10: Disorders of sexual development

Question 1

What is the primary determinant of testis development in normal sexual development?
A. SRY gene on the Y chromosome
B. SRY gene on the X chromosome
C. Presence of an additional X chromosome
D. Presence of a Y chromosome

Answer 1

A. SRY gene on the Y chromosome

Question 2

During what time frame in development are the gonadal ridge, germ cells, internal ducts, and external genitalia bipotential in both 46,XY and 46,XX embryos?
A. First trimester
B. First 6 weeks
C. Second trimester
D. Third trimester

Answer 2

B. First 6 weeks

Question 3

What is the term used to describe disruption of any of the three interactions of normal sexual development?
A. Normal sexual development
B. Chromosomal sex
C. Phenotypic sex
D. Disorder of sexual development (DSD)

Answer 3

D. Disorder of sexual development (DSD)

Question 4

Explain the three processes of normal sexual development.

Answer 4

Normal sexual development involves three processes: establishment of genotypic (chromosomal) sex, establishment of phenotypic sex, and formation of gender identity. Establishment of genotypic sex refers to the sex chromosomes an individual inherits from their parents. Establishment of phenotypic sex refers to the development of internal and external genitalia and other physical characteristics that define an individual’s biological sex. Formation of gender identity refers to an individual’s subjective sense of themselves as male, female, or somewhere in between.

Question 5

How does disruption of normal sexual development lead to a disorder of sexual development (DSD)?

Answer 5

Disruption of any of the three interactions of normal sexual development can lead to a disorder of sexual development (DSD). This can occur due to genetic or hormonal abnormalities, environmental factors, or a combination of factors. DSDs can lead to atypical development of the gonads, internal and external genitalia, and other physical characteristics. Additionally, DSDs can affect an individual’s gender identity and sexual orientation.

Question 6

What role does the SRY gene play in normal sexual development?

Answer 6

The SRY (sex-determining region Y) gene on the Y chromosome is considered the testis-determining factor in normal sexual development. Under this influence, the bipotential gonadal ridges differentiate into testes, and germ cells develop into spermatocytes. In the absence of SRY, ovarian organogenesis results. The presence or absence of the SRY gene is a critical determinant of an individual’s chromosomal and phenotypic sex.

Question 7

Image
FIG. 10.1 Timetable of normal sexual differentiation. Source: (From White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000;21(3):245-291.)

Answer 7

Question 8

Table 10.1

Common Embryologic Origins of Genital Structures.

Answer 8

Question 9

What is the primary determinant of testis formation during sexual differentiation?

A) Anti-Müllerian hormone
B) Dihydrotestosterone
C) Estrogen
D) Testosterone

Answer 9

D) Testosterone

Explanation: The SRY gene on the Y chromosome is considered the testis-determining factor, which causes the bipotential gonadal ridges to differentiate into testes. Testosterone secretion by the fetal testis Leydig cells occurs at approximately 9 weeks of gestation and promotes virilization of wolffian duct structures, the urogenital sinus, and the genital tubercle.

Question 10

Which of the following hormones promotes Müllerian duct regression during sexual differentiation?

A) Anti-Müllerian hormone
B) Dihydrotestosterone
C) Estrogen
D) Testosterone

Answer 10

A) Anti-Müllerian hormone

Explanation: The Sertoli cells of the testis secrete anti-Müllerian hormone (AMH) at 7 to 8 weeks of gestation, which promotes Müllerian duct regression.

Question 11

Describe the normal process of sexual development in the first 6 weeks of embryonic development.

Answer 11

During the first 6 weeks of embryonic development, the gonadal ridge, germ cells, internal ducts, and external genitalia are bipotential in both 46,XY and 46,XX embryos. Multiple genes are thought to determine chromosomal sex. Specifically, the SRY (sex-determining region Y) gene on the Y chromosome is considered the testis-determining factor. Under the influence of the SRY gene, the bipotential gonadal ridges differentiate into testes, and germ cells develop into spermatocytes. In the absence of SRY, ovarian organogenesis results. The wolffian ducts adjacent to the testes form the epididymis, joining with the rete testes. Distally the wolffian ducts join the urogenital sinus to develop into the seminal vesicles. In the female fetus without testosterone, the wolffian ducts regress. Without AMH, the Müllerian ducts develop into the female internal reproductive tract, including the fallopian tubes and uterus. Contact of the ducts with the urogenital sinus ultimately forms the vagina.

Question 12

Describe the role of androgens in sexual differentiation and the formation of the male external genitalia.

Answer 12

During sexual differentiation, androgens promote virilization of wolffian duct structures, the urogenital sinus, and the genital tubercle. Testosterone secretion by the fetal testis Leydig cells occurs at approximately 9 weeks of gestation. Testosterone enters target tissues by passive diffusion, and wolffian duct virilization does not occur if local androgens are not present. In some cells, testosterone is converted to dihydrotestosterone (DHT) by intracellular 5α-reductase. Testosterone or DHT then binds to an intracellular androgen receptor. DHT binds to the receptor with greater affinity and stability than does testosterone. In tissues equipped with 5α-reductase at the time of sexual differentiation (e.g., prostate, urogenital sinus, external genitalia), DHT is the active androgen. Masculinization of the external genitalia is complete by 12–13 weeks of gestation.

Question 12

Describe the role of androgens in sexual differentiation and the formation of the male external genitalia.

Answer 12

During sexual differentiation, androgens promote virilization of wolffian duct structures, the urogenital sinus, and the genital tubercle. Testosterone secretion by the fetal testis Leydig cells occurs at approximately 9 weeks of gestation. Testosterone enters target tissues by passive diffusion, and wolffian duct virilization does not occur if local androgens are not present. In some cells, testosterone is converted to dihydrotestosterone (DHT) by intracellular 5α-reductase. Testosterone or DHT then binds to an intracellular androgen receptor. DHT binds to the receptor with greater affinity and stability than does testosterone. In tissues equipped with 5α-reductase at the time of sexual differentiation (e.g., prostate, urogenital sinus, external genitalia), DHT is the active androgen. Masculinization of the external genitalia is complete by 12–13 weeks of gestation.

Question 13

Image
FIG. 10.2 Schematic diagram of differentiation of the male external genitalia. Source: (From Martinez-Mora J. Development of the genital tract. In: Martinez-Mora J, ed. Intersexual states: disorders of sex differentiation. Barcelona: Ediciones Doymer, 1994:53.)

