• Patients with ambiguous genitalia have disorders of sexual development (DSD).
  • Previously termed intersex conditions
• The nomenclature used to describe atypical sexual differentiation has changed.
  • Patient advocacy groups were concerned that the terminology was pejorative
• Historically, the term male pseudohermaphrodite was used to describe the patient with incompletely masculinized external genitalia possessing XY chromosomes and a typical number of autosomes (also known as 46, XY karyotype).
  • These conditions are now denoted as 46, XY DSD.
• The term female pseudohermaphrodite was used to describe the patient with 46, XX karyotype and with masculinized external genitalia.
  • Currently, these disorders are denoted as 46, XX DSD.
• In some rare cases, a patient has both ovarian and testicular tissue.
  • These patients had been called true hermaphrodites in the past.
  • They are now considered to have ovotesticular DSD.

• 46, XX disorders of sexual development
  • Occurs in 1 in 14,000 white infant births
  • Late-onset, or nonclassical, 21-hydroxylase deficiency usually occurs in childhood or the teenage years.
  • Defects in 11β-hydroxylation are rarer than defects in 21-hydroxylation, occurring in roughly 1 in 100,000 white infant births.
    • Occurs more frequently in children of Middle Eastern descent

• Disorders of gonadal differentiation (sex chromosome disorders of sexual development)
  • Klinefelter syndrome
    • Most common form of primary hypogonadism in males
    • Incidence of 1 in 1000 males
  • Turner syndrome (syndrome of gonadal dysgenesis)
    • Occurs in 1 in 2500 live-born female infants
    • Occurs in a greater percentage of conceived pregnancies
      • ~ 15% of first-trimester spontaneous abortions have an XO karyotype.
    • Cardiac involvement is common.
      • ~ 10% of patients have coarctation of the aorta leading to hypertension in the upper extremities.
      • An even greater percentage of patients have bicuspid aortic valves, which increases their risk for subacute bacterial endocarditis.
    • In some cases, short stature may be the sole phenotypic manifestation of the syndrome.
• 90% of infants with ambiguous genitalia have congenital adrenal hyperplasia.
  • >50% of these patients experience significant sodium loss.
• Rarely, disorders of either testicular or ovarian differentiation may lead to gonadal dysgenesis and thus anomalous sexual development.

• Disorders of sexual development arise from chromosomal, gonadal, or anatomic abnormalities in the pathway of sexual differentiation.
• Incomplete masculinization of a fetus with testes may result from
  • Decreased synthesis or secretion of testosterone or dihydrotestosterone (DHT)
  • Peripheral tissue resistance to androgen action
  • Defective production or action of antimüllerian hormone (AMH)
• 46, XX DSD may result from abnormally high levels of androgen from either a fetal or exogenous source.

