scrotum, where they can be monitored for tumor development by physical examination and sonography if necessary; the monitoring is typically done annually [37]. (See "Pathogenesis and clinical features of disorders of androgen action".)

When a female assignment is chosen, gonadectomy can be performed at the time of feminizing genitoplasty. After puberty, the risk of tumors is approximately 15 percent for abdominal gonads [82,100].

Complete androgen insensitivity syndrome (CAIS) – Individuals with CAIS have normal female genitalia, but some are identified in infancy because of palpable gonads in the labioscrotal folds or associated with inguinal hernias. In these children, delaying gonadectomy until after puberty is generally recommended because this permits a relatively "natural" female puberty and greater bone density (secondary to aromatization of androgen to estrogen) [23]. However, this must be weighed against the slightly increased risk of malignancy and the potential psychological disadvantage of retaining gonads that are in conflict with the sex of rearing. (See "Pathogenesis and clinical features of disorders of androgen action", section on 'Complete androgen insensitivity (CAIS)'.)

17-beta-hydroxysteroid dehydrogenase (17-beta-HSD) type 3 deficiency – The risk for gonadal malignancy is intermediate (as high as 30 percent in one series) [94]. Active surveillance rather than gonadectomy has been suggested in one guideline [1]. Active surveillance permits retention of the testes in these 46,XY individuals, while monitoring for malignancy.

5-alpha-reductase type 2 deficiency – The risk for gonadal malignancy is modestly increased and is probably similar to the risk associated with cryptorchidism. In our practice, we do not perform gonadectomy, but we continue to monitor the testes for malignancy throughout life.

46,XY congenital adrenal hyperplasia (CAH) – Individuals with 46,XY CAH have a high risk of developing testicular adrenal rest tumors, the prevalence of which increases with age and with poor control of the underlying CAH. The histopathology may resemble Leydig cell tumors. Most information about this association comes from 46,XY individuals with 21-hydroxylase deficiency (who have typical male genitalia) [101]. However, it is likely that patients with other forms of 46,XY CAH DSD (eg, 17-alpha-hydroxylase deficiency, 3-beta-HSD type 2 deficiency) also may have an increased risk for testicular adrenal rest tumors [102-104]. These patients should have regular testicular monitoring, as described below. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Testicular adrenal rests' and "Uncommon congenital adrenal hyperplasias".)

46,XX CAH – Case reports have described ovarian adrenal rest tumors in individuals with 46,XX CAH. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'No role for screening for adrenal rest tumors'.)

Monitoring — Regular abdominal ultrasonography or magnetic resonance imaging should be performed in all patients with DSD who have abdominal testes, and testicular palpation should be performed in those with scrotal testes. Children with PAIS whose families decide to leave scrotal gonads in place through puberty should be monitored regularly with ultrasonography and physical examination.

Sex steroids — 46,XX children with CAH and atypical genital appearance usually are raised as females (as described above) and require lifetime glucocorticoid therapy to minimize the ever-present risk of hyperandrogenemia. For other DSD, sex steroid replacement should be conducted in a manner consistent with the sex of rearing and age of the child.

The long-term sequelae of sex steroid deficiencies or end-organ unresponsiveness to sex steroid on bone mineral density and lipids must be considered. Bone mineral density and physical growth and development may be adversely affected by diminished sex steroid secretion during puberty. Glucocorticoid treatment can negatively affect bone density and adult height in CAH. Height and weight should be monitored regularly, and bone mineral density should be measured at puberty and then every two years, depending upon the normality of the findings. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults".)

SUPPORT GROUPS AND INTERNET SITES — Individuals with DSD and their families often benefit from general or DSD-specific support groups, and participation should be encouraged [37]. The following websites have been helpful to our patients and their families; many of these include materials for patient education:

DSD clinics at children's hospitals

Toronto Hospital for Sick Children – Patient information on sex development

CARES Foundation – Information and support about congenital adrenal hyperplasia (CAH)

Accord Alliance (formerly known as the Intersex Society of North America)

DSD Guidelines – A handbook for parents and clinical guidelines for providers, published by the Accord Alliance

dsdfamilies.org – Helpful information for families and children of different ages from Great Britain

InterConnect – An organization largely for people with androgen insensitivity syndrome but other DSD as well

The MAGIC Foundation

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Classic and nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Society guideline links: Differences of sex development".)

