Management of the infant with atypical genitalia (disorder of develop... https://www-uptodate-com.ezp01.library.qut.edu.au/contents/management-...

Official reprint from UpToDate® www.uptodate.com ©2019 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Authors: Christopher P Houk, MD, Laurence S Baskin, MD, FAAP, Lynne L Levitsky, MD Section Editor: Mitchell E Geffner, MD Deputy Editor: Alison G Hoppin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2019. | This topic last updated: Jan 09, 2019.

INTRODUCTION

Individuals with a congenital discrepancy between the appearance of their external genitalia and gonadal and chromosomal sex are classified as having a disorder of sex development (DSD) [1]. Abnormalities sufficient to prompt evaluation (excluding uncomplicated cases of and ) occur in approximately 1 in 1000 to 4500 live births [2-5].

The birth of an infant with atypical genitalia 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, differences in structure, prenatal 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 irreversible genital surgery [6-8]. Long-term outcome data are now available to help predict gender identity for many infants with DSDs and provide insight into appropriate early management decisions [9-13]. Nonetheless, there is ongoing controversy about some aspects of management, especially for certain types of DSDs for which gender identity remains unpredictable. Thus, uncertainties about adult outcome, gender of rearing, and timing of surgery should contribute to discussions and informed decision-making by the patients (if age appropriate) and parents. Each child and family will have unique characteristics so that all decisions should be made on a case-by-case basis.

The management of infants with clinically significant DSDs will be discussed here. The evaluation of these infants and specific causes of DSDs are discussed separately. (See "Evaluation of the infant with atypical genitalia (disorder of sex development)" and "Causes of disorders of sex development".)

TERMINOLOGY

Disorder of sex development — Although the term disorder of sex development (DSD) has been accepted by the medical community, some patients and support groups question its usefulness and appropriateness based on three criticisms: first, the use of the word "disorder" is seen as unnecessarily negative by some. Second, DSD is an overly broad term that, with current nomenclature, is used to encompass conditions in which no issues with genital

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appearance or gender identity are expected (eg, Turner syndrome, , trisomy X). Third, a broad term like DSD lacks sufficient specificity to be helpful diagnostically and is therefore unnecessary. Many of these support and advocacy groups do not accept the DSD designation and feel that it should be abandoned by the medical community.

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 ""). 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, nonsevere forms of hypospadias.

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

TYPES OF DSDS WITH ATYPICAL GENITALIA

Management depends on the type of disorder of sex development (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 genitalia (disorder 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 DSDs presenting with atypical genitalia and a 46,XX 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 atypical genitalia due to endogenous virilization and without palpable . Rarely, 46,XX individuals with CAH present with normal external male genitalia but without palpable gonads. In the past, these individuals were usually diagnosed later in life after being raised as males. 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 disorders of sex development", section on 'Classic CAH due to 21-hydroxylase deficiency'.)

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

● 45,X/46,XY mosaicism – The second most common category of DSDs with atypical genitalia is 45,X/46,XY mosaicism. Those with atypical genitalia typically have hypospadias (often severe), a descended (but infertile) testis typically on the right side, and a streak with retained müllerian 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 disorders of sex development", section on 'Sex chromosome DSD'.)

The phenotype of this condition is highly variable, ranging from phenotypically normal males (approximately 90 percent of patients, often undiagnosed), to males with gonadal dysgenesis, to those with genitalia and

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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".)

● 46,XY DSD – Several types of 46,XY DSDs 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).

• Partial androgen insensitivity syndrome (PAIS) caused by androgen receptor gene .

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

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

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

● Ovotesticular DSD – Ovotesticular DSD (previously known as ) refers to the presence of ovarian tissue with follicles and testicular tissue with seminiferous tubules in the same individual. Most of these individuals have a 46,XX karyotype. (See "Causes of disorders of sex development", section on 'Gonadal overproduction of androgens' and "Causes of disorders of sex development", section on 'XY gonadal dysgenesis'.)

Management for some of these disorders is outlined below. (See 'Decisions about sex of rearing and surgery' below.)

INITIAL STABILIZATION

The initial stabilization of infants with a DSD presenting with atypical genitalia requires attention to both medical and psychosocial issues. The most important medical issue is the possibility of life-threatening adrenal crisis in infants with congenital adrenal hyperplasia (CAH). The urgent psychosocial issue arises from the anxiety experienced by most parents whose child is born with atypical genitalia. Uncertainty about the sex of rearing complicates or delays the traditional announcement of whether the child is a boy or girl to family members, friends, and community. The period of uncertainty is inevitable because of the time required to make an accurate diagnosis and develop a thoughtful treatment plan.

Risk of adrenal crisis — CAH due to 21-hydroxylase (CYP21A2) deficiency (MIM #201910) is the most common cause of 46,XX DSD (virilization) and 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. If salt-wasting CAH due to 21- hydroxylase deficiency remains undiagnosed and is 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.

Therefore, any infant with atypical genitalia and nonpalpable gonads (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

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or excluded. Blood samples should be urgently obtained for steroid precursors (most importantly, 17- hydroxyprogesterone) to evaluate for CAH; serum and urine electrolytes and plasma glucose should be monitored closely until CAH is definitively diagnosed or excluded.

Laboratory findings suggesting salt-wasting crisis include hyperkalemia with or without hyponatremia, metabolic acidosis, and hypoglycemia [14]. 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 therapeutic 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 [15,16]. The period of uncertainty before a specific diagnosis can be established is a particularly challenging time for the parents. In the rarer forms of DSDs presenting with atypical genitalia, this can be an extended process because of the multiple diagnostic steps required 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 the overwhelming majority of patients) [17]. The genitalia can be described to the parents as "not being fully formed" or being "overly developed." It is helpful to summarize the 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 capacity of the family, and special needs caused by the family's cultural or religious background should be identified and addressed. In the early stages of communication, the provider should take care to avoid overly technical descriptions of the problem, which can both contribute to the family's emotional stress and discourage additional questions from the family.

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 difference in development since some DSDs are associated with fairly predictable gender identity, while others have less predictable gender identity outcomes (see 'DSDs with reasonably predictable gender identity' below). Similarly, the birth certificate should not be completed until the diagnosis and planned sex of rearing are determined. If the diagnosis is clear (eg, 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, the family will require counseling and support to be able to postpone the birth announcement about the baby's sex [1].

Other 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 defect, the defect 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 genitalia often wish to discuss issues of long-term reproductive function and sexuality early in the evaluation. These issues should be discussed in a frank and open way; discussion should be

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facilitated by appropriate members of the health care team, within the limits of family understanding and availability of data concerning the outcomes of the specific diagnosis.

Further evaluation — After initial stabilization, infants with DSDs should be thoroughly evaluated to establish an accurate diagnosis because this information will be an important guide for management. The types of DSDs and steps in the evaluation are discussed in detail separately. The infant should also be evaluated for other nongenital abnormalities that might suggest a syndromic form of DSD. (See "Evaluation of the infant with atypical genitalia (disorder of sex development)".)

Given the complexity of DSD diagnoses and the infrequency with which they are seen, affected infants should be evaluated and managed at centers with experienced DSD teams, if possible [15]. 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 DSDs in 2006 [1], several groups published useful information on the development of collaborative management teams in Western Europe and in North America [18-21]. DSD centers are generally different from centers that manage children and adults with gender dysphoria.

DECISIONS ABOUT SEX OF REARING AND SURGERY

For some DSDs, decisions about sex of rearing and surgery are straightforward. For others, management decisions remain challenging for providers and family, as outlined below.

Long-term outcomes should be judged by the presence of psychosexual and psychosocial well-being and an ability to positively contribute to society [22,23]. In some cases, the child's gender role behavior and gender identity may not be fixed until early adulthood or even later. In addition, experience in non-DSD-related gender expression suggests that gender identity is not necessarily binary, and anecdotal evidence suggests that this observation can be extended to DSD patients.

Overview of decisions about sex of rearing — In accord with available data, guidance given to families about sex of rearing should be based to a large extent upon the most probable adult gender identity and the potential for adult psychosexual and psychosocial function, as outlined in the table (table 2). Factors to be considered in this decision include the specific DSD diagnosis, the degree of virilization as a marker of prenatal androgen exposure, the potential for adult sexual function and fertility, the likely gender identity (for those disorders where this has been established in long-term studies), and the family's sociocultural background and expectations. The relevance of these factors is supported by an increasing number of studies examining gender identity in a variety of DSDs [24-28]. Prenatal androgen exposure may be a particularly important determinant of gender identity [28]. All of these factors must be assessed in every patient, regardless of the type of DSD. Decisions about sex of rearing are ideally made by an informed family after careful evaluation, documentation, and consultation. Ultimately, children with differences in sex development will define their own gender identities over time. This supports a watch and wait approach to genital reconstruction when the diagnosis is uncertain and outcome data unavailable.

