Management of The Infant With Atypical Genitalia (Disorder of Sex Development)

Management of the infant with atypical genitalia (disorder of sex development) - UpToDate 21/12/2018 12'48
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Management of the infant with atypical genitalia (disorder of sex development)
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: Nov 2018. | This topic last updated: Jun 26, 2018.
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 cryptorchidism and hypospadias) occur in approximately one 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, gender
differences in brain structure, prenatal androgen exposure, societal and cultural factors, and family dynamics. In the past,
decisions about sex of rearing were usually based on potential for reproduction and traditional sexual function and were
often accompanied by 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 remain unpredictable. Thus, uncertainties about adult outcome, gender of rearing, and timing of
surgery should contribute to discussions and informed decision-making by the 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 DSD will be discussed here. The evaluation of these infants is
discussed separately. (See "Evaluation of the infant with atypical genitalia (disorder of sex development)".)
TERMINOLOGY — Although the term DSD has been accepted by the medical community, patients and support groups
question its usefulness and appropriateness based on three criticisms: first, that DSD is an overly broad term that applies
to conditions in which no sexual/gender disruption is expected (eg, Turner syndrome, Trisomy X, and others); second,
that this broad term lacks sufficient specificity to be helpful diagnostically; and third, that the use of the word 'disorder' is
seen as pejorative by some. Many of these 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 sexual differentiation (conditions previously captured by the term "intersex"). Many of
these individuals present as newborns with an atypical genital appearance previously termed "ambiguous genitalia." We
will not use DSD to refer to conditions in which genital/gender discordance is not expected, such as Klinefelter syndrome,
undescended testes, or all but the most severe forms of hypospadias. In many patients who present with atypical
genitalia it is now possible to make an accurate diagnosis in a timely fashion, thereby avoiding the use of the term DSD.
TYPES OF DSD WITH ATYPICAL GENITALIA — Management depends on the type of DSD and degree of genital
atypia. The initial management of the patient, including surveillance for adrenal crisis and family coping, occurs
concurrently with the diagnostic process, which is described separately. (See "Evaluation of the infant with atypical
genitalia (disorder of sex development)".)
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For the purposes of management, it is helpful to categorize the DSDs that present with atypical genitalia into five major
groups (table 1), listed here in decreasing order of frequency:
● The most common form of DSD presenting with atypical genitalia and a 46,XX karyotype in the newborn period is
classical 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 gonads. Rarely, 46,XX individuals with CAH present with normal 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 classical CAH
due to 21-hydroxylase deficiency, usually within the first week of life.
● The second most common form of DSD with atypical genitalia is 45,X/46,XY mosaicism. Those with atypical
genitalia typically have hypospadias (often severe), a descended (but infertile) testis on the right side, and a streak
gonad 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. The phenotype of this condition is highly variable, ranging from phenotypically normal males (about 90
percent of patients, often undiagnosed), to males with gonadal dysgenesis, to those with female genitalia and Turner
syndrome-like features. The specific presentation appears to be related to the degree of mosaicism in the gonad
and its consequent hormonal function. (See "Clinical manifestations and diagnosis of Turner syndrome".)
● Other rare forms of DSDs presenting with atypical genitalia are:
• 46,XY DSD, such as 17-beta hydroxysteroid dehydrogenase (17-beta HSD) deficiency, 5-alpha reductase
deficiency, and androgen receptor insensitivity, as well as patients with blocks in androgen synthesis and gene
deletions affecting testicular development (eg, sex-determining region on the Y chromosome [SRY],
steroidogenic factor 1 [SF-1], and Wilms tumor 1 [WT-1]).
• 46,XY DSD with severe genital anomalies (such as some children with micropenis, penile agenesis, and cloacal
exstrophy), which are not associated with presently identified gene or chromosome abnormalities (ie, "non-
hormonal" DSD).
• Ovotesticular DSD (previously known as true hermaphroditism), which refers to the presence of ovarian tissue
with follicles, and testicular tissue with seminiferous tubules, in the same individual.
Management for each of these disorders is discussed 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 most appropriate 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 2). Adrenal crisis also may occur
in some other types of CAH, including 11-beta hydroxylase deficiency. If salt-wasting CAH is not diagnosed and treated,
vomiting, diarrhea, hypotension, and hypovolemic shock can occur, typically between 10 to 20 days of life.
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 excluded.
Blood samples should be urgently obtained for steroid hormone precursors (most importantly, 17-hydroxyprogesterone)
to evaluate for CAH; serum and urine electrolytes and plasma glucose should be monitored.
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 3). (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]. The period of uncertainty
before a specific diagnosis can be established is a particularly challenging time for the parents. In the rarer forms of DSD
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) [16]. The genitalia can be
described to the parents as "not being fully formed" or being "overly developed." It is helpful to summarize the
embryology of genital development, including the presence of indeterminate external genitalia in the early stages of fetal
development, followed by subsequent maturation toward male or female typical genitalia. This discussion should be
tailored to the educational background and emotional 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 they are sure about the sex in which they intend to rear the child. 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 a girl
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].
Many families, even the most sophisticated, 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 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 DSD 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 [17-20]. 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 [21,22]. In some cases, the child's gender role behavior and gender identity may not be