SUMMARY AND RECOMMENDATIONS

Terminology – Individuals born with a discrepancy between external genitalia and gonadal and chromosomal sex are classified as having a difference (or disorder) of sex development (DSD). Some DSD present with a genital appearance that does not permit prompt gender declaration at birth, a condition previously termed "ambiguous genitalia." A glossary of terms used in this field is provided (table 1).

Initial management

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, the most common cause of 46,XX DSD, has a significant risk for salt-wasting adrenal crisis (table 5). Adrenal crisis also may occur in some other types of CAH, including 11-beta-hydroxylase deficiency. Therefore, any newborn infant with atypical genital appearance and nonpalpable gonads should be presumed to have CAH and monitored for salt loss and adrenal crisis until the diagnosis is excluded. (See 'Risk of adrenal crisis' above.)

The remainder of the evaluation to determine the cause of the DSD is discussed separately. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)

The birth of an infant with atypical genital appearance is often confusing and highly distressing for the family; prompt communication and psychosocial support are imperative. (See 'Is it a boy or a girl? Family coping' above.)

Referral to a specialized center for children with DSD is strongly encouraged. (See 'Further evaluation' above.)

Sex of rearing and surgery – Decisions about sex of rearing depend in part on the predicted gender identity, which varies with the type of DSD but is not always predictable (table 2).

46,XX CAH – For individuals with mild to moderate virilization (Prader I through IV) (figure 1A-B), a female gender identity is common. Although the family may choose a female sex of rearing, they should also be counseled that the child will determine their own gender identity with age. Standard treatment with glucocorticoids suppresses endogenous androgen production. (See 'Clinical approach to 46,XX congenital adrenal hyperplasia' above.)

-If feminizing surgery is undertaken, the optimal timing is unclear and decisions should be made collaboratively with the family after discussion of the considerations and clinical outcomes. Some experts and family advocates support performing some components of surgery (repair of the urogenital sinus, vaginoplasty, and labioplasty) during infancy. Other experts and patient advocacy groups argue that all surgery be postponed until the child can fully understand and make choices about surgery. Most experts agree that clitoroplasty is not necessary for children with mild or moderate virilization (Prader II and III); clitoroplasty remains controversial for children with severe virilization (Prader IV and V). (See 'Genital surgery' above and 'Timing and extent of surgery' above.)

-Management decisions are more complex for the rare situation in which a 46,XX child presents with male external genitalia (complete penile urethra [Prader V]), especially if they present after infancy. (See '46,XX congenital adrenal hyperplasia, Prader V' above.)

Mixed gonadal dysgenesis – For most individuals with 45,X/46,XY mosaicism and atypical genital appearance (mixed gonadal dysgenesis), a male gender identity is likely. Infertility is likely even in those with a scrotal testis, and surgical outcomes can be poor if the phallus is poorly responsive to androgen stimulation. (See 'Mixed gonadal dysgenesis (45,X/46,XY mosaicism)' above.)

46,XY 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD) or 5-alpha-reductase deficiency – For these individuals, a male gender identity is likely. These individuals have impaired androgen synthesis but can spontaneously virilize during puberty or with androgen treatment. (See '46,XY 17-beta-HSD and 5-alpha-reductase deficiencies' above.)

Other – For some other rare DSD, gender identity is unclear or difficult to predict (table 2). Thus, decisions about gender of rearing should be individualized. In some of these cases, it is helpful to promote the concept of an evolving gender identity, which recognizes that gender identity may change as the child grows. (See 'Approach to other differences/disorders of sex development' above.)

Long-term issues

Individuals with DSD and their families should be offered long-term support to assist in psychosexual and psychosocial adjustment, as well as decision-making. These adjustments and decisions may change as the child matures. (See 'Psychosexual issues' above.)

Ongoing medical concerns in children with DSD include the potential for malignancy in retained gonadal tissue, effects of altered levels of sex steroid exposure, and decreased bone mineral density. (See 'Medical concerns' above.)

Because of the risk of malignancy, abdominal gonads bearing Y chromosomal material should be surgically removed or repositioned into the scrotum where they can be monitored. However, the malignant potential and optimal age for surgery vary substantially among DSD (table 2). In cases of mixed gonadal dysgenesis, the malignancy risk and related management decisions also depend upon on the patient's phenotype and testicular histology. (See 'Gonads' above.)

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Topic 5807 Version 25.0

References

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