For some DSDs (eg, congenital adrenal hyperplasia [CAH] in a 46,XX individual), gender identity is reasonably predictable and psychosocial outcome is generally positive [29]. In this case, the information can be communicated to the family with confidence and decisions about sex of rearing are straightforward. However, it is important to note that gender dysphoria has been reported in a minority of 46,XX CAH patients, particularly those with severe virilization

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and/or those in whom the diagnosis is delayed.

In contrast, for patients with one of the less common forms of 46,XY DSDs, adult gender identity is variable and difficult to predict. In these cases, we discuss the concept of an evolving gender identity, which recognizes that future gender identity is not entirely predictable at birth and may evolve as the child grows. We explain that "we just do not know yet," and encourage parents or caregivers to assume a supportive role in the but remain flexible enough to permit the child to manifest his or her gender identity as they mature. We discuss this concept with families whose children have uncertain gender outcomes in order to assist in decisions about sex of rearing and surgery. While we endorse the flexibility inherent to this concept, we also recognize that this approach remains untested and unproven in the management of children with DSDs. Further, we recognize that the family will bear the major burden of rearing a child with atypical genitalia. For this reason, we respect the family's right and responsibility to make the decisions regarding sex of rearing and timing of surgery. After providing detailed and sensitive counseling, we support the parents or caregivers in their decisions.

Overview of decisions about surgery — Any decision about genital surgery should be made collaboratively with the family after detailed counseling by an expert team [30]. This contrasts with historical approaches, in which surgery was performed early in childhood. However, DSD advocacy groups have recommended that all genital surgery be deferred until the child is old enough to confirm his or her gender identity and can make an informed decision about surgery [31].

The major controversy relating to surgery is whether to operate on the when severe virilization is present (Prader IV and V). Most practitioners would agree that function is more critical than cosmesis and that preservation of a larger-than-normal clitoris is an acceptable alternative, allowing the patient to determine the need for further surgery when able to consent.

● An advantage of deferring surgery is that it keeps options open for virilized 46,XX in case they turn out to have a male gender identity (which occurs in 5 percent or more of 46,XX CAH individuals [32]). Deferring surgery also permits patients to make their own informed decisions about surgery.

● A disadvantage of deferring surgery is that it obviates the parents' right and responsibility to make an informed decision about what they deem is in the child's best interest. Deferring surgery would also require the parents to raise a child with atypical genitalia, which they may not want or be capable of doing. Moreover, in studies examining the timing of genital surgery, most 46,XX females with CAH and their parents preferred surgery in infancy [33] or at least before [33-35]. Furthermore, difficulties during adolescence were greater for both patients and parents when late genitoplasty was performed. However, families must be made aware that definitive female reconstructive surgery diminishes the possibility that the child can have a functional phallus of an adequate size should the child decide on a male gender.

The extremely rare patient with Prader V virilization who has an essentially normal is the most complex scenario, as discussed below. (See '46,XX CAH, Prader V' below.)

There are no controlled studies comparing the effect of early versus late genital surgery on psychosocial or psychosexual development or quality of life [36,37]. The decision for surgery and the timing must be made after a complete discussion with the child's parents or caregivers of the potential advantages and disadvantages of early surgery [38].

It is useful to structure the conversation around the following goals:

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● Reconstruction of atypical anatomy to normal anatomy (ie, to normal female anatomy for most individuals with CAH) ● Preservation of sexual function and erotic sensation ● Preservation of fertility when possible ● Diminution of gonadal malignancy potential ● Provision of realistic expectations for the patient, family, and surgeon

If surgical intervention is deemed necessary at any point in the life of an individual, only the most skilled and experienced of surgeons should perform the necessary reconstructive procedures. Functional outcome usually should take priority over cosmetic outcome, so care should be taken to spare the neurovascular supply of the genitalia. Surgical planning should include clear communication with the family to promote realistic expectations.

Suggestions about the timing or nature of surgical intervention must be carefully discussed with the family [39,40]. Whether the parents or caregivers choose early or delayed reconstruction, they must be fully informed and actively participate in the decision, and the family and child will need frequent psychosocial and medical support as the child grows to adulthood. Sensitive and age-appropriate sharing of information with the child also is an important part of either management approach. Progressive, benevolent disclosure of information to children within their capacity to understand enhances their adaptability and their ability to participate in decisions and is ethically necessary.

Decisions about surgical management of the gonads, including considerations of malignant potential and fertility, are discussed below. (See 'Gonads' below.)

DSDs with reasonably predictable gender identity — For several of the most common disorders of sex development (DSDs) associated with atypical genitalia, projected gender identity is reasonably predictable and positive and management decisions are straightforward (table 2). These include:

46,XX congenital adrenal hyperplasia — 46,XX individuals with virilizing forms of congenital adrenal hyperplasia (CAH) comprise the majority of those with clinically significant genital atypia.

● Sex of rearing – For infants with 46,XX CAH and mild to severe virilization (Prader I through IV) (figure 1A-B and picture 2), we advise a female sex of rearing [40]. Approximately 90 to 95 percent of such patients who are raised as girls do not experience gender dysphoria as adults, provided that the disorder is diagnosed in infancy and they are given standard treatment with glucocorticoids (which suppresses endogenous androgen production) [24-26,32,38]. The female gender role is also consistent with the individual's internal anatomy, and fertility may be possible. (See " and clinical presentation of classic congenital adrenal hyperplasia due to 21- hydroxylase deficiency" and "Causes of disorders of sex development", section on 'Other types of congenital adrenal hyperplasia'.)

For individuals who are not diagnosed and treated for CAH in infancy (eg, those living in low-resource countries, the Middle East, or China), female gender identity is much less certain. 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 to the benefits of higher social position enjoyed by males in some societies [41]. Indeed, a literature review suggested that gender dysphoria is uncommon among highly virilized 46,XX patients who are reared as males [42]. Because of these observations, it has been suggested that a male sex of rearing be considered in 46,XX patients with Prader V external genitalia [43]. This approach remains controversial in the United States and Europe; important considerations include age of diagnosis and family cultural and social environment. (See '46,XX CAH, Prader V' below.)

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● Surgical considerations – Patients with 46,XX CAH have a normal , , , and , with a common and enlarged clitoris. For those with moderate or severe virilization (Prader III through IV) and female sex assignment, the standard surgical correction is to bring the normal vagina to the perineum, repair the fistula between the vagina and common urogenital channel, and locate the within its normal position [44-48]. For these severely virilized infants, it is reasonable to consider surgery during infancy [30]. However, such surgical decisions should be approached cautiously as an entirely normal sexual outcome may be unrealistic in most settings and because the removal of erectile tissue would be problematic for those children who later redefine their gender as male.

Advances in understanding the neurologic innervation of the vagina and clitoris have influenced surgical technique, permitting preservation of sexual function and sensation [49,50]. Modern techniques include partial urogenital sinus mobilization to bring the vagina to the perineum; when necessary, the vaginal tissue is supplemented with a posterior skin flap and the anterior vagina is supplemented with excess common urogenital sinus tissue [30]. Function is prioritized over cosmesis, which often means advocating to families and patients that it is acceptable to have a clitoris that is larger than average. If clitoral surgery is necessary in patients assigned a female sex of rearing and with more severe forms of virilization (Prader III through V), the reduction is performed through a ventral approach to preserve sensation and sexual function [30]. However, no long-term data are available on the functional capacity of the clitoris after surgery, including in those patients who received the newer nerve-sparing procedures. A review and meta-analysis of the effects of genital reconstructive surgery in females with CAH suggests that although more than 70 percent are satisfied with the surgery, many complain of clitoral insensitivity and difficulties with vaginal penetration. It is unclear how many of these women had newer procedures [32].

Some groups have advocated avoiding all "cosmetic" genital surgery until the child is old enough to make an informed decision, as discussed above. (See 'Overview of decisions about surgery' above.)

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

● Sex of rearing – For most individuals with mixed gonadal dysgenesis (45,X/46,XY mosaicism), we advise a male sex of rearing, with an understanding that is likely and that adult phallus size can be inadequate if the phallus is poorly responsive to androgen stimulation [51,52]. While little information is available on gender outcome in mixed gonadal dysgenesis, sex of rearing is typically male, owing to the presence of at least modest virilization, the presence of a Y chromosome, and the in utero exposure to higher levels of androgen.