46, XX disorders of sexual development

• ~ 90% of cases of congenital adrenal hyperplasia (CAH) are caused by 21-hydroxylase deficiency.
• Virilization of a female fetus results from excess androgen exposure from either a fetal or maternal source.
• Timing is important.
  • If the female fetus is exposed to elevated androgen levels after the 8th week of gestation but before the 13th week, the vaginal opening may fuse posteriorly and appear slitlike.
  • Females with CAH will have posterior fusion of the labia and not clitoromegaly, given their high circulating androgen levels between weeks 8 and 12.
  • Exposure to androgen after the 12th week of gestation (e.g., exogenous administration to the mother) will result in clitoromegaly without fusion of the labioscrotal folds.
• Fetal sources of androgen excess
  • CAH
    • Overproduction of adrenal androgens by the female fetus may occur in virilizing CAH.
    • Group of disorders in which a biochemical defect in cortisol synthesis leads to hyperplasia of the adrenal gland resulting from compensatory elevation in adrenocorticotropic hormone (ACTH)
    • These disorders are inherited in an autosomal-recessive manner.
    • The degree and timing of virilization, as well as the presence or absence of salt wasting, depend on the specific genetic lesion (Table 286-1).
  • P450c21 hydroxylase converts 17-hydroxyprogesterone (17-OHP) to II-deoxycortisol.
    • Deficiency in this enzyme leads to extreme elevation in 17-OHP levels.
    • Defects in 21-hydroxylase will lead to low aldosterone and cause renal salt wasting and potassium retention in approximately 50% of patients.
  • P450c11 hydroxylase deficiency typically results in:
    • Hypertension in either gender as a result of elevated levels of 11-deoxycorticosterone
    • Virilization of the female fetus as a result of increased adrenal androgen production
  • 3β-Hydroxysteroid-dehydrogenase deficiency causes mineralocorticoid, glucocorticoid, and sex-steroid deficiency.
    • Genetic females may be phenotypically normal or have varying levels of clitoromegaly or labial fusion.
    • Virilization occurs in genetic females because of increased levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S).
    • Peripheral conversion of DHEA to testosterone may cause virilization in females.
    • May be a common cause of late-onset CAH
    • Salt loss, as a result of aldosterone deficiency, occurs to varying degrees.
  • Aromatase deficiency
    • In rare cases, deficiency in the enzyme aromatase caused by mutations in the CYP19 gene may lead to virilization of the female fetus and often of the mother during pregnancy.
    • Aromatase catalyzes the conversion of androgen to estradiol.
    • Deficiency leads to elevated levels of androstenedione and testosterone and low levels of estrogens.
• Maternal or exogenous sources of elevated androgen levels
  • Maternal use of androgenic steroids, such as danazol or certain progesterone compounds, during pregnancy may lead to virilization of the female fetus.
  • Exposure to these compounds during weeks 8–12 of gestation may lead to significant ambiguity.
    • Later exposure may result only in an enlarged clitoris.
  • In rare instances, maternal CAH or a virilizing maternal tumor of ovarian or adrenal origin may lead to masculinization of the fetus.
  • Luteomas of pregnancy have been reported to cause genital ambiguity in the newborn.
    • More commonly, result only in maternal virilization

46, XY disorders of sexual development

• Luteinizing hormone (LH) receptor defects
  • Testosterone secretion is controlled by human chorionic gonadotropin (hCG) early in gestation and LH from the fetal pituitary later in gestation.
  • Failure of hCG or LH to stimulate testosterone production at the critical times is due to mutations in the LH/hCG receptor. This will result in incomplete masculinization of a male fetus.
  • This failure may occur in the situation of Leydig cell agenesis or hypoplasia.
  • Stimulation testing with hCG will result in little or no increase in androgen levels.
  • Basal and stimulated LH levels are typically elevated.
• Androgen biosynthesis defects
  • Enzyme defects in the pathways of testosterone biosynthesis may result in incomplete virilization of the male fetus.
    • Some of the defects affect synthesis of corticosteroids and are thus forms of CAH.
  • The initial conversion of cholesterol to delta-5-pregnenolone requires the enzyme P450scc (side chain cleavage), as well as the steroidogenic acute regulatory protein, which transports cholesterol to the inner mitochondrial membrane where P450scc is located.
    • Owing to low testosterone levels, patients with steroidogenic acute regulatory protein or P450scc enzyme deficiencies have:
      • Lipid-laden adrenal glands
      • Adrenal insufficiency
      • Sexual infantilism in males
  • 3β-Hydroxysteroid dehydrogenase deficiency may result in:
    • Mineralocorticoid
    • Glucocorticoid
    • Sex-steroid deficiencies
  • 17-Hydroxylase deficiency caused by a defect in the CPY17 gene results in deficiencies in cortisol and testosterone and thus can result in an incompletely masculinized 46, XY fetus.
    • Excess of the mineralocorticoid deoxycorticosterone leads to:
      • Hypertension in both sexes (caused by increased salt and water resorption)
      • Hypokalemia
      • Suppression of aldosterone production
  • Enzyme defects affecting testosterone biosynthesis without affecting corticosteroid production are described.
    • In a male fetus, 17,20 lyase (also called 17,20 desmolase) deficiency and 17β-hydroxysteroid dehydrogenase-3 deficiency will lead to an incompletely masculinized phenotype without any abnormalities related to mineralocorticoid or glucocorticoid effects.
    • Virilization may occur at puberty in either condition.
    • Gynecomastia may occur at puberty in those with 17,20 lyase deficiency.