Answer 13

Question 14

Image
FIG. 10.3 Schematic diagram of differentiation of the female external genitalia. Source: (From Martinez-Mora J. Development of the genital tract. In: Martinez-Mora J, ed. Intersexual states: disorders of sex differentiation. Barcelona: Ediciones Doymer, 1994:52.)

Answer 14

Question 15

Image
FIG. 10.4 Differentiation of the wolffian and Müllerian duct and urogenital sinus in the male and female. Source: (From Wilson JD. Embryology of the genital tract. In: Harrison HH, Gittes RF, Perlmutter AD, et al., eds. Campbell’s urology. 4th ed. Philadelphia, PA: WB Saunders, 1979:1473.)

Answer 15

Question 16

What is the most widely used terminology for the conditions of abnormal sexual differentiation?
a) Difference of sex development
b) Intersex
c) Disorders of sexual development
d) Androgen insensitivity syndrome

Answer 16

c) Disorders of sexual development

Explanation: The most widely used terminology for the myriad conditions of abnormal sexual differentiation is disorders of sexual development (DSD), or disorders of sexual differentiation.

Question 17

What are the potential causes of disorders of sexual development, and how are they diagnosed?

Answer 17

Answer: Disorders of sexual development can have a variety of causes, including genetic abnormalities, hormonal imbalances, and environmental factors. In some cases, the cause may be unknown. Diagnosis of DSD involves a thorough medical history and physical examination, as well as laboratory testing to evaluate hormone levels and genetic testing to assess chromosomal abnormalities. Imaging studies may also be performed to evaluate the internal reproductive organs.

Question 18

What is the term used to describe a condition in which the individual has external female genitalia but has undescended testes instead of ovaries?
a) Turner syndrome
b) Klinefelter syndrome
c) Androgen insensitivity syndrome
d) 5-alpha-reductase deficiency

Answer 18

) Androgen insensitivity syndrome

Explanation: Androgen insensitivity syndrome (AIS) is a condition in which the individual has external female genitalia but has undescended testes instead of ovaries

Question 19

What is the difference between Turner syndrome and Klinefelter syndrome, and how do these conditions impact sexual development?

Answer 19

Turner syndrome is a genetic condition that affects females, and is caused by a missing or incomplete X chromosome. This can lead to a variety of physical and developmental abnormalities, including underdeveloped or absent ovaries, which can result in infertility and delayed or absent puberty. In contrast, Klinefelter syndrome is a genetic condition that affects males, and is caused by an extra X chromosome. This can lead to a variety of physical and developmental abnormalities, including reduced testosterone production, which can result in delayed or incomplete puberty and infertility.

Question 20

What is the most common cause of congenital adrenal hyperplasia (CAH)?
a) Genetic mutations
b) Hormonal imbalances
c) Environmental factors
d) Unknown causes

Answer 20

a) Genetic mutations

Explanation: Congenital adrenal hyperplasia (CAH) is a genetic condition caused by mutations in genes that produce enzymes involved in the production of steroid hormones. This can lead to hormonal imbalances and a variety of physical and developmental abnormalities.

Question 21

What are the potential long-term health implications of disorders of sexual development, and how are these conditions managed?

Answer 21

The long-term health implications of disorders of sexual development can vary depending on the specific condition and its management. Some conditions may increase the risk of certain health problems, such as osteoporosis or certain types of cancer. Management of DSD typically involves a multidisciplinary approach, including medical and surgical interventions, hormone replacement therapy, and psychological support. The goal of management is to optimize physical and psychosocial outcomes, improve quality of life, and address any associated health risks.

Question 22

Table 10.2

Overview of Nomenclature and Classification for Disorders of Sexual Development

Answer 22

Question 23

Which of the following factors should be assessed in the history of a newborn with ambiguous genitalia?
a. Maternal diet during pregnancy
b. Neonatal weight
c. Prenatal testing
d. Father’s occupation

Answer 23

c. Prenatal testing

Question 24

Which of the following is a possible cause of ambiguous genitalia in a newborn?
a. Postnatal exposure to exogenous hormones
b. Overweight mother during pregnancy
c. High neonatal weight
d. Congenital adrenal hyperplasia

Answer 24

d. Congenital adrenal hyperplasia

Question 25

Family history should assess all of the following except:
a. Neonatal deaths
b. Infertility
c. History of diabetes
d. Consanguinity

Answer 25

c. History of diabetes

Question 26

What is consanguinity?

Answer 26

Consanguinity refers to the degree of blood relationship between two individuals, such as first cousins or siblings. In some cultures and populations, consanguineous marriages are more common, which can increase the likelihood of certain genetic disorders being passed down through generations. A family history of consanguinity may be relevant in the evaluation of a newborn with ambiguous genitalia.

Question 27

What is ambiguous genitalia in newborns and what are some of the possible causes?

Answer 27

Ambiguous genitalia in newborns refers to a condition in which the genitalia are not clearly male or female. This can be due to a variety of factors, including genetic abnormalities, hormonal imbalances, and environmental factors. Some possible causes include congenital adrenal hyperplasia, androgen insensitivity syndrome, and abnormalities in the production or response to hormones such as testosterone or estrogen.

Question 28

Why is a thorough history important in the diagnosis and management of newborns with ambiguous genitalia?

Answer 28

A thorough history is important in the diagnosis and management of newborns with ambiguous genitalia because it can provide important information about possible causes and guide further testing and management. Factors such as level of prematurity, exposure to exogenous hormones by mother, and prenatal testing such as fetal karyotype or appearance of genitalia on sonogram can all provide important clues. Family history is also important, as certain conditions such as congenital adrenal hyperplasia may be inherited and may affect multiple family members.

Question 29

What are some of the factors that should be assessed in the family history of a newborn with ambiguous genitalia?

Answer 29

In the family history of a newborn with ambiguous genitalia, it is important to assess for a variety of factors that may provide important clues to the underlying cause. These may include neonatal deaths (suggestive of congenital adrenal hyperplasia [CAH]), urologic diagnoses in children or adults, precocious puberty, infertility, amenorrhea, hirsutism, or consanguinity. By assessing these factors, healthcare providers may be able to better identify possible causes and guide further testing and management.