● Surgical considerations – Hypospadias surgery is performed at 6 to 15 months of age [53]. Patients with 45,X/46,XY DSD are more likely to require preoperative androgen treatment to stimulate penile growth prior to the repair compared with infants with hypospadias and a normal karyotype (see "Hypospadias: Pathogenesis, diagnosis, and evaluation"). The scrotal gonad (testis) requires careful follow-up because it is dysplastic and has a higher tumor risk than a typical scrotal testis [54]. A biopsy of scrotal testis is recommended postpubertally to rule out the presence of carcinoma in situ, a premalignant condition. Many advocate biopsy of the scrotal testis because of the increased cancer risk, especially after puberty [51]. The streak gonad is typically removed because of tumor risk and lack of function [55]. The müllerian remnant (hemi-uterus) is typically removed at the same time as the streak gonad (image 1). (See 'Gonads' below.)

In the rare patient with mild or moderate virilization assigned a female sex of rearing, it is prudent to defer feminizing surgery until a female gender identity is confirmed because suboptimal outcomes have been reported

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in the past with early feminizing surgery in these patients. The vagina/müllerian cavity is typically more narrow and rigid than in patients with 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 deficits

● Sex of rearing – For individuals with 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD) type 3 (MIM 605573) or 5-alpha reductase type 2 (MIM 607306) deficiencies, we advise a male sex of rearing for most patients [38,56]. These individuals have impaired androgen synthesis but are capable of responding to androgens and can virilize during endogenous puberty or with androgen treatment. Case series suggest a male gender identity in approximately 60 percent of 46,XY patients with 5-alpha reductase deficits (or a higher proportion if gonads have been left intact) and at least 50 percent of those with 17-beta-HSD defects [38]. Thus, it is reasonable to raise most of these patients as males. Modern molecular diagnostic techniques permit an early and accurate diagnosis of both of these enzymatic defects (see "Causes of disorders of sex development", section on 'Abnormal 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 these DSDs often underwent early feminizing surgery (including gonadectomy) and were raised in the female gender role. 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 [57,58], perhaps as a result of male typical fetal androgen exposure and virilization at puberty (in those with intact testes), and that gender identity evolves from female to male in many, especially around puberty [27].

● Surgical considerations – Once the diagnosis of either of these types of DSDs is confirmed, we initiate androgens to stimulate penile growth before proceeding to surgical reconstruction of the hypospadias, which is typically performed between 6 and 15 months of age [53] (see "Hypospadias: Pathogenesis, diagnosis, and evaluation"). In patients with undescended testes, orchiopexy 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 where the individual has a female gender identity, surgical reconstruction needs to take into account the benefit of gonadectomy to prevent virilization at puberty [56].

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.

DSDs with less predictable gender identity and other challenges — For infants with the following disorders, gender identity is unpredictable and management decisions are consequently complex. These disorders are:

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).

● Gender identity – Historically, many patients with PAIS underwent feminizing reconstruction even if they had a predominantly male phenotype [56]. Although practice varies, the trend is to raise these children as males when

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possible. Case series suggest that a significant minority (5 to 15 percent) of children raised in either sex role will experience gender dysphoria [59,60]. The response to androgen treatment in patients with PAIS is variable. A consensus statement suggests that decisions about sex of rearing should be based upon response of the phallus to therapy, and female assignment must be considered for those with no evidence of androgen effects [38]. 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 'Partial androgen insensitivity syndrome'.)

PAIS should not be confused with complete androgen insensitivity syndrome (CAIS), which is characterized by a 46,XY karyotype, typical female genitalia, absent müllerian structures, and strong female gender identity [61]. (See "Diagnosis and treatment of disorders of the androgen receptor", section on 'Complete androgen insensitivity syndrome'.)

● 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 [62]. The response of the phallus to androgen stimulation is important to determining the optimal timing for surgery. Orchiopexy should also be performed to facilitate testicular self-examination and ultrasound surveillance because these patients are at increased risk for developing testicular cancer in adulthood (approximately 15 percent) [63-65].

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 and removal of the gonads and sometimes clitoral recession.

Ovotesticular DSD — Individuals with ovotesticular disorder of sex development (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, , or ovotestis) and 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.

● Gender identity – Data from small case series suggest that patients reared in either sex can be satisfied with their sex assignment [66,67], but that gender dysphoria also may occur [38]. 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 [68].

● Surgical considerations – Surgical decisions for patients with ovotesticular DSD remain complex [63-65]. 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 appears to be approximately 2.6 percent [1,69].

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,XX CAH, Prader V — Rarely, a 46,XX child with congenital adrenal hyperplasia (CAH) will present with

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essentially normal male external genitalia (complete penile urethra [Prader V]). Historically, in such cases, the child was often identified as male at birth and the DSD not recognized until late childhood. However, with the implementation of newborn screening, most cases are identified soon after birth.

● Sex of rearing – If the diagnosis of CAH with Prader V genitalia is made in the neonatal period, many practitioners advise a female sex of rearing because of the high likelihood of female gender identity and the potential for normal ovarian function and fertility in adulthood, with the understanding that these data do not necessarily reflect outcomes from 46,XX CAH patients with Prader V genitalia [70]. On the other hand, the surgical reconstruction to female anatomy can be technically difficult, and there are several reports documenting successful outcomes in patients raised as males [43,71,72]. Therefore, it is reasonable for families to consider a male sex of rearing. Uncommonly, these individuals may later self-identify as female and choose to have feminizing surgery, which is irrevocable [40]. For individuals with this phenotype, it is essential to engage the family in a complete discussion of options, including limitations of knowledge about psychosexual outcomes, so that they can make an informed decision [38].

● Surgical considerations – For patients who are raised as females or those who later self-identify as female, surgical reconstruction can be performed to approximate typical female genitalia and bring the vagina to the perineum. These patients typically have a high insertion of the vagina close to the bladder neck (image 2). Separation of the high common urogenital channel should only be attempted by an experienced surgeon and typically requires a posterior approach. The rectum may need to be reflected or even split and reconstructed. A temporary diverting colostomy and combined perineal abdominal approach may be required [44-47].

Patients with CAH 46,XX DSD and severe virilization (Prader IV or V) who are raised as males may undergo "hypospadias repair" in infancy. If the child accepts the male gender identity, he will ultimately require a and removal of the internal gonads (ovaries). 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 , similar to the risk seen in patients with an enlarged prostatic utricle. The gonadectomy should be done prior to puberty to prevent menstruation and breast development. Alternatively, treatment with a GnRH analog can be initiated prior to puberty and the surgery deferred until later in adolescence or early adulthood, when the patient can affirm his or her gender identity and participate in the decisions about further surgery.

46,XY with severe genital anomalies

● Sex of rearing – The genital anomalies of 46,XY individuals with cloacal exstrophy (picture 3), micropenis, or penile agenesis are not associated with disruption of sex . Testicular function and male fertility potential are normal, although patients will require assisted reproductive techniques. Accordingly, the practice is to raise these individuals as males, despite the technical challenges of phallic reconstruction.

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 [73-75]. 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 [57,73,74,76]. 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. For these patients, it may be particularly prudent to delay surgery until gender identity is confirmed and the patient can participate in

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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".)

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

46,XY patients with penile agenesis can be offered phallic reconstruction. Short-term results have been promising for phalloplasty performed in the neonatal period or early childhood [77]. Patients will typically require further phallic reconstruction after puberty to create an adult-sized phallus for cosmesis [78].

Consensus statement — An international consensus statement on DSDs was published in 2006 [40] and updated in 2016 [38]. It is important to note that this report represents a consensus from a group of DSD experts from many countries, rather than a unanimous opinion. The statement may not necessarily represent current views or the special needs of patients or providers in other cultures. In particular, there is increasing appreciation for a flexible approach to sex of rearing to permit a child to determine their own gender identity (see 'Overview of decisions about sex of rearing' above). In addition, there is a trend towards avoiding all or most feminizing surgery during infancy or childhood, given that some individuals may ultimately identify as male. (See 'Overview of decisions about surgery' above.)

This report suggests:

● All virilized 46,XX children with CAH, even those with normal-appearing male external genitalia, should be raised in the female role given that a high proportion of these patients identify as females in adulthood. Feminizing surgery should be reserved for those with severe virilization (Prader III, IV, V) (figure 1A-B). Anatomically-based clitoral reduction should be performed in conjunction with repair of the common urogenital sinus.

● Mild or moderate clitoral hypertrophy should not be surgically treated until the patient is able to make a mature decision about this.

● In children with a high proximal junction (confluence) between the vagina and urethra, early and clitoroplasty is an appropriate choice if it can be performed at a center with large experience.

● For fully masculinized individuals with a 46,XX karyotype who are identified later in life, the decision to reassign gender should only be initiated by the patient and include careful consultation and psychological evaluation.

LONG-TERM MANAGEMENT

The long-term care of children born with a 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 [79].

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 [17]. This strategy is in the best interest of the child,

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given the cultural constraints of raising a child with atypical genitalia and an undefined gender.