Defects in androgen action

• Syndrome of complete androgen resistance (androgen insensitivity syndrome or testicular feminization) results from a defect in the androgen receptor.
• Affected individuals are phenotypic females with a 46, XY karyotype and bilateral testes that secrete elevated levels of testosterone.
• At puberty, LH increases and leads to elevations in testosterone, some of which is converted peripherally to estrogens.
• Incomplete forms of androgen resistance are caused by mutations in the androgen receptor.

5α-reductase-2 deficiency

• Mutations in the SRD5A2 gene coding for 5α-reductase-2, an enzyme that converts testosterone to dihydrotestosterone, lead to deficiency of DHT.
  • At birth, affected males may have ambiguous genitalia or be phenotypically female as a result of decreased conversion of testosterone to DHT in the sexual skin during the critical times of male genital development.
  • These patients have well-developed wolffian ducts (given that these structures are testosterone and not DHT responsive) and absent müllerian structures (given that AMH is produced from the normal testes).
  • During puberty, virilization occurs with growth of the phallus and testes, probably secondary to expression of a different form of the 5α-reductase enzyme (type 1) in the liver and other tissues at that time, with subsequent increases in circulating DHT levels.

Disorders of gonadal differentiation (sex chromosome disorders of sexual development)

• Turner syndrome (syndrome of gonadal dysgenesis)
  • Classic manifestations of Turner syndrome are linked to the absence of the SHOX gene on the X chromosome.
• Other disorders of gonadal development
  • Additional disorders of testicular development may be caused by:
    • Complete XY gonadal dysgenesis (Swyer syndrome)
    • Partial gonadal dysgenesis
    • Gonadal regression
  • Gonadal dysgenesis is descriptive and bears no etiologic relationship to the syndrome of gonadal dysgenesis or Turner syndrome.
  • 15–20% of these cases are caused by mutations in the SRY gene.
  • Partial gonadal dysgenesis in 46, XY individuals leads to variable amount of testosterone and AMH production.
  • Anorchia must be considered in all phenotypic male patients with bilaterally nonpalpable testes.
  • Gonadal dysgenesis may occur in patients with a 46, XX karyotype who may have streak gonads and sexual infantilism, but none of the other characteristics of Turner syndrome.
  • Genetic abnormalities, such as translocation of the SRY gene, can result in a 46, XX genotypic patient developing testicular instead of ovarian tissue.

History

• Evaluation of an infant with a disorder of sexual differentiation must include a detailed obstetric and family history.
• The patient’s mother should be asked about medication use and symptoms of virilization during pregnancy.
  • May occur in aromatase deficiency or with androgen-secreting maternal ovarian or adrenal tumors
• Family history should not focus solely on genital abnormalities but should include
  • History of consanguinity
  • Unexplained neonatal deaths, especially in apparently phenotypic males
  • Infertility
  • Disorders of puberty
• Many conditions associated with ambiguous genitalia are sporadic or inherited in an autosomal-recessive manner.

Physical examination

• Initial physical examination should begin with an assessment of the general health of the patient and an evaluation for malformations or dysmorphic features.
• Physical findings in patients with DSD may range from an apparently normal phenotype to complete ambiguity.
• Unstable vital signs or hypoglycemia with no apparent cause should raise concern about cortisol deficiency associated with CAH.
• Typically, shock in patients with CAH does not develop until day 4–5 of life.
• Patients with ambiguous genitalia may benefit from earlier diagnosis of salt loss and signs of cortisol deficiency than phenotypically normal patients.
• Midline abnormalities, such as cleft palate, may be associated with hypopituitarism and low gonadotropin levels, leading to microphallus.
• Increased skin pigmentation caused by elevated levels of ACTH occurs well after the newborn period and thus is not helpful in early diagnosis.
• Stretched penile length in a term male infant should be >2 cm.
  • Average length is ~ 3.5 cm.
• A normally formed phallus and scrotum indicate that testosterone production in the critical window of male differentiation was appropriate.
• Micropenis (penile length < 2 cm) often indicates gonadotropin deficiency and may be a sign of hypopituitarism.
  • Congenital growth hormone deficiency can also cause microphallus.
  • Proper examination technique is critical, as an infant with chordee or a generous suprapubic fat pad may be thought mistakenly to have micropenis.
• Position of the urethral meatus should be noted.
  • Sometimes requires observation of urination
  • A urogenital sinus can be mistaken for the urethra.
  • Indentation at the end of the glans penis can be mistaken for the penile urethra.
• The labioscrotal folds should be examined for:
  • Degree of fusion
  • Symmetry
  • Rugosity
  • Color
• Presence or absence of a vaginal opening should be established.
• Gonads, when palpable bilaterally, are most often testes, but might be ovaries or ovotestes as well.
• A unilaterally palpable and symmetrical gonad may be a testis, an ovotestis, or an ovary.
• Sweeping the fingers down the path of the inguinal canal with soap may allow palpation of gonads that might not otherwise be located.
• If gonads are palpable, then the infant is not a virilized female with CAH, because these patients have nonpalpable gonads (ovaries) that are normally situated in the pelvis.