fixed until early adulthood or even later. In addition, it is now well-recognized that gender identity may not be purely
binary.
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 1). 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 socio-cultural background and expectations. The relevance of these factors is supported
by an increasing number of studies examining gender identity in a variety of DSDs [23-26]. 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.
For some DSDs (eg, congenital adrenal hyperplasia [CAH] in a 46,XX individual), gender identity is reasonably
predictable and psychosocial outcome is generally positive [27]. 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 in those with severe virilization 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 encourage parents or caregivers to
assume a supportive role in the sex assignment 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 DSD. 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 — Historically, surgery to restore normal female anatomy in girls with CAH was
performed early in childhood. The goal of surgery is to restore functional female anatomy by separating the vagina from
the urethra and bringing the vagina out to the perineum. 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 [28].
● An advantage of deferring surgery is that it keeps options open for virilized 46,XX females, in case they turn out to
have a male gender identity (which occurs in about 5 percent of 46,XX CAH). Deferring surgery also permits the
patient to make their own informed decision 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 [29] or at
least before puberty [29-31]. Furthermore, difficulties during adolescence were greater for both patients and parents
when late genitoplasty was performed.
There are no controlled studies comparing the effect of early versus late genital surgery on psychosocial or psychosexual
development, or quality of life [32,33]. 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 [34].
It is useful to structure the conversation around the following goals:
● 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 [35,36].
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 predictable gender identity — For several of the most common DSDs associated with atypical genitalia,
projected gender identity is reasonably predictable and positive, and management decisions are straightforward (table 1).
These include:
46,XX CAH — 46,XX individuals with virilizing forms of 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 [36]. About 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) [23-25,34]. The
female gender role is also consistent with the individual's internal anatomy, and fertility may be possible.
For individuals who are not diagnosed and treated for CAH in infancy (eg, those living in low-resource countries),
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 [37]. Indeed, a literature review suggested that gender dysphoria
is uncommon among highly virilized 46,XX patients who are reared as males [38]. 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 [39].
This approach remains controversial in the United States and Europe; important considerations include age of
diagnosis and social setting in which the family lives. (See '46,XX CAH, Prader V' below.)
● Surgical considerations – Patients with 46,XX CAH have a normal vagina, cervix, uterus, and ovaries, with a
common urogenital sinus 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 urethra within its normal position [40-
44].
Advances in understanding the neurological innervation of the vagina and clitoris have influenced surgical
technique, permitting preservation of sexual function and sensation [45,46]. 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. 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. 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.
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 infertility is likely and that adult phallus size can be inadequate if the
phallus is poorly responsive to androgen stimulation [47,48]. 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 [49]. 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 [50]. A biopsy of scrotal testis is recommended post-pubertally, 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 [47]. The streak gonad is typically removed because of tumor
risk and lack of function [51]. 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 may be prudent to defer
feminizing surgery until a female gender identity is confirmed, since suboptimal outcomes have been reported in the
past with early feminizing surgery in these patients. The vagina/müllerian cavity is typically more narrow and rigid
than in patients with CAH. As a result, the outcome of vaginal surgery may be less than ideal in this form of DSD
and typically requires post-surgical 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 (HSD) type 3 (MIM 605573) or 5-alpha
reductase type 2 (MIM 607306) deficiencies, we advise a male sex of rearing for most patients [34,52]. 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 and at least 50 percent of those with 17-beta HSD defects
[34]. 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. 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 [53,54], 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 [26].
● Surgical considerations – Once the diagnosis of either of these types of DSD 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 [49] (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 [52].
If gender identity is fluid or inconsistent with the sex of rearing, a gonadotropin-releasing hormone 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 (PAIS) — Patients with 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 [52]. Although practice varies, the trend is to raise these children as males when
possible. Case series suggest that a significant minority (5 to 15 percent) of children raised in either sex role will
experience gender dysphoria [55,56]. 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
testosterone therapy; and female assignment must be considered for those with no evidence of androgen effects
[34]. 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 (CAIS), which is characterized by a 46,XY
karyotype, typical female genitalia, absent müllerian structures, and strong female gender identity [57]. (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 [58]. 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 (about 15 percent) [59-61].
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.
Ovotesticular DSD — Individuals with ovotesticular DSD (previously known as "true" hermaphrodism) present
particularly complex management decisions. This is an extremely rare form of DSD, in which both male and female