Children with atypical genitalia 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 his or her condition. A multidisciplinary team specializing in DSDs can facilitate the child's participation in any decision-making process, as appropriate to the child's age [15].

For both the child and parents, long-term follow-up with mental health workers with special expertise in this area is critical [16]. 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 [17]. Counseling should be detailed and honest. 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 [59].

Medical concerns — Ongoing medical concerns in children with DSDs include the potential for malignancy in gonadal tissue, the effects of altered levels of sex steroid exposure, and decreased bone mineral density. Several DSDs 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) mutations may have Denys-Drash syndrome, which includes progressive renal disease and Wilms tumor.

Gonads — The gonadal tissue of infants who have a 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 Consensus Statement and review articles [1,38,80,81].

DSDs with atypical genitalia and an increased risk for gonadal tumors are (table 2):

● Mixed gonadal dysgenesis (45,X/46,XY ) – This disorder is associated with substantially increased risk of gonadal malignancy (>30 percent in some series) [1]. The heightened 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 [82-84]. Many experts advocate biopsy of the scrotal testis because of the tumor risk, especially after puberty [40]. (See 'Mixed gonadal dysgenesis (45,X/46,XY mosaicism)' above and "Anatomy and pathology of testicular tumors", section on 'Mixed GCT and SCST'.)

● Partial androgen insensitivity syndrome (PAIS) – For those raised male, the risk for gonadal tumors is minimal until late puberty [83,84]. Bilateral orchiopexies are performed during infancy to bring the testes into the scrotum, where they can be monitored for tumor by physical examination and sonography if necessary; the monitoring is typically done annually [38].

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When a female assignment is chosen, gonadectomy can be performed at the time of feminizing genitoplasty. After puberty, the risk of tumors is high for abdominal gonads (approximately 50 percent) and intermediate for scrotal gonads (risk is poorly defined but probably less than 30 percent) [1].

● Complete androgen insensitivity syndrome (CAIS) – Individuals with CAIS have normal female genitalia, but some are identified in infancy because of palpable gonads in the labio-scrotal folds or associated with inguinal hernias. In these children, delaying gonadectomy until after puberty may permit a relatively "natural" female puberty and greater bone density [17]. 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) [80]. 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) – For these individuals, there is 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) [85]. However, it is likely that patients with other forms of 46,XY CAH DSD (eg, 17-alpha-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase type 2 deficiency) also may have an increased risk for testicular adrenal rest tumors [86-88]. These patients should have regular testicular monitoring, as described below. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Testicular adrenal rests' and "Uncommon congenital adrenal hyperplasias".)

Monitoring — Regular abdominal ultrasonography or magnetic resonance imaging should be performed in all patients with DSDs 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 genitalia usually should be raised as females (as described above) but often have relative hyperandrogenemia, which can be managed by adjusting the glucocorticoid dose. For other DSDs, 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

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classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults".)

SUPPORT GROUPS AND INTERNET SITES

Individuals with DSDs and their families often benefit from general or DSD-specific support groups, and participation should be encouraged [38]. 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

● 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: Disorders of sex development".)

SUMMARY AND RECOMMENDATIONS

● Individuals born with a discrepancy between external genitalia and gonadal and chromosomal sex are classified as having a disorder of sex development (DSD). Some DSDs present with a genital appearance that does not permit prompt gender declaration at birth, a condition previously termed "ambiguous genitalia."

Initial management

● Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common cause of 46,XX DSD and 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 genitalia 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 first steps to determine the cause of the DSD are a karyotype and fluorescence in situ hybridization (FISH) for the sex-determining region on the Y chromosome (SRY), and a pelvic ultrasound. (See "Evaluation of the infant with atypical genitalia (disorder of sex development)".)

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

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

Sex of rearing and surgery

● For many types of DSDs, gender identity and function are reasonably predictable and decisions about sex of rearing and genital surgery are straightforward (table 2). These include:

• For 46,XX individuals with CAH and mild to moderate virilization (Prader I through IV) (figure 1A-B), we advise a female sex of rearing. Standard treatment with glucocorticoids suppresses endogenous androgen production. Management decisions are more complex for the rare 46,XX child with CAH who presents with male external genitalia (complete penile urethra [Prader V]), especially if they present after infancy. (See '46,XX congenital adrenal hyperplasia' above and '46,XX CAH, Prader V' above.)

• For most individuals with 45,X/46,XY mosaicism and atypical genitalia (mixed gonadal dysgenesis), we advise a male sex of rearing. Infertility is likely even in those with scrotal testes, 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.)

• For 46,XY individuals with 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD) or 5-alpha reductase deficiencies, we generally advise a male sex of rearing. 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 deficits' above.)

● For some other rare DSDs, gender identity is unclear or difficult to predict (table 2). Thus, decisions about gender of rearing and surgery 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 'DSDs with less predictable gender identity and other challenges' above.)

Long-term issues

● Individuals with DSDs 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 change as the child matures. (See 'Psychosexual issues' above.)

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

● Because of malignant potential in abdominally positioned gonads bearing Y chromosomal material, surgical removal or repositioning into the scrotum is recommended. However, the malignant potential and optimal age for surgery vary substantially among DSDs (table 2). (See 'Gonads' above.)

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65. Abacı A, Çatlı G, Berberoğlu M. Gonadal malignancy risk and prophylactic gonadectomy in disorders of sexual development. J Pediatr Endocrinol Metab 2015; 28:1019.

66. Verkauskas G, Jaubert F, Lortat-Jacob S, et al. The long-term followup of 33 cases of true hermaphroditism: a 40-year experience with conservative gonadal surgery. J Urol 2007; 177:726.

67. Sircili MH, Denes FT, Costa EM, et al. Long-term followup of a large cohort of patients with ovotesticular disorder of sex development. J Urol 2014; 191:1532.

68. Schultz BA, Roberts S, Rodgers A, Ataya K. Pregnancy in true and all male offspring to date.

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Obstet Gynecol 2009; 113:534.

69. van Niekerk WA, Retief AE. The gonads of human true hermaphrodites. Hum Genet 1981; 58:117.

70. Slijper FM, Drop SL, Molenaar JC, de Muinck Keizer-Schrama SM. Long-term psychological evaluation of intersex children. Arch Sex Behav 1998; 27:125.

71. Chan-Cua S, Freidenberg G, Jones KL. Occurrence of male phenotype in genotypic females with congenital virilizing adrenal hyperplasia. Am J Med Genet 1989; 34:406.

72. Woelfle J, Hoepffner W, Sippell WG, et al. Complete virilization in congenital adrenal hyperplasia: clinical course, medical management and disease-related complications. Clin Endocrinol (Oxf) 2002; 56:231.

73. Reiner WG, Kropp BP. A 7-year experience of genetic males with severe phallic inadequacy assigned female. J Urol 2004; 172:2395.

74. Reiner WG, Gearhart JP. Discordant sexual identity in some genetic males with cloacal exstrophy assigned to female sex at birth. N Engl J Med 2004; 350:333.

75. Meyer-Bahlburg HF. Gender identity outcome in female-raised 46,XY persons with penile agenesis, cloacal exstrophy of the bladder, or penile ablation. Arch Sex Behav 2005; 34:423.

76. Pasterski V, Acerini CL, Dunger DB, et al. Postnatal penile growth concurrent with mini-puberty predicts later sex-typed play behavior: Evidence for neurobehavioral effects of the postnatal androgen surge in typically developing boys. Horm Behav 2015; 69:98.

77. De Castro R, Rondon A, Barroso U Jr, et al. Phalloplasty and urethroplasty in a boy with penile agenesis. J Pediatr Urol 2013; 9:108.e1.

78. Garaffa G, Spilotros M, Christopher NA, Ralph DJ. Total phallic reconstruction using radial artery based forearm free flap phalloplasty in patients with -exstrophy complex. J Urol 2014; 192:814.

79. Liao LM, Tacconelli E, Wood D, et al. Adolescent girls with disorders of sex development: A needs analysis of transitional care. J Pediatr Urol 2010; 6:609.

80. Looijenga LH, Hersmus R, Oosterhuis JW, et al. Tumor risk in disorders of sex development (DSD). Best Pract Res Clin Endocrinol Metab 2007; 21:480.

81. Hersmus R, de Leeuw BH, Wolffenbuttel KP, et al. New insights into type II germ cell tumor pathogenesis based on studies of patients with various forms of disorders of sex development (DSD). Mol Cell Endocrinol 2008; 291:1.

82. Gourlay WA, Johnson HW, Pantzar JT, et al. Gonadal tumors in disorders of . 1994; 43:537.

83. Verp MS, Simpson JL. Abnormal sexual differentiation and neoplasia. Cancer Genet Cytogenet 1987; 25:191.

84. Manuel M, Katayama PK, Jones HW Jr. The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. Am J Obstet Gynecol 1976; 124:293.

