Differences (Disorders) of Sex Development (DSDS) : Practice Essentials

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Differences (Disorders) of Sex

Development (DSDs)
Updated: Nov 20, 2023
Author: Ahmed Abdelhalim, MD, MSc, MRCS; Chief Editor: Marc Cendron, MD
Overview
Practice Essentials
Key points in the management of differences (disorders) of sex development (DSDs) include the following:
Infants born with ambiguous or abnormal genitalia may have indeterminate phenotypic sex
DSDs, formerly termed intersex conditions, are classified on the basis of genetics and the state of the gonads
DSDs may be caused by virilization of a child with 46,XX or undervirilization of a child with 46,XY
Some individuals with DSDs have genetic mosaicism and may have abnormal gonads (streak ovary, ovotestis,
dysgenetic testis)
Karyotype to rule out DSDs should be considered in a male-looking patient with bilateral undescended testes or
unilateral undescended testis and hypospadias, whether the genitalia appear ambiguous or not
Congenital adrenal hyperplasia (CAH) is the most common cause of DSDs
The incidence of CAH is 1 in 15,000
The most common cause of CAH is 21-hydroxylase deficiency resulting in virilization of a child with 46,XX
Prompt diagnosis of the underlying cause of DSD is essential; 75% of those with 21-hydroxylase deficiency have salt-
wasting nephropathy
Gender identity is not necessarily the same as phenotypic or chromosomal sex
A team or multidisciplinary approach to treatment is essential; thus, gender assignment of a child with a DSD is best
made after parents have been counseled by a gender medicine team
Background
Differences (disorders) of sex development (DSDs), formerly termed intersex conditions, are seen in infants who are born
with ambiguous or abnormal genitalia and may have indeterminate phenotypic sex. In most cases today, clinicians can
promptly make an accurate diagnosis and counsel parents on therapeutic options. However, the paradigm of early gender
assignment has been challenged by the results of clinical and basic science research, which show that gender identity
development likely begins in utero and may not be the same as chromosomal or phenotypic sex.
Whereas surgical genital reconstruction has been widely applied to infants with DSDs in the past, the growing understanding
of the psychological and social implications of gender assignment has shifted the paradigm away from early reconstruction
in some cases. This article focuses on newborn evaluation and the differential diagnoses in children with DSDs, including
children with ambiguous genitalia.[1, 2]
Classification
In 2006, the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Paediatric Endocrinology
(ESPE) published proposed changes to the previously used nomenclature and definitions of disorders in which the
development of chromosomal, gonadal, or phenotypic sex is atypical.[3, 4] The rationale behind these proposals was to
change the terminology to reflect advances in the understanding of the pathophysiology of these disorders while being
sensitive to the needs and concerns of patients affected by them.[5, 6]
The previous terminology and the revised LWPES-ESPE nomenclature are compared in Table 1 below. The LWPES-ESPE
terminology mainly reflects the chromosomal sex or the gonadal tissue associated with the disorder.
Table 1. Previous Terminology and Revised Nomenclature of Disorders of Sex Development (Open Table in a new window)
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Previous Term Revised Term
Female pseudohermaphrodite 46,XX DSD
Male pseudohermaphrodite 46,XY DSD
True hermaphrodite Ovotesticular DSD
XX male 46,XX testicular DSD
XY sex reversal 46,XY complete gonadal dysgenesis
As examples, classifications of sex chromosome DSD include the following:
45,X ( Turner syndrome and variants)

47,XXY ( Klinefelter syndrome and variants)
45,X/46,XY (mixed gonadal dysgenesis, ovotesticular DSD)
46,XX/46,XY (chimeric, ovotesticular DSD)
Classifications of 46,XY DSD include the following:
Disorders of testicular development (complete and partial gonadal dysgenesis, gonadal regression, ovotesticular
DSD)
Disorders of androgen synthesis (Leydig cell agenesis, Leydig cell unresponsiveness, androgen biosynthesis defect)
Defect of androgen action (complete and partial androgen insensitivity)
Disorders of antimüllerian hormone (AMH) or its receptors
Other conditions (severe hypospadias, cloacal exstrophy)
Classifications of 46,XX DSD include the following:
Disorders of ovarian development (ovotesticular DSD, testicular DSD, gonadal dysgenesis)

