10: Disorders of sexual development Flashcards
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
A. SRY gene on the Y chromosome
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
B. First 6 weeks
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)
D. Disorder of sexual development (DSD)
Explain the three processes of normal sexual development.
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.
How does disruption of normal sexual development lead to a disorder of sexual development (DSD)?
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.
What role does the SRY gene play in normal sexual development?
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.
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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.)
Table 10.1
Common Embryologic Origins of Genital Structures.
What is the primary determinant of testis formation during sexual differentiation?
A) Anti-Müllerian hormone
B) Dihydrotestosterone
C) Estrogen
D) Testosterone
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.
Which of the following hormones promotes Müllerian duct regression during sexual differentiation?
A) Anti-Müllerian hormone
B) Dihydrotestosterone
C) Estrogen
D) Testosterone
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.
Describe the normal process of sexual development in the first 6 weeks of embryonic development.
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.
Describe the role of androgens in sexual differentiation and the formation of the male external genitalia.
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.
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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.)
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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.)
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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.)
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
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.
What are the potential causes of disorders of sexual development, and how are they diagnosed?
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.
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
) 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
What is the difference between Turner syndrome and Klinefelter syndrome, and how do these conditions impact sexual development?
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.
What is the most common cause of congenital adrenal hyperplasia (CAH)?
a) Genetic mutations
b) Hormonal imbalances
c) Environmental factors
d) Unknown causes
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.
What are the potential long-term health implications of disorders of sexual development, and how are these conditions managed?
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.
Table 10.2
Overview of Nomenclature and Classification for Disorders of Sexual Development
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
c. Prenatal testing
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
d. Congenital adrenal hyperplasia
Family history should assess all of the following except:
a. Neonatal deaths
b. Infertility
c. History of diabetes
d. Consanguinity
c. History of diabetes
What is consanguinity?
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.
What is ambiguous genitalia in newborns and what are some of the possible causes?
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.
Why is a thorough history important in the diagnosis and management of newborns with ambiguous genitalia?
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.
What are some of the factors that should be assessed in the family history of a newborn with ambiguous genitalia?
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.
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
C. A palpable gonad in the inguinal canal or scrotum is highly suggestive of the presence of a testicle.
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
D. Stretched penile length should be measured during phallic examination.
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
B. The presence of a uterus can sometimes be determined on physical exam by palpation of an anterior midline cordlike structure on rectal examination.
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?
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.
What other dysmorphic features should be noted during the physical examination of a newborn with ambiguous genitalia?
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.
How is the presence of an ovotestis diagnosed in a newborn with ambiguous genitalia?
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.
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)
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.
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
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.
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)
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.
What is the role of karyotyping in the evaluation of newborns with ambiguous genitalia?
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.
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: b) Ambiguous genitalia
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
e) All of the above
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
b) Diagnosis
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
c) Based on diagnosis, anatomy, and functional potential of the genital and reproductive tract
What are the most common causes of DSD in the newborn, and how are they diagnosed and managed?
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.
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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.
Table 10.3
Clinical Presentation for Disorders of Sexual Development After the Newborn Period
What is the most common major abnormality of sexual development?
a) Turner syndrome
b) Klinefelter syndrome
c) Congenital adrenal hyperplasia
d) Androgen insensitivity syndrome
b) Klinefelter syndrome
What is the classic karyotype associated with Klinefelter syndrome?
a) 47,XXX
b) 46,XX
c) 47,XY
d) 47,XXY
d) 47,XXY
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
c) Seminiferous tubules degeneration
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
c) Both a) and b)
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%
c) 40%-50%
What is the pathophysiology of Klinefelter syndrome?
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.
What are the clinical manifestations of Klinefelter syndrome?
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.
How is Klinefelter syndrome diagnosed and evaluated?
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.
What is the recommended management for Klinefelter syndrome?
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.
What does nonmosaic mean?
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.
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
B
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
A
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FIG. 10.6 Gross appearance of streak gonad during diagnostic laparoscopy. Source: (Courtesy of D. Diamond, MD.)
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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.
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FIG. 10.8 Steroid biosynthetic pathway for mineralocorticoid, glucocorticoid, and sex steroid hormone production.
Table 10.4
Enzyme Deficiencies Involved in Congenital Adrenal Hyperplasia
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FIG. 10.9 Urogenital sinus in a patient with intersex.
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FIG. 10.10 Pure urogenital sinus abnormality.
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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.)
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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.)