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85. Claahsen-van der Grinten HL, Sweep FC, Blickman JG, et al. Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur J Endocrinol 2007; 157:339.

86. Vukina J, Chism DD, Sharpless JL, et al. Metachronous Bilateral Testicular Leydig-Like Tumors Leading to the Diagnosis of Congenital Adrenal Hyperplasia (Adrenogenital Syndrome). Case Rep Pathol 2015; 2015:459318.

87. García-Mayor RV, Sopeña B, Fluiters E, et al. Testicular adrenal-like tissue in a patient with 17 alpha- hydroxylase deficiency. Horm Res 1992; 38:241.

88. Walker BR, Skoog SJ, Winslow BH, et al. Testis sparing surgery for steroid unresponsive testicular tumors of the adrenogenital syndrome. J Urol 1997; 157:1460.

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GRAPHICS

Glossary of terms for disorders of sex development (DSDs)

Term Definition

Ambiguous genitalia External genitalia that do not have a typical male or female appearance (the term "atypical genitalia" is also used).

Androgen A natural or synthetic steroid hormone that has "male-type" activity (ie, activates the androgen receptor).

Androgen insensitivity A condition in which a mutation in the androgen receptor causes reduced responsiveness of target tissues to syndrome androgens.

Atypical genitalia Refer to entry on ambiguous genitalia, above.

Chimerism A condition in which an individual has cells with distinct genomes as the result of fusion of 2 (in contrast, refer to entry on mosaicism below). A DSD can occur if chimerism results in the presence of a Y chromosome in some cells but not others.

Chordee Ventral curvature of the phallus.

Clitoromegaly A clitoral length/width that is ≥2 standard deviations larger than the mean for age.

Congenital adrenal A group of congenital conditions that disrupts one of the many steps in synthesis of cortisol from cholesterol. hyperplasia

Cryptorchidism Failure of the to descend fully into the scrotum.

Difference in sex Refer to entry on DSD, below. development

Disorder of sex Defined in a 2006 consensus statement as "congenital conditions in which development of chromosomal, development (DSD) gonadal, or anatomical sex is atypical." The word "difference" is sometimes substituted for "disorder." The adjective "sexual" is sometimes used instead of "sex" but can be confusing because it can refer to either biological sex or the act of sex. The term "differentiation" is sometimes used instead of "development." Though commonly used by clinical providers, the term "DSD" is not universally accepted by patients and support groups (refer to UpToDate content on evaluation of atypical genitalia).

Gonadal dysgenesis Failure of a gonad to develop properly.

Gonadal dysgenesis, Gonadal dysgenesis resulting in a complete loss of gonadal function. In XY individuals, it is sometimes called complete Swyer syndrome.

Gonadal dysgenesis, A situation in which the 2 gonads show different degrees of dysgenesis, eg, a normal or mildly dysgenetic mixed gonad on the right and a streak gonad on the left. The term is sometimes used synonymously with a 45,X/46,XY karyotype, but the term properly refers to the gonads rather than to the sex chromosomes, and the 45,X/46,XY karyotype is associated with a broader range of gonadal phenotypes.

Gonadal dysgenesis, Gonadal dysgenesis resulting in a partial but not complete loss of gonadal function. partial

Hermaphrodite A now disfavored term used for individuals who have both male and female gonads.

Hypospadias Position of the urethral meatus at a location other than the tip of the glans penis.

Intersex Having an atypical genital appearance. Some reserve "intersex" as a term for social identity, but others do not make this distinction. The term is disfavored by some.

Labioscrotal folds Primitive structures that give rise to the labia majora, the scrotum, or an intermediate structure.

Micropenis A penis with a stretched length that is ≥2 standard deviations shorter than the mean for age.

Ovotestis A gonad that has both testicular and ovarian components.

Phallus A general term for the structure that derives from the primitive phallus. This may be a penis, clitoris, or an intermediate structure.

Phenotype In the context of DSDs, often used to refer to the appearance of the external genitalia.

Pseudohermaphrodite A now disfavored term used for individuals who have atypical genital appearance but do not have both male and female gonads.

Mosaicism A condition in which the genetic complement of some cells in the body differs from that of other cells that all derive from a single (in contrast, refer to chimerism above). A DSD occurs and ambiguous genitalia may result if the Y chromosome is affected.

Sex chromosome DSD This subtype of DSD is defined by the presence of a sex chromosome complement other than XX or XY. It includes conditions with mosaicism or chimerism affecting the Y chromosome, which may or may not result in atypical genitalia. The term is sometimes used to include that do not result in atypical genitalia, such 45,X (Turner syndrome).

Streak gonad A severely dysgenetic gonad that cannot be identified as a testis or ovary on gross appearance; refer to entry on gonadal dysgenesis, complete.

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Swyer syndrome Complete gonadal dysgenesis in an XY individual.

Testicular regression A condition in which the testes are absent but the external genitalia have a typical male appearance, indicating syndrome that testicular function was intact during genital differentiation in early gestation. This is also known as congenital , or (historically) vanishing testis syndrome.

Virilization Emergence of characteristic male features. When referring to the external genitalia (also called "androgenization" or "masculinization"), these features include growth of the phallus, fusion of the labioscrotal folds, and positioning of the urethral meatus at the tip of the phallus. When referring to changes at puberty or in adulthood, these features include terminal hair growth on the face and chest, deepening of the voice, and increased muscularity.

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Selected disorders of sex development presenting with atypical genitalia at birth

Prevalence (as Projected a cause of Risk of adrenal Risk of gonadal Diagnosis gender identity References atypical crisis tumor and fertility genitalia)

46,XX DSD

CAH* Common (1:15,000) Yes (in most Female; fertile Yes∆ [1-6] common forms)¶ (for 46,XX types of CAH)

Mixed gonadal Rare No Usually male; High◊ [7,8] dysgenesis infertile (45,X/46,XY mosaicism with atypical genitalia)

46,XY DSD

5-alpha-reductase Very rare No Usually male; fertile Low◊ [9-11] type 2 deficiency

17-beta- Extremely rare No Usually male Intermediate◊ [9,11,12] hydroxysteroid dehydrogenase type 3 deficiency

Disorders of Very rare No Unknown; infertile Nonscrotal gonads: [13-15] incomplete or High ◊ unknown androgen Scrotal gonads: action: Intermediate◊ Partial androgen insensitivity Incomplete gonadal dysgenesis

46,XY with severe Rare No Male Low◊ [16-18] genital anomaly ("non-hormonal" DSD): Micropenis Penile agenesis (ablatio penis) Cloacal exstrophy

Ovotesticular DSD§ Extremely rare No Unknown Unknown [3]

DSD: disorder of sex development; CAH: congenital adrenal hyperplasia; OART: ovarian adrenal rest tumor; TART: testicular adrenal rest tumor. * Types of CAH that may present with atypical genitalia in 46,XX infants are 21-hydroxylase deficiency (by far most common), 11-beta- hydroxylase deficiency, P450 oxidoreductase deficiency, and 3-beta-hydroxysteroid dehydrogenase type 2 deficiency. ¶ The risk of adrenal crisis refers primarily to CAH due to 21-hydroxylase deficiency or 11-beta-hydroxylase deficiency. Adrenal crisis is not associated with 17-alpha-hydroxylase deficiency, which is a rare cause of CAH affecting 46,XY infants. ∆ Females with poorly controlled CAH secondary to 21-hydroxylase deficiency appear to be at increased risk for OARTs.[19] There are rare forms of CAH (eg, 3-beta-hydroxysteroid dehydrogenase deficiency) that present with atypical genitalia in 46,XY infants. These infants may have a risk of developing TARTs.[20,21] These forms of CAH are discussed in UpToDate topics on uncommon CAHs. ◊ The risk of gonadal tumor is characterized as "high" for risks around 30% and higher, "intermediate" for 5 to 30%, and "low" for less than 5%. The "low" risk category is similar to the risk for individuals with cryptorchidism. [3,4] § Ovotesticular DSD refers to histologically confirmed presence of ovarian follicles and testicular tubules in the same individual. This disorder tends to raise difficult challenges regarding gender of rearing and reconstruction surgery. Most patients have a 46,XX karyotype, and fertility has been reported in those who have a functional ovary. The testicular tissue is usually dysgenetic, and fertility has not been reported in those raised as males. The risk of testicular tumor is probably low if the karyotype is 46,XX.[4,22]

References: 1. Berenbaum SA, Bailey JM. Effects on gender identity of prenatal androgens and genital appearance: evidence from girls with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2003; 88:1102. 2. Dessens AB, Slijper FM, Drop SL. Gender dysphoria and gender change in chromosomal females with congenital adrenal hyperplasia. Arch Sex Behav 2005; 34:389.