Androgen excess (fetal [eg, congenital adrenal hyperplasia (CAH)], fetoplacental, maternal)
Other conditions (müllerian agenesis, vaginal atresia, cloacal exstrophy)
Pathophysiology
Adequate comprehension of normal and abnormal sexual differentiation is essential to understanding DSDs. A summary of
current knowledge regarding the embryology and classification of these conditions provides an appropriate introduction to
the topic.
Embryology of sexual differentiation
Phenotypic sex determination begins with genetic sex and follows a logical cascade: Chromosomal sex determines gonadal
sex, which determines phenotypic sex. The type of gonad present determines the differentiation/regression of the internal
ducts (ie, müllerian and wolffian ducts) and ultimately determines the phenotypic sex. Gender identity is determined not only
by the phenotypic appearance of the individual but also by the brain's antenatal and postnatal development as influenced by
the environment.
Gonadal differentiation
During the second month of fetal life, the indifferent gonad is guided to develop into a testis by genetic information present
on the short arm of the Y chromosome. Testis-determining factor (TDF) is a 35-kilobase pair (kbp) sequence on the 11.3
subband of the Y chromosome, an area termed the sex-determining region of the Y chromosome (SRY). When this region is
absent or altered, the indifferent gonad develops into an ovary.
The existence of patients with 46,XX testicular DSD, who have testicular tissue in the absence of an obvious Y chromosome
or SRY genetic material, clearly requires other genetic explanations. Other genes important to testicular development
include DAX1 on the X chromosome, SF1 on band 9q33, WT1 on band 11p13, SOX9 on bands 17q24-q25, and AMH on
band 19q13.3. Fetal ovaries develop when the TDF gene (or genes) is absent.
Differentiation of internal ducts
Development of the internal ducts results from a paracrine effect from the ipsilateral gonad. Jost's classic research with
rabbits greatly clarified the gonad's role in controlling the subsequent development of internal sex ducts and external genital
phenotype.[7]
When testicular tissue is absent, the fetus morphologically begins and completes the internal sex duct development and
external phenotypic development of a female. When testicular tissue is present, two produced substances appear to be
critical for the development of male internal sex ducts and an external male phenotype: testosterone and müllerian-inhibiting
substance (MIS; ie, AMH).
Testosterone is produced by testicular Leydig cells and induces the primordial wolffian (mesonephric) duct to develop into
the epididymis, vas deferens, and seminal vesicle.
A spatial relation is important in the effect of testosterone. Wolffian structures located closest to the source of testosterone
undergo the greatest degree of male differentiation. Thus, patients with ovotesticular DSDs often have a degree of wolffian
development near testicular tissue, even when joined with an ovary as an ovotestis. No wolffian development is expected in
association with a streak gonad or a non-testosterone-producing dysgenetic testis.
High local testosterone levels (paracrine effect) appear to be necessary for wolffian duct differentiation because maternal
ingestion of androgens does not cause male internal differentiation in a female fetus, nor does this differentiation occur in
females with CAH (also termed adrenogenital syndrome).
MIS (AMH) is produced by the Sertoli cells of the testis and is critical to normal male internal duct development. MIS is a 15-
kd protein that is secreted by the testis beginning in fetal week 8. Its prime role is to repress the passive development of the
müllerian ducts (eg, fallopian tubes, uterus, upper vagina). In a male fetus with normal testicular function, MIS represses
müllerian duct development, whereas testosterone stimulates wolffian duct development.
The influences of testosterone and estrogen apparently modulate but do not isolate the role of MIS. Local testosterone
production appears to enhance the inhibition of müllerian duct development produced by MIS, whereas estrogens may
interfere with MIS action, resulting in a degree of müllerian duct development. This suggests that müllerian development
may be more complex than was initially appreciated, and the research helps explain the variable internal sex duct anatomy
that occurs in some of the more complex DSDs.
Differentiation of external genitalia
The external genitalia of male and female sexes are identical during the first 7 weeks of gestation. Without the hormonal
action of the androgens testosterone and dihydrotestosterone (DHT), external genitalia appear phenotypically female.
In the gonadal male, differentiation toward the male phenotype actively occurs over the next 8 weeks. This differentiation is
moderated by testosterone, which is converted to 5-DHT by the action of an enzyme, 5-alpha reductase, present within the
cytoplasm of cells of the external genitalia and the urogenital sinus. DHT is bound to cytosol androgen receptors within the
cytoplasm and is subsequently transported to the nucleus, where it leads to translation and transcription of genetic material.
In turn, these actions lead to normal male external genital development from primordial parts, forming the scrotum from the
genital swellings, forming the shaft of the penis from the folds, and forming the glans penis from the tubercle. The prostate
develops from the urogenital sinus.
Incomplete masculinization occurs when testosterone fails to convert to DHT or when DHT fails to act within the cytoplasm
or nucleus of the cells of the external genitalia and urogenital sinus. The timing of this testosterone-related developmental
change begins at approximately 6 weeks of gestation with a testosterone rise in response to a surge of luteinizing hormone
(LH).
Testosterone levels remain elevated until week 14. Most phenotypic differentiation occurs during this period. After week 14,
fetal testosterone levels settle at a lower level and are maintained more by maternal stimulation through human chorionic
gonadotropin (hCG) than by LH. Testosterone's continued action during the latter phases of gestation is responsible for the
continued growth of the phallus, which is directly responsive to testosterone and to DHT.
Etiology
46,XX DSDs
46,XX DSDs can be caused by CAH or maternal androgens.
Congenital adrenal hyperplasia
Overall, CAH is the most frequent cause of ambiguous genitalia in the newborn, constituting approximately 60% of all DSDs.
Excessive production of adrenal androgens results in a gonadal female with a virilized phenotype (46,XX DSD, formerly
termed female pseudohermaphroditism).
The basic biochemical defect is an enzymatic block that prevents sufficient cortisol production. Biofeedback via the pituitary
gland causes the precursor to accumulate above the block. Metabolic byproducts are shifted towards the production of
adrenal androgens. Clinical manifestations of CAH depend on which enzymatic defect is present.
CAH may result from several metabolic defects. In 90% of patients with CAH, the block is at the 21-hydroxylation enzyme
(21-hydroxylase deficiency). This leads to glucocorticoid and mineralocorticoid deficiency with a compensatory increase in
the secretion of adrenocorticotropic hormone (ACTH) secretion and concomitant buildup of androgenic byproducts, which
causes masculinization of a female fetus. The result is a female infant with varying degrees of virilization.
Biochemically, 75% of patients have salt-wasting nephropathy. Before this condition was commonly recognized, as many as
one third of patients presented with evidence of vascular collapse. The 21-hydroxylase defect is inherited as an autosomal
recessive trait closely linked to the human leukocyte antigen (HLA) locus on chromosome 6. The transmitted trait may have
two varieties, which helps account for the clinical heterogenicity seen in patients with salt-wasting nephropathy.
Another cause of CAH is 11-hydroxylase deficiency. Patients who have CAH with 11-hydroxylase deficiency accumulate
deoxycorticosterone (DOC) and 11-deoxycortisol. This form of the syndrome exhibits salt retention and hypertension
because DOC is a potent mineralocorticoid. This enzymatic deficiency is suspected in a 46,XX child with ambiguous
genitalia in whom the 17-OHP level is only mildly elevated. The diagnosis can be confirmed by a steroid screen of the
serum.
A less frequently seen version of CAH is caused by 3-beta-hydroxysteroid dehydrogenase deficiency. This version causes
less severe virilization of a female infant than the virilization caused by 21-hydroxylase or 11-hydroxylase deficiency. The
buildup of pregneninolone, which is subject to hepatic conversion into testosterone, produces virilization.
Prompt diagnosis of DSD secondary to CAH is important. The diagnosis is suspected antenatally when there is discordance
between the phenotypic sex diagnosed on antenatal ultrasonography (US) and the female karyotype on fetal DNA testing.
The diagnosis is confirmed by noting an elevated amniotic fluid level of 17-hydroxyprogesterone (17-OHP) during the
second trimester or by HLA typing of the amniotic cells.
Following birth, CAH is diagnosed more often during the evaluation of a 46,XX child with ambiguous genitalia and
nonpalpable gonads. Patients with CAH have variations in the degree of phallic enlargement, the extent of genital fold
fusion, and the size and level of entry of the vagina into the urogenital sinus. Although the degree of virilization seen in CAH
can be extreme, internal müllerian structures are consistently present.
Rectal examination, retrograde genitography, or US reveals the presence of internal müllerian structures. Newborn
screening has reliably increased the rate of diagnosis and shortened the time to achieving it, especially in males with salt-
wasting and simple virilizing forms. The diagnosis is biochemically confirmed by an elevated serum level of 17-OHP. The
reference range for 17-OHP in the newborn cord blood can be as high as 900-5000 ng/dL, but the serum level rapidly
decreases by day 2 or 3 of life. A repeat elevated serum value exceeding 500 ng/dL at this point makes the diagnosis highly