• Differential diagnosis of the infant born with developmental anomalies of the external genitalia is extensive, given the complicated process of human sexual differentiation.
• Table 286-1 lists differential diagnosis of adrenal enzyme defects.

46, XX disorders of sexual development

• Late-onset, or nonclassical, 21-hydroxylase deficiency begins with excessive or premature acne and sexual hair.
  • May be associated with increased growth and bone age advancement
• 17-Hydroxylase deficiency
  • Females are phenotypically normal at birth but will not progress through pubertal changes.
  • Primary amenorrhea may be the presenting feature.
• 3β-Hydroxysteroid dehydrogenase deficiency
  • Genetic females may be phenotypically normal or have varying levels of clitoromegaly or labial fusion.
  • Varying degrees of salt loss, as a result of aldosterone deficiency
• Aromatase deficiency
  
  • Females may exhibit mild virilization in addition to osteopenia and delayed bone age (given the estrogen deficiency).

46, XY disorders of sexual development

• 3β-Hydroxysteroid dehydrogenase deficiency
  • Affected males may be incompletely masculinized at birth.
  • Often experience salt loss or adrenal crisis in infancy
  • May experience gynecomastia around the time of puberty
  • Elevated levels of enzyme substrates, such as DHEA and delta-5-pregnenolone
• Aromatase deficiency
  • Males with aromatase deficiency will be tall and have delayed bone age and osteoporosis caused by estrogen deficiency.

Defects in androgen action

• Development of female secondary sexual characteristics
  • Pubic and axillary hair is sparse, if present at all.
  • Menarche cannot occur.
• Incomplete forms of androgen resistance have great phenotypic variability.
  • External genitalia may range in appearance from completely ambiguous to mildly hypoplastic male genitalia with a small but normally formed phallus.
  • Hypoplastic wolffian duct structures are typically present.
  • Müllerian derivatives are absent because of production of AMH.
  • At puberty, virilization is usually incomplete.
  • Gynecomastia often becomes apparent.
  • Axillary and pubic hair is normal in amount and distribution.
• External genitalia are phenotypically female, given the inability of the tissue to respond to dihydrotestosterone.
• Müllerian structures, such as the cervix and uterus, are absent or hypoplastic.
  • Production of AMH by the fetal Sertoli cells is normal.
  • The vagina ends in a blind pouch.

5α-reductase-2 deficiency

• Secondary sexual characteristics, such as increased muscle mass and voice deepening

Disorders of gonadal differentiation (sex chromosome disorders of sexual development)