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3. Lee PA, Houk CP, Ahmed SF, et al. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics 2006; 118:e488. 4. Lee PA, Nordenström A, Houk CP, et al. Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care. Horm Res Paediatr 2016; 85:158. 5. Meyer-Bahlburg HF, Dolezal C, Baker SW, New MI. Sexual orientation in women with classical or non-classical congenital adrenal hyperplasia as a function of degree of prenatal androgen excess. Arch Sex Behav 2008; 37:85. 6. Meyer-Bahlburg HF, Dolezal C, Baker SW, et al. Gender development in women with congenital adrenal hyperplasia as a function of disorder severity. Arch Sex Behav 2006; 35:667. 7. Martinerie L, Morel Y, Gay CL, et al. Impaired puberty, fertility, and final stature in 45,X/46,XY mixed gonadal dysgenetic patients raised as boys. Eur J Endocrinol 2012; 166:687. 8. Szarras-Czapnik M, Lew-Starowicz Z, Zucker KJ. A psychosexual follow-up study of patients with mixed or partial gonadal dysgenesis. J Pediatr Adolesc Gynecol 2007; 20:333. 9. Kolesinska Z, Ahmed SF, Niedziela M, et al. Changes over time in sex assignment for disorders of sex development. Pediatrics 2014; 134:e710. 10. Imperato-McGinley, Peterson RE, Gautier T, Sturla E. Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5alpha-reductase deficiency. N Engl J Med, 1979. 300:1233. 11. Cohen-Kettenis PT. Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency. Arch Sex Behav 2005; 34:399. 12. Imperato-McGinley, Peterson RE, Stoller R, Goodwin WE. Male secondary to 17 beta-hydroxysteroid dehydrogenase deficiency: gender role change with puberty. J Clin Endocrinol Metab 1979; 49:391. 13. Reiner WG. Gender identity and sex-of-rearing in children with disorders of sexual differentiation. J Pediatr Endocrinol Metab 2005; 18:549. 14. Jurgensen M, Hiort O, Holterhus PM, Thyen U. Gender role behavior in children with XY karyotype and disorders of sex development. Horm Behav 2007; 51:443. 15. Migeon CJ, Wisiewski AB, Gearhart JP, et al. Ambiguous genitalia with perineoscrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcome. Pediatrics 2002; 110:e31. 16. Meyer-Bahlburg. Gender identity outcome in female-raised 46,XY persons with penile agenesis, cloacal exstrophy of the bladder, or penile ablation. Arch Sex Behav 2005; 34:423. 17. Reiner WG, Gearhart JP. Discordant sexual identity in some genetic males with cloacal exstrophy assigned to female sex at birth. N Engl J Med 2004; 350:333. 18. Reiner WG, Kropp BP. A 7-year experience of genetic males with severe phallic inadequacy assigned female. J Urol 2004; 172:2395. 19. Claahsen-van der Grinten HL, Hulsbergen-van de Kaa CA, Otten BJ.Ovarian adrenal rest tissue in congenital adrenal hyperplasia--a patient report. J Pediatr Endocrinol Metab. 2006; 19:177. 20. Vukina J, Chism DD, Sharpless JL, et al. Metachronous Bilateral Testicular Leydig-Like Tumors Leading to the Diagnosis of Congenital Adrenal Hyperplasia (Adrenogenital Syndrome). Case Rep Pathol 2015; 459318. 21. Claahsen-van der Grinten HL, Sweep FC, Blickman JG, et al. Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur J Endocrinol. 2007; 157:339. 22. Nistal M, Paniagua R, Gonzalez-Peramato P, Reyes-Mugica M: Ovotesticular DSD (true hermaphroditism). Pediatr Dev Pathol 2015;18:345.

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Genes involved in XX disorders of sex development (DSDs) that are associated with atypical genital appearance

Associated Disorder Müllerian Gene Protein Inheritance Gonad features/variant (MIM phenotype) structures phenotypes

Adrenal overproduction of androgens (genes involved in adrenal hormone synthesis)

21-alpha-hydroxylase CYP21A2 Enzyme (converts AR Ovary + CAH, phenotypic deficiency 17OHP to 11- spectrum from severe (MIM #201910) deoxycortisol) salt-losing forms associated with adrenal failure to simple virilizing forms with compensated adrenal function. 17OHP markedly elevated.

11-beta-hydroxylase CYP11B1 Enzyme (converts AR Ovary + CAH, hypertension deficiency 11- caused by 11- (MIM #202010) deoxycorticosterone deoxycortisol and 11- to corticosterone deoxycorticosterone. and 11-deoxycortisol to cortisol)

3-beta- HSD3B2 Enzyme (converts AR Ovary + CAH, primary adrenal hydroxysteroid dehydrogenase pregnenolone to insufficiency, partial type 2 deficiency progesterone, 17- androgenization (MIM #201810) hydroxypregnenolone caused by DHEAS. to 17OHP, and DHEA to androstenedione)

P450 oxidoreductase POR Cofactor for 17- AR Ovary + CAH with combined deficiency alpha-hydroxylase, features of 21- (MIM #613571) 21-hydroxylase, and hydroxylase (MIM #201750) aromatase deficiency, 17-alpha- hydroxylase/17,20- lyase deficiency, and aromatase deficiency. May be associated with craniosynostosis and limb abnormalities (Antley-Bixler syndrome). May cause mild maternal virilization during pregnancy.

Glucocorticoid resistance NR3C1 Nuclear receptor TF AR Ovary + Elevated (atypical) (glucocorticoid adrenocorticotropin, (MIM #615962) receptor) 17OHP, and cortisol; failure of dexamethasone suppression.

Gonadal overproduction of androgens (XX testicular or ovotesticular DSD) due to mutations involved in gonadal (ovarian) development

46,XX sex reversal, SRY - SRY (sex- TF Translocation Testis or –Presence of SRY in an positive determining ovotestis XX individual (eg, due (MIM #400045) region on the to translocation to Y the X chromosome) chromosome) activates testicular pathways in the developing gonad.

NR5A1 mutation NR5A1 (SF1)TF AD Testis or +/– NR5A1 (SF1) (MIM #617480) ovotestis mediates gonadal development and testicular differentiation, and is responsible for 10 to

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15% of XX testicular or ovotesticular DSD.

Aromatase deficiency CYP19A1 Enzyme AR Ovary + Maternal virilization (MIM #613546) during pregnancy due to deficiency in placental aromatase. Absent breast development in offspring at puberty, except in partial cases.

SOX9 overexpression SOX9M TF dup17q24 Not – SOX9 encodes a (MIM #278850) determined that is both necessary and sufficient for testicular development.

SOX3 overexpression SOX3 TF Duplication Testis Inappropriate (MIM #300833) expression of SOX3 activates testicular pathways in the developing gonad.

WNT4 deficiency WNT4 Signaling molecule AR SERKAL syndrome (MIM #611812) (sex reversal with dysgenesis of kidneys, adrenals, and lungs).

RSPO1 deficiency RSPO1 Regulator of WNT Palmoplantar (MIM #610644) signaling keratosis.

Chromosomal rearrangements likely to include key genes are included.

MIM: Mendelian Inheritance in Man; 17OHP: 17-hydroxyprogesterone; AR: autosomal recessive; CAH: congenital adrenal hyperplasia; DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulfate; TF: transcription factor; SF1: ; AD: autosomal dominant (or de novo mutation).

Adapted from: 1. Barbaro M, Wedell A, Nordenström A. Disorders of sex development. Semin Fetal Neonatal Med 2011; 16:119. 2. Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics 2006; 118:e488.

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Genital asymmetry

Genital asymmetry strongly suggests mixed gonadal dysgenesis. Mixed gonadal dysgenesis occurs due to Y chromosome mosaicism (most commonly a 45,X/46,XY karyotype), typically with a descended, partially dysgenetic testis on 1 side (usually the right), a streak gonad with retained müllerian remnants on the other side, and genital ambiguity. The genital examination in this individual with 45,X/46,XY mosaicism reveals: Phallus much larger than a typical clitoris but short for a penis. Scrotal hypospadias (with single elongated orifice for urethra and vagina), and urogenital sinus (due to incomplete fusion of the genital plate and failure of separation of the urethra from the vagina). Partially fused labioscrotal folds, with minimal rugation (wrinkling) and pigmentation. Gonad in the labioscrotal fold on the right but not on the left.

Courtesy of Laurence Baskin, MD.

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Asymmetric internal genital structures

Imaging in a patient with mixed gonadal dysgenesis due to a mosaic 45,X/46,XY karyotype. (A) Sagittal image from a genitogram study. A catheter (arrowhead) introduced through the urogenital sinus delivered contrast that filled the hemi-uterus (asterisk) and single (arrow). (B) Sagittal view from an ultrasound showing the hemi-uterus (arrow) with its characteristic central endometrial stripe.