Question 30

Which of the following is highly suggestive of the presence of a testicle in a newborn with ambiguous genitalia?
A. A nonpalpable gonad
B. A palpable gonad in the abdomen
C. A palpable gonad in the inguinal canal or scrotum
D. A palpable gonad in the labioscrotal folds

Answer 30

C. A palpable gonad in the inguinal canal or scrotum is highly suggestive of the presence of a testicle.

Question 31

What should be assessed during phallic examination of a newborn with ambiguous genitalia?
A. The degree of rugation and pigmentation of the labioscrotal folds
B. The number and location of perineal orifices
C. The presence of a uterus
D. Stretched penile length

Answer 31

D. Stretched penile length should be measured during phallic examination.

Question 32

How can the presence of a uterus be determined on physical exam in a newborn with ambiguous genitalia?
A. By visual inspection of the external genitalia
B. By palpation of an anterior midline cordlike structure on rectal examination
C. By measuring stretched penile length
D. By assessing the degree of rugation and pigmentation of the labioscrotal folds

Answer 32

B. The presence of a uterus can sometimes be determined on physical exam by palpation of an anterior midline cordlike structure on rectal examination.

Question 33

What is the significance of a nonpalpable testicle or a unilateral nonpalpable testis in the presence of any degree of hypospadias in a newborn with ambiguous genitalia?

Answer 33

Bilaterally nonpalpable testicles or a unilateral nonpalpable testis in the presence of any degree of hypospadias should be treated as disorders of sexual development (DSD) until proven otherwise. This is because these findings suggest an underlying hormonal or genetic abnormality that may require further evaluation and management.

Question 34

What other dysmorphic features should be noted during the physical examination of a newborn with ambiguous genitalia?

Answer 34

In addition to genital examination, it is important to note other dysmorphic features suggestive of genetic disorders, such as short, broad neck associated with Turner syndrome. This is because DSD can be associated with various genetic disorders and other systemic abnormalities that may require further evaluation and management.

Question 35

How is the presence of an ovotestis diagnosed in a newborn with ambiguous genitalia?

Answer 35

An ovotestis is a rare condition in which both ovarian and testicular tissue are present in the same gonad. In some cases, an ovotestis may undergo descent and be palpable in the inguinal canal or scrotum. However, the diagnosis of an ovotestis usually requires histological examination of the gonad after surgical removal.

Question 36

Which of the following is NOT included in the immediate serum laboratory evaluation for newborns with ambiguous genitalia?
a. Karyotype
b. Serum electrolytes
c. 17-hydroxyprogesterone
d. Prostate-specific antigen (PSA)

Answer 36

d. Prostate-specific antigen (PSA)

Explanation: The immediate serum laboratory evaluation for newborns with ambiguous genitalia includes karyotype, serum electrolytes, 17-hydroxyprogesterone, testosterone, LH, and FSH. PSA is not part of the evaluation.

Question 37

What is the purpose of the human chorionic gonadotropin (hCG) stimulation test in newborns with ambiguous genitalia?
a. To determine the presence of testicular tissue
b. To determine the presence of Müllerian structures
c. To evaluate for functional anorchia
d. To evaluate for salt-wasting form of CAH

Answer 37

a. To determine the presence of testicular tissue

Explanation: The hCG stimulation test is used to determine the presence or absence of testicular tissue in newborns with ambiguous genitalia. A failure to respond to hCG in combination with other laboratory findings can indicate functional anorchia.

Question 38

Which imaging modality can be helpful in determining the presence of Müllerian structures and/or gonads in newborns with ambiguous genitalia?
a. X-ray
b. Pelvic ultrasound
c. Computed tomography (CT)
d. Magnetic resonance imaging (MRI)

Answer 38

d. Magnetic resonance imaging (MRI)

Explanation: Pelvic ultrasound or MRI can be helpful in determining the presence of Müllerian structures and/or gonads in newborns with ambiguous genitalia.

Question 39

What is the role of karyotyping in the evaluation of newborns with ambiguous genitalia?

Answer 39

Answer: Karyotyping is an important part of the evaluation of newborns with ambiguous genitalia, as it can help to identify X and Y chromosome material and determine the genetic sex of the baby. This information can be used to guide further evaluation and management.

Question 40

What is the most common presentation of DSD in the newborn?
a) Abnormal reproductive tract development
b) Ambiguous genitalia
c) Undescended testicles
d) Delayed puberty

Answer 40

Answer: b) Ambiguous genitalia

Question 41

Which of the following specialties should be included in the multidisciplinary team for management of DSD in the newborn?
a) Urologist
b) Endocrinologist
c) Geneticist
d) Psychiatrist/Psychologist/Social worker
e) All of the above

Answer 41

e) All of the above

Question 42

What are the initial goals of care for a newborn with suspected DSD?
a) Psychological stabilization
b) Diagnosis
c) Reproductive tract development
d) Sex reassignment surgery

Answer 42

b) Diagnosis

Question 43

How is sex of rearing determined for a newborn with DSD?
a) Based on the parent’s preference
b) Based on the child’s gender identity
c) Based on diagnosis, anatomy, and functional potential of the genital and reproductive tract
d) Based on the child’s external appearance

Answer 43

c) Based on diagnosis, anatomy, and functional potential of the genital and reproductive tract

Question 44

What are the most common causes of DSD in the newborn, and how are they diagnosed and managed?

Answer 44

The most common causes of DSD in the newborn are congenital adrenal hyperplasia (CAH), androgen insensitivity syndrome (AIS), and 5-alpha-reductase deficiency. Diagnosis involves a combination of clinical examination, imaging studies, and laboratory testing. Treatment of CAH involves hormone replacement therapy, while AIS and 5-alpha-reductase deficiency may require surgery to reconstruct the external genitalia.

Question 45

Image
FIG. 10.5 Diagnostic algorithm for DSD based on number of gonads palpated. 17-OHP, 17-Hydroxyprogesterone; AMH, anti-Müllerian hormone; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; LH, luteinizing hormone; MRI, magnetic resonance imaging.