gonadal tissue (testis, ovary, or ovotestis) 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 [62,63], but that gender dysphoria also may occur [34]. 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 [64].
● Surgical considerations – Surgical decisions for patients with ovotesticular DSD remain complex [59-61]. 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
around 2.6 percent [1,65].
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 CAH will present with 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 [66]. 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 [39,67,68]. 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 [36].
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 [34].
● 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 [40-43].
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
hysterectomy 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 urinary tract infection, 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 hormones. 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 about one-third of
patients with a female sex of rearing [69-71]. 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 [53,69,70,72]. 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 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 spinal cord.
Renal anomalies such as a solitary or blocked kidney are common, as well as müllerian abnormalities such as
duplication of the vagina. In males, surgical reconstruction may include phalloplasty, depending on the degree of the
penile atypia, which can range from hypospadias to a split penis. (See "Body stalk anomaly and cloacal exstrophy".)
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 [73]. Patients will typically require further phallic
reconstruction after puberty to create an adult-sized phallus [74].
Consensus statement — An international consensus statement on DSDs was published in 2006 [36] and updated in
2016 [34]. It is important to note that this report represents a consensus of 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. 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 more than 95 percent 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) and anatomically-based
clitoral reduction should be performed in conjunction with repair of the common urogenital sinus.
● Modest clitoral hypertrophy should not be surgically treated until the patient is able to make a mature decision about
this. However, early vaginoplasty and separation of the vagina and urethra is recommended because of the potential
beneficial effects of estrogen on tissue in early infancy and avoidance of urinary tract infections and other urinary
tract complications caused by the urogenital sinus.
● In children with a high proximal junction (confluence) between the vagina and urethra, early vaginoplasty 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 [75].
Psychosexual issues — It is unlikely that psychosexual identity can be "assigned" as readily as the traditional model
suggests. However, to the extent that it is possible, sex of rearing should be congruent with anticipated gender identity
[16]. This strategy is in the best interest of the child, 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 provide continued and various management
issues for their parents. 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 skilled in this area is critical to improve
outcome. 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 [16]. 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 [55].
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 (WT-1) 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 [1,34,76,77].
DSDs with atypical genitalia and an increased risk for gonadal tumors are (table 1):
● Mixed gonadal dysgenesis (45,X/46,XY mosaic) – This disorder is associated with substantially increased risk of
gonadal malignancy (>30 percent in some series) [1]. The 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 [78-80]. Many experts
advocate biopsy of the scrotal testis because of the tumor risk, especially after puberty [36]. (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 [79,80]. 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 [34].
When a female assignment is chosen, gonadectomy can be performed at the time of feminizing genitoplasty. After
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puberty the risk of tumors is high for abdominal gonads (about 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 [16]. 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 manifestations of disorders of androgen action", section on 'Complete androgen insensitivity (CAIS)'.)
● 17-beta-hydroxysteroid dehydrogenase (HSD) type 3 deficiency – The risk for gonadal malignancy is intermediate
(as high as 30 percent in one series) [76]. 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) [81]. 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 [82-84]. 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 (MRI) 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 exam.
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. Height and weight should be monitored regularly and bone
mineral density should be measured at puberty and then every two years depending upon the normality of the findings.
(See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and
"Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults".)
SUPPORT GROUPS AND INTERNET SITES — Individuals with DSDs and their families often benefit from general or
DSD-specific support groups, and participation should be encouraged [34]. 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 (www.caresfoundation.org)
● Accord Alliance (formerly known as the Intersex Society of North America) (www.accordalliance.org)
● DSD guidelines: A handbook for parents and clinical guidelines for providers, published by the Accord Alliance
(www.dsdguidelines.org)
● The Magic Foundation (www.magicfoundation.org)
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 2). 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.)
● 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 are positive, and decisions
about sex of rearing and genital surgery are straightforward (table 1). 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 CAH' 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 individuals with 17-beta-hydroxysteroid dehydrogenase 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 1). 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 1). (See 'Gonads' above.)
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83. 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.
84. 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.
Topic 5807 Version 18.0
GRAPHICS
Selected disorders of sex development (DSD) presenting with atypical genitalia at birth
Prevalence Projected
Risk of
(as a cause Risk of gender
Diagnosis gonadal References
of atypical adrenal crisis identity and
tumor
genitalia) fertility
46,XX DSD
Congenital Common Yes (in most Female; fertile Yes Δ [1-6]