• Klinefelter syndrome
  • Before puberty, patients have:
    • Decreased upper segment to lower segment ratios
    • Small testes
    • Increased incidence of developmental delay (mainly in the areas of speech and language)
    • Behavioral problems
  • Puberty is not usually delayed because Leydig cell function is characteristically less affected than seminiferous tubule function.
  • Testosterone is often adequate to stimulate pubertal development.
  • Serum gonadotropin levels increase after the onset of puberty, as the testes become firm and rarely grow >3.5 cm in diameter.
  • After the onset of puberty, histologic changes of seminiferous tubule hyalinization and fibrosis, adenomatous changes of the Leydig cells, and impaired spermatogenesis occur.
  • Gynecomastia is common.
  • Variable degrees of male secondary sexual development
• Turner syndrome (syndrome of gonadal dysgenesis)
  • Turner syndrome (45, XO karyotype) is associated with:
    • Sexual infantilism
    • Short stature
    • Characteristic female phenotype often includes webbing of the neck
  • Patients have streak gonads consisting of fibrous tissue without germ cells.
  • Pubic hair may appear late and is usually sparse.
    • Adrenarche progresses even in the absence of gonadarche.
  • Serum gonadotropin concentrations are extremely high between birth and age 4 years.
    • Decrease toward the normal range in prepubertal patients and then increase again dramatically after age 10 years
  • Because of decreased ovarian secretion of estrogens, puberty does not usually begin spontaneously.
    • Patients have no pubertal growth spurt and reach a mean final height of 143 cm.
    • Growth hormone function is usually normal.
  • Various mosaic forms have been identified, with such karyotypes as 45, X/46, XX, or 45,X/46,XY.
  • These patients may have any phenotype varying from normal female to normal male to manifestations of many of the features of Turner syndrome.
    • Some have apparently normal gonadal function.
    • Others have abnormality of 1 X chromosome, such as a ring X, or other abnormalities, which are out of the scope of this chapter.
• Other disorders of gonadal development
  • In complete gonadal dysgenesis, 46, XY karyotype individuals fail to develop normal testes.
  • Instead, they have:
    • Gonadal streaks
    • Müllerian duct development
    • Wolffian duct regression
    • Female external genitalia
  • Usually associated with ambiguous genitalia and partial development of both the wolffian and müllerian ducts
  • In gonadal regression or vanishing testes syndrome, the testes are lost after the external genitalia and internal structures have formed.
  • These 46, XY individuals will be phenotypically male except for absence of both testes.
  • Patients may phenotypically resemble those with Klinefelter syndrome.

• Ovotesticular disorders of sexual development
  • Patients with ovotesticular DSD have both ovarian and testicular tissue present.
  • The majority of patients have a 46, XX phenotype, and the remainder have a 46, XY karyotype or 46, XX/46, XY chimerism.
  • Great phenotypic variability exists in both the internal and external genitalia in these patients.

• Diagnostic algorithms for evaluation of infants with indeterminate gender, as well as some infants with relatively subtle genital findings are shown in Figure 1 and Figure 2.
• In males, even very mild hypospadias can be considered to represent incomplete masculinization.
  • Most uncomplicated cases do not need diagnostic evaluation.
  • More severe degrees of hypospadias, especially when a testis is not palpable, should raise concern about an identifiable abnormality.
  • In an apparently phenotypic female, mild clitoromegaly may represent
    • Severe undervirilization in a genetic male who has undescended testes
    • Masculinization of a female fetus
• Specific recommendations for which genital findings should elicit concern for a sexual development disorder
  • An apparent male born at term with the following characteristics:
    • Bilateral nonpalpable testes
    • Micropenis
    • Perineal hypospadia
    • Single undescended testis with hypospadia of any degree
  • An apparent female with the following characteristics:
    • Clitoral hypertrophy of any degree
    • Posterior labial fusion (but not just labial adhesions)
    • Inguinal or labial mass
  • All infants with truly ambiguous genitalia and thus indeterminate gender
  • Infants with family history of DSD or discordance between apparent gender and a previously obtained prenatal karyotype
  • Because the testes do not normally descend until ~ 34 weeks of gestation, significantly preterm males with nonpalpable testes alone do not necessarily require evaluation.
• No individual patient should be assumed to have virilizing adrenal hyperplasia.
• Newborn screening should eliminate cortisol and aldosterone deficiency in diagnostic time.
• Diagnosis of P450c11 hydroxylase deficiency is usually made after the discovery of elevated levels of 11-deoxycortisol (compound S).
• Diagnosis of aromatase deficiency is made around the time of puberty.
• Defects in androgen action are suggested by elevated levels of testosterone.
• 5α-reductase-2 deficiency
  • Ovotesticular disorders of sexual development
    • Ovotesticular DSD should be considered in all patients with DSD.
    • A 46, XX/46, XY karyotype or a bilobate gonad in the inguinal region or labioscrotal folds should raise suspicion.