Answer 45

Question 46

Table 10.3

Clinical Presentation for Disorders of Sexual Development After the Newborn Period

Answer 46

Question 47

What is the most common major abnormality of sexual development?
a) Turner syndrome
b) Klinefelter syndrome
c) Congenital adrenal hyperplasia
d) Androgen insensitivity syndrome

Answer 47

b) Klinefelter syndrome

Question 48

What is the classic karyotype associated with Klinefelter syndrome?
a) 47,XXX
b) 46,XX
c) 47,XY
d) 47,XXY

Answer 48

d) 47,XXY

Question 49

What is the most common cause of infertility in Klinefelter syndrome?
a) Low testosterone levels
b) Elevated estradiol levels
c) Seminiferous tubules degeneration
d) Hyaline replacement of testicles

Answer 49

c) Seminiferous tubules degeneration

Question 50

What is the recommended management for gynecomastia in Klinefelter syndrome?
a) Androgen supplementation
b) Reduction mammoplasty
c) Both a) and b)
d) Intracytoplasmic sperm injection

Answer 50

c) Both a) and b)

Question 51

What is the retrieval rate for sperm in microdissection testicular sperm extraction in nonmosaic Klinefelter syndrome patients?
a) 10%-20%
b) 20%-30%
c) 40%-50%
d) 50%-60%

Answer 51

c) 40%-50%

Question 52

What is the pathophysiology of Klinefelter syndrome?

Answer 52

Klinefelter syndrome is characterized by the presence of at least one Y chromosome and at least two X chromosomes. This results in testicular dysgenesis, where seminiferous tubules degenerate and are replaced by hyaline, leading to small and firm testicles. The decreased testosterone levels and increased estrogen levels result in gynecomastia, breast carcinoma, and extragonadal germ cell tumors. The majority of patients are infertile with azoospermia.

Question 53

What are the clinical manifestations of Klinefelter syndrome?

Answer 53

Patients with Klinefelter syndrome may present with small and firm testicles, gynecomastia, reduced body hair, decreased libido, and infertility. They are also at an increased risk for breast carcinoma, extragonadal germ cell tumors, and Leydig/Sertoli cell tumors.

Question 54

How is Klinefelter syndrome diagnosed and evaluated?

Answer 54

The diagnosis of Klinefelter syndrome is confirmed by a karyotype analysis, which typically shows a 47,XXY chromosomal pattern. The serum testosterone levels are low-normal, while the gonadotropins and estradiol levels are elevated. Imaging studies, such as testicular ultrasound or magnetic resonance imaging, may reveal small and firm testicles.

Question 55

What is the recommended management for Klinefelter syndrome?

Answer 55

Treatment for Klinefelter syndrome includes androgen supplementation to improve libido and reduce gynecomastia. Reduction mammoplasty may also be necessary for severe cases of gynecomastia. Assisted reproductive technology, such as microdissection testicular sperm extraction and intracytoplasmic sperm injection, may be used for nonmosaic patients who desire to have children. Patients should also undergo regular surveillance for breast carcinoma and other malignancies.

Question 56

What does nonmosaic mean?

Answer 56

Nonmosaic patients are those with Klinefelter syndrome who have the same chromosomal pattern in all of their cells. In contrast, mosaic patients have more than one chromosomal pattern in their cells, meaning that only some cells in their body have the extra X chromosome. The distinction between mosaic and nonmosaic Klinefelter syndrome can impact the severity of the condition and the success of treatments such as assisted reproductive technology.

Question 57

What is the hypothesized mechanism for 46,XX male development?
A. Deletion of SRY on the Y chromosome
B. Translocation of Y chromosome material, including SRY, to the X chromosome
C. Mutation of SRY on the X chromosome
D. Overexpression of SRY on the X chromosome

Answer 57

B

Question 58

What is the endocrinologic profile of individuals with 46,XX male?
A. High testosterone and low LH and FSH levels
B. Low testosterone and high LH and FSH levels
C. High estrogen and low LH and FSH levels
D. Low estrogen and high LH and FSH levels

Answer 58

A

Question 59

What is the role of hormonal treatment in individuals with 46,XX male?
A. It can induce fertility and sperm retrieval
B. It can correct the external genitalia abnormalities
C. It can correct the endocrinologic imbalances
D. It has no role due to lack of germ cells

Answer 59

C

Question 60

What is the pathophysiology of 46,XX male and how does it present clinically?

Answer 60

What is the pathophysiology of 46,XX male and how does it present clinically?
46,XX male is a disorder of gonadal differentiation and development characterized by testicular development in individuals with no Y chromosome. The hypothesized mechanism is translocation of Y chromosome material, including SRY, to the X chromosome. This leads to the expression of SRY, which is responsible for initiating male gonadal differentiation. Most individuals with 46,XX male have normal male external genitalia or hypospadias, but all are infertile due to lack of germ cells.

Question 61

How is 46,XX male diagnosed and what is the endocrinologic profile of affected individuals?

Answer 61

Diagnosis of 46,XX male is based on karyotyping, which reveals the presence of two X chromosomes and no Y chromosome. In terms of endocrinologic profile, individuals with 46,XX male have high testosterone levels and low LH and FSH levels, similar to Klinefelter syndrome.

Question 62

What is the management of 46,XX male and why is hormonal treatment important?

Answer 62

The management of 46,XX male involves correcting the endocrinologic imbalances through hormonal treatment, which is similar to the treatment of Klinefelter syndrome. Testosterone replacement therapy can be used to maintain normal male secondary sexual characteristics and bone health. However, because of the lack of germ cells, there is no role for sperm retrieval. Hormonal treatment is important for long-term health and well-being of individuals with 46,XX male.

Question 63

What is the pathophysiology of Turner syndrome?
A. One normal functioning X chromosome and one abnormal Y chromosome
B. Two normal X chromosomes and one abnormal Y chromosome
C. One normal functioning X chromosome and the other sex chromosome may be absent, abnormal or with mosaicism
D. Two abnormal X chromosomes and one normal Y chromosome

Answer 63

C

Question 64

What is a hallmark of Turner syndrome?
a. Lack of development of secondary sex characteristics.
b. Early onset of puberty.
c. Development of male secondary sex characteristics.
d. Normal development of secondary sex characteristics.

Answer 64

a. Lack of development of secondary sex characteristics.

Question 65

What is the risk of gonadoblastoma in patients with Turner syndrome?
a. Less than 5%.
b. 10-12%.
c. 20-25%.
d. More than 30%.

Answer 65

b. 10-12%.

Question 66

Describe the pathophysiology of Turner syndrome.

Answer 66

Turner syndrome is characterized by one normal functioning X chromosome and one absent, abnormal, or mosaic sex chromosome. By birth, gonads are mostly devoid of oocytes, resulting in characteristic streak gonads. The lack of oocytes and the absence of estrogen production lead to a lack of pubertal development of the external genitalia and lack of development of secondary sex characteristics.