likely.
It should be kept in mind that 17-OHP levels may be markedly elevated in the 11-hydroxylase form of CAH, as well as in the
rare child with the 3-beta-hydroxysteroid dehydrogenase form. Serum levels of dehydroepiandrosterone or its sulfate
metabolite are also characteristically elevated. In these children, endocrine stabilization must be individualized, a process
that usually takes several weeks.
It should be kept in mind that 3-beta-hydroxysteroid dehydrogenase deficiency is the only common form of CAH that can
also cause ambiguity in a genetic male. This ambiguity occurs because the enzyme defect is present in both the adrenal
glands and the testes, leading to inadequate production of testosterone in utero.
Maternal androgens
In rare cases, 46,XX DSDs may be drug-induced. Virilization of a female fetus may occur if progestational agents or
androgens are used during the first trimester of pregnancy. After the first trimester, these drugs cause only phallic
enlargement without labioscrotal fusion. The incriminated drugs were formerly administered to avoid spontaneous
miscarriages in patients who had a history of habitual abortion or to treat endometriosis.
Endocrine abnormality in the mother as a source of virilizing hormones is even rarer because these abnormalities, if initially
present, usually prevent the development of a pregnancy. However, various ovarian tumors (eg, arrhenoblastomas,
Krukenberg tumors, luteomas, lipoid tumors of the ovary, and stromal cell tumors) reportedly have produced virilization of a
female fetus.
Aromatase deficiency is a rarer cause of virilization of the female fetus. Normally, weak androgens produced by the fetal
adrenal gland are converted to estrogens by placental aromatase. Mutations of the aromatase gene can result in virilization
of the mother and female fetus during pregnancy. Maternal virilization resolves postnatally, but it recurs in subsequent
pregnancies.
46,XY DSDs
Common causes of 46,XY DSDs include deficient biosynthesis of testosterone, complete androgen insensitivity syndrome
(also known as testicular feminization syndrome), partial androgen insensitivity syndrome, 5-alpha-reductase deficiency, and
isolated MIS deficiency (also known as persistent müllerian duct syndrome [PMDS]).
Deficient testosterone biosynthesis
Production of testosterone from cholesterol involves five enzymatic steps, and defects have been identified at each step. Of
these five enzymes, three (cholesterol side chain cleavage enzyme, 3-beta-hydroxysteroid dehydrogenase, and 17-alpha
hydroxylase) are shared with the adrenal glands, and their deficiency leads to ambiguous genitalia and symptoms of CAH.
Both 17,20 desmolase and 17-ketosteroid reductase occur only as part of normal androgen synthesis; thus, their defects,
while associated with genital abnormalities, are not associated with CAH.
Theoretically, biochemical diagnosis of these syndromes is possible, but as a practical matter, diagnosis usually is not
feasible, because few centers offer the research-based endocrinologic assays necessary to identify the buildup of precursor
products. During the newborn period, these patients present as 46,XY gonadal males with poor virilization and ambiguous
genitalia. The genitalia respond to exogenously administered testosterone. Children with CAH manifestations also require
treatment with steroid and mineralocorticoid replacement.
Genetic counseling is desirable because 17-alpha hydroxylase and 3-beta-hydroxysteroid dehydrogenase deficiencies are
transmitted as autosomal recessive traits.
Additional rare causes for deficiencies in testosterone production include Leydig cell agenesis, Leydig cell hypoplasia,
abnormal Leydig cell gonadotropin receptors, and delayed receptor maturation.
Complete androgen insensitivity syndrome
Complete androgen insensitivity syndrome (testicular feminization syndrome) involves a failure of the end organs (external
genitalia and prostate) in a 46,XY gonadal male fetus to respond to appropriately produced levels of dihydrotestosterone
(DHT), resulting in testicular feminization.
The basic pathophysiology of the lack of androgen effect on the genitalia has come to be understood more fully. Some
patients are receptor-negative; their cytosol receptors cannot bind DHT. Others are receptor-positive; their receptors
apparently permit DHT binding, but DHT does not lead to normal differentiation toward the male phenotype. An assay of
genital skin fibroblasts elucidates the difference between receptor-negative and receptor-positive types.
Inheritance appears to be X-linked. Complete androgen insensitivity is diagnosed in infancy if a child with phenotypic female
external genitalia has palpable gonads (testes) on physical examination or if testes were discovered in a phenotypic female
during hernia repair. Patients with complete androgen insensitivity have a 46,XY karyotype, bilateral testes, female external
genitalia, and no müllerian derivatives.
Endocrine evaluation in the neonatal period demonstrates normal male levels of testosterone and DHT. At puberty,
gonadotropin levels rise, leading to increased levels of testosterone, which is peripherally converted to estradiol, resulting in
feminization and breast development.
Inguinal hernias are common in testicular feminization (50% frequency), and the condition is occasionally diagnosed when a
gonad is present in the hernia and a fallopian tube cannot be seen during inguinal herniorrhaphy of a phenotypic female.
Failure to identify an internal müllerian structure in a phenotypic female with an inguinal hernia should always raise the
possibility of testicular feminization. If the condition is not detected in this fashion, the diagnosis usually is not made until
puberty, when the patient presents with amenorrhea.
Although these patients have a normal female phenotype, they have deficient axillary and pubic hair as they go into puberty,
and their breasts, though well formed, characteristically are deficient in stroma. Their external genitalia are unequivocally
female; however, the vagina is short, with a blind ending.
Despite a 46,XY karyotype and gonads with the typical appearance of testes (perhaps altered similarly to those of patients
with cryptorchidism), a feminine gender assignment is unquestionable because of the completely feminine phenotype and
because end-organ failure prevents endocrinologically produced masculinization. Confirmation of the diagnosis is crucial
because the syndrome is associated with a 1-2% risk of gonadal malignancies, usually gonadoblastoma or seminoma.
Sertoli cell, Leydig cell tumors, and malignant transformation of tubular cell adenomas have been reported.
Disagreement exists on the best timing for gonadectomy. Some experts prefer to leave testes in situ until puberty is
complete so as to benefit from estradiol produced by the testes, which is important for the development of the female
phenotype. This opinion is supported by the extremely low risk of gonadal malignancy before puberty. The youngest age at
the incidence of gonadal malignancy was 14 years. In contrast, others have preferred to remove the testes early because
morbidity is minimal in a young child.
Pubertal changes are easily induced with hormone replacement, a requirement for all patients following gonadectomy.
Although a vaginoplasty may be required later, many of these patients have an adequate vagina, requiring no therapy or
possibly only vaginal dilation.
Partial androgen insensitivity syndrome
An incomplete form of androgen insensitivity also occurs. These patients demonstrate a spectrum of external genitalia
ranging from very feminine (eg, Lubs syndrome) to increasingly masculine (eg, Gilbert-Dreyfus syndrome) to most masculine
(eg, Reifenstein syndrome).
A diagnosis of incomplete androgen insensitivity is suggested by elevated LH levels, with reference-range levels of plasma
DHT and 5-alpha-reductase activity in genital skin fibroblasts. Exogenously administered androgens do not cause adequate
virilization; therefore, incomplete androgen insensitivity raises questions regarding the preferred sex in which to rear the
child.
Management is individualized according to the degree of virilization and genital ambiguity. Patients assigned a female
gender require gonadectomy, surgical reconstruction, and estrogen-progestin replacement at puberty. Those assigned a
male gender require genital reconstruction of hypospadias, treatment of cryptorchidism, and reduction of gynecomastia. The
risk of gonadal tumors is higher than with complete androgen insensitivity syndrome.
5-Alpha-reductase deficiency
A 46,XY fetus with normal testes but without the enzyme 5-alpha reductase in the cells of the external genitalia and
urogenital sinus cannot produce DHT. Consequently, the fetus is born with minimally virilized external genitalia (eg,
pseudovagina, perineoscrotal hypospadias), though there is usually some degree of phallic enlargement, reflecting the direct
action of testosterone.
One characteristic feature of patients with 5-alpha reductase deficiency is improved virilization at puberty, presumably
caused by the direct action of testosterone on the phallus. At puberty, penile growth is increased, and the individual develops
a masculine voice and muscle mass. The only characteristics that do not develop are those that depend on DHT (eg,
prostatic enlargement, facial hair, acne). A spectrum of 5-alpha-reductase deficiency apparently occurs in different
pedigrees, which probably accounts for some of the variation in the phenotypes seen in infancy.
Diagnosis of this deficiency can be confirmed in a patient with a 46,XY karyotype by the presence of a high ratio of serum
testosterone to DHT. During the first 60 days of life, infants experience a surge of LH that obviates the need to carry out
human chorionic gonadotropin (hCG) stimulation, which may be useful to exaggerate the testosterone-to-DHT ratio
characteristic of this syndrome. The reference-range testosterone-to-DHT ratio is 8-16:1, whereas patients with 5-alpha-
reductase deficiency characteristically have a ratio greater than 35:1.
Urinary metabolites of testosterone and DHT can be used to establish the diagnosis in a similar fashion. Imperato-McGinley