• Basic serum chemistries should be obtained immediately to evaluate for salt wasting or hyperkalemia associated with CAH.
  • Abnormalities may take days to become apparent.
• Normal electrolyte values in the few days after birth do not exclude salt losing.
• Karyotype will establish whether the patient is genotypically XX or XY (or other) and should always be performed.
  • Results from an urgently ordered karyotype can be available within ~ 3 days in some cytogenetics laboratories.
• Endocrine testing generally consists of measurement of:
  • 17-OHP
  • Testosterone
  • DHT
  • Androstenedione
  • Follicle-stimulating hormone
  • LH
  • AMH
• Tests should be performed in a national specialty laboratory with pediatric standards rather than the local laboratory.
  • Most local laboratories are unlikely to have pediatric standards or appropriately sensitive techniques.
  • On the basis of these results, additional tests may be performed.
• In the first weeks after birth, measurement of testosterone may reveal the amplitude of the episodic spike of testosterone.
• After this period, hCG administration will help determine whether functional Leydig cells are present (given that functional cells will secrete testosterone in response to the hCG).
• Serum testing of the steroid hormones involved in the pathways for cortisol and testosterone is indicated in many cases because the forms of CAH rarer than 21-hydroxylase deficiency will not cause elevations in 17-OHP levels.
• In some cases, stimulatory testing with ACTH is necessary.
• Newborn screening for 21-hydroxylase deficiency (but not other forms of CAH) is currently done in 46 states.
  • Testing is required but not yet implemented in 3 of the 4 remaining states.
  • Results can be returned several days after the specimens are drawn.
  • Available within the first week of life, but not always before clinical symptoms develop
  • This screening test is most helpful in diagnosing the condition in males who appear normal but are affected.
• 5α-reductase-2 deficiency
  • Laboratory testing reveals abnormally high testosterone/DHT ratios with normal to elevated testosterone and low to undetectable DHT.
• Confirmatory testing via mutation analysis of the 5α-reductase-2 gene is currently only available as a research tool.

• Imaging is useful to determine internal anatomy.
• Ultrasonography
  • Determination of the presence and appearance of müllerian structures
    • Lack of müllerian structures implies that AMH was produced from testicular tissue and that the underlying problem is an abnormality of testosterone or DHT synthesis or action.
  • Renal problems (eg, in Frasier syndrome)
  • Visualization of the adrenal glands
  • Visualization of the gonads
    • Magnetic resonance imaging may be required, particularly if the gonads are intraabdominal.
  • Defects in androgen action
    • Shown by absence of the corpus and cervix and the presence of testes

• A team to address the multiple issues surrounding management of patients with DSD may include:
  • Endocrinologist
  • Urologist and/or pediatric surgeon and/or plastic surgeon
  • Gynecologist
  • Neonatologist
  • Geneticist
  • Ethics specialist
  • Psychologist or psychiatrist
  • Social worker
• Gender assignment should be avoided after delivery and during evaluation.
  • The infant should be referred to using gender-neutral terms such as your baby or the baby rather than he or she.
• Goal is to establish a diagnosis as rapidly as possible.
• Gender assignment should occur with the participation of the family.
  • The family must realize that not all patients with a given abnormality identify themselves in the same way.
  • Considerations may need to include cultural practices.
• Factors to consider include:
  • Underlying diagnosis
  • Fertility
  • Capacity for sexual function
  • Appearance of the genitalia
  • Surgical options
  • Potential hormonal therapies
• Surgical issues include:
  • Preventing patient dissatisfaction with genital reconstruction discordant with his/her gender identity
  • Timing and feasibility of surgery
  • Potential for malignant degeneration of a gonad in certain disorders of sexual development involving Y chromosome material
    • In the case of a streak gonad of an XY cell line, the gonad should be removed at the time of diagnosis.
    • In androgen resistance syndrome, the testis may be brought into the scrotum, where it can be observed for potential cancer.
• Long-term psychological support is required for the majority of patients with DSD.
  • Help should be provided by a mental health professional, preferably experienced in DSD.
  • National and local support groups are available for families.
• Gender identity is the personal conception of oneself as male or female.
  