adrenal (1:15,000) common forms) ¶ (for 46,XX types
hyperplasia of CAH)
(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; Low ◊ [9-11]

type 2 deficiency fertile
17-beta- Extremely rare No Usually male Intermediate ◊ [9,11,12]

hydroxysteroid
dehydrogenase
type 3 deficiency
Disorders of Very rare No Unknown; infertile Nonscrotal [13-15]

incomplete or gonads: High ◊
unknown Scrotal gonads:
androgen action: Intermediate ◊
Partial
androgen
insensitivity
Incomplete
gonadal
dysgenesis
46,XY with Rare No Male Low ◊ [16-18]

severe genital
anomaly ("non-
hormonal" DSD):
Micropenis
Penile
agenesis
(ablatio
penis)
Cloacal
exstrophy
Ovotesticular Extremely rare No Unknown Unknown [3]

DSD §
§
* Types of congenital adrenal hyperplasia (CAH) that may present with atypical genitalia in 46,XX
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.
Δ Females with poorly controlled CAH secondary to 21-hydroxylase deficiency appear to be at increased for ovarian adrenal rest
tumors (OARTs). [19] There are rare forms of CAH (eg, 3-beta hydroxysteroid dehydrogenase deficiency) that present with atypical
[20,21]
XY infants. These infants may have a risk of developing testicular adrenal rest tumors (TARTs). [20,21] These forms of
genitalia in 46,XY
CAH are discussed in UpToDate topics on uncommon congenital adrenal hyperplasias.
◊ The risk of gonadal tumor is characterized as "high" for risks around 30% and higher, "intermediate" for 5 to 30 percent, "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.
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 pseudohermaphroditism 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.
Graphic 57610 Version 8.0
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 one 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. (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.
https://www.uptodate.com/contents/management-of-the-infant-wit…ch_result&selectedTitle=6~61&usage_type=default&display_rank=6 Página 20 de 31
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 hemiuterus
(asterisk) and single fallopian tube (arrow).
(B) Sagittal view from an ultrasound showing the hemiuterus (arrow) with its
characteristic central endometrial stripe.
Characteristics of different forms of congenital adrenal hyperplasia that may present with
atypical genitalia
Atypical genitalia Incidence

Defective Adrenal Elevated steroid
Disorder XX XY
(general
gene crisis metabolites
(virilization) (undervirilization) population)
21- CYP21A2 + – + 1:11,000 – 17-

hydroxylase 23,000 hydroxyprogesterone
deficiency (17-OHP).
11-beta- CYP11B1 + – Rare 1:100,000 Deoxycorticosterone

hydroxylase (DOC); 11-
deficiency deoxycortisol. May also
have mild elevation of
17-OHP.
P450 POR* + + + Very rare 17-OHP, progesterone,

oxidoreductase and pregnenolone.
deficiency
3-beta- HSD3B2 + (mild or + + Rare Dehydroepiandrosterone

hydroxysteroid absent) (DHEA), 17-
dehydrogenase hydroxypregnenolone.
deficiency May also have mild
elevation of 17-OHP.
17-alpha- CYP17A1 ¶ Typical female + No Rare Deoxycorticosterone

hydroxylase genitalia, but (DOC); corticosterone.
deficiency no puberty
Lipoid STAR Typical female + (typical female + Very rare None.