et al[8] and Saenger et al[9] demonstrated that cultured skin fibroblasts exhibit decreased 5-alpha-reductase activity.
Gender assignment in these patients has been the subject of considerable debate because of the major virilization that
occurs at puberty. Glassberg argued that all such patients should be raised as males.[10] Others disagree and concur with
Saenger that only the most extremely virilized infant should receive a male assignment.
The surgical results of a masculinizing operation in a mildly virilized infant are poor, and the burden of growing up with
inadequate genitalia hardly seems justified. Accordingly, gonadectomy and feminizing genitoplasty are sometimes
considered for poorly virilized patients. Individuals with unambiguous female external genitalia or extremely small phallic size
can be assigned a female gender. In these patients, gonadectomy should be performed before puberty to prevent
virilization.
Isolated deficiency of MIS
Isolated MIS deficiency (PMDS) is a rare syndrome and usually does not present in the newborn period, because the
genitalia appear to be those of a male with undescended testes. The syndrome is fascinating because the phenotypic
findings are exactly those expected in a 46,XY genetic and gonadal male in whom the isolated defect in the testis is a
complete failure to produce MIS.
These patients have normal male external genitalia with unilateral or bilateral undescended testes, bilateral fallopian tubes, a
uterus, and a vagina draining into a prostatic utricle. The most common presentation is a phenotypic male with an inguinal
hernia on one side and an impalpable contralateral gonad. Herniorrhaphy reveals a uterus and a fallopian tube in the hernia
sac. Because the testis produces reference-range levels of testosterone, a vas deferens presents bilaterally, usually running
close to the uterus; therefore, damage to the vas is likely when müllerian remnants are excised. At times, the vas deferens
ends blindly.
Appropriate surgical management is straightforward and includes orchiopexy for undescended testes. Attempts to excise
müllerian remnants may incur damage to the adjacent vas. The incidence of malignancy, as compared with that in the usual
cryptorchid testis, is unknown. Removal of müllerian remnants is unnecessary, given that the remnants rarely produce
symptoms and that malignant transformation has been limited to case reports.
Ovotesticular DSDs
Both ovarian and testicular tissues are present in ovotesticular DSD (formerly termed true hermaphroditism), an uncommon
cause of genital ambiguity in North America, accounting for fewer than 10% of DSD cases. The appearance of the genitalia
varies widely in this condition. Although ambiguity is the rule, the tendency is toward masculinization.
The most common karyotype is 46,XX, though mosaicism is common. A translocation of the gene coding for HY antigen
from a Y chromosome to either an X chromosome or an autosome presumably explains the testicular material in a patient
with a 46,XX karyotype. More difficult to understand is how a patient with a 46,XY karyotype can have ovarian tissue, given
that two X chromosomes are believed to be necessary for normal ovarian development. Possibly, unidentified XX cell lines
are present in these patients.
Gonadal findings may include any combination of ovary, testis, or ovotestis. An ovotestis is most common and is found in
approximately two thirds of patients. When an ovotestis is present, one third of the patients exhibit bilateral ovotestes. A
palpable gonad is present in 61% of patients; of these, 60% are found to be an ovotestis.
In 80% of patients with ovotestes, testicular and ovarian tissues are aligned in an end-to-end fashion, emphasizing the need
for a long longitudinal biopsy. In 20% of patients with ovotestes, testicular tissue is found in the hilar region of the gonad,
reemphasizing the need for an adequate and deep biopsy. Ovarian tissue is usually more developed and possibly has
fertility potential, whereas testicular tissue is dysgenetic and is associated with malignancy risk.
An ovary, when found, is situated most commonly in the normal anatomic intra-abdominal position, though Van Niekerk
reported an ovary in the hemiscrotum.[11] The least common gonad in ovotesticular DSD is the testis; when present, a
testis is found approximately two thirds of the time in the scrotum, emphasizing that normal testicular tissue is most likely to
descend fully.
Ovotestes may present with either a fallopian tube or a vas deferens but usually not with both. If a fallopian tube has a
fimbriated end, the end is closed in most patients, perhaps contributing to the usual lack of fertility. Although fertility is rare in
this setting, it has been reported. Gonadal tumors also are rare but have been reported.
Gonadal dysgenesis
Gonadal dysgenesis can be either partial or pure.
Partial gonadal dysgenesis
Partial gonadal dysgenesis can be classified either as 46,XY DSD or as sex chromosome DSD if there is mosaicism
(45,X/46,XY). These conditions represent a spectrum of disorders in which the gonads are abnormally developed. Typically,
at least one gonad is either dysgenetic or a streak. For example, in mixed gonadal dysgenesis (MGD), a streak gonad is
usually present on one side and a testis (usually dysgenetic) on the opposite side.
In 1967, Federman used the term dysgenetic male pseudohermaphroditism (DMP) to describe patients with bilaterally
dysgenetic testes and incomplete virilization of the internal sex ducts and external genitalia. Federman indicated the
similarities in karyotype, gonadal histology, and phenotype that this group shares with patients with MGD and those with
ovotesticular DSD.[12]
A dysgenetic testis histologically demonstrates immature and hypoplastic testicular tubules in a stroma similar to that seen in
streak gonads and may help to explain the similarities of these syndromes. Federman described a spectrum of faulty
testicular differentiation, with streak gonad at the extreme end of the spectrum and dysgenetic testis lying between streak
gonad and a normal testis.
Patients with MGD have a streak gonad on one side with a contralateral dysgenetic testis, variable degrees of virilization,
and persistent mullerian structures, at least on the side of the streak gonad. Most patients with MGD have a mosaic
karyotype, 45,X/46,XY. A characteristic of patients with a 45,X karyotype is short stature. Patients who have no internal
müllerian remnants usually have no 45,X component.
The risk of gonadal malignancy is increased when a Y chromosome is present in the karyotype. In MGD, 25% of gonads,
including streak gonads, are expected to undergo malignant change, most often to gonadoblastoma, unless the patient has
a gonadectomy before adulthood. In addition to gonadoblastomas, seminomas, and embryonal cell carcinomas may
develop. A small series reported that 15-30% of DMP patients had gonadal malignancies, most often a gonadoblastoma.
Manuel et al reported the incidence of gonadoblastoma or dysgerminoma to be 46% by the age of 40 years.[13]
Early gonadectomy appears wise because tumors may arise in the first decade in both MGD and DMP. It is important to
keep in mind that patients with MGD have an increased risk of Wilms tumor. Proper screening of Wilms tumor should be part
of their care.
Gender assignment for patients with DMP and MGD remains under debate. For example, Glassberg argued for assigning a
male gender to patients who are sufficiently virilized.[10] However, Rajfer and Walsh preferred an elective feminine gender
assignment for patients with MGD because of the high incidence of inadequate external virilization and the high risk of
gonadal malignancy.[14]
Estrogen support is required if these patients are assigned a female gender. Estrogen therapy should be combined with a
progestational agent if a uterus is present to lower the risk of endometrial carcinoma,
Pure gonadal dysgenesis
This class of DSD, with bilateral streak gonads appearing as ovarian stroma without oocytes, usually goes unrecognized in
newborns because the phenotype is typically completely female. Patients tend to present at puberty, at which point they do
not undergo normal pubertal changes. Girls with Turner syndrome (45,XO) may be diagnosed earlier by noting the
characteristic associated somatic features of short stature, webbed neck, and wide-spaced nipples. Neither Turner
syndrome nor the 46, XX type of pure gonadal dysgenesis appears to be associated with an increased risk of gonadal
malignancy unless a Y chromosome is present in the mosaic forms.
Therapy in these children is primarily limited to appropriate estrogen and progesterone replacement and growth hormone
support. Prophylactic gonadectomy is advised in the Y mosaic Turner syndrome because the risk of gonadoblastoma is
estimated to be 12%.[15]
The 46,XY type of pure gonadal dysgenesis poses a different problem because the bilateral streak gonads carry a significant
potential for malignancy. Nearly one third of patients develop a dysgerminoma or gonadoblastoma; therefore, gonadectomy
becomes important as soon as the diagnosis is recognized followed by cyclic hormone replacement with estrogen and
progestins
Pure gonadal dysgenesis syndromes represent opportunities for genetic counseling. Turner syndrome appears sporadically,
suggesting a postzygotic error; however, the 46,XX type of pure gonadal dysgenesis appears to have an autosomal
recessive transmission, and the 46,XY type is apparently an X-linked recessive trait.
Epidemiology
DSDs vary in frequency, depending on their etiology. CAH is the most common cause of DSDs, with a reported incidence
ranging from 1 in 5000 to 1 in 15,000 in the United States and Europe. The frequency is highest in neonates of European
Jewish, Hispanic, Slavic, or Italian descent or the Alaskan Eskimo population.[16] MGD is the second most common cause
of DSDs. In a series from the Children’s Hospital of Boston DSDs were found in 50% of children with hypospadias with
unilateral or bilateral nonpalpable cryptorchid testes.[17] Therefore, clinicians should suspect the possibility of a DSD in
patients with both hypospadias and cryptorchidism.
Age- and sex-related demographics