Question 67

What are the common manifestations of 45,X type in Turner syndrome?

Answer 67

Manifestations of 45,X type may include short stature, broad chest, widespread nipples, webbing of the neck, peripheral edema at birth, short fourth metacarpal, hypoplastic nails, multiple pigmented nevi, coarctation of the aorta, bicuspid aortic valve, and renal anomalies.

Question 68

How is Turner syndrome diagnosed?

Answer 68

The diagnosis should be considered in any infant with lymphedema or young woman with short stature, lack of secondary sex characteristics, or primary amenorrhea. Karyotype analysis is required to confirm the diagnosis.

Question 69

What is the risk of gonadoblastoma in patients with Turner syndrome, and how is it managed?

Answer 69

Risk of gonadoblastoma is estimated at 12%–20% and has been reported as early as 5 months of age. Determination of Y chromosome material in Turner syndrome is critical because it predisposes to masculinization and gonadoblastoma. Prophylactic gonadectomy in the Y mosaic Turner syndrome patient is advised but not required in the 45,XO patient.

Question 70

What is the management of Turner syndrome?

Answer 70

Endocrinologic evaluation is needed. Growth hormone or sex hormones may be needed for growth and development. Although spontaneous fertility is rare, pregnancy is a possibility for some patients with spontaneous menses. Regular follow-up and monitoring of cardiac and renal function is also recommended.

Question 71

Image
FIG. 10.6 Gross appearance of streak gonad during diagnostic laparoscopy. Source: (Courtesy of D. Diamond, MD.)

Answer 71

Question 72

What is the main characteristic of 46,XX “pure” gonadal dysgenesis?
a. Male external genitalia
b. Absence of Müllerian ducts
c. Elevated serum gonadotropins
d. Presence of wolffian structures

Answer 72

c. Elevated serum gonadotropins

Explanation: Patients with 46,XX “pure” gonadal dysgenesis have normal female external genitalia, normal Müllerian ducts with the absence of wolffian structures, normal height, and bilateral streak gonads. Due to the presence of streak gonads, they have elevated serum gonadotropins. Management involves estrogen and progesterone replacement and gonadectomy is not recommended.

Question 73

What is the recommended management for 46,XX “pure” gonadal dysgenesis?
a. Testosterone replacement
b. Gonadectomy
c. Androgen blockers
d. Estrogen and progesterone replacement

Answer 73

d. Estrogen and progesterone replacement

Explanation: Management of 46,XX “pure” gonadal dysgenesis involves estrogen and progesterone replacement since there is no Y chromosome material and gonadectomy is not recommended.

Question 74

What is gonadal dysgenesis and what are its types?

Answer 74

Gonadal dysgenesis refers to a group of conditions characterized by abnormal gonadal development. There are several types of gonadal dysgenesis, including:

45,X (Turner syndrome)
46,XY gonadal dysgenesis
46,XX gonadal dysgenesis
46,XX/46,XY gonadal dysgenesis (mixed gonadal dysgenesis)

Question 75

What is the second most common cause of ambiguous genitalia in the neonatal period?
A. Turner Syndrome
B. Klinefelter Syndrome
C. Mixed Gonadal Dysgenesis
D. Androgen Insensitivity Syndrome

Answer 75

C. Mixed Gonadal Dysgenesis

Question 76

What is the risk of gonadoblastoma or dysgerminoma in patients with mixed gonadal dysgenesis?
A. 5%-10%
B. 15%-35%
C. 40%-60%
D. 70%-80%

Answer 76

B. 15%-35%

Question 77

What syndrome is associated with nephropathy, genital ambiguity, and Wilms tumor in patients with mixed gonadal dysgenesis?
A. Denys-Drash Syndrome
B. Klinefelter Syndrome
C. Turner Syndrome
D. Frasier Syndrome

Answer 77

A. Denys-Drash Syndrome

Question 78

Define Mixed Gonadal Dysgenesis (MGD). What is the pathophysiology and presentation of MGD?

Answer 78

Mixed Gonadal Dysgenesis (MGD) is a disorder of sexual development characterized by a unilateral testis, a contralateral streak gonad, and persistent Müllerian structures associated with varying degrees of masculinization. Most patients with MGD have a 45,XO/46,XY karyotype. MGD can also present with phenotypic internal asymmetry, where a dysgenetic or streak gonad on one side will be associated with an ipsilateral uterus and fallopian tube, and a testicle on the contralateral side can be associated with wolffian duct structures (e.g., epididymis, vas deferens). This underscores the effects of local testosterone and AMH secretion. MGD is the second most common cause of ambiguous genitalia in the neonatal period.

Question 79

What is the risk of gonadoblastoma or dysgerminoma in patients with mixed gonadal dysgenesis? What syndromes are associated with mixed gonadal dysgenesis?

Answer 79

The risk of gonadoblastoma or dysgerminoma in patients with mixed gonadal dysgenesis is 15%-35%. Denys-Drash syndrome and Frasier syndrome are associated with mutations in the Wilms tumor suppressor gene and are associated with mixed gonadal dysgenesis. Denys-Drash syndrome is associated with nephropathy, genital ambiguity, and Wilms tumor. The risk of gonadal tumor in patients with Denys-Drash syndrome is up to 40%. Frasier syndrome is not associated with an increased risk of Wilms tumor but a 60% risk of gonadoblastoma in the presence of Y chromosome material.

Question 80

What are the primary considerations for the management of mixed gonadal dysgenesis? What are the screening recommendations for patients with mixed gonadal dysgenesis?

Answer 80

Sex assignment, gonadectomy if indicated, and screening for Wilms tumor are the primary considerations for the management of mixed gonadal dysgenesis. If male gender is selected and the testicle can be brought to the scrotum, physical exam and ultrasound screening for gonadoblastoma must be weighed against prophylactic gonadectomy and androgen replacement. Screening recommendations for patients with mixed gonadal dysgenesis include regular abdominal ultrasounds for Wilms tumor and periodic evaluation of sex hormone levels.