  • It is distinct from sexual orientation and gender role.
  • Influences on gender identity include:
    • Hormonal effects (specifically androgen effect on the prenatal brain)
    • Brain structural differences
    • Assigned sex of rearing
    • Sex-steroid effects at the time of puberty
  • Some patients who are assigned a particular gender are later dissatisfied.
• Outcome data for gender identity in DSD are relatively sparse; the largest study to date showed that:
  • Genetic males with active prenatal androgen effects should be raised as males.
  • Female infants virilized as a result of CAH should be given a female gender assignment.
• Gender identity outcomes are more difficult to predict in other disorders.

Equivocal cases

• A trial of testosterone injections (eg, 25 mg of testosterone enanthate intramuscularly every month for 3 months) is given in some equivocal cases to assess whether phallus size responds to androgen, eliminating substantial androgen resistance.
  • The effect of this cannot be assessed for several months.

Defects in androgen action

• Removal of the testicular tissue is indicated, given the increased risk of neoplasm after puberty.
  • The timing of removal is controversial.
  • After removal of the testes, estrogen replacement is provided.

5α-reductase-2 deficiency

• Some patients change gender identity from female to male at the time of puberty.

Disorders of gonadal differentiation (sex chromosome disorders of sexual development)

• Turner syndrome (syndrome of gonadal dysgenesis)
  • Growth hormone treatment increases growth rate and adult stature.
  • Estrogen treatment is initiated in adolescence in these patients to allow feminization.

• Patients with significant electrolyte abnormalities, such as hyponatremia and hyperkalemia
• Patients with dehydration
• Patients with hypoglycemia

• All patients with ambiguity of the external genitalia should be evaluated immediately by an experienced multidisciplinary team that includes a pediatric endocrinologist.
• This process necessitates transfer of the patient to a medical center with a neonatal intensive care unit and the appropriate pediatric subspecialists.
• The patient should never be sent home and referred to subspecialty care as an outpatient.
• Indications for referral include:
  • In a male infant born at term
    • Bilateral nonpalpable testes
    • Micropenis
    • Perineal hypospadias
    • Single undescended testes with hypospadias of any degree
  • In a female infant
    • Clitoral hypertrophy of any degree
    • Posterior labial fusion (not adhesion)
    • Inguinal or labial mass

• DSD is considered an endocrine emergency.
  • In the majority of cases, the genital findings may be accompanied by:
    • Life-threatening electrolyte abnormalities
    • Hypotension
    • Shock
• The psychological stress to the family cannot be overstated.

• In its most serious form, cortisol and aldosterone deficiency are severe enough to result in:
  • Severe hyponatremia
  • Hyperkalemia
  • Dehydration
  • Hypotension
  • Shock
  • Death
• Male infants die more frequently than female infants.
  • As a result of their visibly normal phenotype at birth, the condition is not suspected.
• Female infants with virilization are usually evaluated quickly.

• Disorders of gonadal differentiation (sex chromosome disorders of sexual development)
  • In Klinefelter syndrome, the risk of breast cancer is increased.

• Lee PA, Houk CP, Ahmed SF, Hughes IA; International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics. 2006;118:e488-500.  [PMID:16882788]. AAP endorsed.

• Achermann JC, Hughes IA. Disorders of Sex Development. In: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, eds. Williams Textbook of Endocrinology. Philadelphia, PA: WB Saunders; 2008.
• Conte FA, Grumbach MM. Abnormalities of sexual determination and differentiation. In: Gardner DG, Shoback D, eds. Greenspan’s Basic and Clinical Endocrinology. 8th ed. New York, NY: McGraw-Hill Medical; 2007.
• Lee PA, Houk CP, Ahmed SF, Hughes IA; International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics. 2006;118:e488-500.  [PMID:16882788] AAP endorsed.
• Reiner WG. Gender identity and sex-of-rearing in children with disorders of sexual differentiation. J Pediatr Endocrinol. 2005;18:549-553.  [PMID:16042322]
• Styne DM. Sexual differentiation. In: DM Styne, ed. Pediatric Endocrinology (Core Handbook Series in Pediatrics). Philadelphia, PA: Lippincott Williams & Wilkins; 2003.