DSDs typically are diagnosed at birth in infants with ambiguous genitalia. Disorders associated with phenotypic males and
females may be diagnosed much later. The classic presentation of MIS deficiency is a boy with a hernia on one side and an
impalpable contralateral gonad. At the time of surgery, a uterus and fallopian tubes are noted along with normal wolffian
structures. Diagnosis in 46,XY phenotypic females with complete androgen insensitivity usually occurs after puberty during
an evaluation for primary amenorrhea.
Prognosis
Among all causes of DSDs, only salt-wasting CAH is considered a true medical emergency. Salt-wasting nephropathy
occurs in 75% of infants born with CAH, the most common cause of ambiguous genitalia. If unrecognized, the resulting
hypotension can cause vascular collapse and death. Male infants with this syndrome may be phenotypically normal, and the
diagnosis may be missed.
Other causes of DSDs are not considered medical emergencies. Time pressure should be avoided. Modern treatment of
infants with ambiguous genitalia involves a team-oriented approach. This gender-assignment team usually involves
neonatologists, geneticists, endocrinologists, surgeons, counselors, and ethicists. The goal is to provide appropriate medical
support and counseling regarding care and therapy. Management decisions should only be made after all the available
information is explained to the family and thoroughly discussed with the multidisciplinary team. The topic of early gender
reassignment remains contentious.
Patient Education
Parents of children with DSDs are often overwhelmed and confused by their child's condition. The family should be offered
congratulations and support. Gender-neutral terminology (eg, "your baby”) should be used. Although gender assignment
and naming of the child are pressing issues, these actions should not be unduly rushed. Parents should be provided with as
much information as possible so that they can make informed decisions. Time pressure should be avoided. Certain
legislations, such as the German Law, demand that the legal gender of a child born with ambiguous genitalia be left open at
birth.
Adequate counseling and support for parents should include education regarding sexual development in utero (including
brain imprinting of gender identity), genetic counseling, and ethical considerations of the child's rights to make decisions
regarding gender. All communications to the parents must be in the form of a proposal. Parents must clearly understand that
the care of DSD patients is a dynamic process in which different disciplines are involved.[18]
Communication and information-giving should be gradual and repeated because information must be imparted repeatedly
for the often complex and new information on the person’s own body status, diagnostic interventions, and diagnostic results
to be fully grasped. All communications must be documented, and a copy of any information provided should be handed out
to the parents. Children and adolescents born with DSDs should be gradually informed about their condition. They should be
allowed to grow up accepting their bodies and conditions and achieving the best quality of life possible.
Presentation
History
Evaluation of a newborn with ambiguous genitalia requires a team effort. The most common difference (disorder) of sex
development (DSD), congenital adrenal hyperplasia (CAH), results in virilization of a 46,XX female and thus is classified
under the heading of 46,XX DSD. The clinician's challenge is to distinguish CAH from other, less common causes of
ambiguous genitalia. A detailed family history is essential; the following considerations should be kept in mind:
A family history of genital ambiguity, early newborn death, infertility, precocious puberty, unexpected changes at
puberty, or consanguinity may suggest a genetically transmitted trait; a history of early death of infants in a family
may suggest a previously missed adrenogenital deficiency
Maternal drug ingestion is important, particularly during the first trimester, when virilization may be produced
exogenously in a gonadal female
Although this is extremely rare, a history of maternal virilization may suggest an androgen-producing maternal tumor
(arrhenoblastoma); a history of virilization of female siblings and maternal virilization during previous pregnancies that
regresses following delivery may suggest placental aromatase deficiency
All fetal testing, including sonographic examination of the fetal genitalia and fetal karyotyping by amniocentesis or free fetal
DNA, should be documented.[19]
Late presentations
DSD may present beyond the neonatal period with primary amenorrhea; abnormal incidental findings on laparoscopy,
exploratory laparotomy, or imaging studies; inguinal hernia in a female child; masculinization of a female child; or an
abnormal karyotype on genetic evaluation for other conditions, such as short stature, infertility, and developmental delay.
Physical Examination
Certain physical characteristics may suggest the direction toward which a successful investigation might be pursued.
Examination of the external genitalia should include the following:
Size and degree of differentiation of the phallus (variations may represent clitoromegaly or hypospadias) - Stretched
penile length should be measured and documented
Position of the urethral meatus and degree of clitorophallic curvature, if present
Morphology and pigmentation of the labioscrotal folds - Folds may be separate or fused in the midline, giving the
appearance of a scrotum (see the image below); increased pigmentation of the labioscrotal folds suggests the
possibility of increased corticotropin levels as part of adrenogenital syndrome; the Prader scale is commonly used to
assess the degree of virilization of external genitalia [20]
Patient with 46,XX disorder of sex development (DSD). Note masculinized appearance of genitalia, with enlarged phallus
and scrotal appearance of labia.
Gonadal examination should include the following:
Documentation of palpable gonads - Although complete descent of ovotestes to the bottom of labioscrotal folds has
been reported, only testicular material descends fully in most patients; if the examination reveals the presence of at
least one palpable gonad, the diagnoses of a gonadal female, overvirilized female (46,XX DSD), Turner syndrome,
and pure gonadal dysgenesis can be eliminated
Documentation of impalpable gonads - Impalpable gonads, even in an apparently fully virilized infant, should raise
the possibility of a severely virilized 46,XX DSD patient with CAH; patients with bilateral nonpalpable testes or
unilateral nonpalpable testis and hypospadias should be regarded as having DSD until proved otherwise, even if the
genitalia do not appear ambiguous
Documentation of dysmorphic somatic features (eg, webbed neck or widely spaced nipples)
Rectal examination should include the following:
Identification of the presence of müllerian structures - The uterus is palpated as an anterior midline cordlike structure;
it is relatively enlarged in a newborn because of the effects of maternal estrogen, permitting easy identification; pelvic
ultrasonography (US) is a more reliable means of assessing müllerian anatomy and can be immediately performed in
the neonatal period [21]
Complications
Patients with CAH are at risk for the following:
Adrenocortical insufficiency and vascular collapse