hyperplasia genitalia, but external genitalia)
no puberty
CYP21A2: steroid 21-hydroxylase; CYP11B1: steroid 11-beta hydroxylase; POR: cytochrome P450 oxidoreductase; HSD3B2: 3-beta-
hydroxysteroid dehydrogenase 2; CYP17A1: steroid 17 hydroxylase, 17,20 lyase; STAR: steroid acute regulatory protein.
* POR encodes a co-factor for 17-alpha-hydroxylase, 21-hydroxylase, and aromatase.
¶ 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.
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 congenital adrenal hyperplasia (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 one hour. If shock is persistent, repeat up to a total of 60
mL/kg within one 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/m 2 IV. ¶Δ 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 four 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
- Hyperkalemia typically improves promptly with fluids and hydrocortisone therapy. Rarely, severe and symptomatic hyperkalemia
requires administration of glucose and insulin. (Refer to topic on the management of hyperkalemia in children).
- Monitor and treat other electrolyte abnormalities and fluid balance
* Refer to UpToDate content on classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
¶ Dosing based on body surface area (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.
Δ Hydrocortisone also may be given intramuscularly (IM) if intravenous access is not readily available.
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 grade 5).
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.
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.
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 has 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.
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 high insertion of the vagina close to the
bladder neck, representing a high confluence (arrow), and a long
common urogenital sinus.
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.
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 Consultant/Advisory Boards:
Daiichi-Sankyo [Type 2 diabetes (Colesevelam)]; NovoNordisk [Growth (Somatropin)]; Nutritional Growth Solutions
[Growth]; Pfizer [Growth (Somatropin)]. Spruce Biosciences [congenital adrenal hyperplasia]. Other Financial Interest:
McGraw-Hill [Pediatric endocrinology (Textbook royalties)]. 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.
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● Other rare forms of DSDs presenting with atypical genitalia are:

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

● 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

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

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

surgery typically involves vaginal dilation and removal of the gonads.

46,XY with severe genital anomalies

● DSD clinics at Children's Hospitals

● Toronto Hospital for Sick Children: Patient information on sex development

● The Magic Foundation (www.magicfoundation.org)

SUMMARY AND RECOMMENDATIONS

Sex of rearing and surgery

• For individuals with 17-beta-hydroxysteroid dehydrogenase or 5-alpha reductase deficiencies, we generally

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 5807 Version 18.0

Congenital Common Yes (in most Female; fertile Yes Δ [1-6]

Mixed gonadal Rare No Usually male; High ◊ [7,8]

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

17-beta- Extremely rare No Usually male Intermediate ◊ [9,11,12]

Disorders of Very rare No Unknown; infertile Nonscrotal [13-15]

46,XY with Rare No Male Low ◊ [16-18]

Ovotesticular Extremely rare No Unknown Unknown [3]

Graphic 57610 Version 8.0

Genital asymmetry strongly suggests mixed gonadal dysgenesis. Mixed gonadal

Courtesy of Laurence Baskin, MD.

Graphic 60214 Version 6.0

Asymmetric internal genital structures

Imaging in a patient with mixed gonadal dysgenesis due to a mosaic 45,X/46,XY

Courtesy of Laurence Baskin, MD.

Graphic 106091 Version 4.0

Atypical genitalia Incidence

21- CYP21A2 + – + 1:11,000 – 17-

11-beta- CYP11B1 + – Rare 1:100,000 Deoxycorticosterone

P450 POR* + + + Very rare 17-OHP, progesterone,

3-beta- HSD3B2 + (mild or + + Rare Dehydroepiandrosterone

17-alpha- CYP17A1 ¶ Typical female + No Rare Deoxycorticosterone

Lipoid STAR Typical female + (typical female + Very rare None.

Graphic 107536 Version 4.0

Rapid overview: Adrenal crisis in children and adolescents

Signs and symptoms that may indicate adrenal crisis:

• Serum electrolyte abnormalities:

- Hypoglycemia (especially in young children)

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

Consider the diagnosis in:

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

• Electrolytes: if hyperkalemia is present, perform EKG to evaluate:

- Monitor and treat other electrolyte abnormalities and fluid balance

Graphic 61357 Version 24.0

Virilization (cross-sectional view)

Graphic 73502 Version 9.0

Virilization (external view)

Graphic 52525 Version 7.0

Different degrees of virilization in 46,XX infants with

Examples of atypical external genitalia in 46,XX infants with congenital adrenal

(D,E) Severe virilization, Prader IV

Courtesy of Laurence Baskin, MD.

Graphic 106149 Version 3.0