Question 81

Which of the following is a characteristic of partial gonadal dysgenesis?
a) 46,XX karyotype
b) Only one dysgenetic testis
c) Low risk of gonadal malignancy
d) None of the above

Answer 81

b) Only one dysgenetic testis

Question 82

What is the estimated risk of gonadal malignancy in individuals with partial gonadal dysgenesis by 40 years of age?
a) Less than 10%
b) Around 20%
c) More than 40%
d) No risk of malignancy

Answer 82

c) More than 40%

Question 83

What is the management approach for partial gonadal dysgenesis?

Answer 83

d) Similar to mixed gonadal dysgenesis

Question 84

What is partial gonadal dysgenesis and what karyotype is typically present in affected individuals?

Answer 84

Partial gonadal dysgenesis is a disorder of gonadal differentiation and development that is characterized by two dysgenetic testes and variable phenotypic presentation. Individuals typically have a 45,X/46,XY or 46,XY karyotype.

Question 85

What are the clinical features of partial gonadal dysgenesis?

Answer 85

The phenotype of partial gonadal dysgenesis is variable, depending on the production of anti-Müllerian hormone (AMH) and testosterone. Some common features include ambiguous genitalia, undescended testes, and infertility. Other features may include shortened stature, hearing loss, and skeletal abnormalities.

Question 86

What is the risk of gonadal malignancy in individuals with partial gonadal dysgenesis and how is it managed?

Answer 86

The risk of gonadal malignancy has been estimated to be more than 40% by 40 years of age. Therefore, regular monitoring with physical examination, imaging studies, and tumor markers is recommended. The management approach is similar to that of mixed gonadal dysgenesis, which may involve surgical removal of the dysgenetic testes. Hormonal replacement therapy may also be necessary. Genetic counseling is recommended for affected individuals and their families.

Question 87

What is the definition of Swyer Syndrome?
a. Lack of testis formation despite a Y chromosome, with bilateral streak gonads, normal female genitalia, and well-developed Müllerian structures.
b. A condition in which a person has both male and female reproductive organs.
c. A genetic disorder that affects the development of the reproductive system in males.

Answer 87

a. Lack of testis formation despite a Y chromosome, with bilateral streak gonads, normal female genitalia, and well-developed Müllerian structures.

Question 88

What is the common presentation of Swyer Syndrome?
a. Delayed puberty and amenorrhea.
b. Ambiguous genitalia and sexual infantilism.
c. Precocious puberty and breast development.

Answer 88

a. Delayed puberty and amenorrhea.

Question 89

What is the risk of germ cell tumors in Swyer Syndrome?
a. 10%
b. 25%
c. 35%

Answer 89

c. 35%

Question 90

Describe the pathophysiology of Swyer Syndrome.

Answer 90

Swyer Syndrome is a disorder of gonadal differentiation and development. It is characterized by a lack of testis formation despite having a Y chromosome. Bilateral streak gonads are present, and the individual has normal female genitalia and well-developed Müllerian structures. The absence of testis formation is due to mutations in genes that regulate the differentiation and development of the gonads.

Question 91

What are the common clinical features of Swyer Syndrome?

Answer 91

The majority of individuals with Swyer Syndrome present in adolescence with delayed puberty and amenorrhea. There is no genital ambiguity, but there is sexual infantilism. High levels of serum gonadotropins are observed, which can lead to elevated androgen levels and clitoromegaly in some individuals. In addition, there may be other associated features such as short stature and osteoporosis.

Question 92

What is the management of Swyer Syndrome?

Answer 92

The risk of germ cell tumors in Swyer Syndrome is up to 35% by 30 years of age. Therefore, management includes gonadectomy and cyclic hormone replacement therapy. The gonads are removed to prevent the development of tumors. Hormone replacement therapy is given to induce puberty and to replace the hormones that are normally produced by the gonads. Counseling and support may also be necessary to help individuals cope with the psychological and social issues associated with the disorder.

Question 93

What is the etiology of Embryonic Testicular Regression and Bilateral Vanishing Testes Syndrome?
A) Genetic mutation
B) Trauma
C) Infection
D) None of the above

Answer 93

A) Genetic mutation, teratogen, or bilateral testicular torsion

Explanation: The etiology of Embryonic Testicular Regression and Bilateral Vanishing Testes Syndrome is postulated to be caused by a genetic mutation, teratogen, or bilateral testicular torsion.

Question 94

What is the phenotype range of patients with Embryonic Testicular Regression and Bilateral Vanishing Testes Syndrome?
A) Only typical female
B) Only ambiguous
C) Only male
D) Range from typical female to ambiguous to male

Answer 94

D) Range from typical female to ambiguous to male

Explanation: The phenotype range of patients with Embryonic Testicular Regression and Bilateral Vanishing Testes Syndrome ranges from typical female to ambiguous to male.

Question 95

How is diagnosis made for Embryonic Testicular Regression and Bilateral Vanishing Testes Syndrome?
A) Physical examination
B) Imaging studies
C) Karyotype, castrate levels of testosterone, and elevated gonadotropins during mini-puberty from 2-6 months of age
D) Blood tests

Answer 95

C) Karyotype, castrate levels of testosterone, and elevated gonadotropins during mini-puberty from 2-6 months of age

Explanation: Diagnosis for Embryonic Testicular Regression and Bilateral Vanishing Testes Syndrome can be made with karyotype, castrate levels of testosterone, and elevated gonadotropins during mini-puberty from 2-6 months of age.

Question 96

What is the treatment for Embryonic Testicular Regression and Bilateral Vanishing Testes Syndrome?

Answer 96

C) Individualized

Explanation: Treatment for Embryonic Testicular Regression and Bilateral Vanishing Testes Syndrome is individualized.

Question 97

Image
FIG. 10.7 Human intraoperative photographs (A) Intraabdominal testis at internal ring. (B) High intraabdominal testis. (C) Normal ovary. (D) Streak gonads in a patient with XY gonadal dysgenesis. (E) Ovotestis in ovotesticular syndrome.

Answer 97

Question 98

What is ovotesticular DSD?

Answer 98

Ovotesticular DSD is a condition where individuals have both testicular and ovarian tissue. The gonads may take the form of one ovary and one testis, or more commonly, one or two ovotestes. The chromosomal makeup in order of frequency is 46,XX, mosaicism with Y chromosome material, and 46,XY.

Question 99

What is the presentation of ovotesticular DSD?