Progressive penile or clitoral enlargement
Development of premature pubic hair (puberache), axillary hair, and acne
Rapid growth during childhood followed by premature epiphyseal maturation, resulting in adult short stature
Impaired fertility
Complications of chronic glucocorticoid treatment
Disorders of gender role behavior and cognition
DDx
Diagnostic Considerations
A difference (disorder) of sex development (DSD) should be suspected in any newborn who has bilateral nonpalpable
undescended testes or hypospadias with unilateral undescended testis.
Differential Diagnoses
3-Beta-Hydroxysteroid Dehydrogenase Deficiency
5-Alpha-Reductase Deficiency
Androgen Insensitivity Syndrome
Congenital Adrenal Hyperplasia
Denys-Drash Syndrome
Gender Identity
Genital Anomalies
Gonadoblastoma
Hypogonadism
Hypospadias
Menstruation Disorders in Adolescents
Microphallus
Pediatric Hydrocele and Hernia Surgery
Pediatric Hypopituitarism
Precocious Puberty
Workup
Workup
Laboratory Studies
Routine workup in infants born with ambiguous genitalia should include genetic testing and endocrine screening.
Genetic testing
Chromosomal analysis is a basic examination. The diagnosis is evident if a difference (disorder) of sex development (DSD)
is caused by chromosomal abnormalities. Chromosomal analysis allows for the differentiation of 46,XX and 46,XX DSD,
which can guide further diagnostic testing.
Molecular cytogenetic examinations can detect specific structural rearrangements. For example, fluorescence in-situ
hybridization (FISH) can help define the sex-determining region of the Y chromosome (SRY) in some cases of testicular
DSD. Array-comparative genomic hybridization can detect microdeletions or duplications and is important in cases of XY
gonadal dysgenesis or the Mayer-Rokitansky-Kuster-Hauser syndrome. Single gene testing, whole exome sequencing, and
whole genome sequencing are sometimes indicated in patients with DSD. Advanced genetic testing is optional, based on
initial evaluation, family preference, availability, and cost.
Endocrine screening
Hormonal diagnostics and serum electrolytes/chemistry levels are essential right after birth. These tests mainly aim at
excluding a salt-wasting form of CAH. Basic values to be determined include 17-hydroxyprogesterone, cortisol, estradiol,
androstenedione, testosterone, and dihydrotestosterone. 17-hydroxyprogesterone levels should not be measured until day 3
or 4, because the stress of delivery may result in physiologic elevation of its levels in the first two days of life.
In the absence of palpable testes, markedly elevated luteinizing hormone (LH) levels or lack of testosterone elevation in
response to human chorionic gonadotropin (hCG) stimulation can indicate the absence of normally functioning testicular
tissue in patients with nonpalpable gonads. The hCG stimulation test can also help to diagnose 5-alpha-reductase deficiency
and distinguish impaired testosterone synthesis from androgen insensitivity. The hCG stimulation test is not needed in the
first 3 months of life, when there is a natural surge of gonadotropin with a subsequent increase in the testosterone level. LH,
follicle-stimulating hormone (FSH), and testosterone levels are most informative at one week of life.
Other less frequently ordered tests include 5-alpha-reductase type II levels and antimüllerian hormone (AMH)/müllerian-
inhibiting substance (MIS) levels. Androgen-receptor characterization is performed in specialized laboratories.
Imaging Studies
A complete ultrasonographic (US) examination of the pelvic structures, as well as the perineal region and of the entire
urinary tract, is recommended.[22] Pelvic US is helpful for precisely defining the müllerian anatomy, and it can be helpful for
evaluating the location and anatomy of nonpalpable gonads. A cyst in the gonad could be suggestive of ovotestis.
Renal-bladder US is recommended in view of the high prevalence of congenital anomalies of the kidney and urinary tract in
patients with DSD. The newborn adrenal glands may be enlarged in patients with CAH and usually depict a cribriform
appearance. However, it is important to note that normal-appearing adrenal glands on US do not exclude CAH. Ambiguous
genitalia, enlarged adrenal glands, and the presence of müllerian structures in a newborn are virtually pathognomonic for
CAH.
Genitography can help determine the ductal anatomy. In a neonate with ambiguous genitalia, a catheter can be inserted into
the distal urogenital sinus (urethra). Contrast is injected to outline the internal ductal anatomy. Findings may indicate normal
urethral anatomy, an enlarged utricle in a male, or a common urogenital sinus in a female and can help define the level of
vaginal and urethral confluence. Contrast-enhanced US genitography may be used as an alternative.[23] For operative
planning, some surgeons prefer endoscopic evaluation to genitography.
Magnetic resonance imaging (MRI) is usually not indicated, but it may help identify the internal anatomy, intra-abdominal
gonads, or an associated suspected spinal cord pathology. Cost and the need for general anesthesia are obvious limitations
on its use.
Other Tests
Cystourethroscopy before or during the definitive reconstructive surgical procedure may help better define the anatomy of
the urogenital sinus and determine the exact location of the confluence where the vagina meets the urethra (ie, high,
intermediate, or low).
Procedures
Laparoscopy allows the identification and biopsy of intra-abdominal gonads. Ideally, bilateral deep and longitudinal biopsies
are required for optimal histologic evaluation. Furthermore, laparoscopy can help delineate the internal duct anatomy without
the morbidity associated with open exploration. Currently, open exploration is rarely used to help identify the internal duct
anatomy and obtain biopsy specimens of gonadal tissue for histologic characterization. Removal of the gonads and
reproductive organs should be avoided until a diagnosis is made and a gender has been assigned.
Histologic Findings
Histologic analysis of gonadal biopsy specimens may identify ovarian tissue, testicular tissue, ovotestes, or streak gonads.
Treatment
Approach Considerations
Factors that should be considered when planning for definitive management of differences (disorders) of sex development
(DSDs) include the following:
Phenotype
Functional potential of the external and internal genitalia
Tumor risk of the gonads
Fertility potential
Psychosexual issues (gender identity and sexual orientation)
Several professional organizations have published guidance for the management of patients with these conditions, including
the Consortium on the Management of Disorders of Sex Development[24] ; the Global DSD Update Consortium[25] ; the
DSD-TRN Psychosocial Workgroup, the DSD-TRN Advocacy Advisory Network, and the Accord Alliance[26] ; the Society for
Endocrinology UK[27] ; and the British Society for Paediatric Endocrinology and Diabetes.[28]
The extraordinary complexity of each of these conditions renders their grouping under one broad title in some of the
statements referred to above unrealistic. Additionally, even within each of these categories there exists a spectrum of
anomalies, adding to the difficulty of making generalizations regarding management and outcomes.
Gender Assignment
Assigning a gender on the basis of anatomic (phenotype) and biologic criteria without being certain of the individual’s
ultimate gender identity is one of the major challenges of DSD management. Because each patient is unique, as is each
situation, the aim of the multidisciplinary team should be to provide individualized treatment. The therapeutic approaches to
the spectrum of DSDs vary widely, and it would be an oversimplification to generalize the management of these conditions.
After a diagnosis is made and the anatomy is defined, the multidisciplinary team should have a thorough and candid
discussion with the patient and family regarding future potential sexual function, fertility, and malignancy risk.
In 46,XX overvirilized females, gender assignment is typically female. These patients have normal ovaries and female
internal organs with normal reproductive potential. In patients with 46,XY DSD, however, gender assignment is more
complex and relies on several factors, including penile length, androgen insensitivity, and future fertility potential.
Legislative considerations
Legislation of genital surgery in children has come the attention of several international organizations, including the United
Nations (UN) and Human Rights Watch (HRW). Some organizations or advocacy groups have called for banning of
medically unnecessary genital surgeries in children, including even circumcision, surgery for undescended testis, and
isolated hypospadias repair. Formal legalization has been enacted in some countries (eg, Germany and Greece) but has not
yet occurred in the United States, though it has been explored in some states (eg, California and New York). These efforts
were largely driven by unsatisfactory patient experiences with genital surgeries performed several decades ago.
The pooling of data from patients with different DSD conditions when outcomes are reported is another fundamental problem
that calls for research limited to individual diagnoses. Patient and parent dissatisfaction with the information provided to them
about their condition and the procedures proposed or performed for management of that condition appears to be a common
problem.
Major medical organizations responsible for providing and refining the care of individuals with DSDs have also generated
several position statements. The common theme of these efforts has been the patient’s right to make well-informed
decisions about their health and necessary interventions. Additionally, these efforts have also highlighted the responsibility of
medical professionals in providing balanced and accurate information to patients and their families, as well as the
importance of a multidisciplinary team approach.[29]
In pediatric patients, decisions about DSD management are made by parents on behalf of their children. The American
Medical Association (AMA) continues to support parents’ rights in making shared and informed decisions on behalf of their
children while also supporting children's involvement in their own care and right to self-determination when possible. Parent
counseling should include all treatment options, including medical management, surgical intervention, gender assignment,
and nonintervention. The goal should be the development of happy and healthy children and adults throughout their lives.
Treatment decisions should be made jointly between parents and the multidisciplinary team.
Medical Care
Medical therapy for DSDs depends on the underlying cause. Glucocorticoid and mineralocorticoid replacement is indicated
in patients with congenital adrenal hyperplasia (CAH). Sex hormone replacement with estrogen or testosterone may be
implemented if gonadal function is compromised, after gonadectomy, or if hormone production is discordant with the
assigned sex. Progesterone should be given with estrogen if a uterus is present to lower the risk of endometrial carcinoma.
Surgical Care
Timing of surgical reconstruction
There are several controversies surrounding the management of DSD. There is no disagreement regarding the need to
address and treat underlying physiologic problems, such as those associated with CAH. The controversies primarily involve
issues of gender reassignment and the timing of reconstructive genital surgical procedures.
The gender assigned by the physician and family may not correlate with the gender preferred by the patient upon reaching
adulthood. Therefore, some guidelines and advocacy groups recommend delaying surgical intervention until patients are
able to make their own decisions about it. Various activists and some healthcare professionals have even called for a
moratorium on gender reassignment and genital surgeries in childhood until studies have been completed on the long-term
effects of such surgeries. Several long-term follow-up studies are being conducted, including a study by the North American
Task Force on Intersexuality. The proposed moratorium has been opposed by many healthcare professionals.
A critical issue is the timing of genital reconstruction. Some favor early surgery to restore a more normal visible anatomy and
avoid ambiguity (which is often the parents’ wish), whereas others favor performing reconstruction later, when the individual
is able to express his or her own preferences. Supporters of the first option claim that early genital surgery is technically
easier and possibly has less psychological impact than later surgery. Genital surgery in adolescence carries a much higher
physical and psychological morbidity, and fewer surgeons have substantial experienced with genital surgery in this age
group. It is important to note that opponents of early surgery have no evidence that late surgery is better.
Although most of these controversies remain unresolved at present, one point that has been established is that treatment
must be individualized. Attempts to develop broad management policies for such a disparate spectrum of anomalies would
be ill-conceived and would disregard the multidisciplinary knowledge that has accrued over the past few decades.
Surgery for virilized females
The surgical procedure for a virilized female, termed feminizing genitoplasty, includes separation of the urethra and
vagina, vaginoplasty, labioplasty, and clitoroplasty (see the images below).[30] In modern management of DSDs,
clitoroplasty is a highly debatable practice and is rarely done except in highly virilized female patients with Prader stage 4 or
5. The optimal timing of feminizing genitoplasty (ie, early or delayed) remains to be determined and requires shared
decision-making with the family.[31, 32]
Patient with congenital adrenal hyperplasia (CAH; 46,XX DSD). Note phalluslike clitoris and empty scrotal appearance of
labia majora.
Same patient with congenital adrenal hyperplasia (CAH; 46,XX DSD), after feminizing genitoplasty surgery. Note
achievement of three components of surgery: clitoroplasty, vaginoplasty. and labiaplasty. Upper catheter is in urethra and
lower one in vagina.
Surgery for undervirilized males
Undervirilized males typically have hypospadias requiring surgical reconstruction, undescended testes requiring orchiopexy,
or both. The limited data available on the ideal timing of hypospadias repair in patients with DSDs is derived mainly from the
hypospadias literature and from expert opinions. It may be reasonable to advocate early surgery (ie, between the ages of 6
and 18 months) unless gender assignment is questionable.[33] Gender reassignment may be considered in patients with
46,XY DSD and genital inadequacy.[30]
Gonadectomy
Gonadectomy should be carefully considered if the risk of gonadal malignancy is increased or if sex hormone production is
discordant with the chosen sex. Gonadectomy at an early age for conditions associated with an increased risk of malignancy
at an early age remains an ethical dilemma. Regular screening must be guaranteed for patients with increased gonadal
malignancy risk who retain their gonads into adulthood. If gonadectomy is considered, cryopreservation should be discussed
if vital spermatozoa are found.[34]
Consultations
The following consultations may be obtained:
Genetics/genetic counseling
Endocrinology
Pediatric gynecology
Pediatric urology
Psychology
Social work
Medication
Medication Summary
Medications used in disorders of sex development (DSDs) depend on the underlying cause.
Glucocorticoids
Class Summary
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's
immune response to diverse stimuli. Patients with congenital adrenal hyperplasia (CAH) require lifelong corticosteroid
replacement for survival. Replacement also reduces the production of corticotropin and, therefore, the overproduction of
androgens.
Hydrocortisone (Hydrocortone, Cortef)