Courtesy of Laurence Baskin, MD.

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Genes involved in XY disorders of sex development (DSDs) that are associated with atypical genital appearance

Disorder Associated Müllerian (MIM Gene Protein Inheritance Gonad features/variant structures phenotype) phenotypes

Global defects in testicular function (genes involved in gonadal development)

NR5A1 mutation NR5A1 (SF1) Nuclear receptor TF AD/AR Dysgenetic +/– Homozygous mutations (MIM #612965) testis associated with primary adrenal failure; heterozygous mutations associated with isolated gonadal dysgenesis.

SRY -related SRY TF Y Dysgenetic +/– Loss of SRY function can result in gonadal testis or complete or partial testicular dysgenesis ovotestis dysgenesis, XY ovarian DSD, or (MIM #400044) ovotesticular DSD.

SOX9 deficiency SOX9 TF AD Dysgenetic +/– Camptomelic dysplasia (a (MIM #114290) testis or skeletal dysplasia syndrome). ovotestis 17q24 rearrangements have milder phenotype than point mutations.

WT1 mutation WT1 TF AD Dysgenetic +/– Wilms tumor, renal (MIM #194072, testis abnormalities, gonadal tumors WAGR) (WAGR, Denys-Drash, and Frasier (MIM #194080, syndromes). Denys-Drash) (MIM #136680, Frasier)

MAP3K1-related MAP3K1 Signal transduction AD Dysgenetic gonadal testis dysgenesis (MIM #613762)

DHH-related DHH Signaling molecule AR Dysgenetic + The severe phenotype of one gonadal testis patient included minifascicular dysgenesis neuropathy; other patients have (MIM #233420) isolated gonadal dysgenesis.

NR0B1 NR0B1 Nuclear receptor TF dupXp21 Dysgenetic +/– duplication (DAX1) testis or (MIM #300018) ovary

Lissencephaly, ARX TF X Dysgenetic – X-linked lissencephaly, epilepsy, X-linked 2 testis temperature instability. (MIM #300215)

ATRX-related ATRX Helicase (chromatin XDysgenetic– Alpha-thalassemia, mental gonadal remodeling) testis retardation. dysgenesis (MIM #301040)

DMRT1-related DMRT1 TF Monosomic Dysgenetic +/– Mental retardation. gonadal deletion, testis dysgenesis chromosome (MIM #154230) 9p24

SOX8 SOX8 TF AD Dysgenetic testis

WNT4 WNT4 Signaling molecule dup1p35 Dysgenetic + Mental retardation. overexpression testis (MIM *603490)

ZFPM2 deficiency ZFPM2 (FOG2) Modulator of GATA4 AD Gonadal +/– Dysgenetic gonads; rudimentary (MIM #616067) activity dysgenesis müllerian structures; learning and language difficulties (some patients).

Disrupted müllerian inhibition

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Persistent AMH Signaling molecule AR Testis + External genitalia are müllerian duct phenotypically male (not syndrome type 1 atypical), but there may be (MIM #261550) cryptorchidism; persistent müllerian duct structures Persistent AMHR2 (AMH Serine-threonine AR Testis + (uterus, fallopian tubes, and müllerian duct receptor) kinase upper vagina). syndrome type 2 transmembrane (MIM #261550) receptor

Disorders of androgen synthesis

Leydig cell LHCGR G-protein receptor AR Testis – Range of phenotypes, depending hypoplasia (LH/hCG on severity of LH/hCG receptor (MIM #238320) receptor) inactivation.

Smith-Lemli- DHCR7 Enzyme (converts AR Testis – Coarse facies, second-third toe Opitz syndrome 7-dehydrocholesterol syndactyly, , (MIM #270400) to cholesterol) developmental delay, cardiac and visceral abnormalities.

17-beta HSD17B3 Enzyme (converts AR Testis – Partial androgenization at hydroxysteroid androstenedione to puberty, elevated dehydrogenase testosterone) androstenedione:testosterone type 3 deficiency ratio. (MIM #264300)

5-alpha reductase SRD5A2 Enzyme (converts AR Testis – Partial androgenization at type 2 deficiency testosterone to puberty, elevated (MIM #264600) dihydrotestosterone) testosterone:dihydrotestosterone ratio.

Forms of CAH associated with underproduction of testosterone

3-beta HSD3B2 Enzyme (several AR Testis – CAH, defective production of hydroxysteroid steps in testosterone, but partial dehydrogenase steroidogenesis) androgenization caused by DHEA. type 2 Both XX and XY infants may deficiency have atypical genitalia. (MIM #201810)

17-alpha CYP17A1 Enzyme (17-alpha- AR Testis – CAH, hypertension caused by hydroxylase hydroxylase and corticosterone and 11- deficiency 17,20-lyase) deoxycorticosterone (except in (MIM isolated 17,20-lyase deficiency). #202110)

P450 POR CYP enzyme AR Testis – CAH, with mixed features of 21- oxidoreductase electron donor hydroxylase deficiency, 17-alpha- deficiency (cofactor for 21- hydroxylase/17,20-lyase (MIM hydroxylase, 17- deficiency, and aromatase #201750) alpha-hydroxylase, deficiency; sometimes (MIM and aromatase) associated with Antley-Bixler #613571) craniosynostosis. Both XX and XY infants may have atypical genitalia. May cause mild maternal virilization during pregnancy.

Lipoid CAH STAR Mitochondrial AR Testis – CAH (primary adrenal failure), (MIM (steroidogenic membrane protein high risk for salt-losing crisis; #201710) acute (transports phenotypic female external regulatory cholesterol to genitalia; pubertal failure. protein) mitochondrion)

P450scc CYP11A1 Enzyme (converts AR Testis – CAH, pubertal failure. deficiency cholesterol to (MIM pregnenolone) #613743)

Disorders of androgen insensitivity

Androgen AR (androgen Nuclear receptor TF X Testis – PAIS presents with a range of insensitivity receptor) phenotypes from predominantly syndrome female (with mild virilization) to (MIM #312300) typical male genitalia with

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infertility. Patients with CAIS have typical female external genital appearance.

Chromosomal rearrangements likely to include key genes are included. Other genes that have been implicated but not proven to be associated with DSDs include WWOX, GATA4, AKR1C2, and AKR1C4.

MIM: Mendelian Inheritance in Man; SF1: steroidogenic factor 1; TF: transcription factor; AD: autosomal dominant (often de novo mutation); AR: autosomal recessive; WAGR: Wilms tumor, aniridia, genitourinary anomalies, and mental retardation syndrome; AMH: anti-müllerian hormone; LH: luteinizing hormone; cGR: choriogonadotropin receptor; hCG: human chorionic gonadotropin; CAH: congenital adrenal hyperplasia; scc: side-chain cleavage; DHEA: dehydroepiandrosterone; PAIS: partial androgen insensitivity syndrome; CAIS: complete androgen insensitivity syndrome.

Adapted from: 1. Barbaro M, Wedell A, Nordenström A. Disorders of sex development. Semin Fetal Neonatal Med 2011; 16:119. 2. Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics 2006; 118:e488.

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Characteristics of different forms of congenital adrenal hyperplasia that may present with atypical genitalia

Atypical genitalia Incidence Elevated Defective Adrenal Disorder (general steroid XY gene XX (virilization) crisis (undervirilization) population) metabolites

21-hydroxylase CYP21A2 + – + 1:11,000 to 17-OHP deficiency 1:23,000

11-beta- CYP11B1 + – Rare 1:100,000 DOC; 11- hydroxylase deoxycortisol deficiency May also have mild elevation of 17-OHP

3-beta- HSD3B2 + (mild or ++RareDHEA; 17- hydroxysteroid absent) hydroxypregnenolone dehydrogenase May also have mild deficiency elevation of 17-OHP

17-alpha- CYP17A1* Typical female + No Rare DOC; corticosterone hydroxylase genitalia, but no deficiency puberty

P450 POR¶ + + + Very rare 17-OHP, oxidoreductase progesterone, and deficiency pregnenolone

Lipoid ST AR Typical female + (typical female + Very rare None congenital genitalia, but no external genitalia) adrenal puberty hyperplasia

P450scc CYP11A1 Typical female + (typical female + Very rare None deficiency genitalia, but no external genitalia, puberty sometimes with )

CYP21A2: steroid 21-hydroxylase; 17-OHP: 17-hydroxyprogesterone; CYP11B1: steroid 11-beta hydroxylase; DOC: deoxycorticosterone; HSD3B2: 3-beta-hydroxysteroid dehydrogenase 2; DHEA: dehydroepiandrosterone; CYP17A1: steroid 17-hydroxylase, 17,20 lyase; POR: cytochrome P450 oxidoreductase; STAR: steroid acute regulatory protein; P450scc: cytochrome P450 side-chain cleavage enzyme; CYP11A1: cytochrome P450 side- chain cleavage gene. * CYP17A1 encodes an enzyme that catalyzes both the 17-hydroxylase reaction, which forms 17-hydroxysteroids, and the 17,20-lyase reaction, which cleaves 21-carbon 17-hydroxysteroids to 19-carbon 17-keto androgen precursors. ¶ POR encodes a co-factor for 17-alpha-hydroxylase, 21-hydroxylase, and aromatase.