Answer 99

The differentiation of both the external and internal genitalia is variable and related to the function of the ipsilateral gonad. In most, the genitalia are ambiguous. The ovary, most commonly found on the left side, is usually orthotopic. Testes and ovotestes, more commonly found on the right side, can lie anywhere in the path of testicular descent. Fallopian tubes are consistently present along with the ovary, and vas deferens alongside the testis. Ovotestes can have fallopian tube, vas deferens, or both structures. In most patients, a uterus is present. Frequently, the ovarian portion of an ovostestis is normal while the testicular component is dysgenetic.

Question 100

What is the management of ovotesticular DSD?

Answer 100

Although both gonadoblastoma and dysgerminoma have been described, the incidence is low. Gender assignment is based on functional potential of external and internal genital

Question 101

Image
FIG. 10.8 Steroid biosynthetic pathway for mineralocorticoid, glucocorticoid, and sex steroid hormone production.

Answer 101

Question 102

Which of the following is the most common cause of ambiguous genitalia in newborns?
a) 46,XX DSD
b) Congenital adrenal hyperplasia
c) Increased maternal androgens
d) Aromatase deficiency

Answer 102

b) Congenital adrenal hyperplasia

Explanation: Congenital adrenal hyperplasia is the most common cause of ambiguous genitalia in newborns.

Question 103

What is the most common enzymatic defect responsible for congenital adrenal hyperplasia?
a) 5α-reductase deficiency
b) 17α-hydroxylase deficiency
c) 21-hydroxylase deficiency
d) 11β-hydroxylase deficiency

Answer 103

c) 21-hydroxylase deficiency

Explanation: A deficiency in 21-hydroxylase is responsible for 95% of cases of congenital adrenal hyperplasia.

Question 104

What is the main treatment for congenital adrenal hyperplasia?
a) Androgen supplementation
b) Mineralocorticoid treatment
c) Hydrocortisone administration
d) Surgery

Answer 104

c) Hydrocortisone administration

Explanation: Treatment of congenital adrenal hyperplasia consists of hydrocortisone administration in childhood and adolescence.

Question 105

Which of the following is a potential source of increased maternal androgens leading to 46,XX DSD?
a) Maternal ingestion of progestins or androgens
b) Aromatase deficiency in the mother
c) Maternal tumor with virilizing effects on a female fetus
d) All of the above

Answer 105

d) All of the above

Explanation: Maternal ingestion of progestins or androgens, aromatase deficiency in the mother, and maternal tumor with virilizing effects on a female fetus are all potential sources of increased maternal androgens leading to 46,XX DSD.

Question 106

What is 46,XX DSD and how does it present?

Answer 106

46,XX DSD is a phenotypic abnormality of sexual development in which individuals with no chromosomal abnormalities and ovaries have some degree of external masculinization and ambiguous genitalia. The condition presents with variable degrees of clitoromegaly and labial fusion in females, and a common urogenital sinus. Müllerian structures are usually normal.

Question 107

What is congenital adrenal hyperplasia (CAH) and how does it present?

Answer 107

CAH is caused by a defect in one of five enzymes involved in the cortisol biosynthetic pathway, resulting in impaired production of hydrocortisone and a compensatory increase in secretion of adrenocorticotrophic hormone (ACTH). A deficiency in 21-hydroxylase is responsible for 95% of cases, while a deficiency in 11β-hydroxylase accounts for approximately 5% of cases. The most common presentation of CAH is ambiguous genitalia in the newborn, with varying degrees of virilization in females. Patients with 21-hydroxylase deficiency exhibit one of three presentations: salt wasting and virilization, simple virilization without salt wasting, and those without evidence of either. In the salt-losing variant, failure to regain birth weight, weight loss, and dehydration occur in the first few weeks of life, and in severe cases, adrenal crises can occur within the first 10-21 days of life. In males with CAH, there is sexual precocity within the first 2-3 years of life.

Question 108

How is congenital adrenal hyperplasia evaluated and managed?

Answer 108

Evaluation of CAH includes testing for serum electrolytes, serum renin, and cortisol levels. Pelvic ultrasound may be used to demonstrate Müllerian structures in classic 21-hydroxylase deficiency. Management of CAH consists of hydrocortisone administration in childhood and adolescence. Those with the salt-wasting variant require increased salt intake and mineralocorticoid treatment indefinitely. Surgical management in CAH patients is controversial and can include urethroplasty and vaginoplasty to create separate orifices and enlarge the vaginal introitus, clitoroplasty with reduction in size and creation of a clitoral hood, and feminizing vulvoplasty/labioplasty. Proper hormonal supplementation can lead to long-term fertility in males and feminization and menstruation in females.

Question 109

What is 46,XX DSD secondary to increased maternal androgens and how is it treated?

Answer 109

46,XX DSD secondary to increased maternal androgens is a rare diagnosis, historically caused by maternal ingestion of progestins or androgens, aromatase deficiency in the mother, or a maternal tumor with virilizing effects on a female fetus. The diagnosis is recognized postnatally by a normal hormonal profile, and genital reconstruction, if desired, is the only treatment.

Question 110

Table 10.4

Enzyme Deficiencies Involved in Congenital Adrenal Hyperplasia

Answer 110

Question 111

Image
FIG. 10.9 Urogenital sinus in a patient with intersex.

Answer 111

Question 112

Image
FIG. 10.10 Pure urogenital sinus abnormality.

Answer 112

Question 113

Image
FIG. 10.11 Classification by Prader of the various degrees of masculinization of the external genitalia in females with congenital adrenal hyperplasia that has been applied by some authors to intersexual states in general. Source: (From Prader A. Die Haufigkeit der kongenitalen androgenitalen Syndroms. Helv Pediatr Acta 1958;13:426.)

Answer 113

Question 114

Image
FIG. 10.12 (A to C) Schematic illustration of three presentations of persistent Müllerian duct syndrome. Source: (From Hutson JM, Grover SR, O’Connell M, Pennell SD. Malformation syndromes associated with disorders of sex development. Nat Rev Endocrinol 2014;10(8):476-487.)

Answer 114

Question 115

Which of the following enzymes are required for testosterone biosynthesis?
A. 5α-reductase type II isoenzyme
B. Cholesterol side-chain cleavage enzyme
C. 3β-hydroxysteroid dehydrogenase
D. 17α-hydroxylase
E. All of the above

Answer 115

E

Explanation: All of the mentioned enzymes are required for testosterone biosynthesis. Deficiencies in any of these enzymes not only result in abnormal testosterone production but also impaired production of glucocorticoids and mineralocorticoids.