Drug of choice because of mineralocorticoid activity and glucocorticoid effects.
Contributor Information and Disclosures
Author
Ahmed Abdelhalim, MD, MSc, MRCS Assistant Professor, Associate Program Director of Pediatric Urologic Education,
Department of Urology, West Virginia University School of Medicine
Ahmed Abdelhalim, MD, MSc, MRCS is a member of the following medical societies: American Urological Association,
Egyptian Medical Syndicate, Egyptian Urological Association, Mid-Atlantic Section of the American Urological Association,
Royal College of Surgeons of England, Society for Pediatric Urology
Disclosure: Nothing to disclose.
Specialty Editor Board
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-
in-Chief, Medscape Drug Reference
Harry P Koo, MD Chairman of Urology Division, Director of Pediatric Urology, Professor of Surgery, Virginia Commonwealth
University School of Medicine, Medical College of Virginia; Director of Urology, Children's Hospital of Richmond
Harry P Koo, MD is a member of the following medical societies: American Academy of Pediatrics, American College of
Surgeons, American Urological Association
Chief Editor
Marc Cendron, MD Associate Professor of Surgery, Harvard School of Medicine; Consulting Staff, Department of Urological
Surgery, Children's Hospital Boston
Marc Cendron, MD is a member of the following medical societies: American Academy of Pediatrics, American Urological
Association, New Hampshire Medical Society, Societies for Pediatric Urology, Society for Fetal Urology, Johns Hopkins
Medical and Surgical Association, European Society for Paediatric Urology
Additional Contributors
Joel Hutcheson, MD Consulting Staff, Departments of Surgery and Urology, Pediatric Surgical Associates
Joel Hutcheson, MD is a member of the following medical societies: American Academy of Pediatrics, American Urological
Association
Martin David Bomalaski, MD, FAAP Pediatric Urologist, Alaska Urology; Clinical Assistant Professor, Seattle Children's
Hospital
Martin David Bomalaski, MD, FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy
of Pediatrics, American Urological Association
Howard M Snyder, III, MD Professor, Department of Surgery, Division of Pediatric Urology, University of Pennsylvania
School of Medicine and Children's Hospital of Philadelphia
Howard M Snyder, III, MD is a member of the following medical societies: American Academy of Pediatrics, American
College of Surgeons, American Medical Association, American Urological Association, National Kidney Foundation
Osama Al-Omar, MD, MBA, FACS, FEBU Professor and Vice Chair of Surgery, Chief of Pediatric Urology, Associate
Program Director for Pediatric Urology Program, Department of Urology, Division of Pediatric Urology, West Virginia
University School of Medicine
Osama Al-Omar, MD, MBA, FACS, FEBU is a member of the following medical societies: American Academy of Pediatrics,
American Medical Association, American Urological Association, Society for Fetal Urology
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Differences (Disorders) of Sex Development (DSDS) : Practice Essentials