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Rapid overview: Adrenal crisis in children and adolescents

Signs and symptoms that may indicate adrenal crisis:

Vomiting and diarrhea, sometimes with severe abdominal pain or unexplained fever, weight loss, and anorexia.

Serum electrolyte abnormalities:

Hyponatremia with or without hyperkalemia.

Metabolic acidosis.

Hypoglycemia (especially in young children).

Hypotension or shock, particularly if disproportionate to apparent underlying illness.

Consider the diagnosis in:

Neonates with atypical genitalia and/or electrolyte abnormalities, lethargy, hypoglycemia, hypotension or shock, or failure to thrive. These may be presenting features of CAH due to 21-hydroxylase deficiency* or (very rarely) other causes of adrenal insufficiency.

In the United States, 21-hydroxylase deficiency is part of the newborn screen in all states, so most affected infants will be diagnosed prior to presentation with adrenal crisis. Adrenal crisis usually presents between 10 and 20 days of life. Affected females may have atypical genitalia; males usually have no obvious genital abnormalities.

The presentation of adrenal crisis in an infant may mimic that of pyloric stenosis. However, infants with pyloric stenosis typically have hypokalemic alkalosis rather than the hyperkalemic acidosis that is typical of adrenal crisis.

Any patient with known disorders of adrenal insufficiency (eg, CAH), especially if exposed to stress (illness).

Patients on chronic treatment with corticosteroids, especially if exposed to stress or during a tapering of the corticosteroid dose.

Patients with other autoimmune endocrine deficiencies, such as type 1 diabetes mellitus, hypothyroidism, or gonadal failure.

Critically ill patients with septic shock, who are unresponsive to fluid resuscitation and inotropic medications (in this case, adrenal crisis can be caused by bilateral adrenal hemorrhage).

Other patients presenting with the above signs, especially those with hyperpigmentation or vitiligo.

Evaluation:

If adrenal crisis is suspected, then patients should be treated empirically with stress doses of glucocorticoids, as outlined below.

Baseline blood samples should be drawn for subsequent testing for electrolytes, glucose, cortisol and other adrenal steroids (17- hydroxyprogesterone if CAH is suspected),* ACTH, and renin prior to the administration of corticosteroids. Treatment should not be delayed pending results.

Treatment:

Shock – Give a bolus of normal saline (0.9%), 20 mL/kg IV over 1 hour. If shock is persistent, repeat up to a total of 60 mL/kg within 1 hour.

Hypoglycemia – Give an initial bolus of 0.5 to 1 g/kg of dextrose IV (maximum single dose 25 g). The glucose bolus is infused slowly, at 2 to 3 mL per minute.

For all age groups, this can be given as 25% dextrose solution (D25W), 2 to 4 mL/kg. (D25W is 250 mg dextrose/mL.)

An alternative for infants and children up to 12 years of age is to use 10% dextrose solution (D10W), 5 to 10 mL/kg. (D10W is 100 mg dextrose/mL.)

Stress glucocorticoids – Administer hydrocortisone (Solu-Cortef) as a bolus, using a dose of 50 to 100 mg/m2¶ IV.∆ If body surface area is not available, age-based dosing may be used as follows:

Infants and toddlers 0 to 3 years old: 25 mg IV.

Children 3 to 12 years: 50 mg IV.

Children and adolescents 12 years and older: 100 mg IV.

Continue glucocorticoids at the same dose given as a constant rate or as 4 divided doses over the following 24 hours.

Electrolytes – If hyperkalemia is present, perform EKG to evaluate:

EKG changes consistent with hyperkalemia – Initially a tall, peaked T wave with shortened QT interval, followed by progressive lengthening of the PR interval and QRS duration.

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Hyperkalemia typically improves promptly with fluids and hydrocortisone therapy. Rarely, severe and symptomatic hyperkalemia requires administration of glucose and insulin. (Refer to UpToDate topic on the management of hyperkalemia in children.)

Monitor and treat other electrolyte abnormalities and fluid balance.

CAH: congenital adrenal hyperplasia; ACTH: corticotropin; IV: intravenous; EKG: electrocardiogram; BSA: body surface area; IM: intramuscularly. * Refer to UpToDate content on classic CAH due to 21-hydroxylase deficiency. ¶ Dosing based on BSA is preferred if the patient's BSA is known or if the BSA can be promptly calculated based on measured height and weight. A BSA calculator is available in the UpToDate program. ∆ Hydrocortisone also may be given IM if IV access is not readily available.

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Virilization (cross-sectional view)

Normal and abnormal differentiation of the urogenital sinus and external genitalia. Diagrams of normal female and male anatomy flank a series of schematic representations of different degrees of virilization of individuals with an XX karyotype, graded using the scale developed by Prader for XX patients with congenital adrenal hyperplasia (CAH). Because anti-müllerian hormone (AMH) is not produced in high amounts in XX infants with CAH, the uterus persists even when the external genitalia have a completely masculine appearance (Prader V).

Reproduced with permission from: White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000; 21:245. http://edrv.endojournals.org/. Copyright © 2000 The Endocrine Society.

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Virilization (external view)

Normal and abnormal differentiation of the external genitalia. Diagrams of normal female and male anatomy flank a series of schematic representations of different degrees of virilization of individuals with an XX karyotype, graded using the scale developed by Prader for XX patients with congenital adrenal hyperplasia (CAH).

Reproduced with permission from: White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000; 21:245. http://edrv.endojournals.org/. Copyright © 2000 The Endocrine Society.

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Different degrees of virilization in 46,XX infants with congenital adrenal hyperplasia (CAH)

Examples of atypical external genitalia in 46,XX infants with congenital adrenal hyperplasia (CAH), ranging from mild virilization (Prader II) through severe virilization (Prader IV and V). Other 46,XX infants with CAH can have normal female genitalia (Prader I, not shown). None of these patients have palpable gonads, which is an important clue that CAH should be considered as a diagnosis. (A) Mild virilization, Prader II. (B,C) Moderate virilization, Prader III. (D,E) Severe virilization, Prader IV. (F) Severe virilization, Prader V, with a complete penile urethra. This is very rare. Prior to the advent of newborn screening for this disorder, affected children may have been identified as male at birth and the diagnosis was made later in childhood.

Courtesy of Laurence Baskin, MD.

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Congenital adrenal hyperplasia with severe virilization

Infant with congenital adrenal hyperplasia (CAH) and severe virilization (Prader V). (A) The phallus is fully developed, with a complete penile urethra. (B) Genitogram demonstrating a long common urogenital sinus and a high insertion of the vagina close to the bladder neck, representing a high confluence (arrow).

Courtesy of Laurence Baskin, MD.

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Cloacal exstrophy in newborn infants

Cloacal exstrophy in a male (A) and female (B) newborn infant. The anus is imperforate, and the hindgut exits from the lower abdominal wall. In both patients, the bladder is split in half (seen best in the female; arrowheads), separated by the hindgut (asterisks). The umbilicus and omphalocele are seen superior to the split bladder and hindgut. The external genitalia are also split; the male has a small hemiphallus (arrows) associated with the scrotum.

Courtesy of Laurence Baskin, MD.

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Contributor Disclosures

Christopher P Houk, MD Nothing to disclose Laurence S Baskin, MD, FAAP Nothing to disclose Lynne L Levitsky, MD Consultant/Advisory Boards: Eli Lilly [Diabetes (Insulin)]. Mitchell E Geffner, MD Grant/Research/Clinical Trial Support: Novo Nordisk [Growth (Somatropin)]. Consultant/Advisory Boards: Daiichi-Sankyo [Type 2 diabetes (Colesevelam)]; Novo Nordisk [Growth (Somatropin)]; Nutritional Growth Solutions [Growth]; Pfizer [Growth (Somatropin)]; Spruce Biosciences [Congenital adrenal hyperplasia]. Other Financial Interest: McGraw-Hill [Pediatric (Textbook royalties)]; Ascendis [Data safety monitoring board; Growth (Somatropin)]; Tolmar [Data safety monitoring board; Precocious puberty (GnRH analog)]; Millendo [Data safety monitoring board; Prader-Willi syndrome]. Alison G Hoppin, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

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