Question 116

Which of the following disorders is characterized by 46,XY karyotype, bilateral testes, female-appearing external genitalia, and absence of Müllerian derivatives?
A. Leydig cell aplasia
B. Syndrome of complete androgen insensitivity (CAIS)
C. Syndrome of partial androgen resistance (PAIS)
D. Mild androgen insensitivity syndrome (MAIS)
E. Persistent müllerian duct syndrome (PMDS)

Answer 116

B

Explanation: Syndrome of complete androgen insensitivity (CAIS) is characterized by 46,XY karyotype, bilateral testes, female-appearing external genitalia, and absence of Müllerian derivatives (due to AMH secretion). A mutation in the gene for the androgen receptor is identified in 95% of cases.

Question 117

What is the recommended management of Persistent Mullerian Duct Syndrome (PMDS)?
A. Removal of Müllerian structures to prevent vas injury
B. Preservation of Müllerian structures to prevent vas injury
C. Orchiopexies for male gender assignment
D. None of the above

Answer 117

B

Explanation: Management of Müllerian structures in PMDS is controversial, as the vasa deferentia are in close proximity to the uterus and proximal vagina, and preservation of structures to prevent vas injury has been recommended. However, malignancies have been reported in up to 8% of Müllerian remnants, supporting careful excision.

Question 118

What is Leydig cell aplasia and how is it diagnosed and managed?

Answer 118

Leydig cell aplasia is a rare autosomal recessive trait in males that yields absence of Leydig cells or abnormalities of the LH receptor on Leydig cells. The phenotype varies with bilateral testes. Absent rise of serum testosterone after hCG stimulation is characteristic. Histology of the testicles shows absence of Leydig cells with normal Sertoli cells. The diagnosis is made through genetic testing and hormonal evaluation. Management of Leydig cell aplasia is variable and dependent on the enzymatic abnormality determined by genetic testing.

Question 119

What is 5α-reductase deficiency and how does it affect gender assignment?

Answer 119

5α-reductase deficiency is caused by an autosomal recessive mutation in the 5α-reductase type II isoenzyme, which catalyzes conversion of testosterone to DHT. This mutation is expressed at high levels in the prostate and external genitalia. The phenotype of 5α-reductase deficiency ranges from female, to ambiguous genitalia, to penoscrotal hypospadias. The diagnosis is made through genetic testing and hormonal evaluation. Individuals with 5α-reductase deficiency have normal plasma testosterone but low DHT. After hCG stimulation, the testosterone/DHT ratio increases markedly (20:1). This diagnosis is associated with gender reversal at puberty, specifically in a pedigree study from the Dominican Republic, individuals known as guevedoces (“testicles at 12,” or “penis at 12”). Male gender assignment is usually favored, but studies supporting this were performed in a unique sociologic environment.

Question 120

Which of the following is NOT a common presentation of Mayer Rokitansky Küster hauser syndrome (MRKH)?
a. Primary amenorrhea
b. Infertility
c. Cyclic abdominal pain
d. Irregular menstrual cycles

Answer 120

d. Irregular menstrual cycles

Explanation: The primary presentation of MRKH is primary amenorrhea, which means the individual has not experienced menstruation by the age of 16. Infertility, cyclic abdominal pain, or dyspareunia may also occur.

Question 121

What is the pathophysiology of MRKH?
a. Absence of the ovaries and uterus in a 46,XY individual with male phenotype
b. Absence of the uterus and vagina in a 46,XY individual with male phenotype
c. Absence of the uterus and vagina in a 46,XX individual with female phenotype and normal secondary sexual characteristics
d. Absence of the ovaries and uterus in a 46,XX individual with female phenotype and normal secondary sexual characteristics

Answer 121

d. Irregular menstrual cycles

Explanation: The primary presentation of MRKH is primary amenorrhea, which means the individual has not experienced menstruation by the age of 16. Infertility, cyclic abdominal pain, or dyspareunia may also occur.

Question 122

What is the pathophysiology of MRKH?
a. Absence of the ovaries and uterus in a 46,XY individual with male phenotype
b. Absence of the uterus and vagina in a 46,XY individual with male phenotype
c. Absence of the uterus and vagina in a 46,XX individual with female phenotype and normal secondary sexual characteristics
d. Absence of the ovaries and uterus in a 46,XX individual with female phenotype and normal secondary sexual characteristics

Answer 122

c. Absence of the uterus and vagina in a 46,XX individual with female phenotype and normal secondary sexual characteristics

Explanation: MRKH is associated with congenital absence of the uterus and vagina in a 46,XX individual with female phenotype and normal secondary sexual characteristics. Normal ovaries and fallopian tubes are present, but only uterine remnants remain, along with a shallow vaginal pouch.

Question 123

What upper tract urinary anomalies may occur in MRKH?
a. Renal cell carcinoma
b. Bladder cancer
c. Renal agenesis, pelvic kidney, and horseshoe kidney
d. Cystitis

Answer 123

c. Renal agenesis, pelvic kidney, and horseshoe kidney

Explanation: Upper tract urinary anomalies occur in one third of patients with MRKH, including renal agenesis, pelvic kidney, and horseshoe kidney.

Question 124

What is Mayer Rokitansky Küster hauser syndrome (MRKH)? What are the common presentations of this condition?

Answer 124

Mayer Rokitansky Küster hauser syndrome (MRKH) is a congenital disorder that is associated with the absence of the uterus and vagina in a 46,XX individual with female phenotype and normal secondary sexual characteristics. Normal ovaries and fallopian tubes are present, but only uterine remnants remain, along with a shallow vaginal pouch. Upper tract urinary anomalies occur in one third of patients, including renal agenesis, pelvic kidney, and horseshoe kidney. The primary presentation of MRKH is primary amenorrhea, which means the individual has not experienced menstruation by the age of 16. Infertility, cyclic abdominal pain, or dyspareunia may also occur.

Question 125

How is MRKH evaluated and managed?

Answer 125

MRKH is evaluated using abdominal ultrasound or MRI to demonstrate an absent uterus. Hormonal profile can also be used to demonstrate normal female parameters. Management of MRKH involves the creation of a neovagina with dilation or surgery. If present, a hemiuterus should be removed or hormonally suppressed. Upper tract urinary anomalies may also require further management. Psychological counseling and support may also be beneficial for individuals with MRKH.