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Differences (Disorders) of Sex Development (DSDS) : Practice Essentials

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2/1/24, 7:59 AM emedicine.medscape.

Differences (Disorders) of Sex

Previous Term Revised Term

Female pseudohermaphrodite 46,XX DSD

Male pseudohermaphrodite 46,XY DSD

True hermaphrodite Ovotesticular DSD

XX male 46,XX testicular DSD

XY sex reversal 46,XY complete gonadal dysgenesis

As examples, classifications of sex chromosome DSD include the following:

45,X ( Turner syndrome and variants)

Classifications of 46,XY DSD include the following:

Classifications of 46,XX DSD include the following:

Disorders of ovarian development (ovotesticular DSD, testicular DSD, gonadal dysgenesis)

Embryology of sexual differentiation

Differentiation of internal ducts

Differentiation of external genitalia

Congenital adrenal hyperplasia

Deficient testosterone biosynthesis

Complete androgen insensitivity syndrome

Partial androgen insensitivity syndrome

Isolated deficiency of MIS

Gonadal dysgenesis can be either partial or pure.

Partial gonadal dysgenesis

Pure gonadal dysgenesis

Age- and sex-related demographics

Examination of the external genitalia should include the following:

Gonadal examination should include the following:

Rectal examination should include the following:

Adrenocortical insufficiency and vascular collapse

Androgen Insensitivity Syndrome

Congenital Adrenal Hyperplasia

Menstruation Disorders in Adolescents

Pediatric Hydrocele and Hernia Surgery

Surgery for virilized females

Surgery for undervirilized males

Hydrocortisone (Hydrocortone, Cortef)

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